Note: Descriptions are shown in the official language in which they were submitted.
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METHOD AND SYSTEM FOR THE DELIVERY OF CORTICOSTEROIDS HAVING AN ENHANCED
PHARMACOKINETIC PROFILE
FIELD OF THE INVENTION
100011 The present invention relates to methods and systems for the delivery
of a corticosteroid comprising
(1) an inhalable aqueous mixture comprising a corticosteroid and a solubility
enhancer and (2) an inhalable
nebulizer, wherein the delivery of the aqueous mixture comprising the
corticosteroid by the nebulizer results in
an enhanced pharmacokinetic profile of the corticosteroid as compared to
conventional inhalable therapies
and/or increased lung deposition.
BACKGROUND OF THE INVENTION
100021 Inhaled corticosteroids are fundamental to the long-term management of
persistent asthma and are
recommended by national guidelines for therapy of young children diagnosed
with asthma. Numerous clinical
trials support their efficacy and relative safety for children. In addition,
it is believed that early corticosteroid
intervention can play a critical role in the reduction of permanent lung
damage and alter the chronic, progressive
nature of the disease.
j00031 The use of inhaled corticosteroids in the treatment of asthma provides
significant benefit due to the
direct delivery to the site of action, the lung (as used herein, "lung" refers
to either or both the right and left lung
organs). The goal of inhaled corticosteroid therapy is to provide localized
delivery of the corticosteroid with
immediate drug activity at the site of action. It is known that inhaled
corticosteroids are well absorbed from the
lungs. In fact, it can be assumed that substantially all of the drug available
at the receptor site in the lungs will
be absorbed. However, it is also known that current methods and formulations
result in a greater part of an
inhaled corticosteroid dose being swallowed and becoming available for oral
absorption. Thus, due to the
particular method or system employed, some corticosteroids are more likely to
be deposited in the mouth and
throat than the lungs, and may cause adverse effects. For the portion of the
inhaled corticosteroid dose
delivered orally, bioavailability depends upon absorption from the GI tract
and the extent of first pass
metabolism in the liver. Since this oral component of corticosteroid drug
delivery does not provide any
beneficial therapeutic effect and increases the risk of systemic side effects,
it is desirable for the oral
bioavailability of inhaled corticosteroid to be relatively low. Thus, for
inhaled corticosteroids, high pulmonary
availability is more important than high oral bioavailability because the lung
is the target organ.
[0004] As such, a method or system of delivery that provides a corticosteroid
with high pulmonary availability
has greater potential to exert positive effects in the lung. The ideal system
of providing inhaled corticosteroids
would provide minimum oral delivery and reduced administration times thereby
reducing the likelihood of
systemic adverse effects.
[00051 Unfortunately, however, the delivery of a corticosteroid via inhalation
often results in deposition of the
corticosteroid in sections distinct from the respiratory tract, e.g., mouth,
throat, and esophagus. Generally, the
1
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smatler the particle size of the corticosteroid, the longer the particle will
remain suspended in air and the farther
down the respiratory tract the drug can be delivered. Corticosteroids are
delivered by inhalation using
nebulizers, metered dose inhalers, or dry powder inhalers. The principle
advantage of nebulizers over other
methods of pulmonary delivery of a corticosteroid is that nebulizers can more
efficiently deliver higher doses of
medication compared to other methods. The main concerns about nebulizers,
however, are the increased cost,
reduced portability, and the inconvenience of needing to prepare medication
beforehand and the increased time
requirement for administering a treatment. Thus, a method of improving the
delivery of drugs, such as
corticosteroids by nebulization, is desired.
10006] Both particle size and formulation influence the efficacy of an inhaled
corticosteroid. The formulation
of a drug has a significant impact on the delivery of that drug to the lungs,
and therefore its efficacy.
Additionally, it is believed that the most important considerations in the
delivery of drug to the lung are the
aerosol vehicle and the size of the particles delivered.
[0007] The inhalation of drug particles as opposed to dissolved drug is known
to be disadvantageous. Brain et
al. (Bronchial Asthma, 2nd Ed. (Ed. E. B. Weis et al., Little Brown & Co.
(1985), pp.594-603) report that less
soluble particles that deposit on the mucous blanket covering pulmonary
airways and the nasal passages are
moved toward the pharynx by the cilia. Such particles include larger drug
particles which are deposited in the
upper respiratory tract. Mucus, cells and debris coming from the nasal
cavities and the lungs meet at the
pharynx, mix with saliva, and enter the gastrointestinal tract upon being
swallowed. Reportedly, by this
mechanism, particles are removed from the lungs with half-times of minutes to
hours. Accordingly, there is
little time for solubilization of slowly dissolving drugs, including
corticosteroids, e.g., budesonide. In contrast,
particles deposited in the non-ciliated compartments, such as the alveoli,
have much longer residence times.
Since it is difficult to generate very small particles of corticosteroids for
deep lung deposition, much of the
inhaled suspension would likely be found in the upper to middle respiratory
tract. However, it is much easier to
generate small droplets from a solution than it is from a suspension of
solids.
100081 Budesonide (R, S)-11(3, 16a, 17, 21-tetrahydroxypregna-1, 4-diene-3,20-
dione cyclic 16,17-acetal with
butyraldehyde, (C25H3406i MW: 430.5) is employed in particular for the
treatment of bronchial disorders.
Budesonide is a racemate consisting of a mixture of the two diastereomers 22R
and 22S and is provided
commercially as a mixture of the two isomers (22R and 22S). It acts as an anti-
inflammatory corticosteroid that
exhibits potent glucocorticoid activity. Administration of budesonide is
indicated for maintenance treatment of
asthma and as prophylactic therapy in children.
100091 Because of its lipophilicity, budesonide, as well as other lipophilic
corticosteroids, is virtually
insoluble in water but is readily soluble in alcohols. An adequate amount of
active substance can be dissolved
by the use of solubilizers such as organic, water-soluble alcohols. However,
the solutions obtained in this way
generally limited stability for pharmaceutical use because large amounts of
the active substance may decompose
within a short time.
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(00101 Commercial formulations of budesonide are sold by AstraZeneca LP
(Wilmington, DE) under the
trademarks Entocort EC, Pulmicort Respules , Rhinocort Aqua, Rhinocort
Nasal Inhaler and Pulrnicort
Turbuhaler, and under its generic name. Pulmicort Respules"' , which is a
sterile aqueous suspension of
micronized budesonide, is administered by inhalation using a nebulizer, in
particular a compressed air driven jet
nebulizer. Rhinocort Nasal Inhaler is a metered-dose pressurized aerosol unit
containing a suspension of
micronized budesonide in a mixture of propellants. Rhinocort Aqua is an
unscented metered-dose manual-
pump spray formulation containing a suspension of micronized budesonide in an
aqueous medium. In addition,
suspension formulations of budesonide have a propensity to rapidly form coarse
flocs upon dispersion and re-
dispersion which may deleteriously affect dosage reproducibility. There is
also a tendency for budesonide to
deposit from suspension onto the walls of the container.
[0011l Accordingly, there is a need for systems and methods for delivering a
non-suspension formulation
comprising a corticosteroid by nebulization. However, even in light of this
need, the Pulmicort Respule
suspension is the only currently approved therapy for the treatment of
pediatrie asthma with budesonide via
inhalation therapy. In addition, the availability of compositions, methods,
and systems for corticosteroids other
than budesonide is likewise needed. Thus, it would be a significant
advancement to the field of corticosteroid
inhalation therapy to provide a method or system which provides enhanced
pharmacokinetic profiles of the
delivered corticosteroid as compared to the pharmacokinetic profile of
suspension unit dose formulations
containing a corticosteroid, and/or increased lung deposition.
SUMMARY OF THE INVENTION
[00121 In certain embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof, the method
comprising: (a) providing an aqueous
inhalation mixture comprising a corticosteroid and a solubility enhancer; and
(b) delivering the aqueous
inhalation mixture with an inhalation nebulizer wherein the corticosteroid is
administered at a nominal dosage
of less than about 125 g/dose.
(00131 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the volume of the aqueous inhalation
mixture is about 0.5 mL; about 1.0
mL; about 1.5 mL; about 2.0 mL; about 2.5 mL; about 3.0 mL or about 3.5 mL.
(0014) In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein wherein the nebulizer is selected from
the group consisting of a jet
nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a
nebulizer comprising a vibrating mesh or
plate with multiple apertures, or a nebulizer comprising a vibration generator
and an aqueous chamber.
100151 In still embodiments, the bronchoconstrictive disorder is selected from
the group consisting of asthma,
pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic
obstructive pulmonary disease
(COPD), chronic bronchitis, and emphysema.
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100161 In yet other embodiments, the method has a delivery time of less than
about 5, less than about 4, less
than about 3, less than =about 2, or less than about 1.5 minutes.
(00171 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein substantially all of the nominal dosage
is delivered in less than about 5,
less than about 4, less than about 3, less than about 2, or less than about
1.5 minutes.
[00181 In still other embodiments, the present invention provides a method for
the treatment or prophylaxis of
a bronchoconstrictive disorder wherein wherein the inhalation mixture is
administered not more than once a
day. In other embodiments, the inhalation mixture is administered once a day.
In still other embodiments, the
inhalation mixture is administered not more than twice a day. In still yet
other embodiments, the inhalation
mixture is administered twice a day. In yet still other embodiments, the
inhalation mixture is administered in
the evening.
100191 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the inhalation mixture' further comprises
a second therapeutic agent
selected from the group consisting of a B2-adrenoreceptor agonist, a dopamine
(D2) receptor agonist, a
prophylactic therapeutic, and an anti-cholinergic agent.
100201 In still other embodiments, the present invention rovides a method for
the treatment or prophylaxis of a
bronchoconstrictive disorder wherein the solubility enhancer is selected from
the group consisting of propylene
glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate,
phospholipids, lecithin, purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from iecithin,
dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine
(DPPC), distearoyl
phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD
derivatives, SBE-cKCD, SBE-fl-
CD, SBEI-0-CD, SBE4-/3-CD, SBE7-13-CD, SBE--y-CD, hydroxypropyl-(3-
cyclodextrin, 2-HP-(3-CD,
hydroxyethyl-f.3-cyclodextrin, hydroxypropyl-~y-cyclodextrin, hydroxyethyl-
ycyclodextrin, dihydroxypropyl-J3-
cyclodextrin, glucosyl-c~-cyclodextrin, glucosyl-;Q-cyclodextrin, diglucosyl-
/3-cyclodextrin, maltosyl-a-
cyclodextrin, maltosyl-Q-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-
13-cyclodextrin, maltotriosyl-y-
cyclodextrin, dimaltosyl-(3-cyclodextrin, methyl-fl-cyclodextrin, carboxyalkyl
thioether derivatives, ORG
26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone,
copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl
sodium sulfosuccinate, and
combinations thereof.
100211 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the solubility enhancer comprises SBE7-13-
CD. In other embodiments, the
solubility enhancer comprises about 2%, about 5%, about 7% or about 10% w/v
SBE-07-CD.
(00221 In still other embodiments, the present invention provides a method for
the treatment or prophylaxis of
a bronchoconstrictive disorder wherein the nominal dosage is about 60 ug/dose.
In other embodiments, the
nominal dosage is about 40 ug/dose.
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100231 In other embodiments, the present invention provide method for the
treatment or prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof, the method
comprising: (a) providing an aqueous
inhalation mixture comprising a nominal dosage of a corticosteroid and
a'solubility enhancer; and (b)
delivering the aqueous inhalation mixture with an inhalation nebulizer,whereby
the method delivers at
least a two-fold enhanced pharmacokinetic profile of the aqueous inhalation
mixture comprising the nominal
dosage of the corticosteroid, as compared to a pharmacokinetic profile of an
inhalable suspension comprising a
nominal dosage of the corticosteroid administered under the same conditions.
100241 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the ratio of the nominal dosage of the
corticosteroid in the aqueous
inhalation mixture to the nominal dosage the corticosteroid in the inhalable
suspension is from about 0.01:1 to
about 1:100.
100251 In still other embodiments, the present invention provides a method for
the treatment or prophylaxis of
a bronchoconstrictive disorder wherein the enhanced pharmacokinetic profile
comprises a C. of said aqueous
inhalation mixture equivalent to the Cm81C of the inhalable suspension, an
AUCh,t of said aqueous inhalation
mixture equivalent to the AUCI,,,, of the inhalable suspension, a AUCta.~ of
said aqueous inhalation mixture
equivalent to the AUC(o.,) of the inhalable suspension, and/or a T,,,,x of
said aqueous inhalation mixture less
than the T,,,a,, of the inhalable suspension comprising a corticosteroid, and
wherein the aqueous inhalation
mixture is administered at a lower nominal corticosteroid dosage than the
inhalable suspension. In certain
embodiments, the ratio of the nominal dosage of the aqueous inhalation mixture
to the nominal dosage of the
inhalable suspension is from about 1:2 to about 1:10. In certain other
embodiments, the ratio of the nominal
dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is about 1:4.
(00261 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the nebulizer is selected from the group
consisting of a jet nebulizer, an
ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a
vibrating mesh or plate with
multiple apertures, or a nebulizer comprising a vibration generator and an
aqueous chamber.
100271 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein wherein local bioavailability of the
corticosteroid of the aqueous
inhalation mixture delivered by the inhalation nebulizer is greater than the
local bioavailability of the
corticosteroid of the inhalable suspension delivered by an inhalation
nebutizer.
[00281 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the bronchoconstrictive disorder is
selected from the group consisting of
asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma,
chronic obstructive pulmonary
disease (COPD), chronic bronchitis, and emphysema.
100291 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the method has a delivery time of less
than about 5, less than about 4, less
than about 3, less than about 2, or less than about 1.5 minutes. In other
embodiments, substantially all of the
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nominal dosage is delivered in less than about 5, less than about 4, less than
about 3, less than about 2, or less
than about 1.5 minutes.
100301 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the inhalation mixture further comprises
a second therapeutic agent
selected from the group consisting of a B2-adrenoreceptor agonist, a doparnine
(D2) receptor agonist, a
prophylactic therapeutic, and an anti-cholinergic agent.
[00311 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the solubility enhancer is selected from
the group consisting of propylene
glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS,
macrogol-l5-hydroxystearate,
phospholipids, lecithin, purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from lecithin,
dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine
(DPPC), distearoyl
phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD
derivatives, SBE-ca-CD, SBE-f3-
CD, SBEI-/3-CD, SBE4-/3-CD, S13E7-Q-CD, SBE-T-CD, hydroxypropyi-(3-
cyclodextrin, 2-HP-f3-CD,
hydroxyethyl-o-cyclodextrin, hydroxypropyl-ry~cyclodextrin, hydroxyethyl-y-
cyclodextrin, dihydroxypropyl-(3-
cyclodextrin, glucosyl-at-cyclodextrin, glucosyl-0-cyclodextrin, diglucosyl-0-
cyclodextrin, maltosyl-c~-
cyclodextrin, maltosyl-0-cyclodextrin, maltosyi-,y-cyclodextrin, maltotriosyl-
,3-cyclodextrin, maltotriosyl-f-
cyclodextrin, dimaltosyl-J3-cyclodextrin, methyl-0-cyclodextrin, carboxyalkyl
thioether derivatives, ORG
26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone,
copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl
sodium suifosuccinate, and
combinations thereof. In one embodiment, the solubility enhancer comprises
SBE7-0-CD.
[00321 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the corticosteroid of the aqueous
inhalation mixture is administered at a
nominal dosage of less than about 250 ug/dose. In another embodiment, the
aqueous inhalation mixture is
administered at a nominal dosage of about 240 ug/dose, about 120 ug/dose,
about 60 ug/dose or about 40
ug/dose.
[0033] In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder wherein the solubility enhancer comprises SBE-137-
CD.
[0034) In other embodiments, the ratio of the nominal dosage of the aqueous
inhalation mixture to the
nominal dosage of the inhalable suspension is from about 1:2 to about 1:5.
[0035] In other embodiments, the present invention provides an inhalation
system for the treatment or
prophylaxis of a bronchoconstrictive disorder the system comprising: (a) an
aqueous inhalation mixture
comprising a nominal dosage of a corticosteroid and a solubility enhancer; and
(b) an inhalation nebulizer for
delivering the aqueous inhalation mixture
whereupon administration of a nominal dosage of the corticosteroid to the
patient, the system delivers at least a
two-fold enhanced pharmacokinetic profile of the aqueous inhalation mixture
comprising a nominal dosage of
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the corticosteroid as compared to a pharmacokinetic profile of an inhalable
suspension comprising a nominal
dosage of the corticosteroid administered under the same conditions.
100361 In other embodiments, the present invention provides an inhalation
system wherein the ratio of the
nominal dosage of the corticosteroid in the aqueous inhalation mixture to the
nominal dosage the corticosteroid
in the inhalable suspension is from about 0.01:1 to about 1:100.
(0037] In still other embodiments, the present invention provides an
inhalation system wherein the enhanced
pharmacokinetic profile comprises a CR,,,., of said aqueous inhalation mixture
equivalent to the C,,,ax of the
inhalable suspension, an AUCI,,,, of said aqueous inhalation mixture
equivalent to the AUCI,51 of the inhalable
suspension, a AUCt" of said aqueous inhalation' mixture equivalent to the
AUCt" of the inhalable
suspension, and/or a TmaX of said aqueous inhalation mixture less than the
T,,,a,, of the inhalable suspension
comprising a corticosteroid, and wherein the aqueous inhalation mixture is
administered at a lower
corticosteroid nominal dosage than the inhalable suspension.
[0038] In yet other embodiments, the present invention provides an inhalation
systemwherein the ratio of the
nominal dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is from
about 1:2 to about 1:10. In other embodiments, the ratio of the nominal dosage
of the aqueous inhalation
mixture to the nominal dosage of the inhalable suspension is about 1:4.
100391 In other embodiments, the present invention provides an inhalation
system wherein the nebulizer is
selected from the group consisting of ajet nebulizer, an ultrasonic nebulizer,
a pulsating membrane nebulizer, a
nebulizer comprising a vibrating mesh or plate with multiple apertures, or a
nebulizer comprising a vibration
generator and an aqueous chamber.
(0040] In other embodiments, the present invention provides an inhalation
system wherein the .inhalation
mixture further comprises a second therapeutic agent selected from the group
consisting of a B2-adrenoreceptor
agonist, a dopamine (D2) receptor agonist, a prophylactic therapeutic, and an
anti-cholinergic agent.
100411 In other embodiments, the present invention provides an inhalation
system wherein the solubility
enhancer is selected from the group consisting of propylene glycol, non-ionic
surfactants, tyloxapol, polysorbate
80, vitamin E-TPGS, macrogol-l5-hydroxystearate, phospholipids, lecithin,
purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from lecithin, dimyristoyl
phosphatidylcholine (DMPC), dipalmitoyl
phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC),
cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-ot-CD, SBE-R-CD, SBEl-0-CD, SBE4-13-CD, SBE7-(3-CD,
SBE-y-CD,
hydroxypropyl-o-cyclodextrin, 2-HP-,Q-CD, hydroxyethyl-(3-cyclodextrin,
hydroxypropyl-t-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-Q-cyclodextrin, glucosyl-ca-
cyclodextrin, glucosyl-9-
cyclodextrin, diglucosyl-,Q-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-,Q-
cyclodextrin, maltosyl-t-
cyclodextrin, maltotriosyl-)3-cyclodextrin, maltotriosyl-7-cyclodextrin,
dimaltosyl-o-cyclodextrin, methyl-,Q-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
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sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In one
embodiment, the solubility enhancer
comprises SBE7-0-CD.
[0042) In other embodiments, the present invention provides an inhalation
system wherein the corticosteroid
of the aqueous inhalation mixture is administered at a nominal dosage of less
than about 250 ug/dose. In other
embodiments, the corticosteroid of the aqueous inhalation mixture is
administered at a nominal dosage of about
240 ug/dose, about 120 ug/dose, about 60 ug/dose, or about 40 ug/dose.
[00431 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof, the method
comprising: (a) providing an aqueous
inhalation mixture comprising budesonide and a solubility enhancer; and (b)
delivering the aqueous inhalation
mixture with an inhalation nebulizer wherein budesonide is administered at a
nominal dosage of less than about
250 g/dose.
[00441 In other embodiments, the present invention provides a method the
volume of the aqueous inhalation
mixture is about 0.5 mL; about 1.0 mL; about 1.5 mL; about 2.0 mL; about 2.5
mL; about 3.0 mL or about 3.5
mL.
10045) In other embodiments, the present invention provides a method wherein
the nebulizer is selected from
the group consisting of a jet nebulizer, an ultrasonic nebulizer, a pulsating
membrane nebulizer, a nebulizer
comprising a vibrating mesh or plate with multiple apertures, or a nebulizer
comprising a vibration generator
and an aqueous chamber.
[00461 In other embodiments, the present invention provides a method said
bronchoconstrictive disorder is
selected from the group consisting of asthma, pediatric asthma, bronchial
asthma, allergic asthma, intrinsic
asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and
emphysema.
(0047) In other embodiments, the present invention provides a method with a
delivery time of less than about
5, less than about 4, less than about 3, less than about 2, or less than about
1.5 minutes. In yet other
embodiments, substantially all of the nominal dosage is delivered in less than
about 5, less than about 4, less
than about 3, less than about 2, or less than about 1.5 minutes.
(0048) In other embodiments, the present invention provides a method wherein
the inhalation mixture is
administered not more than once a day. In other embodiments, the inhalation
mixture is administered once a
day. In still other embodiments, the inhalation mixture is administered not
more than twice a day. In yet other
embodiments, the inhalation mixture is administered twice a day. In yet still
other embodiments, the inhalation
mixture is administered in the evening.
(0049) In other embodiments, the present invention provides a method wherein
the inhalation mixture further
comprises a second therapeutic agent selected from the group consisting of a
B2-adrenoreceptor agonist, a
dopamine (D2) receptor agonist, a prophylactic therapeutic, and an anti-
cholinergic agent.
[00501 In still other embodiments, the present invention provides a method
wherein the solubility enhancer is
selected from the group consisting of propylene glycol, non-ionic surfactants,
tyloxapol, polysorbate 80,
vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified
and/or enriched lecithin,
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phosphatidylcholine fractions extracted from lecithin, dimyristoyl
phosphatidylcholine (DMPC), dipalmitoyl
phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC),
cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-a-CD, SBE-a-CD, SBEI-/3-CD, SBE4-fl-CD, SBE7-16-CD,
SBE--y-CD,
hydroxypropyl-g-cyclodextrin, 2-HP-Q-CD, hydroxyethyl-Q-cyclodextrin,
hydroxypropyl-y-cyclodextrin,
hydroxyethyl--t-cyclodextrin, - dihydroxypropyl-)3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-,(3-
cyclodextrin, diglucosyl-g-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-o-
cyclodextrin, maltosyl-t-
cyclodextrin, maltotriosyl-0-cyclodextrin, maltotriosyl--~-cyclodextrin,
dimaltosyl-o- cyclodextrin, methyl-S-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In one
embodimen, the solubility enhancer
comprises SBE7-0-CD. In another embodiment, the solubility enhancer comprises
about 2%, about 5%, about
7% or about 10% w/v SBE7-;6-CD.
[0051] In other embodiments, the present invention provides a method wherein
the nominal dosage is less
than about 250 ug/dose. in another embodiment, the nominal dosage is about 240
ug/dose. In another
embodiment,the nominal dosage is about 120 ug/dose. In another embodiment, the
nominal dosage is about 60
ug/dose. In another embodiment, the nominal dosage is about 40 ug/dose.
100521 In other embodiments, the present invention provides a method for the
treatment or prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof, the method
comprising: (a) providing an aqueous
inhalation mixture comprising a nominal dosage of budesonide and a solubility
enhancer; and (b) delivering the
aqueous inhalation mixture with an inhalation nebulizer whereby the method
delivers at least a two-fold
enhanced pharmacokinetic profile of the aqueous mixture comprising the nominal
dosage of budesonide, as
compared to a pharmacokinetic profile of an inhalable suspension comprising a
nominal dosage of budesonide
administered under the same conditions.
10053] In other embodiments, the present invention provides a method wherein
the ratio of the nominal
dosage of budesonide in the aqueous inhalation mixture to the nominal dosage
budesonide in the inhalable
suspension is from about 0.01:1 to about 1:100.
[0054] In other embodiments, the present invention provides a method the
enhanced pharmacokinetic profile
coinprises a C,,,ax of said aqueous inhalation mixture equivalent to the
Cm,,., of the inhalable suspension, an
AUCt,,t of said aqueous inhalation mixture equivalent to the AUCIazt of the
inhalable suspension, a AUCt" of
said aqueous inhalation mixture equivalent to the AUCto_.~ of the inhalable
suspension, and/or a T,,,a, of said
aqueous inhalation mixture less than the Tmj,., of the inhalable suspension
comprising budesonide, and wherein
the aqueous inhalation mixture is administered at a lower nominal budesonide
dosage than the inhalable
suspension.
[0055] In other embodiments, the present invention provides a method wherein
the ratio of the nominal
dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is from about 1:2 to
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about 1:10. In other embodiments, the ratio of the nominal dosage of the
aqueous inhalation mixture to the
nominal dosage of the inhalable suspension is about 1:4.
100561 In other embodiments, the nebulizer is selected from the group
consisting of a jet nebulizer, an
ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a
vibrating mesh or plate with
multiple apertures, or a nebulizer comprising a vibration generator and an
aqueous chamber.
[0057) In other embodiments, the present invention provides a method wherein
local bioavailability of the
budesonide of the aqueous inhalation mixture delivered by the inhalation
nebulizer is greater than the local
bioavailability of the budesonide of the inhalable suspension delivered by an
inhalation nebulizer.
100581 In other embodiments, the bronchoconstrictive disorder is selected from
the group consisting of
asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma,
chronic obstructive pulmonary
disease (COPD), chronic bronchitis, and emphysema.
[0059] In other embodiments, the method has a delivery time of less than about
5, less than about 4, less than
about 3, less than about 2, or less than about 1.5 minutes. In still other
embodiments, substantially all of the
nominal dosage is delivered in less than about 5, less than about 4, less than
about 3, less than about 2, or less
than about 1.5 minutes.
100601 In other embodiments, the inhalation mixture further comprises a second
therapeutic agent selected
from the group consisting of a B2-adrenoreceptor agonist, a dopamine (D2)
receptor agonist, a prophylactic
therapeutic, and an anti-cholinergic agent.
[0061] In other embodiments, the solubility enhancer is selected from the
group consisting of propylene
glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate,
phospholipids, lecithin, purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from lecithin,
dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine
(DPPC), distearoyl
phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD
derivatives, SBE-a-CD, SBE-0-
CD, SBEi-0-CD, SBE4-0-CD, SBE7-13-CD, SBE-ry-CD, hydroxypropyl-J3-
cyclodextrin, 2-NP-0-CD,
hydroxyethyl-p-cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl--t-
cyclodextrin, dihydroxypropyl-)f3-
cyclodextrin, glucosyt-a-cyctodextrin, glucosyl-(3-cyclodextrin, diglucosyl-J3-
cyclodextrin, maltosyl-ce-
cyclodextrin, maltosyl-(i-cyclodextrin, maltosyl--f-cyclodextrin, maltotriosyl-
a-cyclodextrin, maltotriosyl-y-
cyclodextrin, dimaltosyl-a-cyclodextrin, methyl-(3-cyclodextrin, carboxyalkyl
thioether derivatives, ORG
26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone,
copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl
sodium sulfosuccinate, and
combinations thereof. In other embodiments, the solubility enhancer comprises
SBE7-j3-CD.
[0062] In other embodiments, the present invention provides a method wherein
the budesonide of the aqueous
inhalation mixture is administered at a nominal dosage of less than about 250
ug/dose. In other embodiments,
the budesonide of the aqueous inhalation mixture is administered at a nominal
dosage of about 240 ug/dose,
about 120 ug/dose, about 60 ug/dose or about 40 ug/dose. In still other
embodiments, the solubility enhancer
comprises SBE7-0-CD.
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100631 In other embodiments, the present invention provides a method wherein
the ratio of the nominal
dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is from about 1:2 to
about 1:5.
100641 In other embodiments, the present invention provides an inhalation
system for the treatment or
prophylaxis of a bronchoconstrictive disorder in a patient in need thereof,
the system comprising: (a) an
aqueous inhalation mixture comprising a nominal dosage of budesonide and a
solubility enhancer; and (b) an
inhalation nebulizer for delivering the aqueous inhalation mixture, whereupon
administration of a nominal
dosage of the budesonide to the patient, the system delivers at least a two-
fold enhanced pharmacokinetic
profile of the aqueous inhalation mixture comprising a nominal dosage of the
budesonide as compared to a
pharmacokinetic profile of an inhalable suspension comprising a nominal dosage
of budesonide administered
under the same conditions.
(0065) In other embodiments, the present invention provides an inhalation
system wherein the ratio of the
nominal dosage of the budesonide in the aqueous inhalation mixture to the
nominal dosage of the budesonide in
the inhalable suspension is from about 0.01:1 to about 1:100.
[00661 In still other embodiments, the present invention provides an
inhalation system wherein the enhanced
pharmacokinetic profile comprises a C. of said aqueous inhalation mixture
equivalent to the Cmax of the
inhalable suspension, an AUC,as, of said aqueous inhalation mixture equivalent
to the AUCI,51 of the inhalable
suspension, a AUC(o_,,) of said aqueous inhalation mixture equivalent to the
AUCto_o4 of the inhalable
suspension, and/or a Tm. of said aqueous inhalation mixture less than the Tmax
of the inhalable suspension
comprising budesonide, and wherein the aqueous inhalation mixture is
administered at a lower budesonide
nominal dosage than the inhalable suspension.
100671 In other embodiments, the present invention provides an inhalation
system wherein the ratio of the
nominal dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is from
about 1:2 to about I:10. In other embodiments, the ratio of the nominal dosage
of the aqueous inhalation
mixture to the nominal dosage of the inhalable suspension is about 1:4.
[0068] In other embodiments, the present invention provides an inhalation
system wherein the nebulizer is
selected from the group consisting of a jet nebulizer, an ultrasonic
nebulizer, a pulsating membrane nebulizer, a
nebulizer comprising a vibrating mesh or plate with multiple apertures, or a
nebulizer comprising a vibration
generator and an aqueous chamber.
f 0069] In other embodiments, the present invention provides an inhalation
system, wherein the inhalation
mixture further comprises a second therapeutic agent selected from the group
consisting of a B2-adrenoreceptor
agonist, a dopamine (D2) receptor agonist, a prophylactic therapeutic, and an
anti-cholinergic agent.
100701 In other embodiments, the present invention provides an inhalation
system wherein the solubility
enhancer is selected from the group consisting of propylene glycol, non-ionic
surfactants, tyloxapol, polysorbate
80, vitamin E-TPGS, macrogol-l5-hydroxystearate, phospholipids, lecithin,
purified and/or enriched lecithin,
phosphatidyleholine fractions extracted from lecithin, dimyristoyl
phosphatidylcholine (DMPC), dipalmitoy)
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phosphatidylcholine (DPPC); distearoyl phosphatidylcholine (DSPC),
cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-ct-CD, SBE-13-CD, SBE1-/3-CD, SBE4-0-CD, SBE7-,6-CD,
SBE-y-CD,
hydroxypropyl-(3-cyclodextrin, 2-HP-j.3-CD, hydroxyethyl-j3-cyclodextrin,
hydroxypropyl--f cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-,6-cyclodextrin, glucosyl-
ceLcyclodextrin, glucosyl-,fi-
cyclodextrin, diglucosyl-/3-cyclodextrin, maltosyl-ca cyclodextrin, maltosyl-
(3-cyclodextrin, maltosyl--y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl--y-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-0-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In other
embodiments, the solubility enhancer
compiises SBE7-fl-CD.
100711 In other embodiments, the present invention provides an inhalation
system wherein the budesonide of
the inhalation mixture is administered at a nominal dosage of less than about
250 ug/dose. in still other
embodiments, the budesonide of the inhalation mixture is administered at a
nominal dosage of about 240
ug/dose, about 120 ug/dose, about 60 ug/dose or about 40 ug/dose. In yet still
other embodiments, the
solubility enhancer comprises SBE7-j3-CD.
[00721 In other embodiments, the present invention provides an inhalation
system the ratio of the nominal
dosage of the aqueous inhalation mixture to the nominal dosage of the
inhalable suspension is from about 1:2 to
about 1:5.
BRIEF DESCRIPTION OF THE FIGURES
[00731 Figure 1 shows percentage of lung deposition and oropharyngeal
deposition of an inhalable
composition comprising budesonide.
100741 Figure 2 shows total lung deposition of budesonide from scintigraphy
data.
[0075] Figure 3 shows percentage of respirable fraction (RF; particle sizes
less than 5 pm) determined using
different methodologies (laser diffraction 20 L/min, laser diffraction 28.3
L/min, and cascade impaction).
100761 FIG. 4 provides a summary of the mean plasma concentrations following a
single dose of Budesonide
Administrations A to E. Administration A is 60 g 99mTc-DTPA labeled
budesonide + SBE7-(3-CD inhalation
solution delivered with a modified Pari eFlow nebulizer. Administration B is
120 g 99mTc-DTPA labeled
budesonide + SBE7-0-CD inhalation solution delivered with a modified Pari
eFlow nebulizer. Administration
C is 240 g 99mTc-DTPA labeled budesonide + SBE7-Q-CD inhalation solution
delivered with a modified
Pari eFlow nebulizer. Administration D is 500 j.tg budesonide suspension
(Pulmicort Respules'~) delivered
with a Pari LC Plus jet nebulizer. Administration E is 1000 g budesonide
suspension (Pulmicort Respuleso)
delivered with a Pari LC Plus jet nebulizer.
[0077] FIG. 5 provides a summary of the mean plasma concentrations following
twice daily administration of
budesonide for seven days. Treatment A(-A-) is a 60 g Captisol-Enabled
Budesonide Inhalation Solution
(CBIS) inhalation solution delivered with a Pari eFlow nebulizer. Treatment
B(-O-) is a 120 g CBiS
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inhalation solution delivered with a Pari eFlow nebulizer. Treatment C(-O-)
is a 250 g budesonide
suspension (Pulmicort Respules ) delivered with a Pari LC Plus jet nebulizer.
Treatment D(-0-) is a 500 g
budesonide suspension (Pulmicort Respules ) delivered with a Pari LC Plus jet
nebulizer.
DETAILED DESCRIPTION OF THE INVENTION
[00781 Reference will now be made in detail to embodiments of the inhalable
compositions, systems and
methods disclosed herein. Examples of the embodiments are illustrated in the
following Examples section.
100791 Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as is
commonly understood by one of skill in the art to which the inventions
described herein belong. All patents and
publications referred to herein are incorporated by reference.
Certaus Definitions
(0080] As used herein, the terms "comprising," "including," "such as," and
"for example" are used in their
open, non-limiting sense.
l00811 The term "about" is used synonymously with the term "approximately." As
one of ordinary skill in the
art would understand, the exact boundary of "about" will depend on the
component of the composition or other
parameter. Illustratively, the use of the term "about" with regard to a
certain therapeutically effective
pharrnaceutical dose indicates that values slightly outside the cited values,
i.e., plus or minus 0.1% to 10%,
which are also effective and safe.
[00821 "Administered under the same conditions" or "under the same
conditions," as used herein, refers to
two or more methods and/or systems for the delivery of a corticosteroid
wherein the methods and/or systems
have one or more of the same conditions for administration of the
corticosteroid. The conditions for
administration can be selected from the group consisting of, but not limited
to, the corticosteroid that is
administered, the route of delivery of the corticosteroid, the time of
administration, the nominal dosage
administered to the subject, the number of doses administered, the volume of
the dose administered, and the
type of nebulizer used for delivery of the corticosteroid, or any combination
of the above-recited conditions for
administration. In some embodiments, "under the same conditions" can mean that
the corticosteroid that is
administered is the same. In other embodiments, "under the same conditions"
can mean that the route of
delivery of the corticosteroid is the same. In yet other embodiments, "under
the same conditions" means that
the time of administration of the corticosteroid is the same. In still other
embodiments, "under the same
conditions" means that the nominal dosage of the corticosteroid administered
to the subject is the same. In yet
still other embodiments, "under the same conditions" means'that the number of
doses administered is the same.
In other embodiments, "under the same conditions" can mean that the time of
administration for the
corticosteroid is the same, but the nominal dosage of the corticosteroid is
different. In stillother embodiments,
"under the same conditions" can mean that the corticosteroid administered is
the same, but the nominal dosage
of the corticosteroid is different. In yet stillother embodiments, "under the
same conditions" can mean that the
corticosteroid administered is the same, but the nominal dosage of the
corticosteroid and the type of nebulizer
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used for delivery of the corticosteroid is different. In still yetother
embodiments, "under the same conditions"
can mean that the nominal dosage of the corticosteroid is the same, but the
time of administration for the
corticosteroid is different. In other embodiments, "under the same conditions"
can mean that the nominal
dosage of the corticosteroid is the same, but the type of nebulizer used for
delivery of the corticosteroid and the
time of delivery are different. In still other embodiments, under the same
conditions" can mean that the
corticosteroid administered is the same, but the nominal dosage, the type of
nebulizer used for delivery of the
corticosteroid, and the time of administration are different.
[0083] "Bioavaiiability" refers to the percentage of the weight of a
corticosteroid, such as budesonide, dose
that is delivered into the general circulation of the animal or human being
studied. The total exposure (AUC(o_
.~) of a drug when administered intravenously is usually defined as 100%
Bioavailable (F%).
100841 "Blood plasma concentration" refers to the concentration of a
corticosteroid, such as budesonide, in the
plasma component of blood of a subject or patient population. It is understood
that the plasma concentration of
a corticosteroid, such as budesonide, may vary significantly between subjects,
due to variability witli respect to
metabolism and/or possible interactions with other therapeutic agents. In
accordance with one aspect of the
present invention, the blood plasma concentration of a corticosteroid, such as
budesonide, may vary from
subject to subject. Likewise, values such as maximurn plasma concentration
(C,,.) or time to reach maximum
plasma concentration (T,,,ax) or area under the curve from time zero to time
of last measurable concentration
(AUCI.,) or total area under the plasma concentration time curve (AUC(o_.~)
may vary from subject to subject.
Due to this variability, the amount necessary to constitute "a therapeutically
effective amount" of a
corticosteroid, such as budesonide, may vary from subject to subject.
[0085] "Bronchoconstrictive disorders," as used herein, refers to any disease
or condition which can be
physically manifested by the constriction or narrowing of the bronchi.
Examples of bronchoconstrictive
disorders include, but are not limited to, asthma, pediatric asthma, bronchial
asthma, allergic asthma, intrinsic
asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and
emphysema.
[00861 "Conventional inhalable corticosteroid therapies" or "inhalable
suspensions comprising a
corticosteroid," as used herein, refers to the use of an available suspension-
based corticosteroid formulation, for
example, the commercially available Pulmicort Respules (budesonide
suspension), in combination with a
nebulizer, prefrably a jet nebulizer, e.g., Pari LC Jet Plus nebulizer, for
the treatment of asthma and/or chronic
obstructive pulmonary disease (COPD) or other bronchoconstrictive disorders at
therapeutically effective
dosages for a given subject, population or populations or those conventional
dosages known to those of skill in
the art, e.g., for the aforementioned commercial formulation, PulmicortO
Respules, from about 500 g/day to
2000 g/day. In particular, a preferred budesonided suspension comparator is
Pulmicort Respules, which are
commercially available budesonide suspensions comprising either 250 g of
budesonide suspended in a 2 ml
aqueous volume within a unit dose ampoule or 500 pg of budesonide suspended in
a 2 ml aqueous volume
within in a unit dose ampoule. Additional suspension-based corticosteroid
preparations include beclomethasone
dipropionate (Clenil(D) and fluticasone propionate (Flixotide ), wherein the
suspension-based corticosteroid
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preparations are administered by an inhalation nebutizer at therapeutically
effective dosages or those
conventional dosages known to those of skill in the art.
[00871 "Drug absorption" or "absorption" typically refers to the process of
movement of drug from site of
delivery of a drug across a barrier into a blood vessel or the site of action,
e.g., a drug being absorbed in the
pulmonary capillary beds of the alveoli.
[00881 "Equal" or "equivalent," as used herein, refers to two or more
parameters or values having
substantially the same value. As one of ordinary skill in the art will
recognize, the exact boundary of "equal" or
"equivalent" will depend on the particular parameter or value being analyzed.
Illustratively, the use of the
terms "equal" or "equivalent," as used herein, encompasses values slightly
outside the cited values, i.e., plus or
minus 0.1 fo to 25%. For example, in the context of this invention, a C,a, of
578.2 (pg/ml) is equal to a C",,R of
556.74 pg/ml. Similarly, in another example, a C of 1195.3 (pg/ml) is equal to
a C,õ.,, of 1114.83 pg/ml.
[00891 "]nhalation nebulizer," as used herein, refers to a device that turns
medications, compositions,
formulations, suspensions, and mixtures, etc. into a fine mist for delivery to
the lungs.
[0090) "Inhaled aqueous mixture," "aqueous inhalation mixture," or "inhalable
composition," as used herein
generally refer to any aqueous (including partially aqueous) dosage form for
the inhaled delivery of an active
agent other than a suspension. Examples of suitable aqueous mixtures or
inhalable compositions include, but
are not limited to, solutions, dispersions, nanoparticulate dispersions,
nanoparticulate suspensions, emulsions,
colloidal liquids, micelle or mixed micelle liquids, and liposomal liquids.
Other suitable inhaled aqueous
mixtures also include suspensions to which solubility enhancers have been
added and at least part of the initial
suspension has increased solubility.
[0091) In some embodiments of the invention, "inhaled aqueous mixture,"
"aqueous inhalation mixture," or
"inhalable composition" do not include nano-dispersions and/or nano-
suspensions. In other embodiments,
"inhaled aqueous mixture," "aqueous inhalation mixture," or "inhalable
composition" do not include micelle,
mixed-micelle liquids or liposomal liquids. In still other embodiments,
"inhaled aqueous mixture," "aqueous
inhalation mixture," or "inhalable composition" do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
"inhalable compositions" include,
but are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable
composition is a solution comprising a corticosteroid, such as budesonide, and
a solubility enhancer. In another
embodiment, the inhalable composition is an emulsion comprising a
corticosteroid, such as budesonide, and a
solubility enhancer.
f00921 "Local bioavailability" refers to the fractionof the total dose of a
pharmacologic agent that is
bioavailable at the site of pharmacologic activity of that agent upon
administration of the agent to a patient via a
specific delivery route. Local bioavailability is to be contrasted with
systemic bioavailability, which is the
fraction of the total dose of an administered pharmacologic agent that reaches
the systemic circulation of a
patient. By way of a non-limiting example, the local bioavailability of an
agent delivered by inhalation refers to
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the fraction of the total dose of the inhaled agent which is delivered to the
lungs upon administration via the
inhalation route of delivery.
[0093) "Nominal dosage," as used herein, refers to the total amount of the
pharmaceutically active agent, e.g.,
corticosteroid, present in an inhalable dosage form prior to the
administration of the inhalable dosage form
comprising the pharmaceutically active agent. Thus, by way of a non-limiting
example, an aqueous inhalation
mixture comprising budesonide at a nominal dosage of 120 ug/dose refers to an
aqueous inhalation mixture
comprising approximately 120 g of budesonide prior the administration of the
aqueous inhalation mixture to a
patient. Likewise, a unit dose ampoule comprising an inhalable suspension with
1000 g of a corticosteroid,
e.g. budesonide, prior to administration, should have a nominal dosage, as
used herein, of about 1000 }cg/dose if
the entire contents of the unit dose ampoule is put into a delivery device,
e.g. a nebulize, for administration to a
patient.
100941 "Pharmacokinetics" refers to the factors which reflect the attainment
and maintenance of a
concentration of drug at a site of action.
[0095] "Enhanced pharmacokinetic profile," as used herein, in some embodiments
refers to a pharmacokinetic
profile wherein one drug formulation (test formulation) displays increased
absorption or distribution at the
drug's site of action as compared to another drug formulation (reference
formulation). In other embodiments,
an enhanced pharmacokinetic profile results when administration of an aqueous
inhalation mixture provides an
equivalent absorption or distribution at the drug's site of action as compared
to an inhalable suspension wherein
the aqueous inhalation mixture is administered at a lower nominal dosage than
the inhalable suspension (e.g., an
equivalent absorption of the test formulation at a nominal dosage of 1:2 the
reference product equals a two-fold
enhanced pharmacokinetic profile, an equivalent absorption of the test
formulation at a nominal dosage of 1:3
equals a three-fold pharmacokinetic profile, an equivalent absorption of the
test formulation at a nominal dosage
of 1:4 equals a four-fold pharmacokinetic profile, etc.). In other
embodiments, an enhanced pharmacokinetic
profile results when administration of an aqueous inhalation mixture provides
greater absorption or distribution
at the drug's site of action as compared an inhalable suspension wherein the
aqueous inhalation mixture is
administered at the same nominal dosage as the inhalable suspension. In
certain other embodiments, an
enhanced pharmacokinetic profile can be quantified on the basis of the
increase in absorption or distribution at
the drug's site of action of a aqueous inhalation mixture as compared to a
inhalable suspension. For example, in
certain embodiments, a two-fold enhanced phannacokinetic profile results when
administration of an aqueous
inhalation mixture displays a pharmacokinetic profile wherein the numerical
values representing the absorption
or distribution at the drug's site of action values of the aqueous inhalation
mixture are at least twice (2X) the
numerical values representing the absorption or distribution at the drug's
site of action values of an inhalable
suspension. In some embodiments, the inhalable suspension can be Pulmicort
Respules displaying a
pharmacokinetic profile as set forth in the package insert included with the
Pulmicort Respules commercial
product (AstraZeneca LP, Wilmington Delaware, USA).
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[00961 In some embodiments of this invention, "enhanced lung deposition," as
used herein, refers to lung
deposition of a compound wherein one drug formulation (e.g. aqueous inhalation
mixture) displays increased
total lung deposition as compared to another drug formulation (e.g. inhalable
suspension). In some
embodiments of this invention, "enhanced lung deposition," as used herein,
refers to lung deposition of a
compound wherein one drug formulation (e.g. aqueous inhalation mixture)
displays a substantially equivalent
total lung deposition as compared to another drug formulation (e.g. inhalable
suspension), wherein the aqueous
inhalation mixture is administered at a lower nominal dosage than the
inhalable suspension. In some
embodiments, the inhalable suspension can be PulmicortV Respules.
100971 As used herein, "respirable fraction" refers to the mass fraction of
drug-containing particles exiting the
nebulizer or mouthpiece of the nebulizer that is less than about 5 m in
aerodynamic diameter. Respirable
fraction relates to the dose of drug leaving the nebulizer, rather than the
norriinal dose inside the nebulizer.
[0098) A "solubility enhancer," as used herein, includes methods which provide
enhanced solubility with or
without a chemical agent acting. In certain embodiments, "solubility enhancer"
can refer to a chemical agent
thatincreases the solubility of a second chemical compound, such as an active
ingredient, in a solvent. In other
embodiments, the chemical agent can also be a solvent for the second chemical
compound. In still other
embodiments, the chemical agent is not a be a solvent for the second chemical
compound. In yet other
embodiments, "solubility enhancer" can refer to a method of=formulation which
provides enhanced solubility
without a chemical agent acting as the means to increase solubility, e.g., the
use of supercritical fluid production
methods to generate nanoparticles for dispersion in a solvent.
[00991 "Substantially free," as used herein in some embodiments, refers to a
composition or mixture
comprising a single therapeutically active agent. In certain embodiments,
"substantially free" refers to a
composition or mixture comprising a single therapeutically active agent
wherein the composition or mixture
does not comprise an appreciable amount of a second pharmaceutically active
agent, or does not comprise a
second phannaceutically active agent in an amount sufficient to result in
therapeutic activity.
1001001 A "therapeutically effective amount" or "effective amount" is that
amount of a pharmaceutical agent
which achieves a pharmacological effect. The term "therapeutically effective
amount" includes, for example, a
prophylactically effective amount. An "effective amount" of a corticosteroid,
such as budesonide, is an amount
effective to achieve a desired pharmacologic effect or therapeutic improvement
without undue adverse side
effects. The effective amount of a corticosteroid, such as budesonide, will be
selected by those skilled in the art
depending on the particular patient and the disease level. It is understood
that "an effect amount" or "a
therapeutically effective amount" can vary from subject to subject, and
population to population, due to
variation in metabolism of a corticosteroid, such as budesonide, age, weight,
general condition of the subject,
the condition being treated, the severity of the condition being treated, and
the judgment of the prescribing
physician.
[001011 "Treat" or "treatment" as used in the context of a bronchoconstrictive
disorder refers to any treatment
of a disorder or disease related to the contraction of the bronchi, such as
preventing the disorder or disease from
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occurring in a subject which may be predisposed to the disorder or disease,
but has not yet been diagnosed as
having the disorder or disease; inhibiting the disorder or disease, e.g.,
arresting the development of the disorder
or disease, relieving the disorder or disease, causing regression of the
disorder or disease, relieving a condition
caused by the disease or disorder, or stopping the symptoms of the disease or
disorder. Thus, as used herein, the
term "treatment" is used synonymously with the terms "prophylaxis" or
"prevention."
1. Inhalable Compositions Comprising a Corticosteroid Which Provide Enhanced
Lung Deposition
[00102] The present invention provides inhalable compositions comprising an
effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition for the
delivered corticosteroid as compared to a corticosteroid administered via
inhalation in the form of a suspension.
In preferred embodiments, the inhalable compositions described herein can
enable enhanced lung deposition of
the delivered corticosteroid as compared to conventional inhalable
corticosteroid therapies and further provide,
inter alia, a means for reducing the dosage required to provide a local
therapeutic effect. Likewise provided are
methods of generating fine particles from an inhalable composition cornprise
adding a solvent and a solubility
enhancer to an effective amount of corticosteroid, and operating a nebutizer
to produce fine particles. In other
embodiments, the methods provided herein comprise inhalable compositions that
enable enhanced lung
deposition of the delivered corticosteroid as compared to conventional
therapies and further provide, inter alia, a
means for reducing the dosage required to provide a local therapeutic effect.
1001031 In addition, methods and systems for the treatment of
bronchoconstrictive disorders, e.g., asthma
and/or chronic obstructive pulmonary disease (COPD), are provided that can
enable the delivery of a
corticosteroid having enhanced lung deposition as compared to a corticosteroid
administered via inhalation in
the form of a suspension, wherein the administration by the methods and
systems described herein provides one
or more of the following advantages: an increase in the lung deposition of the
delivered corticosteroid; a method
to reduce the nominal dosage of a corticosteroid required to provide a local
therapeutic effect; a method to
reduce the time required to administer an effective dose of the
corticosteroid; a method to increase patient
compliance with a therapeutic regimen comprising inhalation of nebulized
corticosteroids; a method of
enhanced delivery of a corticosteroid; a method for increasing the amount of
corticosteroid deposited in the
lung, e.g., bronchi and alveoli; and a method for reducing the side effects
associated with inhalation of
corticosteroids.
[001041 Certain aspects of the present invention relate to an inhalable
compositions comprising an effective
amount of a corticosteroid, a solvent and a solubility enhancer, wherein upon
administration of the composition
to a subject through a nebulizer, the composition achieves at least about 20%
to about 55%, between about 20%
to about 50%, or between about 20% to about 40% lung deposition e.g., bronchi
and alveoli, based on the
amount of corticosteroid in the mixture prior to administration. In certain
embodiments, the inhalable
compositions comprise an effective amount of a single corticosteroid, a
solvent and a solubility enhancer and
are substantially free of active pharmaceutical agents other than
corticosteroid. In still other embodiments, the
composition can achieve at least about 20% to about 55% lung deposition based
on the amount of corticosteroid
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in the mixture prior to administration. In other embodiments, the composition
can achieve at least 25% to about
45% lung deposition based on the amount of corticosteroid in the mixture prior
to administration. In certain
embodiments, the composition achieves at least about 25% lung deposition based
on the amount of
corticosteroid in the composition prior to administration. In other
embodiments, the composition achieves at
least about 30% lung deposition based on the amount of corticosteroid in the
composition prior to
administration. In still other embodiments, the composition achieves at least
about 35% lung deposition based
on the amount of corticosteroid in the composition prior to administration. In
yet still other embodiments, the
composition achieves at least about 40% lung deposition based on the amount of
corticosteroid in the
composition prior to administration. In other embodiments, the composition
achieves at least about 45% lung
deposition based on the amount of corticosteroid in the composition prior to
administration. In still other
embodiments, the composition achieves at least about 55% lung deposition based
on the amount of
corticosteroid in the composition prior to administration. In one embodiment,
the corticosteroid is budesonide.
In another embodiment, the corticosteroid is budesonide wherein the budesonide
is either an individual
diastereomer or a mixture of the two diastereomers administered individually
or together for a therapeutic
effect. In certain embodiments, the inhalable compositions comprise an
effective amount of a single
corticosteroid and a solubility enhancer and are substantially free of active
pharmaceutical agents other than
corticosteroid. In still other embodiments, the inhalable compositions
comprises an effective amount of a
budesonide, a solvent and a solubility enhancer and are substantially free of
active pharmaceutical agents other
than the budesonide.
[001051 In certain embodiments of this invention, the inhalable compositions
comprising an effective amount
of a corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition also
achieves at least about 60% respirable fraction upon administration. In a more
preferred embodiment of this
invention, the composition also achieves at least about 70% respirable
fraction upon administration. In a still
more preferred embodiment of this invention, the composition also achieves at
least about 80% respirable
fraction upon administration. In the most preferred embodiment of this
invention, the composition also
achieves at least about 85% respirable fraction upon administration. In
certain embodiments, the inhalable
compositions comprise an effective amount of a single corticosteroid, a
solvent and a solubility enhancer and
are substantially free of active pharmaceutical agents other than
corticosteroid.
[001061 In some embodiments of this invention, the inhalable compositions
comprising an effective amount of
a corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
15 to about 2000 pg of a
corticosteroid. In certain embodiments, the inhalable compositions comprise an
effective amount of a single
corticosteroid, a solvent and a solubility enhancer and are substantially free
of active pharmaceutical agents
other than corticosteroid. In other embodiments, the inhalable compositions
comprising an effective amount of
a corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
250 to about 2000 g of a
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corticosteroid. In still other embodiments, the inhalable compositions
comprising an effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
60 to about 1500 g of a
corticosteroid. In yet other embodiments, the inhalable compositions
comprising an effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
100 to about 1000 g of a
corticosteroid. In still other embodiments, the inhalable compositions
comprising an effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
120 to about 1000 jig of a
corticosteroid. In yet still other embodiments, the inhalable compositions
comprising an effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
125 to about 500 jig of a
corticosteroid. In certain embodiments, the inhalable compositions comprising
an effective amount of a
corticosteroid, a solvent, and a solubility enhancer which can provide
enhanced lung deposition comprise an
amount of corticosteroid in the composition prior to administration of about
40, about 60, about 100, about 120,
about 125, about 240, about 250, about 500, about 1000, about 1500, or about
2000 g of a corticosteroid. In
one embodiment, the inhalable composition comprises an amount of
corticosteroid in the composition prior to
administration of about 40 g of a corticosteroid. In another embodiment, the
inhalable composition comprises
an amount of corticosteroid in the composition prior to administration of
about of 60 jig of a corticosteroid. In
still another embodiment, the inhalable composition comprises an amount of
corticosteroid in the composition
prior to administration of about 100 g of a corticosteroid. In yet another
embodiment, the inhalable
composition comprises an amount of corticosteroid in the composition prior to
administration of about 120 g
of a corticosteroid. In still yet another embodiment, the inhalable
composition comprises an amount of
corticosteroid in the composition prior to administration of about 125 g of a
corticosteroid. In yet another
embodiment, the inhalable composition comprises an amount of corticosteroid in
the composition prior to
administration of about 240 pg of a corticosteroid. In yet still another
embodiment, the inhalable composition
comprises an amount of corticosteroid in the composition prior to
administration of less than about 250 pg of a
corticosteroid. In another embodiment, the inhalable composition comprises an
amount of corticosteroid in the
composition prior to administration of less than about 500 pg of a
corticosteroid. In one embodiment, the
corticosteroid is budesonide. In another embodiment, the corticosteroid is
budesonide wherein the budesonide
is either an individual diastereomer or a mixture of the two diastereomers
administered individually or together
for a therapeutic effect. In certain embodiments, the inhalable compositions
comprise an effective amount of a
single corticosteroid, and a solubility enhancer and are substantially free of
active pharmaceutical agents other
than corticosteroid. In still other embodiments, the inhalable compositions
comprises an effective amount of
budesonide, and a solubility enhancer and are substantially free of active
pharmaceutical agerits other than the
budesonide.
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[001071 In certain embodiments, the inhalable compositions can comprise about
40 g budesonide, a solvent
and a solubility enhancer, wherein upon administration of the composition to a
subject through a nebulizer, the
composition achieves lung deposition of at least 15 g of budesonide. In
certain other embodiments, the
inhalable compositions can comprise about 60 g budesonide, a solvent and a
solubility enhancer, wherein upon
administration of the composition to a subject through a nebulizer, the
composition achieves lung deposition of
at least 20 g of budesonide. In still other embodiments, the inhalable
composition can comprise about 120 pg
budesonide, a solvent and a solubility enhancer, wherein upon administration
of the composition to a subject
through a nebulizer, the composition achieves lung deposition of at least 40
pg of budesonide. In yet other
embodiments, the inhalable composition can comprise about 240 g budesonide, a
solvent and a solubility
enhancer, wherein upon administration of the composition to a subject through
a nebulizer, the composition
achieves lung deposition of at least 80 g of budesonide.
[001081 In certain embodiments, the inhalable compositions can comprise about
40 g budesonide, a solvent
and a solubility enhancer, wherein upon administration of the composition to a
subject through a nebulizer, the
composition achieves lung deposition of at least 13 pg of budesonide, wherein
the composition is substantially
free of active phannaceutical agents other than the budesonide. In certain
other embodiments, the inhalable
compositions can comprise about 60 Ng budesonide, a solvent and a solubility
enhancer, wherein upon
administration of the composition to a subject through a nebulizer, the
composition achieves lung deposition of
at least 20 pg of budesonide, wherein the composition is substantially free of
active pharmaceutical agents other
than the budesonide. In still other embodiments, the inhalable composition can
comprise about 120 pg
budesonide, a solvent and a solubility enhancer, wherein upon administration
of the composition to a subject
through a nebulizer, the composition achieves lung deposition of at least 40
pg of budesonide, wherein the
composition is substantially free of active pharmaceutical agents other than
the budesonide. In yet other
embodiments, the inhalable composition can comprise about 240 g budesonide, a
solvent and a solubility
enhancer, wherein upon administration of the composition to a subject through
a nebulizer, the composition
achieves lung deposition of at least 80 g of budesonide, wherein the
composition is substantially free of active
pharmaceutical agents other than the budesonide.
[001091 In some embodiments, suitable inhalable compositions comprising a
corticosteroid include, but are not
limited to, solutions, dispersions, nanoparticulate dispersions, emulsions,
colloidal liquids, micelle or mixed
micelle solutions, and liposomal liquids. In one embodiment, the aqueous
inhalation mixture is a solution
comprising a corticosteroid, such as budesonide, and a solubility enhancer. In
another embodiment, the
aqueous inhalation mixture is a mixed micelle solution comprising a
corticosteroid, such as budesonide, and a
solubility enhancer. In yet another embodiment, the aqueous inhalation
rnixture is a liposomal solution
comprising a corticosteroid, such as budesonide, and a solubility enhancer.
[00110) In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
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inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. ln one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
(001111 The corticosteroids that are useful in the inhalable compositions
described herein included, but are not
limited to, aldosterone, beclomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluolorolone,
flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, RPR 106541,
tixocortol, triamcinolone, and their respective pharmaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
1001121 In some embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solvent. In certain embodiments, the solvent is selected from the
group comprising water, aqueous
alcohol, propylene glycol, or aqueous organic solvent. In preferred
embodiments, the solvent is water.
(001131 In other embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solubility enhancer. In some embodiments, the solubility enhancer
can have a concentration (w/v)
ranging from about 0.001% to about 25%. In other embodiments, the solubility
enhancer can have a
concentration (w/v) ranging from about 0.01% to about 20%. In still other
embodiments, the solubility
enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%.
In yet other embodiments, the
solubility enhancer can have a concentration (w/v) ranging from about 1% to
about 10%. In a preferred
embodiment, the solubility enhancer can have a concentration (w/v) ranging
from about 2% to about 10% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g.,
SBE7-f3-CD (Captisol ). In one
embodiment, the solubility enhancer can have a concentration (w/v) of about 2%
when the solubility enhancer
is a cyclodextrin or cyclodextrin derivative, e.g., SBE7-(3-CD (Captisol ). In
another embodiment, the
solubility enhancer can have a concentration (w/v) of about 5% when the
solubility enhancer is a cyclodextrin
or cyclodextrin derivative, e.g., SBE7-0-CD (Captisol ). In yet another
embodiment, the solubility enhancer
can have a concentration (w/v) about 7% when the solubility enhancer is a
cyclodextrin or cyclodextrin
derivative,e.g., SBE7-/3-CD (Captisol ). In still yet another embodiment, the
solubility enhancer can have a
concentration (w/v) of about 10% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative, e.g.,
SBE7-/3-CD (Captisol ).
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1001141 Chemical agents acting as solubility enhancers suitable for use in the
present invention include, but are
not limited to, propylene glycol, non-ionic surfactants, phospholipids,
cyclodextrins and derivatives thereof, and
surface modifiers and/or stabilizers. In other embodiments, solubility
enhancers refer to a formulation method
which provides enhanced solubility without a chemical agent acting as the
means to increase solubility, e.g. the
use of supercritical fluid production methods to generate nanoparticles for
dispersion in a solvent.
[001151 Additional solubility enhancers suitable for use in the inhalable
compositions described herein are
known in the art and are described in, e.g., U.S. Patent Nos. 5,134,127,
5,145,684, 5,376,645, 6,241,969 and
U.S. Pub. Appl. Nos. 2005/0244339 and 2005/0008707, each of which is
specifically incorporated by reference
herein. In addition, examples of suitable solubility enhancers are described
below.
[00116] Suitable cyclodextrins and derivatives for use in the present
invention are described in the art, for
example, Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent
Nos. 5,134,127, 5,376,645,
5,874,418, each of which is specifically incorporated by reference herein. In
some embodiments, suitable
cyclodextrins or cyclodextrin derivatives for use in the present invention
include, but are not limited to, a<
cyclodextrins, 6-cyclodextrins, -t-cyclodextrins, SAE-CD derivatives (e.g.,
SBE-a-CD, SBE-Q-CD, SBEI-0-
CD, SBE4-,O-CD, SBE7-0-CD (Captisol ), and SBE-7-CD) (Cydex, Inc. Lenexa, KS),
hydroxyethyl,
hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers,
their corresponding mixed
ethers and further mixed ethers with methyl or ethyl groups, such as
methylhydroxyethyl, ethyl-hydroxyethyl
and ethyl- hydroxypropyl ethers of rx ,~(3- and ycyclodextrin; and the
maltosyl, glucosyl and maltotriosyl
derivatives of a-, j3- and y~cyclodextrin, which may contain one or more sugar
residues, e. g. glucosyl or
diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e. g.
a mixture of maltosyl and
dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein
include hydroxypropyl-,Q-cyclodextrin,
hydroxyethyl-g-cyclodextrin, hydroxypropyl-ycyclodextrin, hydroxyethyl-
ycyclodextrin, dihydroxypropyl-0-
cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-(3-cyclodextrin, diglucosyl-,6-
cyclodextrin, maltosyl-c~-
cyclodextrin, maltosyl-j3-cyclodextrin, maltosyl--)~-cyclodextrin,
maltotriosyl-,6-cyclodextrin, maltotriosyl-y-
cyclodextrin, dimaltosyl-,6-cyclodextrin, diethyl-,8-cyclodextrin, glucosyl-cx
cyclodextrin, glucosyl-(3-
cyclodextrin, diglucosyl-(3-cyclodextrin, tri-O-methyl-(3-cyclodextrin, tri-O-
ethyl-a-cyclodextrin, tri-O-butyryl-
0-cyclodextrin, tri-O-valeryl-0-cyclodextrin, and di-O-hexanoyl-/3-
cyclodextrin, as well as methyl-'3-
cyclodextrin, and mixtures thereof such as maltosyl-,9-cyclodextrin/dimaltosyl-
,6-cyclodextrin. Procedures for
preparing such cyclodextrin derivatives are well-known, for example, from U.S.
Patent No. 5,024,998, and
references incorporated by reference therein. Other cyclodextrins suitable for
use in the present invention
include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969
by ORGANON (AKZO-
NOBEL), hydroxybutenyl ether derivatives by EASTMAN, sulfoalkyl-hydroxyalkyl
ether derivatives,
sulfoalkyl-alkyl ether derivatives, and other derivatives, for example as
described in U.S. Patent Application
Nos. 2002/0128468, 2004/0106575, 2004/0109888, and 2004/0063663, or U.S.
Patents Nos. 6,610,671,
6,479,467, 6,660,804, or 6,509,323, each of which is specifically incorporated
by reference herein.
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1001171 Hydroxypropyl-0-cyclodextrin can be obtained ftom Research Diagnostics
Inc. (Flanders, NJ).
Exemplary hydroxypropyl-o-cyclodextrin products include Encapsin (degree of
substitution -4) and
Molecusol (degree of substitution -8); however, embodiments including other
degrees of substitution are also
available and are within the scope of the present invention.
[00118) Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or
Wacker (Iowa). Other
derivatized cyclodextrins suitable for use in the invention include water
soluble derivatized cyclodextrins.
Exemplary water-soluble derivatized cyclodextrins include carboxylated
derivatives; sulfated derivatives;
alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives;
and carboxy-,6-cyclodextrins, e. g.,
succinyl-0- cyclodextrin (SCD). All of these materials can be made according
to methods known in the art
and/or are available commercially. Suitable derivatized cyclodextrins are
disclosed in Modified Cyclodextrins:
Scaffolds'and Templates for Supramolecular Chemistry (Eds. Christopher J.
Easton, Stephen F. Lincoln,
Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and
Derivatives (Ed. Dominique
Duchene, Editions de Sante, Paris, France, 1991).
[001191 Examples of non-ionic surfactants which appear to have a particularly
good physiological
compatibility for use in the present invention are tyloxapol, polysorbates
including, but not limited to,
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan
monopalmitate, polyoxyethylene
(20) sorbitan monostearate (available under the tradename Tweens 20-40-60,
etc.), Polysorbate 80,
Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan
palmitate, sorbitan stearate (available
under the tradename Span 20-40-60 etc.), benzalkonium chloride, PPO-PEO block
copolymers (Pluronics),
Cremophor-EL, vitamin E-TPGS (e.g., d-alpha-tocopheryl-polyethyleneglycol-1000-
succinate), Solutol-HS-15,
oleic acid PEO esters, stearic acid PEO esters, Triton-X100, Nonidet P-40, and
macrogol hydroxystearates such
as macrogol-l 5-hydroxystearate.
[001201 In some embodiments, the non-ionic surfactants suitable for use in the
present invention are
formulated with the corticosteroid to fonn liposome preparations, micelles or
mixed micelles. Methods for the
preparations and characterization of liposomes and liposome preparations are
known in the art. Often, multi-
lamellar vesicles will form spontaneously when amphiphilic lipids are
hydrated, whereas the formation of small
uni-lamellar vesicles usually requires a process involving substantial energy
input, such as ultrasonication or
high pressure homogenization. Further methods for preparing and characterizing
liposomes have been
described, for example, by S. Vemuri et al. (Preparation and characterization
of liposomes as therapeutic
delivery systems: a review. Pharm Acta Helv. 1995, 70(2):95-111) and U.S.
Patent Nos. 5,019,394, 5,192,228,
5,882,679, 6,656,497 each of which is specifically incorporated by reference
herein.
[001211 In some cases, for example, micelles or mixed micelles may be formed
by the surfactants, in which
poorly soluble active agents can be solubilized. In general, micelles are
understood as substantially spherical
structures formed by the spontaneous and dynamic association of amphiphilic
molecules, such as surfactants.
Mixed micelles are micelles composed of different types of amphiphilic
molecules. Both micelles and mixed
micelles should not be understood as solid particles, as their structure,
properties and behavior are much
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different from solids. The amphiphilic molecules which form the micelles
usually associate temporarily. In a
micellar solution, there is a dynamic exchange of molecules between the
micelle-forming amphiphile and
monomolecularly dispersed amphiphiles which are also present in the solution.
The position of the drug
molecules which are solubilized in such micelles or mixed micelles depends on
the structure of these molecules
as well as the surfactants used. For example, it is to be assumed that
particularly non-polar molecules are
localized mainly inside the colloidal structures, whereas polar substances are
more likely to be found on the
surface. In one embodiment of a micellar or mixed micellar solution, the
average size of the micelles may be
less than about 200 nrn (as measured by photon correlation spectroscopy), such
as from about 10 nm to about
100 nm. Particularly preferred are micelles with average diameters of about 10
nm to about 50 nm. Methods of
producing micelles and mixed micelles are known in the art and described in,
for example, U.S. Patent Nos.
5,747,066 and 6,906,042, each of which is specifically incorporated by
reference herein.
1001221 Phospholipids are defined as amphiphile lipids which contain
phosphorus. Phospholipids which are
chemically derived from phosphatidic acid occur widely and are also commonly
used for pharmaceutical
purposes. This acid is a usually (doubly) acylated glycerol-3-phosphate in
which the fatty acid residues may be
of different length. The derivatives of phosphatidic acid include, for
example, the phosphocholines or
phosphatidylcholines, in which the phosphate group is additionally esterified
with choline, furthermore
phosphatidyl ethanolamines, phosphatidyl inositols, etc. Lecithins are natural
mixtures of various
phospholipids which usually have a high proportion of phosphatidyl cholines.
Depending on the source of a
particular lecithin and its method of extraction and/or enrichment, these
mixtures may also comprise significant
amounts of sterols, fatty acids, tryglycerides and other substances.
(00123] Additional phospholipids which are suitable for delivery by inhalation
on account of their
physiological properties comprise, in particular, phospholipid mixtures which
are extracted in the form of
lecithin from natural sources such as soja beans (soy beans) or chickens egg
yolk, preferably in hydrogenated
form and/or freed from lysolecithins, as well as purified, enriched or
partially synthetically prepared
phopholipids, preferably with saturated fatty acid esters. Of the phospholipid
mixtures, lecithin is particularly
preferred. The enriched or partially synthetically prepared medium- to long-
chain zwitterionic phospholipids
are mainly free of unsaturations in the acyl chains and free of lysolecithins
and peroxides. Examples for
enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC),
distearoyl phosphatidyl choline
(DSPC) and dipalmitoyl phosphatidyl choline (DPPC). Of these, DMPC is
currently more preferred.
Alternatively, phospholipids with oleyi residues and phosphatidyl glycerol
without choline residue are suitable
for some embodiments and applications of the invention.
(001241 In some embodiments, the non-ionic surfactants and phospholipids
suitable for use in the present
invention are formulated with the corticosteroid to form colloidal structures.
Colloidal solutions are defined as
mono-phasic systems wherein the colloidal material dispersed within the
colloidal solution does not have the
measurable physical properties usually associated with a solid material.
Methods of producing colloidal
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dispersions are known in the art, for example as described in U.S. Patent No.
6,653,319, which is specifically
incorporated by reference herein.
[001251 Suitable surface modifiers for use in the present invention are
described in the art, for example, U.S.
Patent Nos. 5,145,684, 5,510,118, 5,565,188, and 6,264,922, each of which is
specifically incorporated by
reference herein. Examples of surface modifiers and/or surface stabilizers
suitable for use in the present
invention include, but are not limited to, hydroxypropyl methylcellulose,
hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin,
casein, lecithin (phosphatides),
dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium
chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan
esters, polyoxyethylene alkyl ethers
(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, polyoxyethylene
sorbitan fatty acid esters (e.g., the commercially available TweensTM, e.g.,
Tween 20TM and Tween 80TM (ICI
Specialty Chemicals)), polyethylene glycols (e.g., Carbowaxs 3550TM and 934T"
(Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose
phthalate, noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA), 4-
(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde
(also known as tyloxapol,
superione, and triton), poloxamers (e.g., Pluronics F68TM and F108TM, which
are block copolymers of ethylene
oxide and propylene oxide), poloxamines (e.g., Tetronic 90ST"', also known as
Poloxamine 90ST"', which is a
tetrafunctional block copolymer derived from sequential addition of propylene
oxide and ethylerie oxide 'to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)), Tetronic
1508T"' (T-1508) (BASF
Wyandotte Corporation), Tritons X-20OT"', which is an alkyl aryl polyether
sulfonate (Rohm and I-Iaas),
Crodestas F-100T'", which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.), p-
isononylphenoxypoly-(glycidol), also known as Olin-lOGT"' or Surfactant IOTM
(Oliri Chemicals, Stamford,
Conn.), Crodestas SL-40® (Croda, Inc.), and SA9OHCO, which is C18H37CH2(-
CON(CH3)--
CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.), decanoyl-N-methylglucamide, n-decyl-fl-
D-glucopyranoside,
n-decyl-13-D-maltopyranoside, n-dodecyl /3-D-glucopyranoside, n-dodecyi-13-D-
maltoside, heptanoyl-N-
methylglucamide, n-heptyl-/3-D-glucopyranoside, n-heptyl-o-D-thioglucoside, n-
hexyl-{3-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-"-glucopyranoside, octanoyl-N-
methylglucamide, n-octyl-,6-D-
glucopyranoside, octyl 13-D-thioglucopyranoside, PEG-phospholipid, PEG-
cholesterol, PEG-cholesterol
derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl
pyrrolidone and vinyl
acetate, and the like. (e.g. hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone,
copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate and
dioctyl sodium sulfosuccinate).
(00126] Other useful cationic stabilizers include, but are not limited to,
cationic lipids, sulfonium,
phosphonium, and quartemary ammonium compounds, such as
stearyltrimethylammonium chloride, benzyl-
di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or
bromide, coconut methyl
dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride,
decyl dimethyl
26
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WO 2007/075801 PCT/US2006/048631
hydroxyethyl ammonium chloride or bromide, C12-15 dimethyl hydroxyethyl
ammonium chloride or bromide,
coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl
ammonium methyl sulphate,
lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl
(ethenoxy)4 ammonium chloride or
bromide, N-alkyl (C 12-18) dimethylbenzyl ammonium chloride, N-alkyl (C14-
18)dimethyl-benzyl ammonium
chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride,
N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium chloride,
trimethylammonium halide, alkyl-
trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl
ammonium chloride,
ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt,
dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
N-
tetradecyldimethylbenzyi ammonium, chloride monohydrate, N-alkyl(C12-14)
dimethyl 1-naphthylmethyl
ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl
benzenealkyl ammonium
chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium
chloride, alkyl benzyl dimethyl
ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl
triethyl amrnonium
chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium
chlorides,
alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride,
decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl
trioctylammonium chloride
(ALIQUAT 336TM), POLYQUAT lOT"', tetrabutylammonium bromide, benzyl
trimethylammonium bromide,
choline esters (such as choline esters of fatty acids), benzalkonium chloride,
stearalkonium chloride compounds
(such as =stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl
pyridinium bromide or chloride,
halide salts of quaternized polyoxyethylalkylamines, MirapolT"' and ALKAQUATTM
(Alkaril Chemical
Company), alkyl pyridinium salts, amines, such as alkylamines, dialkylamines,
alkanolamines,
polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine,
amine salts, such as lauryl amine
acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium
salt, and amine oxides, imide
azolinium salts, protonated quaternary acrylamides, methylated quaternary
polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride], and
cationic guar.
1001271 In certain embodiments, the inhalable compositions of the present
invention comprises a solubility
enhancer is selected from the group consisting of propylene glycol, non-ionic
surfactants, tyloxapol, polysorbate
80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin,
purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from lecithin, dimyristoyl
phosphatidylcholine (DMPC), dipalmitoyl
phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC),
cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-a-CD, SBE-J3-CD, SBEl-/3-CD, SBE4-0-CD, SBE7-,f3-CD
(Captisolft SBE-y-CD,
dimethyl /3-CD, hydroxypropyl-(3-cyclodextriri, 2-HP-/3-CD, hydroxyethyl-r3-
cyclodextrin, hydroxypropyl--f-
cyclodextrin, hydroxyethyl--y-cyclodextrin, dihydroxypropyl-a-cyclodextrin,
glucosyl-a-cyclodextrin, glucosyl-
P-cyclodextrin, diglucosyl-13-cyclodextrin, maltosyl-a cyclodextrin, maltosyl-
p-cyclodextrin, maltosyl-7-
cyclodextrin, maltotriosyl-f3-cyclodextrin, maltotriosyl-T-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-(3-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
27
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WO 2007/075801 PCT/US2006/048631
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-(3-CD (Captisol ).
1001281 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-(3-CD, SBEl-,G-CD, SBE4-0-CD, SBE7-;6-CD (Captisol ), SBE-y-CD,
dimethyl a-CD,
hydroxypropyl-Q-cyclodextrin, 2-HP-(3-CD, hydroxyethyl-13-cyclodextrin,
hydroxypropyl--)-cyclodextrin,
hydroxyethyl--y-cyclodextrin, dihydroxypropyl-R-cyclodextrin, glucosyl-cx
cyclodextrin, glucosyl-0-
cyclodextrin, diglucosyl-,6-cyclodextrin, maltosyl-ca cyclodextrin, maltosyl-
19-cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl--y-cyclodextrin,
dimaltosyl-16-cyclodextrin, methyl-0-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-,6-CD
(Captisol ).
[001291 ln addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that in certain embodiments the
aqueous inhalation mixtures or
compositions formulated by methods which provide enhanced solubility are
likewise suitable for use in the
presently disclosed invention. Thus, in the context of the present invention,
a "solubility enhancer" includes
aqueous inhalation mixtures formulated by methods which provide enhanced
solubility with or without a
chemical agent acting as a solubility enhancer. Such methods include, e.g.,
the preparation of supercritical
fluids. In accordance with such methods, corticosteroid compositions, such as
budesonide, are fabricated into
particles with narrow particle size distribution (usually less than 200
nanometers spread) with a mean particle
hydrodynamic radius in the range of 50 nanometers to 700 nanometers. The nano-
sized corticosteroid particles,
such as budesonide particles, are fabricated using Supercritical Fluids (SCF)
processes including Rapid
Expansion of Supercritical Solutions (RESS), or Solution Enhanced Dispersion
of Supercritical fluids (SEDS),
as well as any other techniques involving supercritical fluids. The use of SCF
processes to fonn particles is
reviewed in Palakodaty, S., et al., Pharmaceutical Research 16:976-985 (1999)
and described in Bandi et al.,
Eur, J. Pharm. Sci. 23:159-168 (2004), U.S. Patent No. 6,576,264 and U.S.
Patent Application No.
2003/0091513, each of which is specifically incorporated by reference herein.
These methods permit the
formation of micron and sub-micron sized particles with differing morphologies
depending on the method and
parameters selected. In addition, these nanoparticl.es can be fabricated by
spray drying, lyophilization, volume
exclusion, and any other conventional methods of particle reduction.
[00130] Furthermore, the processes for producing nanometer sized particles,
including SCF, can permit
selection of a desired morphology (e.g., amorphous, crystalline, resolved
racemic) by appropriate adjustment of
the conditions for particle formation during precipitation or condensation. As
a consequence of selection of the
desired particle form, extended release of the selected medicament can be
achieved. These particle fabrication
processes are used to obtain nanoparticulates that have high purity, low
surface imperfections, low surface
charges and low sedimentation rates. Such particle features inhibit particle
cohesion, agglomeration and also
prevent settling in liquid dispersions. Additionally, because processes such
as SCF can separate isomers of
certain medicaments, such separation could contribute to the medicament's
enhanced activity, effectiveness as
28
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WO 2007/075801 PCT/US2006/048631
well as extreme dose reduction. In some instances, isomer separation also
contributes to reduced side effects.
In accordance with the present methods and systems, an aqueous inhalation
mixture can be a composition
fabricated into a powdered form by any process including SCF, spray drying,
precipitation and volume
exclusion, directly into a collection media, wherein the particulate compound
is thus automatically generated
into a dispersed formulation. In some embodiments, this formulation can be the
final formulation.
[00131] In other embodiments of the present invention, the inhalable
composition can further comprise a
second therapeutic agent selected ftom the group consisting of a beta2-
adrenoreceptor agonist, a dopamine (132)
receptor agonist, an anti -cholinergic agent, and a prophylactic therapeutic.
In some embodiments of this
invention, second therapeutic agent is a beta2-adrenoreceptor agonist selected
from the group comprising
albuterol, levalbuterol or pharmaceutical acceptable derivatives thereof.
[001321 Beta2-Adrenoreceptor agonists for use in the inhalable compositions
provided herein include, but are
not limited to, Albuterol (cr l-(((1, 1-dimethylethyl) amino) methyl)-4-
hydroxy-1, 3-benzenedimethanol);
Bambuterol (dimethylcarbamic acid 5-(2-((1,I-dimethylethyl)amino)-1-
hydroxyethyl)-1, 3-phenyleneester);
Bitolterol (4-methylbenzoic acid4-(2-((1, 1-dimethylethyl) amino)-l-
hydroxyethyl)-1, 2-phenyleneester);
Broxaterol (3-bromo-alpha-(((1, l-dimethylethyl) amino) methyl)-5-
isoxazolemethanol); Isoproterenol (4-(1-
hydroxy-2-((1-methylethyl-) amino) ethyl)-1, 2-benzene-diol); Trimetoquinol
(1, 2, 3, 4-tetrahydro-l-((3, 4-,5-
trimethoxyphenyl)-methyl)-6, 7-isoquinolinediol); Clenbuterol (4-amino-3, 5-
dichloro-alpha-(((l,l-
diemthylethyl) amino) methyl) benzenemethanol); Fenoterol (5-(1-hydroxy-2-((2-
(4-hydroxyphenyl)-1-
methylethyl) amino) ethyl)-1,3-benzenediol); Formoterol (2-hydroxy-5-((I RS)-1-
hydroxy-2-(((1 RS)-2-(p-
methoxyphenyl)-t-methylethyl) amino) ethyl)formanilide); (R, R)-Formoterol;
Desformoterol ((R, R) or (S,S)-
3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl) amino) methyl)
benzenemethanol);
Hexoprenaline (4,4'-(I, 6-hexane-diyl)-bis (imino(1-hydroxy-2, 1-ethanediyl)))
bis-1, 2-benzenediol);
Isoetharine (4-(I-hydroxy-2-((i-methylethyl) amino) butyl)-1, 2-benzenediol);
Isoprenaline (4-(1-hydroxy-2-
((1-methylethyl) amino) ethyl)-1, 2-benzenediol); Meta-proterenol (5-(I-
hydroxy-2-((1-methylethyl)
amino)ethyl)-1, 3-benzened- iol); Picumeterol (4-amino-3,5-dichloro-cY (((6-(2-
(2-pyridinyl) ethoxy)hexyl)-
amino) methyl) benzenemethanol); Pirbuterol (a-6-(((1,1-dimethylethyl)-amino)
methyl)-3-hydroxy-2,6-
pyridinemethanol); Procaterol (((R*,S*)-(+-)-8-hydroxy-5-(1-hydroxy-2-((I-
methylethyl) amino)butyl)-2 (1 H)-
quinolin-one); Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)
amino)-propyl)-3, 7-dihydro-1,3-
dimethyl-IH-purine- 2,6-dione) ; Rimiterol(4-(hydroxy-2-piperidinylmethyl)-1,
2-benzenediol); Salbutamol ((+-
)-alphal-(((I,l-dimethylethyl) amino) methyl)-4-hydroxy-1,3-b-
enzenedimethanol); (R)-Salbutamol;
Salmeterol((+-)-4-hydroxy-a-1-(((6-(4-phenylbutoxy)hexyl)- amino) methyl)-I, 3-
benzenedimethanol); (R)-
Salmeterol; Terbutaline (5-(2-((1, 1-dimethylethyl) amino)-1-hydroxyethyl)-1,
3-benzenediol); Tulobuterol (2-
chloro-cx-(((l, 1-dimethylethyl) amino) methyl) benzenemethanol); and TA-2005
(8-hydroxy-5-((1R)-1-hydroxy-
2-(N-((IR)-2-(4-methoxyphenyl)-1-methylethyl) amino) ethyl) carbostyril
hydrochloride).
1001331 Albuterol sulfate, al[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-c4
a"-diol sulfate (2:1)(salt), is a
relatively selective beta2-adrenergic bronchodilator having a chemical formula
(C13H21N03)2=H2SO4.
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WO 2007/075801 PCT/US2006/048631
Albuterol inhalation aerosol is indicated for the prevention and relief of
bronchospasm in patients 4 years of age
and older with reversible obstructive airway disease and for the prevention of
exercise-induced bronchospasm
in patients 4 years of age and older. Aibuterol inhalation solution is
indicated for the relief of bronchospasm in
patients 2 years of age or older with reversible obstructive airway disease
and acute attacks of bronchospasm.
[00134] Levalbuterol HCI, (R)-al-[[(1,1- dimethylethyl)amino]methyl]-4-hydroxy-
1,3-benzenedimethanol
hydrochloride, having chemistry formula as C13H21N03-HCI, a relatively
selective beta2-adrenergic receptor
agonist and is the (R)-enantiomer of the drug albuterbl. Xopenex (levalbuterol
HCI) Inhalation Solution is
supplied in unit-dose vials and requires nodilution before by nebulization.
Each 3 mL unit-dose via] contains
either 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCI) or 1.25 mg of
levalbuterol (as 1.44 mg of
levalbuterol HCI), sodium chloride to adjust tonicity, and sulfuric acid to
adjust the pH to 4.0 (3.3 to 4.5).
Xopenex (levalbuterol HCI) Inhalation Solution is indicated for the treatment
or prevention of bronchospasm in
adults and adolescents 12 years of age and older with reversible obstructive
airway disease.
[00135] Dopamine (D2) receptor agonists include, but are not limited to,
Apomorphine ( (r)- 5,6, 6a, 7-
tetrahydro-6-methyl-4H-dibenzo [de,glquinoline-10, 11-diol); Bromocriptine (
(5'. alpha.)-2-bromo-12'-
hydroxy-2'-(1-methylethy])-5'-(2-methylpropyl)ergotaman-3', 6', 18-trione);
Cabergoline ((8-0)-N-(3-
(dimethylamino) propyl)-N-((ethylamino) carbony-l)-6-(2-propenyl) ergoline-8-
carboxamide); Lisuride (N'-
((8-a-)-9, 10-didehydro-6- methylergolin-8-yl) -N, N-diethylurea); Pergolide
((8-(3-)-8-((methylthio) methyl)-6-
propylergoline); Levodopa (3-hydroxy-L-tryrosine); Pramipexole ((s)-4, 5, 6, 7-
tetrahydro-N6-prop-yl-2, 6-
benzothiazolediamine); Quinpirole hydrochloride (trans-(-)-4aR-4, 4a, 5, 6, 7,
8, 8a, 9-octahydro-5-propyl-IH-
pyrazolo [3,4-g] quinoline hydrochloride); Ropinirole (4-(2- (dipropylamino)
etbyl)-I, 3-dihydro-2H-indol-2-
one); and Talipexole (5, 6, 7, 8-tetrahydro-6-(2-propenyl)-4H-thia-zolo [4,5-
d] azepin-2-amine). Other
dopamine D2 receptor agonists for use herein are disclosed in International
Patent Application Publication No.
WO 99/36095, the relevant disclosure of which is hereby incorporated by
reference.
(00136] Anti-cholinergic agents for use herein include, but are not limited
to, ipratropium bromide, oxitropium
bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna
extract, scopolamine, scopolamine
methobromide, homatropine methobromide, hyoscyamine, isopriopramide,
orphenadrine, benzalkonium
chloride, tiotropium bromide and glycopyrronium bromide.
1001371 Other active ingredients for use in the inhalable compositions
described herein include, but are not
limited to, Ii,-5 inhibitors such as those disclosed in U. S. Patents No.
5,668,110, No. 5,683,983, No. 5,677,280,
No. 6,071,910 and No. 5,654,276, each of which is incorporated by reference
herein; anti-sense modulators of
IL-5 such as those disclosed in U. S. Pat. No. 6,136,603, the relevant
disclosure of which is hereby incorporated
by reference; milrinone (1, 6-dihydro-2-methyl-6-oxo-[3, 4'-bipyridine]-5-
carbonitrile); milrinone lactate;
tryptase inhibitors such as those disclosed in U. S. Pat. No. 5,525,623, which
is incorporated by reference
herein; tachykinin receptor antagonists such as those disclosed in U. S.
Patents No. 5,691,336, No. 5,877,191,
No. 5,929,094, No. 5,750,549 and No. 5,780,467, each of which is incorporated
by reference herein; leukotriene
receptor antagonists such as montelukast sodium (Singular, R-(E)]-1-[[[1-[3-[2-
(7-chloro-2-quinolinyl)-
CA 02634413 2008-06-19
WO 2007/075801 PCT/US2006/048631
ethenyl]-phenyl]-3-[2-(I-hydroxy-l-methylethyl)-phenyl]-propyl]-thio]-methyl]
cyclopro-paneacetic acid,
monosodium salt), 5-lypoxygenase inhibitors such as zileuton (Zyflo@, Abbott
Laboratories, Abbott Park, IL),
and anti-IgE antibodies'such as Xolair (recombinant humanized anti-IgE
monoclonal antibody (CGP 51901;
IGE 025A; rhuMAb-E25), Genentech, Inc. , South San Francisco, CA), and topical
anesthetics such as
lidocaine, N-arylamide, aminoalkylbenzoate, prilocaine, etidocaine (U. S.
Patents No. 5,510,339, No.
5,631,267, and No. 5,837,713, the relevant disclosures of which are hereby
incorporated by reference).
[00138] In some embodiments of this invention, the inhalable composition is
administered to a patient not more
than once a day. In other embodiments, the inhalable composition is
administered to a patient not more than
twice a day. In some embodiments of this invention, the composition is
administered to a patient twice a day or
more than twice a day. In still other embodiments, the inhalable composition
is administered to a patient not
more than once a day in the evening.
[001391 Another aspect of this invention relates to an inhalable composition
comprising an effective amount of
corticosteroid, a solvent and a solubility enhancer, wherein the inhalable
composition achieves a higher
respirabie fraction as compared to an inhalable suspension comprising a
corticosteroid administered under the
same conditions. In certain embodiments, the. inhalable compositions
comprising an effective amount of a
corticosteroid, a solvent and a solubility enhancer are substantially free of
active pharmaceutical agents other
than corticosteroids. In a preferred embodiment of this invention, the
inhalable composition achieves at least
about 10% higher respirable fraction compared to an inhalable suspension
comprising the corticosteroid
administered under the same conditions. In a more preferred embodiment of this
invention, the inhalable
composition achieves at least about 15% higher respirable fraction compared to
an inhalable suspension
comprising the corticosteroid administered under the same conditions. In the
most preferred embodiment of
this invention, the inhalable composition achieves at least about 20% higher
respirable fraction compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions.
1001401 In certain embodiments, the inhalable compositions comprising an
effective amount of a corticosteroid,
a solvent and a solubility enhancer described here achieve at least about 5%
higher lung deposition compared to
an inhalable suspension comprising the corticosteroid administered under the
same conditions. In other
embodiments, the inhalable composition achieves'at least about 10% higher lung
deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In still other
embodiments, the inhalable composition achieves at least about 15% higher lung
deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In yet other
embodiments, the inhalable composition achieves at least about 20% higher lung
deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In still yet other
embodiments, the inhalable composition achieves at least about 25% higher lung
deposition compared to an
inhalabte suspension comprising the corticosteroid administered under the same
conditions. In certain
embodiments, the inhalable compositions comprising an effective amount of a
corticosteroid, a solvent and a
solubility enhancer are substantially free of active pharmaceutical agents
other than corticosteroids.
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WO 2007/075801 PCT/US2006/048631
[001411 In some embodiments of this invention, the inhalable compositions
comprising an effective amount of
a corticosteroid, a solvent and a solubility enhancer achieves about the same
lung deposition of the
corticosteroid as compared to an inhalable suspension comprising the
corticosteroid, wherein the composition is
administered at a lower nominal dosage than the inhalable suspension. In some
embodiments of this invention,
the inhalable composition achieves about 90% to 110% lung deposition of the
corticosteroid as compared to an
inhalable suspension comprising the corticosteroid, wherein the composition is
administered at a lower nominal
dosage than the inhalable suspension. In some embodiments of this invention,
the inhalable composition
achieves about 80% to 120% lung deposition of the corticosteroid as compared
to an inhalable suspension
comprising the corticosteroid, wherein the composition is administered at a
lower nominal dosage than the
inhatable suspension. In some embodiments of this invention, the inhalable
composition achieves about 70% to
130% lung deposition of the corticosteroid as compared to an inhalable
suspension comprising the
corticosteroid, wherein the composition is administered at a lower nominal
dosage than the inhalable
suspension. In certain embodiments, the inhalable compositions comprising an
effective amount of a'
corticosteroid, a solvent and a solubility enhancer are substantially free of
active pharmaceutical agents other
than corticosteroids.
[00142] In other embodiments of this invention, the inhalable compositions
comprising an effective amount of
a corticosteroid, a solvent and a solubility enhancer inhalable composition
also achieves at least about 10%
higher fine particle fraction compared to an inhalable suspension comprising
the corticosteroid administered
under the same conditions. In a more preferred embodiment of this invention,
the inhalable composition
achieves also at least about l5 lo higher fine particle fraction compared to
an inhalable suspension comprising
the corticosteroid administered under the same conditions. In the most
preferred embodiment of this invention,
the inhalable composition achieves at least about 20% higher fine particle
fraction compared to an inhalable
suspension comprising the corticosteroid administered under the same
conditions. In certain embodiments, the
inhalable compositions comprising an effective amount of a corticosteroid, a
solvent and a solubility enhancer
are substantially free of active pharmaceutical agents other than
corticosteroids.
(00143] In certain embodiments, compositions of the present invention can also
be administered with a
pressurized metered dose inhaler (pMDI). A typical pMDI comprises a
propellant, surfactant, and a drug in
dissolved or suspended form. The device is designed to be portable and
inexpensive as well as protecting the
drug from light, oxygen, of moisture, and providing constant metering volume
upon administration. Small
spray particle size can be achieved after complete propellant evaporation.
More volatile propellant used
(evaporates faster), smaller particle size can be achieved. The most common
technical difficulty is the drug's
solubility in propellant. Therefore, solubility enhancers of this invention
provide methods and systems for
effective administration of corticosteroid, beta2-adrenreceptor agonist, or
their combination using MDI.
1001441 In some embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
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WO 2007/075801 PCT/US2006/048631
,
nebulizer is selected from the group consisting of Pari LC Jet Plus,
intertech, Baxter Misty-Neb, Hudson T-
Updraft Ii, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain other
embodiments, the nebulizer is
a Pari eFlow nebulizer.
(00145] In still other embodiments, the inhalable composition of the present
invention is delivered in a
significantly shorter period of time than conventional inhalable
corticosteroid therapies. For example, the
nebulization time for Pulmicort Respules administered by a Pari LC Plus jet
nebulizer typically takes at least 5
minutes to 8 minutes, and in some cases in excess of 10 minutes. By contrast,
the inhalable composition
comprising a corticosteroid, such as a budesonide, although not limited to a
particular administration time, in
preferred embodiments may be administered over a delivery time of less than
about 5 minutes to less than
about 1.5 minutes. In some embodiments, the delivery time can be about 5
minutes. In other embodiments, the
delivery time can be less than about 5 minutes. In certain embodiments, the
delivery time can be about 4.5
minutes. In certain other embodiments, the delivery time can be less than
about 4.5 minutes. In still other
embodiments, the delivery time can be about 4 minutes. In yet other
embodiments, the delivery time can be less
than about 4 minutes. In still yet other embodiments, the delivery time can be
about 3.5 minutes. In other
embodiments, the delivery time can be less than about 3.5 minutes. In yet
still other embodiments, the delivery
time can be about 3 minutes. ln other embodiments, the delivery time can be
less than about 3 minutes. In
certain embodiments, the delivery time can be about 2.5 minutes. In other
certain embodiments, the delivery
time can be less than about 2.5 minutes. In still other embodiments, the
delivery time can be about 2 minutes.
In yet still other embodiments, the delivery time can be less than about 2
minutes. In a preferred embodiment,
the delivery time can be about 1.5 minutes. In a more preferred embodiment,
the delivery time can be less than
about 1.5 minutes.
(00146] Another aspect of this invention relates to an inhalable composition
comprising albuterol and a
solubility enhancer, wherein the composition achieves an enhanced lung
deposition as compared to albuterol
administered under the same conditions. An aspect of this invention also
relates to an inhalable composition
comprising albuterol and a solubility enhancer, wherein the composition
achieves an enhanced phannacokinetic
profile as compared to albuterol administered under the same conditions. Also
an aspect of this invention
relates to a method of generating fine particles from an inhalable composition
comprising an effective amount
of albuterol, operating a Pari eFlow nebulizer, and generating an enhanced
lung deposition of albuterol upon
administration to a patient. Also another aspect of this invention relates to
a method of generating fine particles
from an inhalable composition comprising an effective amount of albuterol,
operating a Pari eFlow nebulizer,
and generating an enhanced pharmacokinetic profile of albuterol upon
administration to a patient. In some
embodiments of this invention, the inhalable composition comprises a
corticosteroid.
li. Inhalable Compositions Comprising a Corticosteroid Which Provide a
Decreased Increase in the
Concentration of the Corticosteroid within a Device
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[001471 Another aspect of this invention relates to an inhalable composition
comprising corticosteroid, a
solvent and a solubility enhancer, wherein upon administration of the
composition to a subject through a device,
the composition achieves a rate of increasing concentration of the
corticosteroid inside the device of about 5
g/ml per minute or less over administration of the corticosteroid through the
device. In certain embodiments,
the composition achieves a rate of increasing concentration of the
corticosteroid inside the device of about 5
Fcg/ml per minute or less over the first three minutes of administration. In
certain other embodiments, the
composition achieves a rate of increasing concentration of the corticosteroid
inside the device of about 3.5
itg/ml per minute or less over the first three minutes of administration. In
certain embodiments, the inhalable
compositions comprise about 500 Itg or less of a corticosteroid. In certain
other embodiments, the inhalable
compositions comprise about 250 g or less of a corticosteroid. In other
embodiments, the inhalable
compositions comprise about 240 g or less of a corticosteroid. In yet other
embodiments, the inhalable
compositions comprise about 120 g or less of a corticosteroid. In still other
embodiments, the inhatable
compositions comprise about 60 g or less of a corticosteroid. In yet still
other embodiments, the inhalable
compositions comprise about 40 g or less of a corticosteroid. in one
embodiment, the corticosteroid is
budesonide. In another embodiment, the corticosteroid is budesonide wherein
the budesonide is either an
individual diastereomer or a mixture of the two diastereomers administered
individually or together for a
therapeutic effect. In certain embodiments, the inhalable compositions
comprise an effective amount of a single
corricosteroid, a solvent and a solubility enhancer and are substantially free
of active pharmaceutical agents
other than corticosteroid. In srill other embodiments, the inhalable
compositions comprises an effective amount
of a budesonide, a solvent and a solubility enhancer and are substantially
free of active pharmaceutical agents
other than the budesonide.
[00148] In certain other embodiments, the inhalable compositions comprising
corticosteroid, a solvent and a
solubility enhancer achieve a rate of increase in concentration of the
corticosteroid inside the device of about
5% per minute or less over the first three minutes of administration. In some
embodiments of this invention, the
corticosteroid is budesonide or a pharmaceutical acceptable derivative. In
certain other embodiments, the
inhalable compositions comprising an effective amount of a corticosteroid, a
solvent and a solubility enhancer
are substantially free of active pharmaceutical agents other than
corticosteroids.
[001491 In certain other embodiments, the inhalable composition comprising an
effective amount of a
corticosteroid, a solvent and a solubility enhancer, wherein upon
administration of the composition to a subject
through a device, the composition achieves rate of increasing concentration of
the corticosteroid inside the
device of about 60% or less or a rate of increasing concentration of the
corticosteroid inside the device achieved
by an inhalable suspension comprising the corticosteroid without a solubility
enhancer administered under the
same conditions.
1001501 In one embodiment, the rate of increasing concentration of the
corticosteroid inside the device is
achieved over the first 3 minutes of administration. In another embodiment,
the rate of increasing concentration
of the corticosteroid inside the device is achieved during the second and
third minute of administration. In still
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WO 2007/075801 PCT/US2006/048631
another embodiment, the rate of increasing concentration of the
corticosteroi.d inside the device is achieved
during the third minute of administration. In certain embodiments, the
inhalable compositions comprising an
effective amount of a corticosteroid, a solvent and a solubility enhancer are
substantially free of active
pharmaceutical agents other than corticosteroids. In some embodiments of this
invention, the corticosteroid is
budesonide or a pharmaceutical acceptable derivative.
1001511 In one embodiment, the invention relates to an inhalable composition
wherein administration of the
composition through the device is achieved over five minutes or less, and
administration of the inhalable
suspension is achieved over five minutes or less. In another embodiment, the
invention relates to an inhalable
composition wherein the time of administration of the composition through the
device and the time of
administration of the inhalable suspension are the same. In still other
embodiments, the invention relates to an
inhalable composition wherein the time of administration of the composition
through the device and the time of
administration of the inhalable suspension are different.
[00152] In a preferred embodiment of this invention, the composition also
achieves at least about 60%
respirable fraction upon administration. In a more preferred embodiment of
this invention, the composition also
achieves at least about 70% respirable fraction upon administration. In a
still more preferred embodiment of
this invention, the composition also achieves at least about 80% respirable
fraction upon administration. In the
most prefeired embodiment of this invention, the composition also achieves at
least about 85 Po respirable
fraction upon administration.
[00153] In some embodiments of this invention, the inhalable compositions
comprising corticosteroid, a
solvent and a solubility enhancer composition which can achieve a rate of
increasing concentration of the
corticosteroid inside the device of about 5 g/ml per minute or less over the
timeof administration comprise
about 15 to about 500 g of a corticosteroid. In other embodiments, the
inhalable composition comprises about
50 to about 500 }cg of a corticosteroid. In still other embodiments, the
inhalable composition comprises about
60 to about 250 g of a corticosteroid. In yet still other embodiments, the
composition comprises about 125 to
about 500 ug of a corticosteroid. In certain embodiments, the inhalable
composition comprises about 40, 60,
120, 125, 240, 250, 500, 1000, 1500, or 2000 g of a corticosteroid. In one
embodiment, the inhalable
composition comprises nominal dosage about of about 40 g of a corticosteroid.
In another embodiment, the
inhalable composition comprises nominal dosage about of about 60 g of a
corticosteroid. In yet another
embodiment, the inhalable composition comprises nominal dosage about of about
100 g of a corticosteroid.
In still yet another embodiment, the inhalable composition comprises nominal
dosage about of about 120 g of
a corticosteroid. In still another embodiment, the inhalable composition
comprises nominal dosage about of
about 125 pg of a corticosteroid. In still yet another embodiment, the
inhalable composition comprises nominal
dosage about of about 240 g of a corticosteroid. In yet still another
embodiment, the inhalable composition
comprises nominal dosage about of less than about 250 g of a corticosteroid.
In one embodiment, the
corticosteroid is budesonide. In another embodiment, the corticosteroid is
budesonide wherein the budesonide
is either an individual diastereomer or a mixture of the two diastereomers
administered individually or together
CA 02634413 2008-06-19
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for a therapeutic effect. In certain embodiments, the inhalable compositions
comprise an.effective amount of a
single corticosteroid, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than corticosteroid. In still other embodiments, the inhalable
compositions comprises an effective
amount of a budesonide, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than the budesonide.
[001541 In some embodiments, suitable inhalable compositions comprising a
corticosteroid include, but are not
limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
[001551 In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
ernbodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
[001561 The corticosteroids that are useful in the inhalable compositions
described herein included, but are not
limited to, aldosterone, beclomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone,
flumethason'e, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, RPR 106541,
tixocortol, triamcinolone, and their respective pharmaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
[001571 In certain embodiments, the systems and methods described herein
comprise a solvent, In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
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1001581 In other embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solubility enhancer. In some embodiments, the solubility enhancer
can have a concentration (w/v)
ranging from about 0.001% to about 25%. In other embodiments, the solubility
enhancer can have a
concentration (w/v) ranging from about 0.01% to about 20%. In still other
embodiments, the solubility
enhancer can have a concentration (w/v) ranging from about 0.1 1o to about
15%. In yet other embodiments, the
solubility enliancer can have a concentration (w/v) ranging from about 1%o to
about 10%. In a preferred
embodiment, the solubility enhancer can have a concentration (w/v) ranging
from about 2% to about 10% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative, e.g.
SBE7-/3-CD (Captisol ). In one
embodiment, the solubility enhancer can have a concentration (w/v) of about 2%
when the solubility enhancer
is a cyclodextrin or cyclodextrin derivative, e.g. SBE7-,6-CD (Captisol(D). In
another embodiment, the solubility
enhancer can have a concentration (w/v) of about 5% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-Q-CD (Captisol0). In yet another
embodiment, the solubility enhancer can
have a concentration (w/v) about 7% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,
e.g. SBE7-(3-CD (Captisol ). In still yet another embodiment, the solubility
enhancer can have a concentration
(w/v) of about 10% when the solubility enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-(3-CD
(Captisol ).
1001591 Chemical agents acting as solubility enhancers suitable for use in the
present invention include, but are
not limited to, propylene glycol, non-ionic surfactants, phospholipids,
cyclodextrins and derivatives thereof, and
surface modifiers and/or stabilizers. In other embodiments, solubility
enhancers refer to a formulation method
which provides enhanced solubility without a chemical agent acting as the
means to increase solubility, e.g. the
use of super cri tical fluid production methods to generate nanoparticles for
dispersion in a solvent.
1001601 Additional solubility enhancers suitable for use in the inhatable
compositions described herein are
known in the art and are described in, e.g., U.S. Patent Nos. 5,134,127,
5,145,684, 5,376,645, 6,241,969 and
U.S. Pub. Appl. Nos. 2005/0244339 and 2005/0008707, each of which is
specifically incorporated by reference
herein. In addition, examples of suitable solubility enhancers are described
below.
[001611 Suitable cyclodextrins and derivatives for use in the present
invention are described in the art, for
example, Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent
Nos. 5,134,127, 5,376,645,
5,874,418, each of which is specifically incorporated by reference herein. In
some embodiments, suitable
cyclodextrins or cyclodextrin derivatives for use in the present invention
include, but are not limited to, cx-
cyclodextrins, 0-cyclodextrins, -f-cyclodextrins, SAE-CD derivatives (e.g.,
SBE-a-CD, SBE-,6-CD, SBEI-g-
CD, SBE4-13-CD, SBE7-0-CD (Captisol0), and SBE--y<-CD) (Cydex, Inc. Lenexa,
KS), hydroxyethyl,
hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers,
their corresponding mixed
ethers and further mixed ethers with methyl or ethyl groups, such as
methylhydroxyethyl, ethyl-hydroxyethyl
and ethyl- hydroxypropyl ethers of rx-, 0- and -y-cyclodextrin; and the
maltosyl, glucosyl and maltatriosyl
derivatives of tK-, 6- and 7-cyclodextrin, which may contain one or more=
sugar residues, e. g. glucosyl or
diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e. g.
a mixture of maltosyl and
37
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WO 2007/075801 PCT/US2006/048631
dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein
include hydroxypropyl-(3-cyclodextrin,
hydroxyethyl-{3-cyclodextrin, hydroxypropyl-y-cyclodextrin, hydroxyethyl-
ycyclodextrin, dihydroxypropyl-/3-
cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-13 cyclodextrin, diglucosyl-i3-
cyclodextrin, maltosyl-a-
cyclodextrin, rnaltosyl-Q-cyclodextrin, maltosyl-ycyclodextrin, maltotriosyl-
(3-cyclodextrin, maltotriosyl-y
cyclodextrin, dimaltosyl-fl-cyclodextrin, diethyl-a-cyclodextrin, glucosyl-iy-
cyclodextrin, glucosyl-0-
cyclodextrin, diglucosyl-f.3-cyclodextrin, tri-O-methyl-iC3-cyclodextrin, tri-
O-ethyl-13-cyclodextrin, tri-O-butyryl-
13-cyclodextrin, tri-O-valeryl-(3-cyclodextrin, and di-O-hexanoyl-(3-
cyclodextrin, as well as methyl-(.3-
cyclodextrin, and mixtures thereof such as maltosyl-,6-cyclodextrin/dimaltosyl-
0-cyclodextrin. Procedures for
preparing such cyclodextrin derivatives are well-known, for example, from U.S.
Patent No. 5,024,998, and
references incorporated by reference therein. Other cyclodextrins suitable for
use in the present invention
include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969
by ORGANON (AKZO-
NOBEL), hydroxybutenyl ether derivatives by EASTMAN, sulfoalkyl-hydroxyalkyl
ether derivatives,
sulfoalkyl-alkyl ether derivatives, and other derivatives, for example as
described in U.S. Patent Application
Nos. 2002/0128468, 2004/0106575, 2004/0109888, and 2004/0063663, or U.S.
Patents Nos. 6,610,671,
6,479,467, 6,660,804, or 6,509,323, each of which is specifically incorporated
by reference herein.
[001621 Hydroxypropyl-(3-cyclodextrin can be obtained from Research
Diagnostics Inc. (Flanders, NJ).
Exemplary hydroxypropyl-(3-cyclodextrin products include Encapsin (degree of
substitution -4) and
Molecusol (degree of substitution -8); however, embodiments including other
degrees of substitution are also
available and are within the scope of the present invention.
1001631 Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or
Wacker (Iowa). Other
derivatized cyclodextrins suitable for use in the invention include water
soluble derivatized cyclodextrins.
Exemplary water-soluble derivatized cyclodextrins include carboxylated
derivatives; sulfated derivatives;
alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives;
and carboxy-(3-cyclodextrins, e. g.,
succinyl-13- cyclodextrin (SCD). All of these materials can be made according
to methods known in the art
and/or are available commercially. Suitable derivatized cyclodextrins are
disclosed in Modified Cyclodextrins:
Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J.
Easton, Stephen F. Lincoln,
Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and
Deriva'tives (Ed. Dominique
Duchene, Editions de Sante, Paris, France, 1991).
[001641 Examples of non-ionic surfactants which appear to have a particularly
good physiological
compatibility for use in the present invention are tyloxapol, polysorbates
including, but not limited to,
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan
monopalmitate, polyoxyethylene
(20) sorbitan monostearate (available under the tradename Tweens 20-40-60,
etc.), Polysorbate 80,
Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan
palmitate, sorbitan stearate (available
under the tradenanie Span 20-40-60 etc.), benzalkonium chloride, PPO-PEO block
copolymers (Pluronics),
Cremophor-EL, vitamin E-TPGS (e.g., d-alpha-tocopheryl-polyethyleneglycol-1000-
succinate), Solutol-HS-15,
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oleic acid PEO esters, stearic acid PEO esters, Triton-X 100, Nonidet P-40,
and macrogol hydroxystearates such
as macrogol-l5-hydroxystearate.
[001651 In some embodiments, the non-ionic surfactants suitable for use in the
present invention are
formulated with the corticosteroid to form liposome preparations, micelles or
mixed micelles. Methods for the
preparations and characterization of liposomes and liposome preparations are
known in the art. Often, multi-
lamellar vesicles will form spontaneously when amphiphilic lipids are
hydrated, whereas the fonmation of small
uni-lamellar vesicles usually requires a process involving substantial energy
input, such as ultrasonication or
high pressure homogenization. Further methods for preparing and characterizing
liposomes have been
described, for example, by S. Vemuri et al. (Preparation and characterization
of liposomes as therapeutic
delivery systems: a review. Pharm Acta Helv. 1995, 70(2):95-111) and U.S.
Patent Nos. 5,019,394, 5,192,228,
5,882,679, 6,656,497 each of which is specifically incorporated by reference
herein.
[00166) In some cases, for example, micelles or mixed micelles may be formed
by the surfactants, in which
poorly soluble active agents can be solubilized. In general, micelles are
understood as substantially spherical
structures formed by the spontaneous and dynamic association of amphiphilic
molecules, such as surfactants.
Mixed micelles are micelles composed of different types of amphiphilic
molecules. Both micelles and mixed
micelles should not be understood as solid particles, as their structure,
properties and behavior are much
different from solids. The amphiphilic molecules which form the micelles
usually associate ternporarily. In a
micellar solution, there is a dynamic exchange of molecules between the
micelle-forming amphiphile and
monomolecuiarly dispersed amphiphiles which are a[so present in the solution.
The position of the drug
molecules which are solubilized in such micelles or mixed micelles depends on
the structure of these molecules
as well as the surfactants used. For example, it is to be assumed that
particularly non-polar molecules are
localized mainly inside the colloidal structures, whereas polar substances are
more likely to be found on the
surface. In one embodiment of a micellar or mixed micellar solution, the
average size of the micelles may be
less than about 200 nm (as measured by photon correlation spectroscopy), such
as from about 10 nm to about
100 nm. Particularly preferred are micelles with average diameters of about 10
to about 50 nm. Methods of
producing micelles and mixed micelles are known in the art and described in,
for example, U.S. Patent Nos.
5,747,066 and 6,906,042, each of which is specifically incorporated by
reference herein.
[001671 Phospholipids are defined as amphiphile lipids which contain
phosphorus. Phospholipids which are
chemically derived from phosphatidic acid occur widely and are also commonly
used for pharmaceutical
purposes. This acid is a usually (doubly) acylated glycerol-3-phosphate in
which the fatty acid residues may be
of different length. The derivatives of phosphatidic acid include, for
example, the phosphocholines or
phosphatidylcholines, in which the phosphate group is additionally esterified
with choline, furthermore
phosphatidyl ethanolamines, phosphatidyl inositols, etc. Lecithins are natural
mixtures of various
phospholipids which usually have a high proportion of phosphatidyl cholines.
Depending on the source of a
particular lecithin and its method of extraction and/or enrichment, these
mixtures may also comprise significant
amounts of sterols, fatty acids, tryglycerides and other substances.
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[001681 Additional phospholipids which are suitable for delivery by inhalation
on account of their
physiological properties comprise, in particular, phospholipid mixtures which
are extracted in the form of
lecithin from natural sources such as soja beans (soy beans) or chickens egg
yolk, preferably in hydrogenated
form and/or freed from lysolecithins, as well as purified, enriched or
partially synthetically prepared
phopholipids, preferably with saturated fatty acid esters. Of the phospholipid
mixtures, lecithin is particularly
preferred. The enriched or partially synthetically prepared medium- to long-
chain zwitterionic phospholipids
are mainly free of unsaturations in the acyl chains and free of lysolecithins
and peroxides. Examples for
enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC),
distearoyl phosphatidyl choline
(DSPC) and dipalmitoyl phosphatidyl choline (DPPC). Of these, DMPC is
currently more preferred.
Alternatively, phospholipids with oleyl residues and phosphatidyl glycerol
without choline residue are suitable
for some embodiments and applications of the invention.
[001691 In some embodiments, the non-ionic surfactants and phospholipids
suitable for use in the present
invention are formulated with the corticosteroid to form colloidal structures.
Colloidal solutions are defined as
mono-phasic systems wherein the colloidal material dispersed within the
colloidal solution does not have the
measurable physical properties usually associated with a solid material.
Methods of producing colloidal
dispersions are known in the art, for example as described in U.S. Patent No.
6,653,319, which is specifically
incorporated by reference herein.
1001701 Suitable surface modifiers for use in the present invention are
described in the art, for example, U.S.
Patent Nos. 5,145,684, 5,510,118, 5,565,188, and 6,264,922, each of which is
specifically incorporated by
reference herein. Examples of surface modifiers and/or surface stabilizers
suitable for use in the present
invention include, but are not limited to, hydroxypropyl methylcellulose,
hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin,
casein, lecithin (phosphatides),
dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium
chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan
esters, polyoxyethylene alkyl ethers
(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, potyoxyethylene
sorbitan fatty acid esters (e.g., the commercially available TweensTM, e.g.,
Tween 20TM and Tween 80TM (ICI
Specialty Chemicals)), polyethylene glycols (e.g., Carbowaxs 3550TM and 934TM
(Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose
phthalate, noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA), 4-
(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde
(also known as tyloxapol,
superione, and triton), poloxamers (e.g., Pluronics F68TM and Fl08TM, which
are block copolymers of ethylene
oxide and propylene oxide), poloxamines (e.g., Tetronic 908TM, also known as
Poloxamine 908TM, which is a
tetrafunctional block copolymer derived from sequential addition of propylene
oxide and ethylene oxide to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)), Tetronic
1508TM (T-1508) (BASF
Wyandotte Corporation), Tritons X'20OTM, which is an alkyl aryl polyether
sulfonate (Rohm and Haas),
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Crodestas F-100TM, which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.), p-
isononylphenoxypoly-(glycidol), also known as Olin-l4GT"' or Surfactant 10T'"
(Olin Chemicals, Stamford,
Conn.), Crodestas SL-40® (Croda, Inc.), and SA9OHCO, which is C18H37CH2(-
CON(CH3)--
CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.), decanoyl-N-methylglucamide, n-decyl-(3-
D-glucopyranoside,
n-decyl-f.3-D-maltopyranoside, n-dodecyl Q-D-glucopyranoside, n-dodecyl-j3-D-
maltoside, heptanoyl-N-
methylglucamide, n-heptyl-fl-D-glucopyranoside, n-heptyl-(3-D-thioglucoside, n-
hexyl-O-D-gtucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-13-D-glucopyranoside, octanoyl-N-
methylglucamide, n-octyl-13-D-
glucopyranoside, octyl (3-D-thioglucopyranoside, PEG-phospholipid, PEG-
cholesterol, PEG-cholesterol
derivative, PEG-vitamin A, PEG-vitamin E, lysozyrne, random copolymers of
vinyl pyrrolidone and vinyl
acetate, and the like. (e.g. hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone,
copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate and
dioctyl sodium sulfosuccinate).
(001711 Other useful cationic stabilizers include, but are not limited to,
cationic lipids, sulfonium,
phosphonium, and quarternary ammonium compounds, such as
stearyltrimethylammonium chloride, benzyl-
di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or
bromide, coconut methyl
dihydroxyethyl ammoniurn chloride or bromide, decyl triethyl ammonium
chloride, decyl dimethyl
hydroxyethyl ammonium chloride or bromide, C12-15 dimethyl hydroxyethyl
ammonium chloride or bromide,
coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl
ammonium methyl sulphate,
lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl
(ethenoxy)4 ammonium chloride or
bromide, N-alkyl (C12-18) dimethylbenzyl ammonium chloride, N-alkyl (C14-
18)dimethyl-benzyl ammonium
chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride,
N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium chloride,
trimethylammonium halide, alkyl-
trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl
ammonium chloride,
ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt,
dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
N-
tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14)
dimethyl 1-naphthylmethyl
ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl
benzenealkyl ammonium
chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium
chloride, alkyl benzyl dimethyl
ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl
triethyl ammonium
chloride, poly-diallytdimethylammonium chloride (DADMAC), dimethyl ammonium
chlorides,
alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride,
decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl
trioctylamrnonium chloride
(ALIQUAT 336TM), POLYQUAT lOT"', tetrabutylammonium bromide, benzyl
trimethylammonium bromide,
choline esters (such as choline esters of fatty acids), benzalkonium chloride,
stearalkonium chloride compounds
(such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl
pyridinium bromide or chloride,
halide salts of quaternized polyoxyethylalkylamines, MirapolTm and ALKAQUATTm
(Alkaril Chemical
Company), alkyl pyridinium salts, amines, such as alkylamines, dialkylamines,
alkanolamines,
polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine,
amine salts, such as lauryl amine
41
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acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium
salt, and amine oxides, imide
azolinium salts, protonated quaternary acrylamides, methylated quaternary
polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chioride], and
cationic guar.
1001721 In certain embodiments, the inhalable compositions of the present
invention comprises a solubility
enhancer is selected from the group consisting of propylene glycol, non-ionic
surfactants, tyloxapol, polysorbate
80, vitamin E-TPGS, macrogol-l5-hydroxystearate, phospholipids, lecithin,
purified and/or enriched lecithin,
phosphatidylcholine fractions extracted from lecithin, dimyristoyl
phosphatidylcholine (DMPC), dipalmitoyl
phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC),
cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-a-CD, SBE-Q-CD, SBE1-P-CD, SBE4-(3 CD, SBE7-13-CD
(Captisot(D), SBE-y-CD,
dimethyl /3-CD, hydroxypropyl-A-cyclodextrin, 2-HP-0-CD, hydroxyethyl-Q-
cyclodextrin, hydroxypropyl--t-
cyclodextrin, hydroxyethyl-y-cyclodextrin, dihydroxypropyl-0-cyclodextrin,
glucosyl-o&.cyclodextrin, glucosyl-
0-cyclodextrin, diglucosyl-(3-cyclodextrin, maltosyl-w-cyclodextrin, maltosyl-
(3-cyclodextrin, maltosyl--)-
cyclodextrin, maltotriosyl-fi-c,yclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-o-cyclodextrin, methyl-0-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-(3-CD (CaptisolO).
100173] In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-0-CD, SBE1-f3-CD, SBE4-0-CD, SBE7-0-CD (Captisol ), SBE--y-CD,
dimethyl (3-CD,
hydroxypropyl-fl-cyclodextrin, 2-HP-,6-CD, hydroxyethyl-0-cyclodextrin,
hydroxypropyl-y-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-/3-cyclodextrin, glucosyl-cx
cyclodextrin, glucosyl-f3-
cyclodextrin, diglucosyl-(3-cyclodextrin, maltosyl-cx-cyclodextrin, maltosyl-Q-
cyclodextrin, maltosyl-Y,
cyclodextrin, maltotriosyl-fl-cyclodextrin, maltotriosyl--y,-cyclodextrin,
dimaltosyl-/3-cyclodextrin, methyl-,6-
cyclodextrin. In certain other embodiments, the solubility enhancer is SBE7-(3-
CD (Captisol ).
[00174] In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
42
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WO 2007/075801 PCT/US2006/048631
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein. These methods permit the formation of micron
and sub-micron sized particles
with differing morphologies depending on the method and parameters selected.
In addition, these nanoparticles
can be fabricated by spray drying, lyophilization, volume exclusion, and any
other conventional methods. of
particle reduction.
1001751 Furthermore, the processes for producing nanometer sized particles,
including SCF, can permit
selection of a desired morphology (e.g., amorphous, crystalline, resolved
racemic) by appropriate adjustment of
the conditions for particle formation during precipitation or condensation. As
a consequence of selection of the
desired particle form, extended release of the selected medicament can be
achieved. These particle fabrication
processes are used to obtain nanoparticulates that have high purity, low
surface imperfections, low surface
charges and low sedimentation rates. Such particle features inhibit particle
cohesion, agglomeration and also
prevent settling in liquid dispersions. Additionally, because processes such
as SCF can separate isomers of
certain medicaments, such separation could contribute to the medicament's
enhanced activity, effectiveness as
well as extreme dose reduction. In some instances, isomer separation also
contributes to reduced side effects.
In accordance with the present methods and systems, an aqueous inhalation
mixture can be a composition
fabricated into a powdered form by any process including SCF, spray drying,
precipitation and volume
exclusion, directly into a collection media, wherein the particulate compound
is thus automatically generated
into a dispersed formulation. In some embodiments, this formulation can be the
final formulation.
[00176[ In some embodiments of this invention, the inhalable -composition
further comprises a second
therapeutic agent selected from the group consisting of a beta2-adrenoreceptor
agonist, a prophylactic
therapeutic, and an anti-cholinergic agent. In some embodiments of this
invention, the beta2-adrenoreceptor
agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
[001771 In some embodiments of this invention, the inhalable composition is
administered to a patient not more
than once a day. In other embodiments, the inhalable composition is
administered to a patient not more than
twice a day. In some embodiments of this invention, the composition is
administered to a patient twice a day or
more than twice a day. In still other embodiments, the inhalable composition
is administered to a patient not
more than once a day in the evening.
[00178] In some embodiments of this invention, the device is a nebulizer. In
certain embodiments, the
nebulizer is ajet nebulizer, an ultrasonic nebulizer, a pulsating membrane
nebulizer, a nebulizer with a vibrating
mesh or plate with multiple apertures, or a nebulizer comprising a vibration
generator and an aqueous chamber.
In certain other embodiments of this invention, the nebulizer is selected from
the group consisting of Pari LC
Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft Il, Hudson Ava-Neb,
Aiolos, Pari LC Jet, DeVilbiss
Pulmo-Neb, Hudson Iso-Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and
AeroTech with T-piece. In
certain other embodiments, the nebulizer is a Pari eFlow nebulizer.
43
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III. Methods for Generating Fine Particles from an Inhalable Composition
Comprising Corticosteroids
which Provides Enhanced Lung Deposition
[001791 The present invention further provides a method of generating fine
particles from an inhalable
composition comprising adding a solvent and a solubility enhancer to an
effective amount of corticosteroid, and
operating a nebulizer to produce fine particles of said composition, wherein
upon administration of the
composition to a subject through the nebulizer, the method achieves at least
about 20% to about 40%, between
about 20% to about 50%, or between about 20% to about 55% lung deposition
e.g., bronchi and alveoli, based
on the amount of corticosteroid in the mixture prior to administration. In
certain embodiments, the inhalable
compositions comprising an effective amount of a single corticosteroid, a
solvent and a solubility enhancer and
are substantially free of active pharmaceutical agents other than
corticosteroids. In some embodiments, the
methods can achieve at least about 25% to about 45% lung deposition based on
the amount of corticosteroid in
the mixture prior to administration. In other embodiments, the methods can
achieve at least 35% to about 40%
lung deposition based on the amount of corticosteroid in the mixture prior to
administration. In certain
embodiments, the composition achieves at least about 25% lung deposition based
on the amount of
corticosteroid in the composition prior to administration. In other
embodiments, the composition achieves at
least about 30% lung deposition based on the amount of corticosteroid in the
composition prior to
administration. In still other embodiments, the composition achieves at least
about 35% lung deposition based
on the amount of corticosteroid in the composition prior to administration. In
yet still other embodiments, the
composition achieves at least about 40% lung deposition based on the amount of
corticosteroid in the
composition prior to administration. In other embodiments, the composition
achieves at least about 45% lung
deposition based on the amount of corticosteroid in the composition prior to
administration. In one
embodiment, the corticosteroid is budesonide. In another embodiment, the
corticosteroid is budesonide wherein
the budesonide is either an individual diastereomer or a mixture of the two
diastereomers administered
individually or together for a therapeutic effect. In certain embodiments, the
inhalable compositions comprise
an effective amount of a single corticosteroid and a solubility enhancer and
are substantially free of active
pharmaceutical agents other than corticosteroid. In still other embodiments,
the inhalable compositions
comprises an effective amount of a budesonide, and a solubility enhancer and
are substantially free of active
pharmaceutical agents otlier than the budesonide.
[001801 In a preferred embodiment, the methods of generating fine particles
from an inhalable composition
also achieve at least about 60% respirable fraction upon administration. In a
more preferred embodiment of this
invention, the methods also achieve at least about 70% respirable fraction
upon administration. In a still more
preferred embodiment of this invention, the methods also achieve at least
about 80% respirable fraction upon
administration. In the most preferred embodiment of this invention, the
methods also achieve at least about
85% respirable fraction upon administration.
44
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[001811 In some embodiments of this invention, the methods of generating fine
particles from an inhalable
composition comprising a corticosteroid comprise an amount of corticosteroid
in the composition prior to
administration of about 15 to about 2000 pg of a corticosteroid. In other
embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 250 to about 2000 g of a corticosteroid. In still
other embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 60 to about 1500 g of a corticosteroid. In yet other
embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 100 to about 1000 pg of a corticosteroid. In still
other embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 120 to about 1000 pg of a corticosteroid: In yet still
other embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 125 to about 500 pg of a corticosteroid. In certain
embodiments, the inhalable
compositions comprising an effective amount of a corticosteroid, a solvent,
and a solubility enhancer which can
provide enhanced lung deposition comprise an amount of corticosteroid in the
composition prior to
administration of about 40, about 60, about 100, about 120, about 125, about
240, about 250, about 500, about
1000, about 1500, or about 2000 pg of a corticosteroid. In one embodiment, the
inhalable composition
comprises an amount of corticosteroid in the composition prior to
administration of about 40 g of a
corticosteroid. In another embodiment, the inhalable composition comprises an
amount of corticosteroid in the
composition prior to administration of about of 60 g of a corticosteroid. In
still another embodiment, the
inhalable composition comprises an amount of corticosteroid in the composition
prior to administration of about
100 pg of a corticosteroid. In yet another embodiment, the inhalable
composition comprises an amount of
corticosteroid in the composition prior to administration of about 120 g of a
corticosteroid. In still yet another
embodiment, the inhalable composition comprises an amount of corticosteroid in
the composition prior to
administration of about 125 g of a corticosteroid. In yet another embodiment,
the inhalable composition
comprises an amount of corticosteroid in the composition prior to
administration of about 240 g of a
corticosteroid. In yet still another embodiment, the inhalable composition
comprises an amount of corticosteroid
in the composition prior to administration of less than about 250 pg of a
corticosteroid. In another embodiment,
the inhalable composition comprises an amount of corticosteroid in the
composition prior to administration of
less than about 500 g of a corticosteroid. In one embodiment, the
corticosteroid is budesonide. In another
embodiment, the corticosteroid is budesonide wherein the budesonide is either
an individual diastereomer or a
mixture of the two diastereomers administered individually or together for a
therapeutic effect. In certain
CA 02634413 2008-06-19
WO 2007/075801 PCT/US2006/048631
embodiments, the inhalable compositions comprise an effective amount of a
single corticosteroid, a solvent and
a solubilityenhancer and are substantially free of active pharmaceutical
agents other than corticosteroid. In still
other embodiments, the inhalable compositions comprises an effective amount of
a budesonide, a solvent and a
solubility enhancer and are substantially free of active pharmaceutical agents
other than the budesonide.
1001821 In some embodiments, suitable inhalable compositions comprising a
corticosteroid include, but are not
limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
Cn yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
1001831 In some embodiments of the invention, the inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
f00184] The corticosteroids that are useful in the inhalable compositions
described herein included, but are not
limited to, aldosterone, beclomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone,
flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, RPR 106541,
tixocortol, triamcinolone, and their respective pharmaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
(00185] ln some embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solvent. In certain embodiments, the solvent is selected from the
group comprising water, aqueous
alcohol, propylene glycol, or aqueous organic solvent. ln preferred
embodiments, the solvent is water.
1001861 In other embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solubility enhancer. In some embodiments, the solubility enhancer
can have a concentration (w/v)
ranging from about 0.001% to about 25%. In other embodiments, the solubility
enhancer can have a
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CA 02634413 2008-06-19
WO 2007/075801 PCT/US2006/048631
concentration (w/v) ranging from about 0.01% to about 20%. In still other
embodiments, the solubility
enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%.
In yet other embodiments, the
solubility enhancer can have a concentration (w/v) ranging from about 1% to
about 10%. In a preferred
embodiment, the solubility enhancer can have a concentration (w/v) ranging
from about 2% to about 10% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-
J3-CD (Captisol ). In one
embodiment, the solubility enhancer can have a concentration (w/v) of about 2%
when the solubility enhancer
is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-0-CD (Captisol(D). In
another embodiment, the solubility
enhancer can have a concentration (w/v) of about 5% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative,e.g. SBE7-,3-CD (Captisol ). In yet another
embodiment, the solubility enhancer can
have a concentration (w/v) about 7% when the solubility enhancer is a
cyclodextrin or cyclodextrin
derivative,e.g. SBE7-i6-CD (Captisol ). In still yet another embodiment, the
solubility enhancer can have a
concentration (w/v) of about 10% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g.
SBE7-fl--CD (Captisol ).
[001871 [n other embodiments, the inhalable composition for use in the present
methods further comprises a
solubility enhancer. In certain embodiments, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-I5-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-O-CD, SBEI-Q-CD, SBE4-0-CD, SBE7-0-CD (Captisol(D), SBE--)-CD,
dimethyl (3-CD,
hydroxypropyl-/3-cyclodextrin, 2-HP-j6-CD, hydroxyethyl-j3-cyclodextrin,
hydroxypropyl-y-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-/3
cyclodextrin, diglucosyl-l'3-cyclodextrin, maltosyl-a'-cyclodextrin, maltosyl-
fl-cyclodextrin, maitosyl-ry-
cyclodextrin, maltotriosyl-13-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-g-cyclodextrin, methyl-(3-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In preferred
embodiments, the solubility
enhancer is SBE7-(3-CD (Captisol(D).
~00188] ln certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-ft-CD, SBE1-fl-CD, SBE4-/3-CD, SBE7-,6-CD (Captisol ), SBE-IR-
CD, dimethyl (j-CD,
hydroxypropyl-(j-cyclodextrin, 2-HP-(3-CD, hydroxyethyl-,6-cyclodextrin,
hydroxypropyl-t-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-/3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-a-
cyclodextrin, diglucosyl-/.i-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-
,6-cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl-ycyclodextrin,
dimaltosyl-i3-cyclodextrin, methyl-(3-
cyclodextrin. In certain other embodiments, the solubility enhancer is SBE7-0-
CD (Captisol ).
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1001891 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
fonnulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein.
[001901 In some embodiments of this invention, the inhalable composition for
use in the present methods
further comprises a second therapeutic agent selected from the group
consisting of a beta2-adrenoreceptor
agonist, a prophylactic therapeutic, and an anti-cholinergic agent. In other
embodiments of this invention, the
beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical
acceptable derivative.
[001911 In some embodiments of this invention, the present methods comprise
administering the inhalable
composition described herein to a patient no more than once a day. In other
embodiments of this invention,
present methods comprise administering the inhalable composition described
herein to a patient twice a day or
more than twice a day.
1001921 Any known inhalation nebu]izer is suitable for use in the presently
described invention. Such
nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating
membrane nebulizers, nebulizers with a
vibrating mesh or plate with multiple apertures, and nebulizers comprising a
vibration generator and an aqueous
chamber (e.g., Pari eFlow ). Commercially available air driven jet, ultrasonic
or= pulsating membrane
nebulizers suitable for use in the present invention include the Aeroneb ,
Aeroneb GO (Aerogen, San
Francisco, CA), Pari LC PLUS , Pari Boy N and Pari Duraneb (PARI Respiratory
Equipment, Inc.,
Monterey, CA), MicroAirfl (Omron Healthcare, Inc, Vemon Hills, Illinois),
Halolite(D (Profile Therapeutics
Inc, Boston, MA), Respimat (Boehringer lngelheim Ingelheim, Germany),
Aerodose (Aerogen, Inc,
Mountain View, CA), Omron Elite (Omron Healthcare, Inc, Vernon Hills,
Illinois), Omron Microah-0
(Omron Healthcare, Inc, Vemon Hills, Illinois), Mabismist II (Mabis
Healthcare, Inc, Lake Forest, Illinois),
Lumiscope 6610, (The Lumiscope Company, Inc, East Brunswick, New Jersey),
Airsep Mystique , (AirSep
Corporation, Buffalo, NY), Acorn-I and Acom-Il (Vital Signs, Inc, Totowa, New
Jersey), Aquatower
(Medical Industries America, Adel, Iowa), Ava-Neb (Hudson Respiratory Care
Incorporated, Temecula,
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California), Cirrus (Intersurgical Incorporated, Liverpool, New York), Dart
(Professional Medical Products,
Greenwood, South Carolina), Devilbissg Pulmo Aide (DeVilbiss Corp. Somerset,
Pennsylvania), DowndraftCD
(Marquest, Englewood, Colorado), Fan Jet (Marquest, Englewood, Colorado), MB-
5 (Mefar, Bovezzo, Italy),
Misty Neb (Baxter, Valencia, California), Salter 8900 (Salter Labs, Arvin,
California), Sidestream (Medic-
Aid, Sussex, UK), Updraft-IIO (Hudson Respiratory Care ; Temecula, Califomia),
Whisper Jeto (Marquest
Medical Products, Englewood, Colorado), AiolosO (Aiolos Medicnnsk Teknik,
Karlstad, Sweden), InspironqD
(Intertech Resources, Inc., Bannockbum, Illinois), Optimist (Unomedical Inc.
, McAllen, Texas), Prodomo ,
Spira (Respiratory Care Center, Hameenlinna, Finland), AERx (Aradigm
Corporation, Hayward, California),
SonikO LDI Nebulizer (Evit Labs, Sacramento, California), and Swirler W
Radioaerosol System (AMICI, Inc.,
Spring City, PA).
1001931 Any of these and other known nebulizers can be used to deliver the
aqueous inhalation mixtures
described in the present invention. In some embodiments, the nebulizers are
available from, e.g., Pari GmbH
(Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne,
Vital Signs, Baxter, Allied
Health Care, lnvacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana,
Siemens, Aerogen, Mountain
Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby,
Warwickshire, UK), Bard Ltd.
(Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy),
Henleys Medical Supplies
(London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies
(Leies, UK), Medic-Aid Ltd. (West
Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK), and
many others.
(00194] Other nebulizers suitable for use in the methods and systems describe
herein include, but are not
limited to, jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet
nebulizers for use herein include Pari LC plus/ProNeb, Pari LC plus/ProNeb
Turbo, Pari LCPIus/Dura Neb
1000 & 2000 Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star,
Omron CompAir XL Portable
Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron compare Elite
Compressor Nebulizer
System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star
nebulizer with Proneb Ultra
compressor, Pulomo- aide, Pulmo-aide LT, Pulmo-aide traveler, lnvacare
Passport, Inspiration Healthdyne 626,
Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, AcornIl, Misty-Neb, Allied
aerosol, Schuco Home Care,
Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-
DraftlI, T Up-Draft, ISO-NEB,
Ava-Neb, Micro Mist, and PulmoMate.
(001951 Exemplary ultrasonic nebulizers for use herein include MicroAir,
UltraAir, Siemens Ultra Nebulizer
145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb,
5004 Desk Ultrasonic
Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana
Ultrasonic Nebulizer, Microstat
Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other
nebulizers for use herein include
5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb,
Lumineb I Piston Nebulizer
5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse
Breath Actuated Nebulizer.
Exemplary nebulizers comprising a vibrating mesh or plate with multiple
apertures are described by R. Dhand
in New Nebuliser Technology-Aerosol Generation by Using a Vibrating Mesh or
Plate with Multiple
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Apertures, Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4 and
Respiratory Care, 47: 1406-1416
(2002), the entire, disclosure of each of which is hereby incorporated by
reference.
[001961 Additional nebulizers suitable for use in the presently described
invention include nebulizers
comprising a vibration generator and an aqueous chamber. Such nebulizers are
sold commercially as, e.g., Pari
eFlow, and are described in U.S. Patent Nos. 6,962,151, 5,518,179, 5,261,601,
and 5,152,456, each of which is
specifically incorporated by reference herein.
[001971 The parameters used in nebulization, such as flow rate, mesh membrane
size, aerosol inhalation
chamber size, mask size and materials, valves, and power source may be varied
in accordance with the
principles of the present invention to maximize their use with different types
and aqueous inhalation mixtures or
different types of corticosteroids.
1001981 In addition to the above cited nebulizers, atomizers are also suitable
for the systems and methods
described herein for the delivery of an aqueous inhalation solution comprising
a corticosteroid and a solubility
enhancer. Atomizers are known in the art and are described in, for example,
U.S. Patent Nos. 5,954,047,
6,026,808, 6,095,141 and 6,527,151, each of which is specifically incorporated
by reference.
[001991 In certain embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
cornprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-
Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain other
embodiments, the nebulizer is
a Pari eFlow nebulizer.
IV. Methods for Generating Fine Particles from an Inhalable Compositions
Comprising a Corticosteroid
Which Provide a Decreased Increase in the Concentration of the Corticosteroid
within a Device
1002001 Another aspect of this invention relates to a method of generating
fine particles from an inhalable
composition comprising forming the composition by adding a solvent and a
solubility enhancer to an effective
amount of corticosteroid, and operating a nebulizer to produce fine particles
of said composition, wherein upon
administration of the composition to a subject through the nebulizer, the
composition achieves rate of increasing
concentration of the corticosteroid inside the device of about 60% or less of
a rate of increasing concentration of
the corticosteroid inside the device achieved by an inhalable suspension
comprising the corticosteroid without a
solubility enhancer administered under the same conditions. In certain
embodiments, the methods comprise an
inhalable composition comprising a single corticosteroid that is substantially
free of active pharmaceutical
agents other than the corticosteroid.
[002011 In certain embodiments, the rate of increasing concentration of the
corticosteroid inside the device is
achieved over the first 3 minutes of administration. In other embodiments, the
rate of increasing concentration
of the corticosteroid inside the device is achieved during the second and
third minute of administration. In still
CA 02634413 2008-06-19
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other embodiments, the rate of increasing concentration of the corticosteroid
inside the device is achieved
during the third minute of administration.
[002021 In one embodiment, the invention relates to an inhalable composition
wherein administration of the
composition through the device is achieved over five minutes or less, and
administration of the inhalable
suspension is achieved over fi've minutes or less. In another embodiment, the
invention relates to an inhalable
composition wherein the time of administration of the composition through the
device and the time of
administration of the inhalable suspension are the same. In still other
embodiments, the invention relates to an
inhalable=composition wherein the time of administration of the composition
through the device and the time of
administration of the inhalable suspension are different.
1002031 In certain embodiments of this invention, the inhalable composition
also achieves at least about 60%
respirable fraction upon administration. In a more preferred embodiment of
this invention, the inhalable
composition also acbieves at least about 70% respirable fraction upon
administration. In a still more preferred
embodiment of this invention, the inhalable composition also achieves at least
about 80% respirable fraction
upon administration. In the most preferred embodiment of this invention, the
inhalable composition also
achieves at least about 85%respirable fraction upon administration
(002041 In some embodiments of this invention, the inhalable composition
comprises about 15 to about 2000
gg of a corticosteroid. In other embodiments, the composition comprises about
50 to about 2000 g of a
corticosteroid. In still other embodiments, the composition comprises about 60
to about 1500 pg of a
corticosteroid. In yet other embodiments, the composition comprises about 120
to about 1000 pg of a
corticosteroid. In yet still other embodiments, the composition comprises
about 125 to about 500 g of a
corticosteroid. In some embodiments of this invention, the composition
comprises about 40, 60, 120, 125, 240,
250, 500, 1000, 1500, or 2000 g of said corticosteroid. In some embodiments
of this invention, the
composition comprises a nominal dosage of from about 60 to 2000 gg of said
corticosteroid. In one
embodiment, the inhalable composition comprises a nominal dosage of about 40
g of a corticosteroid. In
another embodiment, the inhalable composition comprises a nominal dosage of
about 60 g of a corticosteroid.
In yet another embodiment, the inhalable composition comprises a nominal
dosage of about 100 g of a
corticosteroid. In yet another embodiment, the inbalable composition comprises
anominal dosage of about 120
g of a corticosteroid. In still another embodiment, the inhalable composition
comprises a nominal dosage of
about 125 g of a corticosteroid. In yet still another embodiment, the
inhalable composition comprises a
nominal dosage of a~out 240 g of a corticosteroid. In still yet another
embodiment, the inhalable composition
comprises a nominal dosage of less than about 250 g of a corticosteroid. In
one embodiment, the
corticosteroid is budesonide. In another embodiment, the corticosteroid is
budesonide wherein the budesonide
is either an individual diastereomer or a mixture of the two diastereomers
administered individually or together
for a therapeutic effect. In certain embodiments, the inhalable compositions
comprise an effective amount of a
single corticosteroid, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than corticosteroid. In still other embodiments, the inhalable
compositions comprises an effective
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WO 2007/075801 PCT/US2006/048631
amount of a budesonide, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than the budesonide.
[00205] In some embodiments, suitable inhalable compositions comprising a
corticosteroid include, but are not
limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
[002061 fn some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
[002071 The corticosteroids that are useful in the inhalable compositions
described herein included, but are not
limited to, aldosterone, bectomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone,
flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, RPR 106541,
tixocortol, triamcinolone, and their respective pharmaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
[002081 In some embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solvent. In certain embodiments, the solvent is selected from the
group comprising water, aqueous
alcohol, propylene glycol, or aqueous organic solvent. In preferred
embodiments, the solvent is water.
[00209] In other embodiments of the inhalable compositions described herein,
the inhalable composition
comprises a solubility enhancer. In some embodiments, the solubility enhancer
can have a concentration (w/v)
ranging from about 0.001% to about 25%. In other embodiments, the solubility
enhancer can have a
concentration (w/v) ranging from about 0.01% to about 20%. In still other
embodiments, the solubility
enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%.
In yet other embodiments, the
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solubility enhancer can have a concentration (w/v) ranging from about 1% to
about 10%. In a preferred
embodiment, the solubility enhancer can have a concentration (w/v) ranging
from about 2% to about 10% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative, e.g.
SBE7-,6-CD (Captisol(D). In one
embodiment, the solubility enhancer can have a concentration (w/v) of about 2%
when the solubility enhancer
is a cyclodextrin or cyclodextrin derivative, e.g. SBE7-0-CD (Captisol(&). In
another embodiment, the solubility
enhancer can have a concentration (w/v) of about 5% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-,6-CD (Captisol(D). In yet another
embodiment, the solubility enhancer can
have a concentration (wlv) about 7% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,
e.g. SBE7-,6-CD (Captisol ). In still yet another embodiment, the solubility
enhancer can have a concentration
(wlv) of about 10% when the solubility enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-13-CD
(Captisol ).
[00210] In other embodiments, the inhalable composition for use in the present
methods further comprises a
solubility enhancer. In certain embodiments, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidyicholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-(3-CD, SBE1-(3-CD, SBE4-(3-CD, SBE7-,6-CD (CaptisolQ), SBE-y-CD,
dimethyl (3-CD,
hydroxypropyl-J3-cyclodextrin, 2-HP-0-CD, hydroxyethyl-0-cyclodextrin,
hydroxypropyi-ycyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-,6-cyclodextrin, glucosyl-c~-
cyclodextrin, glucosyl-(3-
cyclodextrin, diglucosyl-/3-cyclodextrin, maltosyl-cx cyclodextrin, maltosyl-o-
cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-0-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-,6-cyclodextrin, methyl-Q-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropy] methylce3lulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In preferred
embodiments, the solubility
enhancer is SBE7-19-CD (Captisol(D).
1002111 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-(3-CD, SBEI-0-CD, SBE4-9-CD, SBE7-(3-CD (Captisol ), SBE-yCD,
dimethyl (3-CD,
hydroxypropyl-,Q-cyclodextrin, 2-HP-/3-CD, hydroxyethyl-(3-cyclodextrin,
hydroxypropyl--y-cyclodextrin,
hydroxyethyl-ycyclodextrin, dihydroxypropyl-/3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-;6-
cyclodextrin, diglucosyl-a-cyclodextrin, rnaltosyl-a-cyclodextrin, maltosyl-13-
cyclodextrin, maltosyl-y
cyclodextrin, maltotriosyl-0-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-0-
cyclodextrin. In certain other embodiments, the solubility enhancer is SBE7-)3-
CD (Captisol ).
1002121 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
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methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein. These methods permit the formation of micron
and sub-micron sized particles
with differing morphologies depending on the method and parameters selected.
In addition, these nanoparticles
can be fabricated by spray drying, lyophilization, volume exclusion, and any
other conventional methods of
particle reduction.
1002131 In some embodiments of this invention, the inhalable composition for
use in the present methods
further comprises a second therapeutic agent selected from the group
consisting of a beta2-adrenoreceptor
agonist, a prophylactic therapeutic, and an anti-cholinergic agent. In other
embodiments of this invention, the
beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical
acceptable derivative.
[00214) In some embodiments of this invention, the inhalable composition is
administered to a patient not more
than once a day. In other embodiments, the inhalable composition is
administered to a patient not more than
twice a day. In some embodiments of this invention, the composition is
administered to a patient twice a day or
more than twice a day. In still other embodiments, the inhalable composition
is administered to a patient not
more than once a day in the evening.
(002151 In certain embodiments of this invention, the device is a nebulizer.
In certain other embodiments, the
nebulizer is ajet nebulizer, an ultrasonic nebulizer, a pulsating membrane
nebulizer, a nebulizer with a vibrating
mesh or plate with multiple apertures, or a nebulizer comprising a vibration
generator and an aqueous chamber.
In some embodiments of this invention, the nebulizer is selected from the
group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Aiolos, Pari
LC Jet, DeVilbiss Pulmo-
Neb, Hudson Iso-Neb (B), Hudson T-Updrafft Neb-U-Mist, Pari-Jet 1460, and
AeroTech with T-piece. In
certain other embodiments, the nebulizer is a Pari eFlow nebulizer.
(00216) Any known inhalation nebulizer is suitable for use in the presently
described invention. Such
nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating
membrane nebulizers, nebulizers with a
vibrating mesh or plate with multiple apertures, and nebulizers comprising a
vibration generator and an aqueous
chamber (e.g., Pari eFlow(D). Commercially available air driven jet,
ultrasonic or pulsating membrane
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nebutizers suitable for use in the present invention include the Aeroneb0,
Aeroneb GOO (Aerogen, San
Francisco, CA), Pari LC PLUSO, Pari BoyO N and Pari Duraneb (PARI Respiratory
Equipment, Inc.,
Monterey, CA), MicroAir (Ornron Healthcare, Inc, Vemon Hills, Illinois),
Halolite0 (Profile Therapeutics
Inc, Boston, MA), Respimat0 (Boehringer Ingelheim Ingelbeim, Germany),
Aerodose0 (Aerogen, Inc,
Mountain View, CA), Omron Elite (Omron Healthcare, Inc, Vernon Hills,
Illinois), Omron Microaft9
(Omron Healthcare, Inc, Vernon Hills, Iilinois), Mabismist II (Mabis
Healthcare, Inc, Lake Forest, Illinois),
Lumiscope0 6610, (The Lumiscope Company, Inc, East Brunswick, New Jersey),
Airsep Mystique0, (AirSep
Corporation, Buffalo, NY), Acorn-1 and Acorn-II (Vital Signs, Inc, Totowa, New
Jersey), Aquatoweifl
(Medical Industries America, Adel, Iowa), Ava-NebO (Hudson Respiratory Care
Incorporated, Temecula,
California), CirrusO (Intersurgical Incorporated, Liverpool, New York), Dart
(Professional Medical Products,
Greenwood, South Carolina), Devilbiss Pulmo Aide (DeVilbiss Corp. Somerset,
Pennsylvania), Downdrafl.0
(Marquest, Englewood, Colorado), Fan JetO (Marquest, Englewood, Colorado), MB-
5 (Mefar, Bovezzo, Italy),
Misty Neb (Baxter, Valencia, Califomia), Salter 8900 (Salter Labs, Arvin,
Califomia), Sidestream0 (Medic-
Aid, Sussex, UK), Updraft-II (Hudson Respiratory Care ; Temecula,
California), Whisper Jet (Marquest
Medical Products, Englewood, Colorado), Aiolos (Aiolos Medicnnsk Teknik,
Karlstad, Sweden), Inspiron0
(Intertech Resources, Inc., Bannockburn, Illinois), Optimist (Unomedical Inc.
, McAllen, Texas), Prodomo0,
Spira (Respiratory Care Center, Hameenlinna, Finland), AERx (Aradigm
Corporation, Hayward, California),
SonikO LDI Nebulizer (Evit Labs, Sacramento, California), and Swirler W
Radioaerosol System (AMICI, Inc.,
Spring City, PA).
[002171 Any of these and other known nebulizers can be used to deliver the
aqueous inhalation mixtures
described in the present invention. In some embodiments, the nebulizers are
available from, e.g., Pari GmbH
(Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne,
Vital Signs, Baxter, Allied
Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana,
Siemens, Aerogen, Mountain
Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby,
Warwickshire, UK), Bard Ltd.
(Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy),
Henleys Medical Supplies
(London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies
(Leies, UK), Medic-Aid Ltd. (West
Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK), and
many otbers.
[002181 Other nebulizers suitable for use in the methods and systems describe
herein include, but are not
limited to, jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet
nebulizers for use herein include Pari LC plus/ProNeb, Pari LC plus/ProNeb
Turbo, Pari LCPlus/Dura Neb
1000 & 2000 Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star,
Omron CompAir XL Portable
Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron compare Elite
Compressor Nebulizer
System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star
nebulizer with Proneb Ultra
compressor, Pulomo- aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare
Passport, Inspiration Healthdyne 626,
Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, Acom1l, Misty-Neb, Allied
aerosol, Schuco Home Care,
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Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-
DraftlI, T Up-Draft, ISO-NEB,
Ava-Neb, Micro Mist, and PulmoMate.
(00219] Exemplary ultrasonic nebulizers for use herein include MicroAir,
UltraAir, Siemens Ultra Nebulizer
145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb,
5004 Desk Ultrasonic
Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana
Ultrasonic Nebulizer, Microstat
Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other
nebulizers for use herein include
5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb,
Lumineb I Piston Nebulizer
5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse
Breath Actuated Nebulizer.
Exemplary nebulizers comprising a vibrating mesh or plate with multiple
apertures are described by R. Dhand
in New Nebuliser Technology-Aerosol Generation by Using a Vibrating Mesh or
Plate with Multiple
Apertures, Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4 and
Respiratory Care, 47: 1406-1416
(2002), the entire disclosure of each of which is hereby incorporated by
reference.
[002201 Additional nebulizers suitable for use in the presently described
invention include nebulizers
comprising a vibration generator and an aqueous chamber. Such nebulizers are
sold commercially as, e.g., Pari
eFlow, and are described in U.S. Patent Nos. 6,962,151, 5,518,179, 5,261,601,
and 5,152,456, each of which is
specifically incorporated by reference herein.
[00221] The parameters used in nebulization, such as flow rate, mesh membrane
size, aerosol inhalation
chamber size, mask size and materials, valves, and power source may be varied
in accordance with the
principles of the present invention to maximize their use with different types
and aqueous inhalation mixtures or
different types of corticosteroids.
[00222] In addition to the above cited nebulizers, atomizers are also suitable
for the systems and methods
described herein for the delivery of an aqueous inhalation solution comprising
a corticosteroid and a solubility
enhancer. Atomizers are known in the art and are described in, for example,
U.S. Patent Nos. 5,954,047,
6,026,808, 6,095,141 and 6,527,151, each of which is specifically incorporated
by reference.
Vl. Corticosteroid Inhalation System for Achieving Enhanced, Lung Deposition
[00223) Another aspect of this invention relates to a system for delivering a
therapeutically effective dose of a
corticosteroid to a patient comprising (a) an aqueous inhalation mixture
comprising the corticosteroid and a
solubility enhancer, and (b) a nebulizer, whereby upon administration of the
composition to a subject through a
nebulizer, the system achieves at least about 20% to about 40%, between about
20% to about 50%, or between
about 20% to about 55% lung deposition e.g., bronchi and alveoli, based on the
amount of corticosteroid in the
mixture prior to administration. In some embodiments, the system can achieve
at least about 25% to about 45%
lung deposition based on the amount of corticosteroid in the mixture prior to
administration. In other
embodiments, the system can achieve at least 35% to about 40% lung deposition
based on the amount of
corticosteroid in the mixture prior to administration. In certain embodiments,
the system achieves about 25%
lung deposition based on the amount of corticosteroid in the mixture prior to
administration. In other
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embodiments, the system achieves at least about 30% lung deposition based on
the amount of corticosteroid in
the mixture prior to administration. In still other embodiments, the system
achieves at least about 35% lung
deposition based on the amount of corticosteroid in the mixture prior to
administration. In yet other
embodiments, the system achieves at least about 40% lung deposition based on
the amount of corticosteroid in
the mixture prior to administration. In still other embodiments, the system
achieves at least about 45% lung
deposition based on the amount of corticosteroid in the mixture prior to
administration. 1n yet still other
embodiments, the system achieves at least about 50% lung deposition based on
the amount of corticosteroid in
the mixture prior to administration. In still another embodiment, the system
achieves at least about 40% to about
55% lung deposition based on the amount of corticosteroid in the mixture prior
to administration. In one
embodiment, the corticosteroid is budesonide. In another embodiment, the
corticosteroid is budesonide wherein
the budesonide is either an individual diastereomer or a mixture of the two
diastereomers administered
individually or together for a therapeutic effect. In certain embodiments, the
inhalable compositions comprise
an effective amount of a single corticosteroid, and a solubility enhancer and
are substantially free of active
pharmaceutical agents other than corticosteroid. In still other embodiments,
the inhalable compositions
comprises an effective amount of a budesonide,and a solubility enhancer and
are substantially free of active
pharmaceutical agents other than the budesonide.
1002241 In certain embodiments of this invention, the system for delivering
delivering a therapeutically
effective dose of an aqueous inhalation mixture comprising the corticosteroid
by said nebulizer produces at least
about 60% respirable fraction. In other embodiments, the system for delivering
a therapeutically effective dose
of an aqueous inhalation mixture comprising the corticosteroid by said
nebulizer produces at least about 75%
respirable fraction. In still other embodiments, the system for delivering a
therapeutically effective dose of an
aqueous inhalation mixture comprising the corticosteroid by said nebulizer
produces at least about 80%
respirable fraction. In yet still other embodiments, the system for delivering
a therapeutically effective dose of
an aqueous inhalation mixture comprising the corticosteroid by said nebulizer
produces at least about 85%
respirable fraction. In one embodiment, the corticosteroid is budesonide. In
another embodiment, the
corticosteroid is budesonide wherein the budesonide is either an individual
diastereomer or a mixture of the two
diastereomers administered individually oT together for a therapeutic effect.
In certain embodiments, the
inhalable compositions comprise an effective amount of a single
corticosteroid, a solvent and a solubility
enhancer and are substantially free of active pharmaceutical agents other than
corticosteroid. In still other
embodiments, the inhalable compositions comprises an effective amount of a
budesonide, a solvent and a
solubility enhancer and are substantially free of active phamlaceutical agents
other than the budesonide.
[002251 In some embodiments of this invention, the system comprises an aqueous
inhalation mixture
comprising an amount of corticosteroid in mixture prior to administration of
about 15 to about 2000 g of a
corticosteroid. In other embodiments, the inhalation mixtures comprise an
amount of corticosteroid in mixture
prior to administration of about 250 to about 2000 pg of a corticosteroid. In
still other embodiments, the
inhalation mixtures comprise an amount of corticosteroid in mixture prior to
administration of about 60 to about
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1500 g of a corticosteroid. in yet other embodiments, the inhalation mixtures
comprise an amount of
corticosteroid in mixture prior to administration of about 100 to about 1000
g of a corticosteroid. In still other
embodiments, the inhalation mixtures comprise an amount of corticosteroid in
mixture prior to administration
of about 120 to about 1000 pg of a corticosteroid. In yet still other
embodiments, the inhalation mixtures
comprise an amount of corticosteroid in mixture prior to administration of
about 125 to about 500 g of a
corticosteroid. In certain embodiments, the inhalation mixtures comprise an
amount of corticosteroid in mixture
prior to administration of about about 40, about 60, about 100, about 120,
about 125, about 240, about 250,
about 500, about 1000, about 1500, or about 2000 g of a corticosteroid. In
one embodiment, the inhalation
mixture comprises an amount of corticosteroid in mixture prior to
administration of about 40 g of a
coriicosteroid. In another embodiment, the inhalation mixture comprises an
amount of corticosteroid in mixture
prior to administration of about 60 g of a corticosteroid. In still another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
about 100 g of a corticosteroid. In
yet another embodiment, the inhalation mixture coniprises an amount of
corticosteroid in mixture prior to
administration of about 120 pg of a corticosteroid. In yet still another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
about 125 g of a corticosteroid. In
still another embodiment, the inhalation mixture comprises an amount of
corticosteroid in mixture prior to
administration of about 240 g of a corticosteroid. In still yet another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
less than about 250 g of a
corticosteroid. In one embodiment, the corticosteroid is budesonide. In
another embodiment, the corticosteroid
is budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect. In certain
embodiments, the inhalable
compositions comprise an effective amount of a single corticosteroid,and a
solubility enhancer and are
substantially free of active pharmaceutical agents other than corticosteroid.
In still other embodiments, the
inhalable compositions comprises an effective amount of a budesonide,and a
solubility enhancer and are
substantially free of active pharmaceutical agents other than the budesonide.
[00226J In some embodiments, suitable aqueous inhalation mixture comprising a
corticosteroid include, but are
not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.In some embodiments of the
invention, inhalable compositions
comprising a corticosteroid do not include nano-dispersions and/or nano-
suspensions. In other embodiments,
inhalable compositions comprising a corticosteroid do not include micelle,
mixed-micelle liquids or liposomal
liquids. In still other embodiments, inhalable compositions comprising a
corticosteroid do not include nano-
dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or
liposomal liquids. In other
embodiments, inhalable compositions, include but are not limited to,
solutions, emulsions, and colloidal liquids.
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In one embodiment, the inhalable composition is a solution comprising a
corticosteroid, such as budesonide,
and a solubility enhancer. In another embodiment, the inhalable composition is
an emulsion comprising a
corticosteroid, such as budesonide, and a solubility enhancer.
[002271 The corticosteroids that are useful in the inhalation mixtures
described herein included, but are not
limited to, aldosterone, beolomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone,
flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, IZPR 106541,
tixocortol, triamcinolone, and their respective pharmaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
[002281 In certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
[002291 In other embodiments of the inhalation mixtures described herein, the
inhalation mixture comprises a
solubility enhancer. In some embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 0.001% to about 25%. In other embodiments, the solubility enhancer can
have a concentration (w/v)
ranging from about 0.01% to about 20%. In still other embodiments, the
solubility enhancer can have a
concentration (w/v) ranging from about 0.1 !o to about 15%. In yet other
embodiments, the solubility enhancer
can have a concentration (w/v) ranging from about 1%to about 10%. In a
preferred embodiment, the solubility
enhancer can have a concentration (w/v) ranging from about 2% to about 10%
when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g. SBE7-16-CD (Captisol ). In one
embodiment, the solubility
enhancer can have a concentration (w/v) of about 2% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-(3-CD (Captisol ). In another embodiment,
the solubility enhancer can have
a concentration (wlv) of about 5% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative, e.g.
SB97-0-CD (Captisol ). In yet another embodiment, the solubility enhancer can
have a concentration (w/v)
about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative, e.g. SBE7-f3-CD
(Captisol ). In still yet another embodiment, the solubility enhancer can have
a concentration (w/v) of about
10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,
e.g. SBE7-0-CD (Captisol ).
[002301 In other embodiments, the inhalation mixture for use in the present
methods further comprises a
solubility enhancer. In certain embodiments, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
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fractions extracted from lecithin, dimyristoyl phosphatidytcholine (DMPC),
dipairnitoyl ptiosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-f3-CD, SBE1-0-CD, SBE4-(3-CD, SBE7-13-CD (Captisol ), SBE-y-CD,
dimethyl 6-CD,
hydroxypropyI-o-cyolodextrin, 2-HP-a-CD, hydroxyethyl-,6-cyclodextrin,
hydroxypropyl--}R-cyclodextrin,
hydroxyethyl--y-cyclodextrin, dihydroxypropyl-(3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-f.i-
cyclodextrin, diglucosyl-fl-cyclodextrin, maltosyl-Otcyclodextrin, maltosyl-,O-
cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-j3-cyclodextrin, maltotriosyl-ycyclodextrin,
dimaltosyl-13-cyclodextrin, methyl-(3-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In preferred
embodiments, the solubility
enhancer is SBE7-13-CD (Captisol(D).
1002311 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-0-CD, SBE1-0-CD, SBE4-(3-CD, SBE7-(3-CD (Captisol ), SBE-.~-CD,
dimethyl (3-CD,
hydroxypropyl-0-cyclodextrin, 2-HP-0-CD, hydroxyethyi-0-cyclodextrin,
hydroxypropyi--)-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-f3-cyclodextrin, glucosyl-cx-
cyclodextrin, glucosyl-,Q-
cyclodextirin, diglucosyl-,6-cyclodextrin, mattosyl-a-cyclodextrin, maltosyl-0-
cyclodextrin, maltosyl-ry-
cyclodextrin, maltotriosyl-13-cyclodextrin, maltotriosyl--i-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-(3-
cyciodextrin. In certain embodiments, the solubility enhancer is SBE7-,6-CD
(Captisol ).
(002321 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical .fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein.
1002331 In still other embodiments, the nebulizer is a jet nebulizer, an
ultrasonic nebulizer, a pulsating
membrane nebulizer, a nebulizer with a vibrating mesh or plate with multiple
apertures, or a nebutizer
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comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-
Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain other
embodiments, the nebulizer is
a Pari eFlow nebulizer.
[002341 An aspect of this invention relates to an inhalation system for
delivering a therapeutically effective
dose of a corticosteroid to a patient comprising (a) an inhalable aqueous
mixture comprising the cortiaosteroid
and a solubility enhancer, and (b) a nebulizer, whereby upon administration of
said inhalable aqueous mixture
through said nebulizer, the system delivers an enhanced lung deposition of the
corticosteroid as compared to an
inhalable suspension comprising a corticosteroid administered under the same
conditions. In a preferred
embodiment of this invention, the system achieves at least about 10% higher
respirable fraction compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In a more preferred
embodiment of this invention, the system achieves at least about 15% higher
respirable fraction compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In the most
preferred embodiment of this invention, the system achieves at least about 20%
higher respirable fraction
compared to an inhalable suspension comprising the corticosteroid administered
under the same conditions.
1002351 In a preferred embodiment of this invention, the system comprising an
inhalable aqueous mixture
comprising a corticosteroid and a solubility enhancer achieves at least about
5% higher lung deposition
compared to an inhalable suspension comprising the corticosteroid administered
under the same conditions. In
another preferred embodiment of this invention, the system comprising an
inhalable aqueous mixture
comprising a corticosteroid and a solubility enhancer achieves at least about
10% higher lung deposition
compared to an inhalable suspension comprising the corticosteroid administered
under the same conditions. In
a more preferred embodiment of this invention, the system comprising an
inhalable aqueous mixture comprising
a corticosteroid and a solubility enhancer achieves at least about 15% higher
lung deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In another more
preferred embodiment of this invention, the system comprising an inhalable
aqueous mixture comprising a
corticosteroid and a solubility enhancer achieves at least about 20% higher
lung deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions. In the most
preferred embodiment of this invention, the system comprising an inhalable
aqueous mixture comprising a
corticosteroid and a solubility enhancer achieves at least about 25% higher
lung deposition compared to an
inhalable suspension comprising the corticosteroid administered under the same
conditions.
[002361 In some embodiments of this invention, the system comprising an
inhalable aqueous mixture
comprising a corticosteroid and a solubility enhancer achieves about the same
lung deposition of the
corticosteroid as compared to an inhalable suspension comprising the
corticosteroid, wherein the composition is
administered at a lower nominal dosage than the inhalable suspension. In some
embodiments of this invention,
the system comprising an inhalable aqueous mixture comprising a corticosteroid
and a solubility enhancer
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achicves about 90% to 110% lung deposition of the corticosteroid as compared
to an inhalable suspension
comprising the corticosteroid. In some embodiments of this invention, the
system comprising an inhalable
aqueous mixture comprising a corticosteroid and a solubility enhancer achieves
about 80% to 120% lung
deposition of the corticosteroid as compared to an inhalable suspension
comprising the corticosteroid. In some
embodiments of this invention, the system comprising an inhalable aqueous
mixture comprising a corticosteroid
and a solubility enhancer achieves about 70% to 130% lung deposition of the
corticosteroid as compared to an
inhalable suspension comprising the corticosteroid.
[002371 The systems described herein can deliver an inhalable aqueous mixture
comprising a corticosteroid,
e.g., budesonide, a solvent and a solubility enhancer to the subject in a
manner wherein the active is delivered in
accordance with good medical practice, taking into account the clinical
condition of the individual patient, the
site and method of administration, scheduling of administration, and other
factors known to medical
practitioners. In human therapy, the systems and methods described herein can
deliver inhalable aqueous
mixtures comprising corticosteroids, e.g., a budesonide solution, that
maintain a therapeutically effective
amount of the corticosteroid, e.g., budesonide, at the site of action which
reduces or mitigates symptoms related
to bronchoconstrictive disorders.
[00238] In another aspect, the inhalable aqueous mixture comprises a
corticosteroid, such as budesonide,
wherein the inhalable aqueous mixture is administered according to the methods
described herein no more than
twice a day (b.i.d). In yet another aspect, the inhalable aqueous mixture
comprises a corticosteroid, such as
budesonide, wherein the inhalable aqueous mixture is administered according to
the methods described herein
no more than once a day. In still another embodiment, the inhalable aqueous
mixture comprises a
corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is
administered no more than once a
day in the evening.
[002391 In still other embodiments, the systems of the present invention can
deliver a therapeutically effective
amount of a corticosteroid in a significantly shorter period of time than
conventional inhalable corticosteroid
therapies. For example, the nebulization time for Pulmicorto Respules
administered by a Pari LC Plus jet
nebulizer takes at least 5 minutes to 8 minutes, and in some cases in excess
of 10 minutes. By contrast, the
methods and systems of the present invention can deliver a therapeutically
effective amount of a corticosteroid,
such as a budesonide, over a delivery time of less than about 5 minutes to
less than about 1.5 minutes. In some
embodiments, the delivery time can be about 5 minutes. In other embodiments,
the delivery time can be less
than about 5 minutes. In certain embodiments, the delivery time can be about
4.5 minutes. In certain other
embodiments, the delivery time can be less than about 4.5 minutes. In still
other embodiments, the delivery
time can be about 4 minutes. In yet other embodiments, the delivery time can
be less than about 4 minutes. In
still yet other embodiments, the delivery time can be about 3.5 minutes. In
other embodiments, the delivery time
can be less than about 3.5 minutes. In yet still other embodiments, the
delivery time can be about 3 rninutes. In
other embodiments, the delivery time can be less than about 3 minutes. In
certain embodiments, the delivery
time can be about 2.5 minutes. In other certain embodiments, the delivery time
can be less than about 2.5
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minutes. In still other embodiments, the delivery time can be about 2 minutes.
In yet still other embodiments,
the delivery time can be less than about 2 minutes. In a preferred embodiment,
the delivery time can be about
1.5 minutes. In a more preferred embodiment, the delivery time can be less
than about 1.5 minutes.
(00240] As previously stated, the nebulization time for Pulmicort Respules
administered by a Pari LC Plus jet
nebulizer can take in excess of 10 minutes. This prolonged administration time
is very burdensome on the
patient, especially when the patient is a pediatric patient. Thus, a system or
method that can reduce the time of
delivery of a corticosteroid by inhalation can increase the patient's
compliance with the therapeutic regimen.
By contrast, the methods and systems of the present invention can deliver a
therapeutically effective amount of
a corticosteroid, such as a budesonide, over a delivery time of less than
about 5 minutes to less than about 1.5
minutes. In some embodiments, the delivery time can be about 5 minutes. In
other embodiments, the delivery
time can be less than about 5 minutes. In certain embodiments, the delivery
time can be about 4.5 minutes. In
certain other embodiments, the delivery time can be less than about 4.5
minutes. In still other embodiments, the
delivery time can be about 4 minutes. In yet other embodiments, the delivery
time can be less than about 4
minutes. In still yet other embodiments, the delivery time can be about 3.5
minutes. In other embodiments, the
delivery time can be less than about 3.5 minutes. In yet still other
embodiments, the delivery time can be about
3 minutes. In other embodiments, the delivery time can be less than about 3
minutes. In certain embodiments,
the delivery time can be about 2.5 minutes. In other certain embodiments, the
delivery time can be less than
about 2.5 minutes. In still other embodiments, the delivery time can be about
2 minutes. In yet still other
embodiments, the delivery time can be less than about 2 minutes. In a
preferred embodiment, the delivery time
can be about 1.5 minutes. In a more preferred embodiment, the delivery time
can be less than about 1.5
minutes.
(002411 In still other embodiments of this invention, the inhalation mixture
for use in the present methods
further comprises a second therapeutic agent selected from the group
consisting of a beta2-adrenoreceptor
agonist, a prophylactic therapeutic, and an anti-cholinergic agent. In other
embodiments of this invention, the
beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical
acceptable derivative.
(002421 Another aspect of this invention relates to an inhalation system for
delivering a therapeutically
effective dose of albuterol to a patient comprising (a) an aqueous inhalation
mixture comprising albuterol, and
(b) a Pari eFlow nebulizer, whereby delivering said inhalation mixture by said
nebulizer delivers an enhanced
lung deposition of the corticosteroid as compared to albuterol with another
nebulizer administered under the
same conditions. Also an aspect of this invention relates to an inhalation
system for delivering a therapeutically
effective dose of albuterol to a patient comprising (a) an aqueous inhalation
mixture comprising albuterol, and
(b) a Pari eFlow nebulizer, whereby delivering said inhalation mixture by said
nebulizer delivers an enhanced
pharmacokinetic profile of the corticosteroid as compared to albuterol
administered with another nebulizer
under the same conditions. In some embodiments of this invention, the
inhalable composition comprises a
corticosteroid.
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VI1. Corticosteroid Inhalation Systems Which Provide a Decreased Increase In
the Concentration of the
Corticosteroid within a Device
1002431 Another aspect of this invention relates to an inhalation system for
delivering a therapeutically
effective dose of a corticosteroid to a patient comprising (a) an aqueous
inhalation mixture comprising the
corticosteroid, a solvent and a solubility enhancer, and (b) a nebulizer,
whereby upon administration of the
composition to a subject through a nebulizer, the system achieves rate of
increasing concentration of the
corticosteroid inside the device of about 60% or less or a rate of increasing
concentration of the corticosteroid
inside the device achieved by an inhalable suspension comprising the
corticosteroid without a solubility
enhancer administered under the same conditions. In certain embodiments, the
aqueous inhalation mixture
comprises a single corticosteroid and is substantially free of active
pharmaceutical agents other than the
corticosteroid.
[002441 In certain embodiments, the rate of increasing concentration of the
corticosteroid inside the device is
achieved over the first 3 minutes of administration. In other embodiments, the
rate of increasing concentration
of the corticosteroid inside the device is achieved during the second and
third minute of administration. In still
other embodiments, the rate of increasing concentration of the corticosteroid
inside the device is achieved
during the third minute of administration.
1002451 In one embodiment, the invention relates to an inhalable composition
wherein administration of the
composition through the device is achieved over five minutes or less, and
administration of the inhalable
suspension is achieved over five minutes or less. In another embodiment, the
invention relates to an inhalable
composition wherein the time of administration of the composition through the
device and the time of
administration of the inhalable suspension are the same. In still other
embodiments, the invention relates to an
inhalable composition wherein the time of administration of the composition
through the device and the time of
administration of the inhalable suspension are different.
[002461 In certain embodiments of this invention, the inhalable composition
also achieves at least about 60%
respirable fraction upon administration. In a more preferred embodiment of
this invention, the inhalable
composition also achieves at least about 70% respirable fraction upon
administration. In a still more preferred
embodiment of this invention, the inhalable composition also achieves at least
about 80% respirable fraction
upon administration. In the most preferred embodiment of this invention, the
inhalable composition also
achieves at least about 85% respirable fraction upon administration.
[00247] In some embodiments of this invention, the system comprises an aqueous
inhalation mixture
comprising about 15 to about 2000 g of a corticosteroid. In other
embodiments, the inhalation mixture
comprises about 50 to about 2000 g of a corticosteroid. In still other
embodiments, the inhalation mixtures
coinprise about 60 to about 1500 g of a corticosteroid. In yet other
embodiments, the inhalation mixtures
comprise about ] 00 to about 1000 jig of a corticosteroid. In still other
embodiments, the inhalation mixtures
comprising comprise about 120 to about 1000 g of a corticosteroid. In yet
still other embodiments, the
inhalation mixtures comprise about 125 to about 500 g of a corticosteroid. In
certain embodiments, the
inhalation mixtures comprise about 40, 60, 100, 120, 125, 240, 250, 500, 1000,
1500, or 2000 pg of a
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corticosteroid. In one embodiment, the inhalation mixture comprises a nominal
dosage of about 40 g of a
corticosteroid. In another embodiment, the inhalation mixture comprises a
nominal dosage of about 60 g of a
corticosteroid. In yet another embodiment, the inhalation mixture comprises a
nominal dosage of about 100 g
of a corticosteroid. In yet still another embodiment, the inhalation mixture
comprises a nominal dosage of
about 120 g of a corticosteroid. In still another embodiment, the inhalation
mixture comprises a nominal
dosage of about 125 g of a corticosteroid. In still yet another embodiment,
the inhalation mixture comprises a
nominal dosage of about 240 g of a corticosteroid. In still yet another
embodiment, the inhalation mixture
comprises a nominal dosage of less than about 250 g of a corticosteroid. In
one embodiment, the
corticosteroid is budesonide. In another embodiment, the corticosteroid is
budesonide wherein the budesonide
is either an individual diastereomer or a mixture of the two diastereomers
administered individually or together
for a therapeutic effect. In certain embodiments, the inhalation mixtures
comprise an effective amount of a
single corticosteroid, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than corticosteroid. In still other embodiments, the inhalation
mixtures comprise an effective
amount of a budesonide, a solvent and a solubility enhancer and are
substantially free of active pharmaceutical
agents other than the budesonide.
(00248) In some embodiments, suitable aqueous inhalation mixture comprising a
corticosteroid include, but are
not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
[002491 In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
(00250) The corticosteroids that are useful in the inhalation mixtures
described herein included, but are not
limited to, aldosterone, beclomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone,
difluorocortolone, fluclorolone,
flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,
fluorocortisone, fluorocortolone,
#luorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone,
icomethasone, meprednisone,
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methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,
rofleponide, RPR 106541,
tixocortol, triamcinolone, and their respective pharrnaceutically acceptable
derivatives. In preferred
embodiments, the corticosteroid is budesonide. In other preferred embodiments,
the corticosteroid is
budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
1002511 In certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
1002521 In certain embodiments of the inhalation mixtures described herein,
the inhalation mixture comprises a
solubility enhancer. In some embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 0.001 fo to about 25%. In other embodiments, the solubility enhancer
can have a concentration (w/v)
ranging from about 0.01% to about 20%. In still other embodiments, the
solubility enhancer can have a
concentration (w/v) ranging from about 0.1% to about 15%. In yet other
embodiments, the solubility enhancer
can have a concentration (w/v) ranging from about 1% to about 10%. In a
preferred embodiment, the solubility
enhancer can have a concentration (w/v) ranging from about 2% to about 10%
when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g. SBE7-0-CD (Captisol ). In one
embadiment, the solubility
enhancer can have a concentration (w/v) of about 2% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-(3-CD (Captisol ). In another embodiment,
the solubility enhancer can have
a concentration (w/v) of about 5% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative, e.g.
SBE7-j3-CD (Captisol ). In yet another embodiment, the solubility enhancer can
have a concentration (w/v)
about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative, e.g. SBE7-a-CD
(Captisol(D). In still yet another embodiment, the solubility enhancer can
have a concentration (w/v) of about
10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,
e.g. SBE7-0-CD (Captisol ).
[002531 In some embodiments of this invention, the solubility enharicer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-l5-hydroxystearate, pbospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-0-CD, SBEI-(3-CD, SBE4-0-CD, SBE7-(3-CD (Captisol ), SBE--t-CD,
dimethyl lfi-CD,
hydroxypropyl-(3-cyclodextrin, 2-HP-/3-CD, hydroxyethyl-fl-cyclodextrin,
hydroxypropyl--)-cyclodextrin,
hydrdxyethyl-ry,cyclodextrin, dihydroxypropyl-(3-cyclodextrin, glucosyl-ce-
cyclodextrin, glucosyl-/3-
cyclodextrin, diglucosyl-fl-cyclodextrin, maltosyl-u-cyclodextrin, maltosyl-/3-
cyclodextrin, maltosyl-'y-
cyclodextrin, maltotriosyl-Q-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-/3-cyclodextrin, methyl-(3,
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylceilulose,
hydroxypropylcellulose, poiyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
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sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-0-CD (Captisolft
[002541 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-ac-CD, SBE-R-CD, SBEl-/3-CD, SBE4-j3-CD, SBE7-0-CD (Captisol(D), SBE-y-CD,
dimethyl ,Q-CD,
hydroxypropyl-(3-cyclodextrin, 2-HP-Q-CD, hydroxyethyl-(3-cyclodextrin,
hydroxypropyl--ys-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-0-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-(3-
cyclodextrin, diglucosyl-("3-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-
,6-cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-j3-cyclodextrin, methyl-0-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-fl-CD
(Captisol ).
[002551 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
rnethods which provide enhanced solubility are likewise suitable for use in
the presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein.
(002561 In some embodiments of this invention, the composition further
comprises a second therapeutic agent
selected from the group consisting of a beta2-adrenoreceptor agonist, a
prophylactic therapeutic, and an anti-
cholinergic agent. In some embodiments of this invention, the beta2-
adrenoreceptor agonist is albuterol,
levalbuterol or a pharmaceutical acceptable derivative.
1002571 In another aspect, the inhalable aqueous mixture comprises a
corticosteroid, such as budesonide,
wherein the inhalable aqueous mixture is administered according to the methods
described herein no more than
twice a day (b.i.d). In yet another aspect, the inhalable aqueous mixture
comprises a corticosteroid, such as
budesonide, wherein the inhalable aqueous mixture is administered according to
the methods described herein
no more than once a day. In still another embodiment, the inhalable aqueous
mixture comprises a
corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is
administered no more than once a
day in the evening.
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(00258] In some embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Interteeh, Baxter Misty-Neb, Hudson T-
Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain
embodiments, the nebulizer is a Pari
eFlow nebulizer.
VIII. Methods of Treatment to Achieve Enhanced Lung Deposition
[002591 In other aspects of the present invention, methods are provided for
the delivery of a therapeutically
effective dose of a corticosteroid to a patient. In certain embodiments, the
methods described herein are
directed to the treatment of a bronchoconstrictive disorder in a patient
comprising providing an inhalable
aqueous mixture comprising a corticosteroid, a solvent and a solubility
enhancer and delivering the aqueous
inhalation mixture via an inhalation nebulizer.
1002601 In certain embodiments, the present invention can provide a method for
the treatment of a
bronchoconstrictive disorder in a patient in need of treatment thereof
comprising forming a mixture by adding a
solvent and a solubility enhancer to an amount of corticosteroid and operating
a nebulizer, wherein upon
administration of the mixture to a subject through the nebulizer, the methods
can achieves at least about 20% to
about 40%, between about 20% to about 50%, or between about 20% to about 55%
lung deposition e.g.,
bronchi and alveoli, based on the amount of corticosteroid in the mixture
prior to administration. In some
embodiments, the methods can achieve at least about 20% to about 35% lung
deposition based on the amount of
corticosteroid in the mixture prior to administration. In other embodiments,
the methods can achieve at least
20% to about 30% lung deposition based on the amount of corticosteroid in the
mixture prior to administration.
In certain embodiments, the methods achieve about 25% lung deposition based on
the amount of corticosteroid
in the composition prior to administration. In other embodiments, the methods
achieve at least about 30% lung
deposition based on the amount of corticosteroid in the composition prior to
administration. In still other
embodiments, the methods achieve at least about 35% lung deposition based on
the amount of corticosteroid in
the composition prior to administration. In yet other embodiments, the methods
achieve at least about 40% lung
deposition based on the amount of corticosteroid in the composition prior to
administration. In yet still other
embodiments, the methods achieve at least about 45% lung deposition based on
the amount of corticosteroid in
the composition prior to administration. In still yet other embodiments, the
methods achieve at least about 50%
lung deposition based on the amount of corticosteroid in the composition prior
to administration. In other
embodiments, the methods achieve at least about 40% to about 55% lung
deposition based on the amount of
corticosteroid in the composition prior to administration. In one embodiment,
the corticosteroid is budesonide.
In another embodiment, the corNcosteroid is budesonide wherein the budesonide
is either an individual
diastereomer or a mixture of the two diastereomers administered individually
or together for a therapeutic
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effect. In certain embodiments, the inhalable compositions comprise an
effective amount of a single
corticosteroid, and a solubility enhancer and are substantially free of active
pharmaceutical agents other than
corticosteroid. In still other embodiments, the inhalable compositions
comprises an effective amount of
budesonide, and a solubility enhancer and are substantially free of active
pharmaceutical agents other than the
budesonide.
[002611 In other embodiments of this invention, the methods also achieve at
least about 60% respirable fraction
upon administration. In more preferred embodiments of this invention, the
methods also achieve at least about
70% respirable fraction upon administration. In still more preferred
embodiments of this invention, the
methods also achieve at least about 80% respirable fraction upon
administration. In the most preferred
embodiments of this invention, the methods also achieve at least about 85%
respirable fraction upon
administration. In one embodiment, the corticosteroid is budesonide. In
another embodiment, the
corticosteroid is budesonide wherein the budesonide is either an individual
diastereomer or a mixture of the two
diastereomers administered individually or together for a therapeutic effect.
In certain embodiments, the
inhalable compositions comprise an effective amount of a single
corticosteroid, and a solubility enhancer and
are substantially free of active pharmaceutical agents other than
cortieosteroid. in still other embodiments, the
inhalable compositions comprises an effective amount of a budesonide, and a
solubility enhancer and are
substantially free of active pharmaceutical agents other than the budesonide.
[00262J In certain embodiments, the methods of treatment of a
bronchoconstrictive disorder comprise the
delivery of an inhalable aqueous mixture comprising a corticosteroid. The
corticosteroids that are useful is in
the present invention include, but are not limited to, aldosterone,
beclomethasone, betamethasone, budesonide,
ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide,
desoximetasone, dexamethasone,
difluorocortolone, fluclorolone, flurnethasone, flunisolide, fluocinolone,
fluocinonide, fluocortin butyl, '
fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone,
fluticasone, balcinonide, hydrocortisone,
icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone,
prednisolone, prednisone,
rofleponide, RPR 106541, tixocortol, triameinolone, and their respective
pharmaceutically acceptable
derivatives. In some embodiments, the corticosteroid is budesonide. In other
embodiments, the corticosteroid
is budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect.
(00263J In some embodiments of this invention, the methods of treatment
comprise an aqueous inhalation
mixture comprising an amount of corticosteroid in mixture prior to
administration of about 15 to about 2000 g
of a corticosteroid. In other embodiments, the inhalation mixtures comprise an
amount of corticosteroid in
mixture prior to administration of about 250 to about 2000 g of a
corticosteroid. In still other embodiments,
the inhalation mixtures comprise an amount of corticosteroid in mixture prior
to administration of about 60 to
about 1500 g of a corticosteroid. In yet other embodiments, the inhalation
mixtures comprise an amount of
corticosteroid in mixture prior to administration of about 100 to about 1000
gg of a corticosteroid. In still other
embodiments, the inhalation mixtures comprise an amount of corticosteroid in
mixture prior to administration
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of about 120 to about ] 000 pg of a corticosteroid. In yet still other
embodiments, the inhalation mixtures
comprise an amount of corticosteroid in mixture prior to administration of
about 125 to about 500 pg of a
corticosteroid. In certain embodiments, the inhalation mixtures comprise an
amount of corticosteroid in mixture
prior to administration of about about 40, about 60, about 100, about 120,
about 125, about 240, about 250,
about 500, about 1000, about 1500, or about 2000 g of a corticosteroid. In
one embodiment, the inhalation
mixture comprises an amount of corticosteroid in mixture prior to
administration of about 40 g of a
corticosteroid. In another embodiment, the inhalation mixture comprises an
amount of corticosteroid in mixture
prior to administration of about 60 pg of a corticosteroid. In still another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
about 100 g of a corticosteroid. In
yet another embodiment, the inhalation mixture comprises an amount of
corticosteroid in mixture prior to
administration of about 120 pg of a corticosteroid. In yet still another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
about 125 g of a corticosteroid. In
still another embodiment, the inhalation mixture comprises an amount of
corticosteroid in mixture prior to
administration of about 240 ug of a corticosteroid. In still yet another
embodiment, the inhalation mixture
comprises an amount of corticosteroid in mixture prior to administration of
less than about 250 pg of a
corticosteroid. In one embodiment, the corticosteroid is budesonide. In
another embodiment, the corticosteroid
is budesonide wherein the budesonide is either an individual diastereomer or a
mixture of the two diastereomers
administered individually or together for a therapeutic effect. In certain
embodiments, the inhalable
compositions comprise an effective amount of a single corticosteroid, a
solvent and a solubility enhancer and
are substantially free of active pharmaceutical agents other than
corticosteroid. In still other embodiments, the
inhalable compositions comprises an effective amount of a budesonide, a
solvent and a solubility enhancer and
are substantially free of active pharmaceutical agents other than the
budesonide.
[00264] In certain embodiments, the inhalable mixtures can comprise about 40
g budesonide, a solvent and a
solubility enhancer, wherein upon administration of the composition to a
subject through a nebulizer, the
composition achieves lung deposition of at least 13 pg of budesonide. In
certain other embodiments, the
inhalable mixtures can comprise about 60 g budesonide, a solvent and a
solubility enhancer, wherein upon
administration of the composition to a subject through a nebulizer, the
composition achieves lung deposition of
at least 20 pg of budesonide. In still other embodiments, the inhalable
composition can comprise about 120 g
budesonide, a solvent and a solubility enhancer, wherein upon administration
of the composition to a subject
through a nebulizer, the composition achieves lung deposition of at least 40
pg of budesonide. In yet other
embodiments, the inhalable composition can comprise about 240 g budesonide, a
solvent and a solubility
enhancer, wherein upon administration of the composition to a subject through
a nebulizer, the composition
achieves lung deposition of at least 80 g of budesonide.
1002651 In certain embodiments, the inhalable mixtures can comprise about 40
g budesonide, a solvent and a
solubility enhancer, ivherein upon administration of the composition to a
subject through a nebulizer, the
composition achieves lung deposition of at least 13 g of budesonide, wherein
the composition is substantially
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free of active pharmaceutical agents other than the budesonide. In certain
other embodiments, the inhalable
mixtures can comprise about 60 g budesonide, a solvent and a solubility
enhancer, wherein upon
administration of the composition to a subject through a nebulizer, the
composition achieves lung deposition of
at least 20 g of budesonide, wherein the composition is substantially free of
active pharmaceutical agents other
than the budesonide. In still other embodiments, the inhalable composition can
comprise about 120 g
budesonide, a solvent and a solubility enhancer, wherein upon administration
of the composition to a subject
through a nebulizer, the composition achieves lung deposition of at least 40
pg of budesonide, wherein the
composition is substantially free of active pharmaceutical agents other than
the =budesonide. In yet other
embodiments, the inhalable composition can comprise about 240 pg budesonide, a
solvent and a solubility
enhancer, wherein upon administration of the composition to a subject through
a nebulizer, the composition
achieves lung deposition of at least 80 g of budesonide, wherein the
composition is substantially free of active
pharmaceutical agents other than the budesonide.
[002661 In some embodiments, suitable aqueous inhalation mixture comprising a
corticosteroid include, but are
not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and Iiposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
[00267] In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalabte composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.ln certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
[002681 In some embodiments, the methods of treatment of a bronchoconstrictive
disorder comprise the
delivery of an inhalable aqueous mixture comprising a corticosteroid and a
solvent. In certain embodiments, the
solvent is selected from the group consisting of water, aqueous alcohol,
propylene glycol, or aqueous organic
solvent. In preferred embodiments, the solvent is water.
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1002691 In certain embodiments of the inhalation mixtures described herein,
the inhalation mixture comprises a
solubility enhancer. In some embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 0.001% to about 25%. In other embodiments, the solubility enhancer can
have a concentration (w/v)
ranging from about 0.01% to about 20%. In still other embodiments, the
solubility enhancer can have a
concentration (w/v) ranging from about 0.1% to about 15%. In yet other
embodiments, the solubility enhancer
can have a concentration (w/v) ranging from about 1% to about 10%. In a
preferred embodiment, the solubility
enhancer can have a concentration (w/v) ranging from about 2% to about 10%
when the solubility enhancer is a
cyclodextrin or' cyclodextrin derivative,e.g. SBE7-0-CD (Captisol ). In one
embodiment, the solubility
enhancer can have a concentration (w/v) of about 2% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol ). In another embodiment,
the solubility enhancer can have
a concentration (w/v) of about 5% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g.
SBE7-/3-CD (Captisol ). In yet another embodiment, the solubility enhancer can
have a concentration (w/v)
about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative,e.g. SBE7-(3-CD
(Captisol ). In still yet another embodiment, the solubility enhancer can have
a concentration (w/v) of about
10% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative,e.g. SBE7-/3-CD (Captisol ).
(002701 In some embodiments of this invention, the methods of treatment of a
bronchoconstrictive disorder
comprise the delivery of an inhalable aqueous mixture comprising a
corticosteroid and a solubility enhancer. In
certain embodiments, the solubility enhancer is a chemical agent selected from
the group consisting of
propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-
TPGS, macrogol-15-
hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin,
phosphatidylcholine fractions
extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl
phosphatidylcholine (DPPC),
distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof,
SAE-CD derivatives, SBE-a-CD,
SBE-/3-CD, SBEI-(i-CD, SBE4-R CD, SBE7-9-CD (Captisolft SBE--y-CD, dimethyl j3-
CD, hydroxypropyl-,&
cyclodextrin, 2-HP-P-CD, hydroxyethyl-(3-cyclodextrin, hydroxypropyl--~-
cyclodextrin, hydroxyethyl--t-
cyclodextrin, dihydroxypropyl-a-cyclodextrin, glucosyl- -cyclodextrin,
glucosyl-o-cyclodextrin, diglucosyl-0-
cyclodextrin, maltosyi-ca cyclodextrin, maltosyl-13-cyclodextrin, maltosyl-y-
cyclodextrin, maitotriosyl-a-
cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-/3-cyclodextrin, methyl-
(.i-cyclodextrin, carboxyalkyl
thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose,
hydroxypropylcellulose,
polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium
lauryl sulfate, dioctyl sodium
sulfosuccinate, and combinations thereof. In other embodiments, the solubility
enhancer is SBE7-16-CD
(Captisol ).
(002711 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a CD, SBE-,6-CD, SBEI-Q-CD, SBE4-(3-CD, SBE7-S-CD (Captisol(D), SBE-y-CD,
dimethyl (3-CD,
hydroxypropyl-0-cyclodextrin, 2-HP-j3-CD, hydroxyethyl-,(3-cyclodextrin,
hydroxypropyl--y-cyclodextrin,
hydroxyethyl--t-cyclodextrin, dihydroxypropyl-a-cyclodextrin, glucosyl-ot-
cyclodextrin, glucosyl-g-
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cyclodextrin, diglucosyl-Q-cyclodextrin, ' maltosyl-a-cyclodextrin, maltosyl-0-
cyclodextTin, maltosyl-y-
cyclodextrin, maltotriosyl-/.3-cyclodextrin, rnaltotriosyl-y-cyclodextrin,
dimaltosyl-0-cyclodextrin, methyl-(3-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-13-CD
(CaptisolO).
[002721 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No. 2003/0091 5
1 3, each of which is specifically
incorporated by reference herein.
[00273) In some embodiments of this invention, the composition further
comprises a second therapeutic agent
selected from the group consisting of a beta2-adrenoreceptor agonist, a
prophylactic therapeutic, and an anti-
cholinergic agent. In some embodiments of this invention, the beta2-
adrenoreceptor agonist is albuterol,
levalbuterol or a pharmaceutical acceptable derivative.
[002741 In certain embodiments of this invention, the bronchoconstrictive
disorder is selected from the group
consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma,
intrinsic asthma, chronic obstructive
pulmonary disease (COPD), chronic bronchitis, and emphysema.
1002751 In another aspect, the inhalable aqueous mixture comprises a
corticosteroid, such as budesonide,
wherein the inhalable aqueous mixture is administered according to the methods
described herein no more than
twice a day (b.i.d). In yet another aspect, the inhalable aqueous mixture
comprises a corticosteroid, such as
budesonide, wherein the inhalable aqueous mixture is administered according to
the methods described herein
no more than once a day. In still another embodiment, the inhalable aqueous
mixture comprises a
corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is
administered no more than once a
day in the evening.
[002761 In some embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-
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Updraft Il, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain
embodiments, the nebulizer is a Pari
eFlow nebulizer.
[00277] In still other embodiments, the present invention can provide a method
for the treatment of a
bronchoconstrictive disorder in a patient comprising providing an inhalable
aqueous mixture comprising a
corticosteroid, a solvent and a solubility enhancer and delivering the aqueous
inhalation mixture via an
inhalation nebulizer, wherein the delivery of the inhalable aqueous mixture
provides that no more than about
10% to about 30% of the corticosteroid is delivered outside of the lung, e.g.,
in the mouth, esophagus, and/or
stomach. In one embodiment, the method can provide the delivery of an
inhalable aqueous mixture wherein no
more than about 10% of the corticosteroid is delivered outside of the lung. In
another embodiment, the method
can provide the delivery of an inhalable aqueous mixture wherein no more than
about 15% of the corticosteroid
is delivered outside of the lung. In yet another embodiment, the method can
provide the delivery of an
inhalable aqueous mixture wherein no more than about 20% of the corticosteroid
is delivered outside of the
lung. In still another embodiment, the method can provide the delivery of an
inhalable aqueous mixture
wherein no more than about 25% of the corticosteroid is delivered outside of
the lung. In yet another
embodiment, the method can provide the delivery of an inhalable aqueous
mixture wherein no more than about
30% of the corticosteroid is delivered outside of the lung.
[00278] In other embodiments, the present invention can provide a method for
the prophylaxis of a
bronchoconstrictive disorder in a patient comprising providing an inhalable
aqueous mixture comprising a
corticosteroid, a solvent and a solubility enhancer and delivering the aqueous
inhalation mixture via an
inhalation nebulizer. In another embodiment, the present invention can provide
a method for reducing the risk
of side effects associated with corticosteroid inhalation therapy whereby a
lower nominal dosage of the
corticosteroid is required to achieve a therapeutic effect as compared to
conventional inhalable corticosteroid
therapies. In one embodiment, the risk of side effects is lowered compared to
conventional inhalable
corticosteroid therapies.
IX. Methods of Treatment which Provide a Decreased Increase in the
Concentration of Corticosteroid
within the Device
[00279] An additional aspect of this invention relates to a method of the
treatment of a bronchoconstrictive
disorder in a patient in need of treatment thereof comprising forming a
composition by adding a solvent and a
solubility enhancer to a corticosteroid and operating a nebulizer, wherein
upon administration of the
composition to a subject through the nebulizer, the composition achieves rate
of increasing concentration of the
corticosteroid inside the device of about 60% or less or a rate of increasing
concentration of the corticosteroid
inside the device achieved by an inhalable suspension comprising the
corticosteroid without a solubility
enhancer administered under the same conditions. In certain embodiments, the
composition comprises a single
corticosteroid and is substantially free of active pharmaceutical agents other
than the corticosteroid. In other
embodiments of this invention, the corticosteroid is budesonide or a
pharmaceutical acceptable derivative. In
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still other embodiments, the corticosteroid is budesonide wherein the
budesonide is either an individual
diastereomer or a mixture of the two diastereomers administered individually
or together for a therapeutic
effect.
[002801 In certain embodiments, the rate of increasing concentration of the
corticosteroid inside the device is
achieved over the first 3 minutes of administration. In other embodiments, the
rate of increasing concentration
of the corticosteroid inside the device is achieved during the second and
third minute of administration. In still
other embodiments, the rate of increasing concentration of the corticosteroid
inside the device is achieved
during the third minute of administration.
1002811 In one embodiment, the invention relates to an inhalable composition
wherein administration of the
composition through the device is achieved over five minutes or less, and
administration of the inhalable
suspension is achieved over five minutes or less. In another embodiment, the
invention relates to an inhalable
composition wherein the time of administration of the composition through the
device and the time of
administration of the inhalable suspension are the same. In still other
embodiments, the invention relates to an
inhalable composition wherein the time of administration of the composition
through the device and the time of
administration of the inhalable suspension are different.
1002821 In certain embodiments of this invention, the inhalable composition
also achieves at least about 60%
respirable fraction upon administration. In a preferred embodiment of this
invention, the inhalable composition
also achieves at least about 70% respirable fraction upon administration. In a
more preferred embodiment of
this invention, the inhalable composition also achieves at least about 80%
respirable fraction upon
administration. In the most preferred embodiment of this invention, the
inhalable composition also achieves at
least about 85% respirable fraction upon administration.'
[00283] In some embodiments of this invention, the system comprises an aqueous
inhalation mixture
comprising about 15 to about 2000 g of a corticosteroid. In other
embodiments, the inhalation mixtures
comprise about 50 to about 2000 g of a corticosteroid. In still other
embodiments, the inhalation mixtures
comprise about 60 to about 1500 g of a corticosteroid. In yet other
embodiments, the inhatation mixtures
comprise about 100 to about 1000 pg of a corticosteroid. In still other
embodiments, the inhalation mixtures
comprising comprise about 120 to about 1000 g of a corticosteroid. In yet
still other embodiments, the
inhalation mixtures comprise about 125 to about 500 g of a corticosteroid. In
certain embodiments, the
inhalation mixtures comprise about 40, 60, 100, 120, 125, 240, 250, 500, 1000,
1500, or 2000 g of a
corticosteroid. In one embodiment, the inhalation mixture comprises a nominal
dosage of about 40 g of a
corticosteroid. In another embodiment, the inhalation mixture comprises a
nominal dosage of about 60 g of a
corticosteroid. In still another embodiment, the inhalation mixture comprises
a nominal dosage of about 100
g of a corticosteroid. In yet another embodiment, the inhalation mixture
comprises a nominal dosage of about
120 g of a corticosteroid. In yet still another embodiment, the inhalation
mixture comprises a nominal dosage
of about 125 g of a corticosteroid. In still another embodiment, the
inhalation mixture comprises a nominal
dosage of about 240 l.tg of a corticosteroid. In still yet another embodiment,
the inhalation mixture comprises a
CA 02634413 2008-06-19
WO 2007/075801 PCT/US2006/048631
nominal dosage of less than about 250 g of a corticosteroid. In other
embodiments of this invention, the
corticosteroid is budesonide or a pharmaceutical acceptable derivative. In
other preferred embodiments, the
corticosteroid is budesonide wherein the budesonide is either an individual
diastereomer or a mixture of the two
diastereomers administered individually or together for a therapeutic effect.
(00284] In some embodiments, suitable aqueous inhalation mixture comprising a
corticosteroid include, but are
not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal
liquids, micelle or mixed micelle
solutions, and liposomal liquids. In one embodiment, the aqueous inhalation
mixture is a solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In another
embodiment, the aqueous inhalation
mixture is a mixed micelle solution comprising a corticosteroid, such.as
budesonide, and a solubility enhancer.
In yet another embodiment, the aqueous inhalation mixture is a liposomal
solution comprising a corticosteroid,
such as budesonide, and a solubility enhancer.
(00285) In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. in one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
1002861 In certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected frorn the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
[00287] In certain embodiments of the inhalation mixtures described herein,
the inhalation mixture comprises a
solubility enhancer. In some embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 0.001 lo to about 25%. In other embodiments, the solubility enhancer can
have a concentration (w/v)
ranging from about 0.01% to about 20%. In still other embodiments, the
solubility enhancer can have a
concentration (w/v) ranging from about 0.1 % to about 15%. In yet other
embodiments, the solubility enhancer
can have a concentration (w/v) ranging from about 1% to about 10%. In a
preferred embodiment, thc solubility
enhancer can have a concentration (w/v) ranging from about 2% to about 10%
when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g. SBE7-R-CD (Captisoi(D). In one
embodiment, the solubility
enhancer can have a concentration (w/v) of about 2% when the solubility
enhancer is a cyclodextrin or
cyclodextrin derivative, e.g. SBE7-(3-CD (Captisol ). In another embodiment,
the solubility enhancer can have
a concentration (w/v) of about 5% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative, e.g.
SBE7-0-CD (Captisol ). In yet another embodiment, the solubility enhancer can
have a concentration (w/v)
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about 7% when the solubility enhancer is a cyciodextrin or cyclodextrin
derivative, e.g. SBE7-fl-CD
(Captisol ). In still yet another embodiment, the solubility enhancer can have
a concentration (w/v) of about
10% when the solubility enhanceris a cyclodextrin or cyclodextrin derivative,
e.g. SBE7-0-CD (Captisol ).
[002881 In some embodiments of this invention, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-l5-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-o:-CD, SBE-J3-CD, SBEI-0-CD, SBE4-0-CD, SBE7-/3-CD (Captisol(D), SBE-yCD,
dimethyl (3-CD,
hydroxypropyl-o-cyclodextrin, 2-HP-(3-CD, hydroxyethyl-(3-cyclodextrin,
hydroxypropyl-ycyclodextrin,
hydroxyethyl--y-cyclodextrin, dihydroxypropyl-0-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-,6-
cyclodextrin, diglucosyl-ft-cyclodextrin, maltosyl-t~-cyclodexthin, maltosyl-
13-cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-fl-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-a-cyclodextrin, methyl-fl-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-13-CD (Captisol ).
1002891 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-oc-CD, SBE-0-CD, SBEI-(3-CD, SBE4-0-CD, SBE7-0-CD (Captisolg), SBE-y-CD,
dimethyl O-CD,
hydroxypropyl-S-cyclodextrin, 2-HP-0-CD, hydroxyethyl-(3-cyclodextrin,
hydroxypropyl-ycyclodextrin,
hydroxyethyl--y-cyclodextrin, dihydroxypropyl-/3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-0-
cyclodextrin, diglucosyl-Q-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-/3-
cyctodextrin, maltosyl-y
cyclodextrin, maltotriosyl-,6-cyclodextrin, maltotriosyl-ycyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-(3-
cyclodextrin. In certain other embodiments, the solubility enhancer is SBE7-0-
CD (Captisol ).
[00290] In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. ln accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
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WO 2007/075801 PCT/US2006/048631
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U,S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein.
(00291) In some embodiments of this invention, the composition further
comprises a second therapeutic agent
selected from the group consisting of a beta2-adrenoreceptor agonist, a
prophylactic therapeutic, and an anti-
cholinergic agent. In some embodiments of this invention, the beta2-
adrenoreceptor agonist is albuterol,
levalbuterol or a pharmaceutical acceptable derivative.
[00292) In another aspect, the inhalable aqueous mixture comprises a
corticosteroid, such as budesonide,
wherein the inhalable aqueous mixture is administered according to the methods
described herein no more than
twice a day (b.i.d). In yet another aspect, the inhalable aqueous mixture
comprises a corticosteroid, such as
budesonide, wherein the inhalable aqueous mixture is administered according to
the methods described herein
no more than once a day. In still another embodiment, the inhalable aqueous
mixture comprises a
corticosteroid, such as budesonide, wherein the inhatable aqueous mixture is
administered no more than once a
day in the evening.
[002931 In some embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-
Updraft Ii, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Iso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain
embodiments, the nebulizer is a Pari
eFlow nebulizer.
[00294j In certain' embodiments of this invention, the bronchoconstrictive
disorder is selected from the group
consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma,
intrinsic asthma, chronic obstructive
pulmonary disease (COPD), chronic bronchitis, and emphysema.
X. Methods of Manufacturing the Inhalable Compositions of the Present
Invention
[002951 Another aspect of this invention relates to use of a corticosteroid in
the manufacture of an inhalable
composition for the treatment or prophylaxis of a bronchoconstrictive disorder
in a patient in need of treatment
thereof, comprising adding a solvent and a solubility enhancer to an amount of
corticosteroid and operating a
nebulizer, wherein the composition achieves at least about 25% lung deposition
based on the amount of
corticosteroid in the composition prior to administration. In some embodiments
of this invention, the
composition also achieves at least about 60% respirable fraction upon
administration. In certain embodiments,
the inhalable compositions comprise a single corticosteroid, a solvent and a
solubility enhancer and are
substantially free of active phannaceutical agents other than corticosteroids.
In some embodiments, the
corticosteroid is budesonide. In other embodiments, the corticosteroid is
budesonide wherein the budesonide is
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either an individual diastereomer or a mixture of the two diastereomers
administered individually or together for
a therapeutic effect.
[002961 An aspect of this invention also relates to use of a corticosteroid in
the manufacture of an inhalable
composition for the treatment of a bronchoconstrictive disorder in a patient
in need of treatment thereof,
comprising adding a solvent and a solubility enhancer to an amount of
corticosteroid and operating a nebulizer,
wherein the composition achieves at least about 5% higher lung deposition
compared to an inhalable suspension
comprising the corticosteroid administered under the same conditions to
deliver a therapeutically effective
amount of said corticosteroid. In certain embodiments, the inhalable
compositions comprise a single
corticosteroid, a solvent and a solubility enhancer and are substantially free
of active pharmaceutical agents
other than corticosteroids.
[002971 An aspect of this invention also relates to use of a' corticosteroid
in the manufacture of an inhalable
composition for the treatment of a bronchoconstrictive disorder in a patient
in need of treatment thereof,
comprising adding a solvent and a solubility enhancer to an amount of
corticosteroid and operating a nebulizer,
wherein the composition achieves about the same lung deposition compared to an
inhalable suspension
comprising the corticosteroid, wherein the composition is administered at a
lower nominal dosage than the
inhalable suspension to deliver a therapeutically effective amount of said
corticosteroid. In certain
embodiments, the inhalable compositions comprise a single corticosteroid, a
solvent and a solubility enhancer
and are substantially free of active pharmaceutical agents other than
corticosteroids.
[002981 In some embodiments of this invention, the system comprises an aqueous
inhalation mixture
comprising a corticosteroid with about 15 to about 2000 g of a
corticosteroid. In other embodiments, the
inhalation mixture comprises about 50 to about 2000 g of a corticosteroid. In
still other embodiments, the
inhalation mixtures comprise about 60 to about 1500 g of a corticosteroid. In
yet other embodiments, the
inhalation mixtures comprise about 100 to about 1000 g of a corticosteroid.
In still other embodiments, the
inhalation rnixtures comprising comprise about 120 to about 1000 pg of a
corticosteroid. In yet still other
embodiments, the inhalation mixtures comprise about 125 to about 500 g of a
corticosteroid. In certain
embodiments, the inhalation mixtures comprise about 40, 60, 100, 120, 125,
240, 250, 500, 1000, 1500, or 2000
g of a corticosteroid. In one embodiment, the inhalation mixture comprises a
nominal dosage of about 40 pg
of a corticosteroid. In another embodiment, the inhalation mixture comprises a
nominal dosage of about 60 pg
of a corticosteroid. In still another embodiment, the inhalation mixture
comprises a nominal dosage of about
100 pg of a corticosteroid. In yet another embodiment, the inhalation mixture
comprises a nominal dosage of
about 120 g of a corticosteroid. In yet still another embodiment, the
inhalation mixture comprises a nominal
dosage of about 125 pg of a corticosteroid. In still another embodiment, the
inhalation mixture comprises a
nominal dosage of about 240 pg of a corticosteroid. In still yet another
embodiment, the inhalation mixture
comprises a nominal dosage of less than about 250 g of a corticosteroid. In
other embodiments of this
invention, the corticosteroid is budesonide or a pharmaceuticaI acceptable
derivative. In other preferred
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WO 2007/075801 PCT/US2006/048631
embodiments, the corticosteroid is budesonide wherein the budesonide is either
an individual diastereomer or a
mixture of the two diastereomers administered individually or together for a
therapeutic effect.
(00299] In certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanol mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
(003001 ln some embodiments of this invention, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylclioline (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-,6-CD, SBE1-0-CD, SBE4-0-CD, SBE7-a-CD (Captisol(D), SBE--t-CD,
dimethyl P-CD,
hydroxypropyl-/3-cyclodextrin, 2-HP-(3-CD, hydroxyethyl-,3-cyclodextrin,
hydroxypropyl-~cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-(3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-13-
cyclodextrin, diglucosyl-a-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-/3-
cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-Q-cyclodextrin, maltotriosyl-y cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyi-fl-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-E3-CD (Captisol(D).
1003011 In certain other embodiments, the inhalable compositions of the
present invention comprises a
solubility enhancer is selected from the group consisting of cyclodextrins and
derivatives thereof, SAE-CD
derivatives, SBE-a-CD, SBE-0-CD, SBE1-13-CD, SBE4-)3-CD, SBE7-0-CD
(Captisol(D), SBE--t-CD, dimethyl
(3-CD, hydroxypropyl-(3-cyclodextrin, 2-HP-(3-CD, hydroxyethyl-/3-
cyclodextrin, hydroxypropyl-y-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-0-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-,B-
cyclodextrin, diglucosyl-(3-cyclodextrin, maitosyl-a-cyclodextrin, maltosyl-13-
cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl--y-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-j3-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-9-CD
(Captisol(D).
(00302] In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
CA 02634413 2008-06-19
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50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein.
1003031 In some embodiments of this invention, the nebulizer is a jet
nebulizer, an ultrasonic nebulizer, a
pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with
multiple apertures, or a nebulizer
comprising a vibration generator and an aqueous chamber. In some embodiments
of this invention, the
nebulizer is selected from the group consisting of Pari LC Jet Plus,
Intertech, Baxter Misty-Neb, Hudson T-
Updraft 11, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson
Tso-Neb (B), Hudson T-
Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain other
embodiments, the nebulizer is
a Pari eFlow nebulizer.
1003041 In some embodiments of this invention, the composition further
comprises a second therapeutic agent
selected from the group consisting of a beta2-adrenoreceptor agonist, a
prophylactic therapeutic, and an anti-
cholinergic agent. In some embodiments of this invention, the beta2-
adrenoreceptor agonist is albuterol,
levalbuterol or a pharmaceutical acceptable derivative.
[003051 In some embodiments of this invention, tiie bronchoconstrictive
disorder is selected from the group
consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma,
intrinsic asthma, chronic obstructive
pulmonary disease (COPD), chronic bronchitis, and emphysema.
[003061 In another aspect, the inhalable compositions comprise a
corticosteroid, such as budesonide, wherein
the inhalable composition is administered according to the methods described
herein no more than twice a day
(b.i.d). In yet another aspect, the inhalable composition comprises a
corticosteroid, such as budesonide,
wherein the inhalable compositin is administered according to the methods
described herein no more than once
a day. In still another embodiment, the inhalable composition comprises a
corticosteroid, such as budesonide,
wherein the inhalable composition is administered no more than once a day in
the evening.
X]. Methods of Treatment with Enhanced pK Profiles
[003071 The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein can provide enhanced pharmacokinetic
profiles for the delivered
corticosteroid as compared to a corticosteroid administered via inhalation in
the form of a suspension. In
preferred embodiments, the methods and systems for the treatment or
prophylaxis of a bronchoconstrictive
disorder in a patient in need thereof described herein can enable increased
local bioavailability of the delivered
corticosteroid as compared to conventional inhalation therapies and further
provide, inter alia, a means for
reducing the dosage required to provide a local therapeutic effect. Likewise
provided are methods and systems
for the treatment of bronchoconstrictive disorders, e.g., asthma, that can
enable the delivery of a corticosteroid
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having enhanced pharmacokinetic properties as compared to a corticosteroid
administered via inhalation in the
form of a suspension, wherein the administration by the methods and systems
described herein provides one or
more of the following advantages: an increase in the local bioavailability of
the delivered corticosteroid; a
method to reduce the nominal dosage of a corticosteroid required to provide a
local therapeutic effect; a method
to reduce the time required to administer an effective dose of the
corticosteroid; a method to increase patient
compliance with a therapeutic regimen comprising inhalation of nebulized
corticosteroids; a method of
enhanced delivery of a corticosteroid; a method for increasing the amount of
corticosteroid deposited in the
lung, e.g., bronchi and alveoli; and a method for reducing the side effects
associated with inhalation of
corticosteroids.
[00308] In some embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof can provide a method
for the treatment of a
bronchoconstrictive disorder in a patient comprising providing an aqueous
inhalation mixture comprising a
corticosteroid and a solubility enhancer and delivering the aqueous inhalation
mixture with an inhalation
nebulizer wherein the corticosteroid is administered at nominal dosage of less
than about 250 g/dose. In one
embodiment, the corticosteroid can be administered at nominal dosage of less
than about 240 g/dose. In
another embodiment, the corticosteroid can be administered at nominal dosage
of less than about 200 g/dose.
In yet another embodiment, the corticosteroid can be administered at nominal
dosage of less than about 150
Ag/dose. In still another embodiment, the corticosteroid can be administered
at nominal dosage of less than
about 125 pg/dose. In another embodiment, the corticosteroid can be
administered at nominal dosage of about
120 pg/dose. In yet still anther embodiment, the corticosteroid can be
administered at nominal dosage of about
100 g/dose. In yet another embodiment, the corticosteroid can be administered
at nominal dosage of about 60
g/dose. In yet still another embodiment, the corticosteroid can be
administered at nominal dosage of about 50
g/dose. In still another embodiment, the corticosteroid can be administered at
nominal dosage of about 40
g/dose. In certain other embodiments of the methods described herein, the
aqueous inhalation mixture can
comprise a corticosteroid nominal dosage ranging from about 15 g/dose to
about 250 g/dose, or about 40
g/dose to about 250 g/dose, or about 60 g/dose to about 250 g/dose, or
about 40 pg/dose to about 200
g/dose, or about 60 g/dose to about 200 g/dose, or about 40 pg/dose to about
150 pg/dose, or about 60
}lg/dose to about 150 pg/dose, or about 40 g/dose to about 125 g/dose, or
about 60 pg/dose to about 125
pg/dose, or about 40 g/dose to about 100 gldose, or about 60 g/dose to
about 100 g/dose, or about 25
pg/dose to about 50 g/dose, or about 25 g/dose to about 60 g/dose. In some
embodiments, the corticosteroid
is budesonide. In other embodiments, the corticosteroid is budesonide wherein
the budesonide is either an
individual diastereomer or a mixture of the two diastereomers administered
individually or together for a
therapeutic effect.
1003091 In other embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof can provide a method
for the treatment of a
bronchoconstrictive disorder in a patient comprising providing an aqueous
inhalation mixture comprising a
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single corticosteroid and a solubility enhancer and delivering the aqueous
inhalation mixture with an inhalation
nebulizer wherein the corticosteroid is administered at nominal dosage of less
than about 250 pg/dose and the
inhalation mixtura is substantially free of pharmaceutically active agents
other than the corticosteroid. In one
embodiment, the corticosteroid can be administered at nominal dosage of less
than about 240 gg/dose and the
inhalation mixture is substantially free of pharmaceutically active agents
other than the corticosteroid. In
another embodiment, the corticosteroid can be administered at nominal dosage
of less than about 200 pg/dose
and the inhalation mixture is substantially free of pharmaceutically active
agents other than the corticosteroid.
In yet another embodiment, the corticosteroid can be administered at nominal
dosage of less than about 150
g/dose and the inhalation mixture is substantially free of pharmaceutically
active agents other than the
corticosteroid. In still another embodiment, the corticosteroid can be
administered at nominal dosage of less
than about 125 g/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other
than the corticosteroid. In another embodiment, the corticosteroid can be
administered at nominal dosage of
120 pg/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other than the
corticosteroid. In yet still anther embodiment, the corticosteroid can be
administered at nominal dosage of
about 100 g/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other than
the corticosteroid. In yet another embodiment, the corticosteroid can be
administered at nominal dosage of
about 60 g/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other than
the corticosteroid. In yet still another embodiment, the corticosteroid can be
administered at nominal dosage of
about 50 pg/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other than
the corticosteroid. In another embodiment, the corticosteroid can be
administered at nominal dosage of about
40 g/dose and the inhalation mixture is substantially free of
pharmaceutically active agents other than the
corticosteroid. In certain other embodiments of the methods described herein,
the aqueous inhalation mixture
can comprise a corticosteroid nominal dosage ranging from about 15 g/dose to
about 250 gg/dose, or about 40
g/dose to about 250 Ng/dose, or about 60 g/dose to about 250 g/dose, or
about 40 g/dose to about 200
g/dose, or about 60 g/dose to about 200 g/dose, or about 40 g/dose to about
150 g/dose, or about 60
g/dose to about 150 pg/dose, or about 40 g/dose to about 125 g/dose, or
about 60 g/dose to about 125
g/dose, or about 40 g/dose to about 100 g/dose, or about 60 gg/dose to about
100 g/dose, or about 25
g/dose to about 50 pg/dose, or about 25 pg/dose to about 60 }ig/dose and
wherein the inhalation mixture is
substantially free of pharmaceutically active agents other than the
corticosteroid. In some embodiments, the
corticosteroid is budesonide. In other embodiments, the corticosteroid is
budesonide wherein the budesonide is
either an individual diastereomer or a mixture of the two diastereomers
administered individually or together for
a therapeutic effect.
[00310] In still other embodiments, the systems and methods described herein
provide the delivery of an
aqueous inhalation mixture comprising a corticosteroid, a solvent, and a
solubility enhancer wherein the
delivery of the corticosteroid provides enhanced pharmacokinetic profiles of
the corticosteroid as compared to
the delivery of the corticosteroid by conventional inhalable suspension-based
therapies. In some embodiments,
the corticosteroid is budesonide. In other embodiments, the corticosteroid is
budesonide wherein the
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budesonide is either an individual diastereomer or a mixture of the two
diastereomers administered individually
or together for a therapeutic effect.
(003111 The corticosteroids that are useful in the present invention include,
but are not limited to, aldosterone,
beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone,
cortivazol, deoxycortone,
desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone,
flumethasone, flunisolide,
fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone,
fluorocortolone, fluorometholone, flurandrenolone,
fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone,
methylprednisolone, mometasone,
paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol,
triamcinolone, and their
respective pharmaceutically acceptable derivatives. In some embodiments, the
corticosteroid is budesonide. In
other embodiments, the corticosteroid is budesonide wherein the budesonide is
either an individual diastereomer
or a mixture of the two diastereomers administered individually or together
for a therapeutic effect. In certain
other embodiments, the corticosteroid is selected group of corticosteroids in
the foregoing paragraph not
including the betamethasone.
(003121 In another embodiment, the present invention can provide a method for
reducing the risk of side effects
associated with corticosteroid inhalation therapy whereby a lower nominal
dosage of the corticosteroid is
required to achieve a therapeutic effect as compared to conventional inhalable
corticosteroid therapies. In one
embodiment, the risk of side effects is lowered compared to conventional
inhalable cordcosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 250 g/dose. In another
embodiment, the risk of side effects is lowered compared to conventionai
inhalabie corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 240 g/dose. In still another
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 200 gg/dose. In yet another
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 150 g/dose. In yet anther
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 125 pg/dose. In still yet another
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 100= g/dose. In yet still another
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 60 gg/dose. In still yet another
embodiment, the risk of side effects is lowered compared to conventional
inhalable corticosteroid therapies
wherein the corticosteroid is administered at nominal dosage of less than
about 50 g/dose. In some
embodiments, the corticosteroid is budesonide administered at nominal dosage
of less than about 250 g/dose.
In other embodiments, the corticosteroid is budesonide administered at nominal
dosage of less than about 125
g/dose. In still other embodiments, the corticosteroid is budesonide
administered at nominal dosage of about
120 g/dose. In yet other embodiments, the corticosteroid is budesonide
administered at nominal dosage of
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about 60 g/dose. In still yet other embodiments, the corticosteroid is
budesonide administered at nominal
dosage of about 40 g/dose.
[003131 The systems and methods described herein provide the delivery of an
aqueous inhalation mixture
comprising a corticosteroid and a solubility enhancer. In some embodiments,
suitable aqueous inhalation
mixtures comprising a corticosteroid include, but are not limited to,
solutions, dispersions, nano-dispersions,
emulsions, colloidal liquids, micelle or mixed micelle solutions, and
liposomal liquids. In one embodiment, the
aqueous inhalation mixture is a solution comprising a corticosteroid, such as
budesonide, and a solubility
enhancer. In another embodiment, the aqueous inhalation mixture is a mixed
micelle solution comprising a
corticosteroid, such as budesonide, and a solubility enhancer. In yet another
embodiment, the aqueous
inhalation mixture is a liposomal solution comprising a corticosteroid, such
as budesonide, and a solubility
enhancer.
[003141 In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
1003151 The systems and metbods described herein provide the delivery of an
aqueous inhalation mixture
comprising a corticosteroid, a solvent and a solubility enhancer. In some
embodiments, suitable aqueous
inhalation mixtures comprising a corticosteroid include, but are not limited
to, solutions, dispersions, nano-
dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions,
and liposomal liquids. In one
embodiment, the aqueous inhalation mixture is a solution comprising a
corticosteroid, such as budesonide, and a
solubility enhancer. In another embodiment, the aqueous inhalation mixture is
a mixed micelle solution
comprising a corticosteroid, such as budesonide, and a solubility enhancer. In
yet another embodiment, the
aqueous inhalation mixture is a liposomal solution comprising a
corticosteroid, such as budesonide, and a
solubility enhancer.
1003161 In some embodiments of the invention, inhalable compositions
comprising a corticosteroid do not
include nano-dispersions and/or nano-suspensions. In other embodiments,
inhalable compositions comprising a
corticosteroid do not include micelle, mixed-micelle liquids or liposomal
liquids. In still other embodiments,
inhalable compositions comprising a corticosteroid do not include nano-
dispersions and/or nano-suspensions,
micelle, mixed-micelle liquids or liposomal liquids. In other embodiments,
inhalable compositions, include but
are not limited to, solutions, emulsions, and colloidal liquids. In one
embodiment, the inhalable composition is
a solution comprising a corticosteroid, such as budesonide, and a solubility
enhancer. In another embodiment,
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the inhalable composition is an emulsion comprising a corticosteroid, such as
budesonide, and a solubility
enhancer.
(00317] In certain embodiments, the systems and methods described herein
comprise a solvent. In certain
embodiments, the solvent is selected from the group consisting of water,
water/ethanot mixture, aqueous
alcohol, propylene glycol, or aqueous organic solvent, or combinations
thereof. In certain embodiments, the
solvent comprises water. In preferred embodiments, the solvent is water.
[003181 In some embodiments of the systems and methods described herein, a
corticosteroid-containing
aqueous inhalation mixture is employed which further comprises a solubility
enhancer. In some embodiments,
the solubility enhancer can have a concentration (w/v) ranging from about
0.001% to about 25%. In other
embodiments, the solubility enhancer can have a concentration (w/v) ranging
from about 0.01% to about 20%.
In still other embodiments, the solubility enhancer can have a concentration
(w/v) ranging from about 0.1% to
about 15%. In yet other embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 1% to about 10%. In a preferred embodiment, the solubility enhancer can
have a concentration (w/v)
ranging from about 2% to about 10% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,
e.g. SBE7-,3-CD (Captisol ). In one embodiment, the solubility enhancer can
have a concentration '(w/v) of
about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative, e.g. SBE7-13-CD
(Captisol ). In another embodiment, the solubility enhancer can have a
concentration (w/v) of about 5% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative, e.g.
SBE7-J3-CD (Captisol ). In yet another
embodiment, the solubiiity enhancer can have a concentration (w(v) about 7%
when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative, e.g. SBE7-0-CD (Caprisol(D). In still
yet another embodiment, the
solubility enhancer can have a concentration (w/v) of about 10% when the
solubility enhancer is a cyclodextrin
or cyclodextrin derivative, e.g. SBE7-13-CD (CaptisolC37).
(003191 Chemical agents acting as solubility enhancers suitable for use in the
present invention include, but are
not limited to, propylene glycol, non-ionic surfactants, phospholipids,
cyclodextrins and derivatives thereof, and
surface modifiers and/or stabilizers. In other embodiments, solubility
enhancers refer to a formulation method
which provides enhanced solubility without a chemical agent acting as the
means to increase solubility, e.g. the
use of super critical fluid production methods to generate nanoparticles for
dispersion in a solvent.
[00320] Additional solubility enhancers are known in the art and are described
in, e.g., U.S. Patent Nos.
5,134,127, 5,145,684, 5,376,645, 6,241,969 and U.S. Pub. Appl. Nos.
2005/0244339 and 2005/0008707, each
of which is specifically incorporated by reference herein. In addition,
examples of suitable solubility enhancers
are described below.
(003211 Suitable cyclodextrins and derivatives for use in the present
invention are described in the art, for
example, Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent
Nos. 5,134,127, 5,376,645,
5,874,418, each of which is specifically incorporated by reference herein. In
some embodiments, suitable
cyclodextrins or cyclodextrin derivatives for use in the present invention
include, but are not limited to, cl-
cyclodextrins, 6-cyclodextrins, -)-cyclodextrins, SAE-CD derivatives (e.g.,
SBE-rx CD, SBE-)3-CD, SBE1-/3-
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CD, SBE4-/3-CD, SBE7-13-CD (Captisol ), and SBE-y-CD) (Cydex, Inc. Lenexa,
KS), hydroxyet'byl,
hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers,
their corresponding mixed
ethers and further mixed ethers with methyl or ethyl groups, such as
methylhydroxyethyl, ethyl-hydroxyethyl
and ethyl- hydroxypropyl ethers of a-, 6- and -y cyclodextrin; and the
maltosyl, glucosyl and maltotriosyl
derivatives of c~-, 13- and -y-cyclodextrin, which may contain one or more
sugar residues, e. g. glucosyl or
diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e. g.
a mixture of maltosyl and
dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein
include hydroxypropyl-(J-cyclodextrin,
hydroxyethyl-p-cyclodextrin, hydroxypropyl--y-cyclodextrin, hydroxyethyl--~-
cyclodextrin, dihydroxypropyl-i'i-
cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-f3-cyclodextrin, diglucosyl-
f.i-cyclodextrin, maltosyl-a-
cyclodextrin, maltosyl-fl-cyclodextrin, maltosyl-y~cyclodextrin, maltotriosyl-
/3-cyclodextrin, maltotriosyl--y-
cyclodextrin, dimaltosyl-,6-cyclodextrin, diethyl-0-cyclodextrin, glucosyl-cx-
cyclodextrin, glucosyl-0-
cyclodextrin, diglucosyl-13-cyclodextrin, tri-O-methyl-Q-cyclodextrin, tri-O-
ethyl-;Q-cyclodextrin, tri-O-butyryl-
fl-cyclodextrin, tri-O-valeryl-13-cyclodextrin, and di-O-hexanoyl-fl-
cyclodextrin, as well as methyl-g-
cyclodextrin, and mixtures thereof such as maltosyl-13-cyclodextrin/dimaltosyl-
/3-cyclodextrin. Procedures for
preparing such cyclodextrin derivatives are well-known, for example, from U.S.
Patent No. 5,024,998, and
references incorporated by reference therein. Other cyclodextrins suitable for
use in the present invention
include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969
by ORGANON (AKZO-
NOBEL), hydroxybutenyl ether derivatives by EASTMAN, sulfoalkyl-hydroxyalkyl
ether derivatives,
sulfoalkyl-alkyl ether derivatives, and other derivatives, for example as
described in U.S. Pateni Application
Nos. 2002/0128468, 2004/0106575, 2004/0109888, and 200410063663, or U.S.
Patents Nos. 6,610,671,
6,479,467, 6,660,804, or 6,509,323, each of which is specifically incorporated
by reference herein.
1003221 Hydroxypropyl-,Q-cyclodextrin can be obtained from Research
Diagnostics Inc. (Flanders, NJ).
Exemplary hydroxypropyl-13-cyclodextrin products include Encapsin (degree of
substitution -4) and
Molecusol (degree of substitution -8); however, embodiments including other
degrees of substitution are also
available and are within the scope of the present invention.
[003231 Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or
Wacker (Iowa). Other
derivatized cyclodextrins suitable for use in the invention include water
soluble derivatized cyclodextrins.
Exemplary water-soluble derivatized cyclodextrins include carboxylated
derivatives; sulfated derivatives;
alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives;
and carboxy-(.i-cyclodextrins, e. g.,
succinyl-(3- cyclodextrin (SCD). All of these materials can be made according
to methods known in the art
and/or are available commercially. Suitable derivatized cyclodextrins are
disclosed in Modified Cyclodextrins:
Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J.
Easton, Stephen F. Lincoln,
Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and
Derivatives (Ed. Dominique
Duchene, Editions de Sante, Paris, France, 1991).
(00324) Examples of non-ionic surfactants -which appear to have a particularly
good physiological
compatibility for use in the present invention are tyloxapol, polysorbates
including, but not limited to,
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polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan
monopalmitate, polyoxyethylene
(20) sorbitan monostearate (available under the tradename Tweens 20-40-60,
etc.), Polysorbate 80,
Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan
palmitate, sorbitan stearate (available
under the tradename Span 20-40-60 etc.), benzalkonium chloride, PPO-PEO block
copolymers (Pluronics),
Cremophor-EL, vitamin E-TPGS (e.g., d-alpha-tocopheryl-polyethyleneglycol-1000-
succinate), Solutol-HS-15,
oleic acid PEO esters, stearic acid PEO esters, Triton-X100, Nonidet P-40, and
macrogol hydroxystearates such
as macrogol- I 5-hydroxystearate.
1003251 In some embodiments, the non-ionic surfactants suitable for use in the
present invention are formulated
with the corticosteroid to form liposome preparations, micelles or mixed
micelles. Methods for the preparations
and characterization of liposomes and liposome preparations are known in the
art. Often, multi-lamellar
vesicles will form spontaneously when amphiphilic lipids are 1-ydrated,
whereas the formation of small uni-
lamellar vesicles usually requires a process involving substantial energy
input, such as ultrasonication or high
pressure homogenization. Further methods for preparing and characterizing
liposomes have been described, for
example, by S. Vemuri et al. (Preparation and characterization of liposomes as
therapeutic delivery systems: a
review. Pharm Acta Helv. 1995, 70(2):95-11 l) and U.S. Patent "Nos. 5,019,394,
5,192,228, 5,882,679,
6,656,497 each of which is specifically incorporated by reference herein.
1003261 In some cases, for example, micelles or mixed micelles may be formed
by the surfactants, in which
poorly soluble active agents can be solubilized. In general, micelles are
understood as substantially spherical
structures formed by the spontaneous and dynamic association of amphiphilic
molecules, such as surfactants.
Mixed micelles are micelles composed of different types of amphiphilic
molecules. Both micelles and mixed
micelles should not be understood as solid particles, as their structure,
properties and behavior are much
different from solids. The amphiphilic molecules which form the micelles
usually associate temporarily. In a
micellar solution, there is a dynamic exchange of molecules between the
micelle-forming amphiphile and
monomolecularly dispersed amphiphiles which are also present in the solution.
The position of the drug
molecules which are solublized in such micelles or mixed micelles depends on
the structure of these molecules
as well as the surfactants used. For example, it is to be assumed that
particularly non-polar molecules are
localized mainly inside the colloidal structures, whereas polar substances are
more likely to be found on the
surface. In one embodiment of a micellar or mixed micellar solution, the
average size of the micelles may be
less than about 200 nm (as measured by photon correlation spectroscopy), such
as from about 10 nm to about
100 nm. Particularly preferred are micelles with average diameters of about 10
to about 50 nm. Methods of
producing micelles and mixed micelles are known in the art and described in,
for example, U.S. Patent Nos,
5,747,066 and 6,906,042, each of which is specifically incorporated by
reference herein.
(00327] Phospholipids are defined as amphiphile lipids which contain
phosphorus. Phospholipids which are
chemically derived from phosphatidic acid occur widely and are also commonly
used for pharmaceutical
purposes. This acid is a usually (doubly) acylated glycerol-3-phosphate in
which the fatty acid residues may be
of different length. The derivatives of phosphatidic acid include, for
example, the phosphocholines or
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phosphatidylcholines, in which the phosphate group is additionally esterified
with choline, furthermore
phosphatidyl ethanolamines, phosphatidyl inositols, etc. Lecithins are natural
mixtures of various
phospholipids which usually have a high propordon of phosphatidyl cholines.
Depending on the source of a
particular lecithin and its method of extraction and/or enrichment, these
mixtures may also comprise significant
amounts of sterols, fatty acids, tryglycerides and other substances.
[003281 Additional phospholipids which are suitable for delivery by inhalation
on account of their
physiological properties comprise, in particular, phospholipid mixtures which
are extracted in the form of
lecithin from natural sources such as soja beans (soy beans) or chickens egg
yolk, preferably in hydrogenated
form and/or freed from lysolecithins, as well as purified, enriched or
partially synthetically prepared
phopholipids, preferably with saturated fatty acid esters. Of the phospholipid
mixtures, lecithin is particularly
preferred. The enriched or partially synthetically prepared medium- to long-
chain zwitterionic phospholipids
are mainly free of unsaturations in the acyl chains and free of lysolecithins
and peroxides. Examples for
enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC),
distearoyl phosphatidyl choline
(DSPC) and dipalmitoyl phosphatidyl choline (DPPC). Of these, DMPC is
currently more preferred.
Alternatively, phospholipids with oleyl residues and phosphatidyl glycerol
without choline residue are suitable
for some embodiments and applications of the invention.
[003291 ln some embodiments, the non-ionic surfactants and phospholipids
suitable for use in the present
invention are formulated with the corticosteroid to form colloidal structures.
Colloidal solutions are defined as
mono-phasic systems wherein the colloidal material dispersed within the
colloidal solution does not have the
measurable physical properties usually associated with a solid material.
Methods of producing colloidal
dispersions are known in the art, for example as described in U.S. Patent No.
6,653,319, which is specifically
incorporated by reference herein.
[003301 Suitable surface modifiers for use in the present invention are
described in the art, for example, U.S.
Patent Nos. 5,145,684, 5,510,118, 5,565,188, and 6,264,922, each of which is
specifically incorporated by
reference herein. Examples of surface modifiers and/or surface stabilizers
suitable for use in the present
invention include, but are not limited to, hydroxypropyl methylcellulose,
hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin,
casein, lecithin (phosphatides),
dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium
chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan
esters, polyoxyethylene alkyl ethers
(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil
derivatives, polyoxyethylene
sorbitan fatty acid esters (e.g., the commercially available Tweens , e.g.,
Tween 20'& and Tween 80 (ICI
Specialty Chemicals)), polyethylene glycols (e.g., Carbowaxs 3550 and 934
(Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose
phthalate, noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA), 4-
(I,I,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde
(also known as tyloxapol,
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superione, and triton), poloxamers (e.g., Pluronics F68 and F108'o, which are
block copolymers of ethylene
oxide and propylene oxide), poloxamines (e.g., Tetronic 9080, also known as
Poloxamine 908 , which is a
tetrafunctional block copolymer derived from sequential addition of propylene
oxide and ethylene oxide to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)), Tetronic 1508
(T-1508) (BASF
Wyandotte Corporation), Tritons X-200 , which is an alkyl aryl polyether
sulfonate (Rohm and Haas),
Crodestas F-100 , which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.), p-
isononylphenoxypoly-(glycidol), also known as Olin-lOG or Surfactant 10
(Olin Chemicals, Stamford,
Conn.), Crodestas SL-40® (Croda, Inc.), and SA9OHCO, which is Cj8H37CH2(-
CON(CH3)--
CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.), decanoyl-N-methylglucamide, n-decyl-,Q-
D-glucopyranoside, n-
decyl-,6-D-maltopyranoside, n-dodecyl (J-D-glucopyranoside, n-dodecyl-(3-D-
maltoside, heptanoyl-N-
methylglucamide, n-heptyl-/3-D-glucopyranoside, n-heptyl-(3-D-thioglucoside, n-
hexyl-(3-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-)3-D-glucopyranoside, octanoyl-N-
methylglucamide, n-octyl-/3-D-
glucopyranoside, octyl /3-D-thioglucopyranoside, PEG-phospholipid, PEG-
cholesterol, PEG-cholesterol
derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl
pyrrolidone and vinyl
acetate, and the like. (e.g. hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone,
copolymers of viny) acetate, vinyl pyrrolidone, sodium lauryl sulfate and
dioctyl sodium sulfosuccinate).
[003311 Other useful cationic stabilizers include, but are not limited to,
cationic lipids, sulfonium,
phosphonium, and quarternary ammonium compounds, such as
stearyltrimethylammonium chloride, benzyl-
di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or
bromide, coconut methyl
dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride,
decyl dimethyl
hydroxyethyl ammonium chloride or bromide, C1Z.15 dimethyl hydroxyethyl
ammonium chloride or bromide,
coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl
ammonium methyl sulphate,
lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl
(ethenoxy)4 ammonium chloride or
bromide, N-alkyl (C12_18) dimethylbenzyl ammonium chloride, N-alkyl
(C,4.18)dimethyl-benzyl ammonium
chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride,
N-alkyl and (C1Z_14) dimethyl 1-napthylmethyl ammonium chloride,
trimethylammonium halide, alkyl-
trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl
ammonium chloride,
ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt,
dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride,
N-
tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C,2.14)
dimethyl 1-naphthylmethyl
ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl
benzenealkyl ammonium
chtoride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium
chloride, alkyl benzyl dimethyl
ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl
triethyl ammonium chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides,
alkyldimethylammonium halogenides, tricety) methyl ammonium chloride,
decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl
trioctylammonium chloride
(ALIQUAT 336 ), POLYQUAT 10 , tetrabutylammonium bromide, benzyl
trimethylammonium bromide,
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choline esters (such as choline esters of fatty acids), benzalkonium chloride,
stearalkonium chloride compounds
(such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl
pyridinium bromide or chloride,
halide salts of quaternized polyoxyethylalkylamines, Mirapol and ALKAQUAT
(Alkaril Chemical
Company), alkyl pyridinium salts, amines, such as alkylamines, dialkylamines,
alkanolamines,
polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine,
amine salts, such as lauryl amine
acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium
salt, and amine oxides, imide
azolinium salts, protonated quaternary acrylamides, methylated quaternary
polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride], and
cationic guar.
1003321 ln addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No.
2003/0091513, each of which is specifically
incorporated by reference herein. These methods permit the formation of micron
and sub-micron sized particles
with differing morphologies depending on the method and parameters selected.
In addition, these nanoparticles
can be fabricated by spray drying, lyophilization, volume exclusion, and any
other conventional methods of
particie reduction.
[003331 Furthermore, the processes for producing nanometer sized particles,
including SCF, can permit
selection of a desired morphology (e.g., amorphous, crystalline, resolved
racernic) by appropriate adjustment of
the conditions for particle formation during precipitation or condensation. As
a consequence of selection of the
desired particle'form, extended release of the selected medicament can be
achieved. These particle fabrication
processes are used to obtain nanoparticulates that have high purity, low
surface imperfections, low surface
charges and low sedimentation rates. Such particle features inhibit particle
cohesion, agglomeration and also
prevent settling in liquid dispersions. Additionally, because processes such
as SCF can separate isomers of
certain medicaments, such separation could contribute to the medicament's
enhanced activity, effectiveness as
well as extreme dose reduction. In some instances, isomer separation also
contributes to reduced side effects.
In accordance with the present methods and systems, an aqueous inhalation
mixture can be a composition
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fabricated into a powdered form by any process including SCF, spray drying,
precipitation and volume
exclusion, directly into a collection media, wherein the particulate compound
is thus automatically generated
into a dispersed formulation. In some embodiments, this formulation can be the
final formulation.
[00334] In some embodiments of this invention, the solubility enhancer is a
chemical agent selected from the
group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl'phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-Q-CD, SBEI-/3-CD, SBE4-0-CD, SBE7-,B-CD (CaptisolC), SBE--t-CD,
dimethyl fl-CD,
hydroxypropyl-0-cyclodextrin, 2-HP-13-CD, hydroxyethyl-a-cyclodextrin,
hydroxypropyl-,rcyclodextrin,
hydroxyethyl--y-cyclodextrin, dihydroxypropyl-i3-cyclodextrin, glucosyl-cx
cyclodextrin, glucosyl-E3-
cyclodextrin, diglucosyl-,(i-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-
/3-cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-,6-cyclodextrin, maltotriosyl--y-cyclodextrin,
dimaltosyl-f3-cyclodextrin, methyl-/3-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-13-CD (Captisol(p).
1003351 In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-,6-CD, SBEI-0-CD, SBE4-0-CD, SBE7-0-CD (Captisolg)), SBE-yCD,
dimethyl 13-CD,
hydroxypropyl-(3-cyclodextrin, 2-HP-fl-CD, hydroxyethyl-f3-cyclodextrin,
hydroxypropyl--f-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-;fi-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-,Q-
cyclodextrin, diglucosyl-0-cyalodextrin, maltosyl-a-cyclodextrin, maltosyl-R-
cyclodextrin, maltosyl-ry-
cyclodextrin, maltotriosyl-0-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-/3-cyclodextrin, methyl-fl-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-/3-CD
(Captisol(l).
[00336] ' Any known inhalation nebulizer is suitable for use in the presently
described invention. Such
nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating
membrane nebulizers, nebulizers with a
vibrating mesh or plate with multiple apertures, and nebulizers comprising a
vibration generator and an aqueous
chamber (e.g., Pari eFlow). Commercially available air driven jet, ultrasonic
or pulsating membrane
nebulizers suitable for use in the present invention include the Aeroneb ,
Aeroneb GO (Aerogen, San
Francisco, CA), Pari LC PLUS(O, Pari Boy N and Pari Duraneb (PARI
Respiratory Equipment, Inc.,
Monterey, CA), MicroAir (Omron Healthcare, Inc, Vemon Hills, Illinois),
Halolite (Profile Therapeutics Inc,
Boston, MA), Respimat (Boehringer Ingelheim Ingelheim, Germany), Aerodose
(Aerogen, Inc, Mountain
View, CA), Omron Elite (Omron Healthcare, Inc, Vernon Hills, Illinois), Omron
Microair (Omron
Healthcare, Inc, Vemon Hills, Illinois), Mabismist Il (Mabis Healthcare, Inc,
Lake Forest, Illinois),
Lumiscope 6610, (The Lumiscope Company, Inc, East Brunswick, New Jersey),
Airsep Mystique , (AirSep
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Corporation, Buffalo, NY), Acorn-I and Acom-II (Vital Signs, Inc, Totowa, New
Jersey), Aquatower
(Medical Industries America, Adel, Iowa), Ava-Neb (Hudson Respiratory Care
Incorporated, Temecula,
California), Cirrus (intersurgical Incorporated, Liverpool, New York), Dart
(Professional Medical Products,
Greenwood, South Carolina), Devilbiss Pulmo Aide (DeVilbiss Corp. Somerset,
Pennsylvania), Downdraf&
(Marquest, Englewood, Colorado), Fan Jet (Marquest, Englewood, Colorado), MB-
5 (Mefar, Bovezzo, Italy),
Misty Neb (Baxter, Valencia, California), Salter 8900 (Salter Labs, Arvin,
California), Sidestream (Medic-
Aid, Sussex, UK), Updraft-Il (Hudson Respiratory Care ; Temecula, Califomia),
Whisper Jet (Marquest
Medical Products, Englewood, Colorado), Aiolos (Aiolos Medicnnsk Teknik,
Karlstad, Sweden), Inspiron
(Intertech Resources, Inc., Bannockbum, Illinois), Optimist (Unomedical Inc.
, McAllen, Texas), Prodomo ,
Spira (Respiratory Care Center, Hameenlinna, Finland), AERx (Aradigm
Corporation, Hayward, Catifornia),
Sonik LDI Nebulizer (Evit Labs, Sacramento, California), and Swirler W
Radioaerosol System (AMICI, Inc. ,
Spring City, PA).
(00337] Any of these and other known nebulizers can be used to deliver the
aqueous inhalation mixtures
described in the present invention. In some embodiments, the nebulizers are
available from, e.g., Pari GmbH
(Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne,
Vital Signs, Baxter, Allied
Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana,
Siemens, Aerogen, Mountain
Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby,
Warwickshire, UK), Bard Ltd.
(Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy),
Henleys Medical Supplies
(London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies
(Leies, UK), Medic-Aid Ltd. (West
Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK), and
many others.
1003381 Other nebulizers suitable for use in the methods and systems describe
herein include, but are not
limited to, jet nebulizers (optionally sold with compressors), ultrasonic
nebulizers, and others. Exemplary jet
nebulizers for use herein include Pari LC plus/ProNeb, Pari LC plus/ProNeb
Turbo, Pari LCPIus/Dura Neb
1000 & 2000 Pari LC plus/Walkhaler, Pari LC pius/Pari Master, Pari LC star,
Omron CompAir XL Portable
Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron compare Elite
Compressor Nebulizer
System (NE-C2 i and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star
nebulizer with Proneb Ultra
compressor, Pulomo- aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare
Passport, Inspiration Healthdyne 626,
Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, Acornll, Misty-Neb, Allied
aerosol, Schuco Home Care,
Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-
DraftIl, T Up-Draft, ISO-NEB,
Ava-Neb, Micro Mist, and PulmoMate.
f003391 Exemplary ultrasonic nebulizers for use herein include MicroAir,
UltraAir, Siemens Ultra Nebulizer
145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb,
5004 Desk Ultrasonic
Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana
Ultrasonic Nebulizer, Microstat
Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other
nebulizers for use herein include
5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb,
Lumineb I Piston Nebulizer
5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse
Breath Actuated Nebulizer.
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Exemplary nebulizers comprising a vibrating mesh or plate with multiple
apertures are described by R. Dhand,
(New Nebuliser Technolog)-Aerosol Generation by Using a Vibrating Mesh or
Plate with Multiple Apertures,
Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4) and Respiratory
Care, 47: 1406-1416 (2002), the
entire disclosure of each of which is hereby incorporated by reference.
1003401 Additional nebulizers suitable for use in the presently described
invention include nebulizers
comprising a vibration generator and an aqueous chamber. Such nebulizers are
sold commercially as, e.g., Pari
eFlowand are described in U.S. Patent Nos. 6,962,151, 5,518,179, 5,261,601,
and 5,152,456, each of which is
specifically incorporated by reference herein.
[00341) The parameters used in nebulization, such as flow rate, mesh membrane
size, aerosol inhalation
chamber size, mask size and materials, valves, and power source may be varied
in accordance with the
principles of the present invention to maximize their use with different types
and aqueous inhalation mixtures or
different types of corticosteroids.
[003421 In addition to the above cited nebulizers, atomizers are also suitable
for the systems and methods
described herein for the delivery of an aqueous inhalation solution comprising
a corticosteroid and a solubility
enhancer. Atomizers are known in the art and are described in, for example,
U.S. Patent Nos. 5,954,047,
6,026,808, 6,095,141 and 6,527,151, each of which is specifically incorporated
by reference.
[003431 In certain preferred embodiments, the methods and systems described
herein comprise a nebulizer
selected from the group consisting of a jet nebulizer, an ultrasonic
nebulizer, a pulsating membrane nebulizer, a
nebulizer comprising a vibrating mesh or plate with multiple apertures, or a
nebulizer comprising a vibration
generator and an aqueous chamber. In some embodiments of this invention, the
nebulizer is selected from the
group consisting of Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-
Updraft 11, Hudson Ava-Neb,
Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T-Updraft
Neb-U-Mist, Pari-Jet 1460,
and AeroTech with T-piece. In certain other embodiments, the nebulizer is a
Pari eFlow nebulizer.
[00344] In other aspects of the invention, the methods and systems described
herein can deliver an aqueous
inhalable mixture comprising a corticosteroid, e.g. budesonide, to a subject
in therapeutically effective amount
for the treatment of a subject that has had or is anticipating a
bronchoconstrictive disorder selected from the
group consisting of asthma, pediatric asthma, bronchial asthma, allergic
asthma, intrinsic asthma, chronic
obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or a
combination of any of the above.
1003451 ln still other aspects of the invention, the methods and systems
described herein comprise an aqueous
inhalation mixture comprising a corticosteroid administered according to the
methods and systems described
herein not more than twice a day (b.i.d). In still another aspect, the aqueous
inhalation mixture comprises a
corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is
administered according to the
methods and systems described herein twice a day. In yet another aspect, the
aqueous inhalation mixture
comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation
mixture is administered
according to the methods and systems described herein not more than once a
day. In still yet another aspect, the
aqueous inhalation mixture comprises a corticosteroid, such as budesonide,
wherein the aqueous inhalation
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mixture is administered according to the methods and systems described herein
once a day. In still another
embodiment, the aqueous inhalation mixture comprises a corticosteroid, such as
budesonide, wherein the
aqueous inhalation mixture is administered according to the methods and
systems described herein not more
than once a day in the evening.
[00346] In other embodiments, the methods and systems described herein can
further include administering
aqueous inhalation mixtures comprising a corticosteroid in combination with
one or more active agents. In
some embodiments, the corticosteroid, e.g., budesonide, can be administered in
combination with one or more
other drugs one or more active agents selected from the group consisting of;
(a) a B2-adrenoreceptor agonist;
(b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as
a steroid; (d) a topical anesthetic;
or (e) an anti-cholinergic agent; either simultaneously with, prior to or
subsequent to the inhalable composition
provided herein.
[003471 In another aspect of the present invention, the systems and methods
described herein can provide a
more efficient dose by weight of a corticosteroid. In some embodiments, a
significantly greater amount of the
corticosteroid dose by weight provided in an aqueous inhalation mixture
according to the systems and methods
described herein can be absorbed into the bloodstream of a patient as compared
to conventional inhalable
corticosteroid therapies. In certain embodiments, the systems and methods
described herein can deliver an
inhalation mixture comprising budesonide and a solubility enhancer wherein
greater than greater than about
55%; or greater than about 50%; or greater than about 45%; or greater than
about 40%; or greater than about
35%; or greater than about 30%; or greater than about 25%; or greater than
about 20% of the budesonide dosed
by weight is absorbed into the bloodstream.
1003481 In still other embodiments, the methods and systems of the present
invention can deliver a
therapeutically effective amount of a corticosteroid in a significantly
shorter period of time than conventional
inhalable corticosteroid therapies. For example, the nebulization time for
Pulmicort Respules administered by
a Pari LC Plus jet nebulizer takes at least S minutes to 8 minutes, and in
some cases in excess of 10 minutes. By
contrast, the methods and systems of the present invention can deliver a
therapeutically effective amount of a
corticosteroid, such as a budesonide, over a delivery time of less than about
5 minutes to less than about 1.5
minutes. In some embodiments, the delivery time can be about 5 minutes. In
other embodiments, the delivery
time can be less than about 5 minutes. In certain embodiments, the delivery
time can be about 4.5 minutes. In
certain other embodiments, the delivery time can be less than about 4.5
minutes. In still other embodiments, the
delivery time can be about 4 minutes. In yet other embodiments, the delivery
time can be less than about 4
minutes. In still yet other embodiments, the delivery time can be about 3.5
minutes. In other embodiments, the
delivery time can be less than about 3.5 minutes. In yet still other
embodiments, the delivery time can be about
3 minutes. In other embodiments, the delivery time can be less than about 3
minutes. In certain embodiments,
the delivery time can be about 2.5 minutes. In other certain embodiments, the
delivery time can be less than
about 2.5 minutes. In still other embodiments, the delivery time can be about
2 minutes. In yet still other
embodiments, the delivery time can be less than about 2 minutes. In a
preferred embodiment, the delivery time
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can be about 1.5 minutes. In a more preferred embodiment, the delivery time
can be less than about 1.5
minutes.
[003491 In other embodiments, the methods and systems of the present invention
can deliver substantially all of
the nominal dosage of a corticosteroid in a significantly shorter period of
time than conventional inhalable
corticosteroid therapies. For example, the nebulization time for PulmicortO
Respules administered by a Pari LC
Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in
excess of 10 minutes. By contrast,
the methods and systems of the present invention can deliver an nominal dosage
of a corticosteroid, such as a
budesonide, over a delivery time of less than about 5 minutes to less than
about 1.5 minutes. In some
embodiments, substantially all of the nominal dosage can be delivered in about
5 minutes. In other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 5 minutes. In certain
embodiments, substantially all of the nominal dosage can be delivered in about
4.5 minutes. In certain other
embodiments, substantially all of the nominal dosage can be delivered in than
about 4.5 minutes. In still other
embodiments, substantially all of the nominal dosage can be delivered in about
4 minutes. In yet other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 4 minutes. In still yet
other embodiments, substantially all of the nominal dosage can be delivered in
about 3.5 minutes. In other
embodiments, substantially all of the nominal dosage can be delivered than
about 3.5 minutes. In yet still other
embodiments, substantially all of the nominal dosage can be delivered in about
3 minutes. In other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 3 minutes. In certain
embodiments, substantially all of the nominal dosage can be delivered in about
2.5 minutes. In other certain
embodiments, substantially all of the nominal dosage can be delivered in less
than about 2.5 minutes. In still
other embodiments, substantially all of the nominal dosage can be delivered
about 2 minutes. In yet still other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 2 minutes. In a
preferred embodiment, substantially all of the nominal dosage can be delivered
in about 1.5 minutes. In a more
preferred embodiment, substantially all of the nominal dosage can be delivered
in less than about 1.5 minutes.
[003501 In certain other embodirnents, the methods and systems of the present
invention can deliver a
therapeutically effective amount of a corticosteroid in a unit dose comprising
a smaller volume than
conventional inhalable corticosteroid therapies. For example, the systems and
methods of the present invention
can deliver a therapeutically effective amount of a coriicosteroid, such as a
budesonide, wherein the volume of
the aqueous inhalation mixture is from about 0.5 ml to less than 5 mis. In
some embodiments, the volume of
the aqueous inhalation mixture can about 3.5 mis. In other embodiments, the
volume of the aqueous inhalation
mixture can be about 3.0 mis. In still other embodiments, the volume of the
aqueous inhalation mixture can be
about 2.5 mis. In yet other embodiments, the volume of the aqueous inhalation
mixture can be about 2.0 mis.
In certain embodiments, the volume of the aqueous inhalation mixture can be
about 1.5 mis. In other certain
embodiments, the volume of the aqueous inhalation mixture can be about 1.0
mis. In a preferred embodiment,
the volume of the aqueous inhalation mixture can be about 0.5 mis.
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[003511 It is to be understood that the aspects of the methods and systems
described herein can comprise one or
more of any or all of the advantages provided by the present invention, and
additional embodiments are within
the scope of the invention. For example, the methods and systems described
herein can provide an aqueous
inhalation mixture comprising a corticosteroid in a nominal dosage of about 60
g/dose and a solubility
enhancer with a volume of the inhalation mixture of about 0.5 mis and an
inhalable nebulizer, wherein the
delivery of the aqueous mixture comprising the corticosteroid by the nebulizer
is less than about 2 minutes, and
wherein the delivery of the aqueous inhalation mixture comprising the
corticosteroid by the nebulizer results in
an enhanced pbarmacokinetic profile of the corticosteroid such that the
Cn,,,,, is equal to the Cn,ax of a inhalable
suspension comprising a corticosteroid when the aqueous inhalation mixture
comprising the corticosteroid at a
nominal dosage of less than about 100 g/dose is about 60% of the nominal
dosage of the inhalable suspension
comprising a corticosteroid. The above embodiment is merely an example of one
embodiment of the invention
that incorporates numerous aspects or variations of the invention, and in no
way is intended to limit the scope of
the invention.
A. Delivery of a Corticosteroid Displaying an Enhanced Pharmacokinetic Profile
[003521 The present invention can also provide a method or system for the
treatment or prophylaxis of a
bronchoconstrictive disorder in a patient comprising providing an aqueous
inhalation mixture comprising a
nominal dosage of a corticosteroid and a solubility enhancer and delivering
the aqueous inhalation mixture via
an inhalation nebulizer. In these embodiments, the methods can provide the
delivery of the corticosteroid
displaying an enhanced pharmacokinetic profile as compared to a suspension-
based corticosteroid formulation,
administered under the same conditions.
[003531 In certain embodiments, the methods and systenis of the present
invention, in certain embodiments,
can provide for treatment or prophylaxis of a bronchoconstrictive disorder in
a patient in need thereof
comprising (a) providing an aqueous inhalation mixture comprising a nominal
dosage of a corticosteroid and a
solubility enhancer and (b) delivering the aqueous inhalation mixture
comprising the corticosteroid with the
nebulizer, whereby the methods and systems provide at least a two-fold
enhanced pharmacokinetic profile of
the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid
as compared to the
pharmacokinetic profile of an inhalable suspension comprising a nominal dosage
of a corticosteroid, e.g.
Pulmicort Respulesadministered under the same conditions. In some embodiments,
the inhalable aqueous
mixtures can display substantially equivalent bioavailability for the
corticosteroid as compared to conventional
inhalable suspensions comprising a corticosteroid, while using significantly
lower nominal dosages. In other
embodiments, the inhalable aqueous mixtures can display increased
bioavailability of the corticosteroid as
compared to conventional inhalable suspensions comprising a corticosteroid
when delivered at the same
nominal dosage. In certain embodiments, the ratio of the nominal dosage of the
corticosteroid in the aqueous
inhalation mixture to the nominal dosage the corticosteroid in the inhalable
suspension is from about 0.01:1 to
about 1:100.
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1003541 In other embodiments, methods and systems of the present invention can
provide for treatment or
prophylaxis of a bronchoconstrictive disorder in a patient in need thereof
comprising (a) providing an aqueous
inhalation mixture comprising a nominal dosage of a single corticosteroid and
a solubility enhancer and (b)
delivering the aqueous inhalation mixture comprising the corticosteroid with
the nebulizer, whereby the
methods and systems provide at least a two-fold enhanced pharmacokinetic
profile of the aqueous inhalation
mixture comprising a nominal dosage of a corticosteroid as compared to the
pharmacokinetic profile of an
inhalable suspension comprising a nominal dosage of a corticosteroid, e.g.
Pulmicort Respules , administered
under the same conditions wherein the inhalation mixture is substantially free
of pharmaceutically active agents
other than the corticosteroid. In some embodiments, the inhalable aqueous
mixtures can display substantially
equivalent bioavailability for the corticosteroid as compared to conventional
inhalable suspensions comprising a
corticosteroid, while using significantly lower nominal dosages. In other
embodiments, the inhalable aqueous
mixtures can display increased bioavailability of the corticosteroid as
compared to conventional inhalable
suspensions comprising a corticosteroid when delivered at the same nominal
dosage. In certain embodiments,
the ratio of the nominal dosage of the corticosteroid in the aqueous
inhalation mixture to the nominal dosage the
corticosteroid in the inhalable suspension is from about 0.01:1 to about
1:100.
(00355] In certain embodiments, the aqueous inhalation mixture comprising a
corticosteroid delivered by the
methods described herein can have a Cm. greater.than the Cn,. of a suspension-
based corticosteroid formulation
administered at the same nominal dosage under the same conditions. In other
embodiments, the aqueous
inhalation mixture comprising a corticosteroid delivered by the methods
described herein can have an AUC(,as,)
greater than the AUC(iast) of a suspension-based corticosteroid formulation
administered at the same nominal
dosage under the same conditions. In still other embodiments, the aqueous
inhalation mixture comprising a
corticosteroid delivered by the method described herein can have an AUCt"
greater than the AUCt" of a
suspension-based corticosteroid formulation administered at the same nominal
dosage under the same
conditions. In yet other embodiments, the aqueous inhalation mixture
comprising a corticosteroid delivered by
the method described herein can have a T,,. less than the T,,,,,, of a
suspension-based corticosteroid formulation
administered under the same conditions.
(003561 In certain other embodiments, the aqueous inhalation mixture
comprising a corticosteroid delivered by
the methods described herein can have a C. equivalent to the Cmax of a
suspension-based corticosteroid
formulation wherein the nominal dosage of the aqueous inhalation mixture is
lower than the nominal dosage of
the suspension-based corticosteroid formulation administered under the same
conditions. In other
embodiments, the aqueous inhalation mixture comprising a corticosteroid
delivered by the methods described
herein can have an AUCt,asq equivalent to the AUCtusq of a suspension-based
corticosteroid formulation wherein
the nominal dosage of the aqueous inhalation mixture is lower than the nominal
dosage of the suspension-based
corticosteroid formulation administered under the same conditions. In still
other embodiments, the aqueous
inhalation mixture comprising a corticosteroid delivered by the method
described herein can have an AUC(o.,4
equivalent to the AUCto..4 of a suspension-based corticosteroid formulation
wherein the nominal dosage of the
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aqueous inhalation mixture is lower than the nominal dosage of the suspension-
based corticosteroid formulation
administered under the same conditions. In yet other embodiments, the aqueous
inhalation mixture comprising
a corticosteroid delivered by the method described herein can have a Tmax less
than the Tmax of a suspension-
based corticosteroid formulation wherein the nominal dosage of the aqueous
inhalation mixture is lower than
the nominal dosage of the suspension-based corticosteroid formulation
administered under the same conditions.
1003571 As previously stated, increased exposure to elevated blood plasma
levels of a corticosteroid can result
in undesirable side effects. Thus, lower doses of a corticosteroid which can
achieve the same or better
therapeutic effects as those observed with larger doses of conventional
inhalable corticosteroid therapies are
desired. Such lower doses can be realized with the methods and system
described herein as a result of the
greater bioavailability of the corticosteroid as compared to conventional
inhatable suspensions comprising a
corticosteroid. The methods and system described herein can deliver a
corticosteroid with an enhanced
pharmacokinetic profile of the aqueous inhalation mixture comprising a nominal
dosage of a corticosteroid as
compared to the pharmacokinetic profile of an inhalable suspension comprising
a nominal dosage of a
corticosteroid, e.g. Pulmicort Respules , administered under the same
conditions in a range of between at least
about 1.5 fold (150%) to about 10 fold (1000%) the specified therapeutic
parameter (e.g., AUC(o.,,t) to provide
an enhanced pharmacokinetic profile. In certain embodiments, the ratio of the
nominal dosage of the
corticosteroid in the aqueous inhalation mixture to the nominal dosage the
corticosteroid in the inhalable
suspension is from about 0.01:1 to about 1:100.
(003581 In other embodiments, the methods and system described herein can
deliver an aqueous inhalation
mixture comprising a nominal dosage of a corticosteroid with an enhanced
pharmacokinetic profile comprising
an equivalent bioavailability (e.g., equivalent AUC(") compared to
conventional inhalable suspensions
comprising a nominal dosage of a corticosteroid wherein the nominal dosage of
the corticosteroid in the
aqueous inhalation mixtures is in a range of between at least about 1:1.5 to
about 1:10 the nominal dose of the
corticosteroid in conventional inhalable suspension to provide an enhanced
pharmacokinetic profile (1.5 fold to
about 10 fold enhanced pharmacokinetic profile).
(00359) In certain embodiments, the methods and systems of the present
invention can provide for treatment or
prophylaxis of a bronchoconstrictive disorder in a patient in need thereof
comprising (a) providing an aqueous
inhalation mixture comprising a nominal dosage of a corticosteroid and a
solubility enhancer and (b) delivering
the aqueous inhalation rnixture comprising the corticosteroid with an
inhalation nebulizer, whereby the methods
and systems deliver about a 1.5 fold (150%) to about a 10 fold (1000%)
enhanced pharmacolCinetic profile of
the aqueous inhalation mixture comprising the nominal dosage of the
corticosteroid as compared to the
pharmacokinetic profile of an inhalable suspension comprising a nominal dosage
of a corticosteroid
administered under the same conditions. In other embodiments, the inhalation
mixture comprises a single
corticosteroid and is substantially free of any other pharmaceutically -active
agent other than the corticosteroid.
In one embodiment, the aqueous inhalation mixture comprising a nominal dosage
of a corticosteroid
administered by the systems and method described herein can deliver about a
1.5 fold (150%) and about a 9 fold
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(900%) an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a
nominal dosage of a corticosteroid administered under the same conditions. In
another embodiment, the
aqueous inhalation mixture comprising nominal dosage of a corticosteroid
administered by the systems and
method described herein can deliver about a 1.5 fold (150%) and about a 8 fold
(800%) have an enhanced
pharmacokinetic profile compared to conventional inhalable suspensions
comprising a nominal dosage of a
corticosteroid administered under the same conditions. In yet another
embodiment, the aqueous inhalation
mixture comprising a nominal dosage of a corticosteroid administered by the
systems and method described
herein can have an enhanced pharmacokinetic profile compared to conventional
inhalable suspensions
comprising nominal dosage of a corticosteroid in a range of between about a
1.5 fold (150%) and about a 7 fold
(700%) enhanced pharmacokinetic profile when administered under the same
conditions. In still another
embodiment, the aqueous inhalation mixture comprising a nominal dosage of a
corticosteroid administered by
the systems and method described herein can have an enhanced pharmacokinetic
profile compared to
conventional inhalable suspensions comprising a nominal dosage of
corticosteroid in a range of between about a
1.5 fold (150%) and about a 6 fold (600%) enhanced pharmacokinetic profile
when administered under the
same conditions. In one embodiment, the aqueous inhalation mixture comprising
a nominal dosage of a
corticosteroid administered by the systems and method described herein can
have an enhanced pharmacokinetic
profile compared to conventional inhalable suspensions comprising a nominal
dosage of a corticosteroid in a
range of between about a 1.5 fold (150%) and about a 5 fold (500%) enhanced
pharmacokinetic profile when
administered under the same conditions. In yet another embodiment, the aqueous
inhalation mixture
comprising a nominal dosage of a corticosteroid administered by the systems
and method described herein can
have an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a
nominal dosage of a corticosteroid in a range of between about a 1.5 fold
(150%) and about a 4 fold (400%)
enhanced pharmacokinetic profile when administered under the same conditions.
In still another embodiment,
the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid
administered by the systems
and method described herein can have an enhanced pharmacokinetic profile
compared to conventional inlialable
suspensions comprising a nominal dosage of a corticosteroid in a range of
between about a 1.5 fold (150%) and
about a 3 fold (300%) enhanced pharmacokinetic profile when administered under
the same conditions. In yet
still another embodiment, the aqueous inhalation mixture comprising a nominal
dosage of a corticosteroid
administered by the systems and method described herein can have an enhanced
pharmacokinetic profile
compared to conventional inhalable suspensions comprising a nominal dosage of
a corticosteroid in a range of
between about a 1.5 fold (150%) and about a 2 fold (200%) enhanced
pharmacokinetic profile when
administered under the same conditions. In one embodiment, the aqueous
inhalation mixture comprising a
nominal dosage of a corticosteroid administered by the systems and method
described herein can have an
enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a nominal
dosage of a corticosteroid of about 2 fold (200%) when administered under the
same conditions. In another
embodiment, the aqueous inhalation mixture comprising a nominal dosage of a
corticosteroid administered by
the systems and method described herein can have an enhanced pharmacokinetic
profile compared to
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conventional inhalable suspensions comprising a nominal dosage of a
corticosteroid of about 3 fold (300%)
when administered under the same conditions. In yet another embodiment, the
aqueous inhalation mixture
comprising a nominal dosage of a corticosteroid administered by the systems
and method described herein can
have an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a
nominal dosage of a corticosteroid of about 4 fold (400%) when administered
under the same conditions. In
still another embodiment, the aqueous inhalation mixture comprising a nominal
dosage of a corticosteroid
administered by the systems and method described herein can have an enhanced
pharmacokinetic profile
compared to conventional inhalable suspensions comprising a nominal dosage of
a corticosteroid of about 5
fold (500%) when administered under the same conditions. In yet still another
embodiment, the aqueous
inhalation mixture comprising a nominal dosage of a corticosteroid
administered by the systems and method
described herein can have an enhanced pharmacokinetic profile compared to
conventional inhalable suspensions
comprising a nominal dosage of a corticosteroid of about 6 fold (600%) when
administered under the same
conditions.
(003601 In certain other embodiments, an aqueous inhalation mixture comprising
a nominal dosage of
budesonide and a solubility enhancer is delivered by the systems and method
described herein and has an
enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a nominal
dosage of budesonide in a range of between at least about a 2 fold (200%) and
about a 6 fold (600%) enhanced
pharmacokinetic profile when administered under the same conditions. In one
embodiment, the aqueous
inhalation mixture comprising a nominal dosage of budesonide administered by
the systems and method
described herein can have an enhanced pharrnacokinetic profile compared to
conventional inhalable suspensions
comprising a nominal dosage of budesonide of about 2 fold (200%) when
administered under the same
conditions. In another embodiment, the aqueous inhalation mixture comprising a
nominal dosage of budesonide
administered by the systems and method described herein can have an enhanced
pharmaeokinetie profile
compared to conventional inhalable suspensions comprising a nominal dosage of
budesonide of about 3 fold
(300%) when administered under the same conditions. In yet another embodiment,
the aqueous inhalation
mixture comprising a nominal dosage of budesonide administered by the systems
and method described herein
can have an enhanced pharrriacokinetic profile compared to conventional
inhalable suspensions comprising a
nominal dosage of budesonide of about 4 fold (400%) when administered under
the same conditions. In still
another embodiment, the aqueous inhalation mixture comprising a nominal dosage
of budesonide administered
by the systems and method described herein can have an enhanced
pharmacokinetic profile compared to
conventional inhalable suspensions comprising a nominal dosage of budesonide
of about 5 fold (500%) when
administered under the same conditions. In yet still another embodiment, the
aqueous inhalation mixture
comprising a nominal dosage of budesonide administered by the systems and
method described herein can have
an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a nominal
dosage of budesonide of about 6 fold (600%) when administered under the same
conditions.
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[00361) Due to the enhanced pharmacokinetic profiles of corticosteroids
provided by the methods and systems
described herein, the present methods and systems for the treatment or
prophylaxis of a bronchoconstrictive
disorder in a patient in need thereof can deliver an aqueous inhalable mixture
comprising a corticosteroid with
the equivalent bioavailability as a inhalable suspension comprising of a
corticosteroid wherein the aqueous
inhalable mixture comprising a corticosteroid has a nominal dosage in a range
of between about 1:1.5 to about
1:10 the nominal dosage of the inhalable suspension comprising a
corticosteroid. In one embodiment, the
methods and systems of the present invention can provide for treatment or
prophylaxis of a bronchoconstrictive
disorder in a patient in need thereof comprising (1) providing an aqueous
inhalation mixture comprising a
corticosteroid and a solubility enhancer and (2) delivering the aqueous
inhalation mixture with a inhalation
nebulizer, wherein the delivery of the aqueous mixture comprising the
corticosteroid by the nebulizer can result
in equivalent bioavailability of the corticosteroid as compared to
conventional inhalable suspensions comprising
a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid is
about 1:1.5 to about 1:10 the nominal dosage of the inhalable suspension
comprising a corticosteroid. . In
another embodiment, the aqueous inhalation mixture comprising a corticosteroid
administered by the systems
and method described herein can have an enhanced pharmacokinetic profile
compared to conventional inhalable
suspensions comprising a corticosteroid wherein the nominal dosage of the
aqueous inhalation mixture
comprising a corticosteroid is about 1:1.5 to about 1:9 the nominal dosage of
the inhalable suspension
comprising a corticosteroid. In still another embodiment, the aqueous
inhalation mixture comprising a
corticosteroid administered by the systems and method described herein can
have an enhanced pharmacokinetic
profile compared to conventional inhalable suspensions comprising a
corticosteroid wherein the nominal dosage
of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5
to about 1:8 the nominal dosage of
the inhaiable suspension comprising a corticosteroid. In yet another
embodiment, the aqueous inhalation
mixture comprising a corticosteroid administered by the systems and method
described herein can have an
enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a corticosteroid
wherein the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid is about 1:1.5 to
about 1:7 the nominal dosage of the inhalable suspension comprising a
corticosteroid. In still another
embodiment, the aqueous inhalation mixture comprising a corticosteroid
administered by the systems and
method described herein can have an enhanced pharmacokinetic profile compared
to conventional inhalable
suspensions comprising a corticosteroid wherein the nominal dosage of the
aqueous inhalation mixture
comprising a corticosteroid is about 1:1.5 to about 1:6 the nominal dosage of
the inhalable suspension
comprising a corticosteroid. In one embodiment, the aqueous inhalation mixture
comprising a corticosteroid
administered by the systems and method described herein can have an enhanced
pharmacokinetic profile
compared to conventional inhalable suspensions comprising a corticosteroid
wherein the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 and
about 1:5 the nominal dosage of the
inhalable suspension comprising a corticosteroid. In yet another embodiment,
the aqueous inhalation mixture
comprising a corticosteroid administered by the systems and method described
herein can have an enhanced
pharmacokinetic profile compared to conventional inhalable suspensions
comprising a corticosteroid wherein
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the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid is about 1:1.5 to about 1:4 the
nominal dosage of the inhalable suspension comprising a corticosteroid. In
still another embodiment, the
aqueous inhalation mixture comprising a corticosteroid administered by the
systems and method described
herein can have an enhanced pharmacokinetic profile compared to conventional
inhalable suspensions
comprising a corticosteroid wherein the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid is about 1:1.5 to about 1:3 the nominal dosage of the inhalable
suspension comprising a
corticosteroid. In yet still another embodiment, the aqueous inhalation
mixture comprising a corticosteroid
administered by the systems and method described herein can have an enhanced
pharmacokinetic profile
compared to conventional inhalable suspensions comprising a corticosteroid
wherein the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 and
about 1:2 the nominal dosage of the
inhalable suspension comprising a corticosteroid.
[00362) In other embodiments, an aqueous inhalation mixture comprising a
corticosteroid and a solubility
enhancer is delivered by the systems and method described herein and has an
enhanced pharmacokinetic profile
compared to conventional inhalable suspensions comprising a corticosteroid
wherein the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid is about 1:2 to about
1:10 the nominal dosage of the
inhalable suspension comprising a corticosteroid In still other embodiments,
an aqueous inhalation mixture
comprising a corticosteroid and a solubility enhancer is delivered by the
systems and method described herein
and has an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a
corticosteroid wherein the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid is
about 1:2 to about I:5 the nominal dosage of the inhalable suspension
comprising a corticosteroid. In yet still
other embodiments, an aqueous inhalation mixture comprising a corticosteroid
and a solubility enhancer is
delivered by the systems and method described herein and has an enhanced
pharmacokinetic profile compared
to conventional inhalable suspensions comprising a corticosteroid wherein the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid is about 1:2 to about 1:4 the
nominal dosage of the inhalable
suspension comprising a corticosteroid. In still other embodiments, an aqueous
inhalation mixture comprising a
corticosteroid and a solubility enhancer is delivered by the systems and
method described herein and has an
enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising a corticosteroid
wherein the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid is about 1:4 the
nominal dosage of the inhalable suspension comprising a corticosteroid.
[00363] In certain other embodiments, an aqueous inhalation mixture comprising
budesonide and a solubility
enliancer is delivered by the systems and method described herein and has an
enhanced pharmacokinetic profile
compared to conventional inhalable suspensions comprising budesonide wherein
the nominal dosage of the
aqueous inhalation mixture is about 1:2 to about 1:10 the nominal dosage of
the inhalable suspension
comprising budesonide. In still other embodiments, an aqueous inhalation
mixture comprising budesonide and a
solubility enhancer is delivered by the systems and method described herein
and has an enhanced
pharmacokinetic profile compared to conventional inhalable suspensions
comprising budesonide wherein the
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nominal dosage of the aqueous inhalation mixture is about 1:2 to about 1:5 the
nominal dosage of the inhalable
suspension comprising budesonide. In yet still other embodiments, an aqueous
inhalation mixture comprising
budesonide and a solubility enhancer is delivered by the systems and method
described herein and has an
enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising budesonide
wherein the nominal dosage of the aqueous inhalation mixture is about 1:2 to
about 1:4 the nominal dosage of
the inhalable suspension comprising budesonide. In still other embodiments, an
aqueous inhalation mixture
comprising budesonide and a solubility enhancer is delivered by the systems
and method described herein and
has an enhanced pharmacokinetic profile compared to conventional inhalable
suspensions comprising
budesonide wherein the nominal dosage of the aqueous inhalation mixture is
about 1:4 the nominal dosage of
the inhalable suspension comprising budesonide.
1003641 In certain embodiments, the methods and systems of the present
invention can deliver a therapeutically
effective amount of a corticosteroid in a unit dose comprising a smaller
volume than conventional inhalable
corticosteroid therapies. For example, the systems and methods of the present
invention can deliver a
therapeutically effective amount of a corticosteroid, such as a budesonide,
wherein the volume of the aqueous
inhalation mixture is from about 0.5 ml to less than 5 mis. In some
embodiments, the volume of the aqueous
inhalation mixture can about 3.5 mis. In other embodiments, the volume of the
aqueous inhalation mixture can
be about 3.0 mis. In still other embodiments, the volume of the aqueous
inhalation mixture can be about 2.5
mis. In yet other embodiments, the volume of the aqueous inhalation mixture
can be about 2.0 mis. In certain
embodiments, the volume of the aqueous inhalation mixture can be about 1.5
mis. In other certain
embodiments, the volume o~the aqueous inhalation mixture can be about 1.0 mis.
In a preferred embodiment,
the volume of the aqueous inhalation mixture can be about 0.5 m1s:
[00365] in still other embodiments, the methods and systems of the present
invention can deliver a
therapeutically effective amount of a corticosteroid in a significantly
shorter period of time than conventional
inhalable corticosteroid therapies. For example, the nebulization time for
PulmicortO Respules administered by
a Pari LC Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in
some cases in excess of 10 minutes. By
contrast, the methods and systems of the present invention can deliver a
therapeutically effective amount of a
corticosteroid, such as a budesonide, over a delivery time of less than about
5 minutes to less than about 1.5
minutes. In some embodiments, the delivery time can be about 5 minutes. In
other embodiments, the delivery
time can be less than about 5 minutes. In certain embodiments, the delivery
time can be about 4.5 minutes. In
certain other embodiments, the delivery time can be less than about 4.5
minutes. In still other embodiments, the
delivery time can be about 4 minutes. In yet other embodiments, the delivery
time can be less than about 4
minutes. In still yet other embodiments, the delivery time can be about 3.5
minutes. In other embodiments, the
delivery time can be less than about 3.5 minutes. In yet still other
embodiments, the delivery time can be about
3 minutes. In other embodiments, the delivery time can be less than about 3
minutes. In certain embodiments,
the delivery time can be about 2.5 minutes. In other certain embodiments, the
delivery time can be less than
about 2.5 minutes. In still other embodiments, the delivery time can be about
2 minutes. In yet still other
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embodiments, the delivery time can be less than about 2 minutes. In a
preferred embodiment, the delivery time
can be about 1.5 minutes. In a more preferred embodiment, the delivery time
can be less than about 1.5
minutes.
E003661 In other embodiments, the methods and systems of the present invention
can deliver substantially all of
the nominal dosage of a corticosteroid in a significantly shorter period of
time than conventional inhalable
corticosteroid therapies. For example, the nebulization time for Pulmicort
Respules administered by a Pari LC
Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in
excess of 10 minutes. By contrast,
the methods and systems of the present invention can deliver substantially all
of the nominal dosage of a
corticosteroid, such as a budesonide, over a delivery time of less than about
5 minutes to less than about 1.5
minutes. In some embodiments, substantially all of the nominal dosage cati be
delivered in about 5 minutes. In
other embodiments, substantially all of the nominal dosage can be delivered in
less than about 5 minutes. In
certain embodiments, substantially all of the nominal dosage can be delivered
in about 4.5 minutes. In certain
other embodiments, substantially all of the nominal dosage can be delivered in
than about 4.5 minutes. In still
other embodiments, substantially all of the nominal. dosage can be delivered
in about 4 minutes. In yet other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 4 minutes. In still yet
other embodiments, substantially all of the nominal dosage can be delivered in
about 3.5 minutes. In other
embodiments, substantially all of the nominal dosage can'be delivered than
about 3.5 minutes. In yet still other
embodiments, substantially all of the nominal dosage can be delivered in about
3 minutes. In other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 3 minutes. In certain
embodiments, substantially all of the nominal dosage can be delivered in about
2.5 minutes. In other certain
embodiments, substantially all of the nominal dosage can be delivered in less
than about 2.5 minutes. In still
other embodiments, substantially all of the nominal dosage can be delivered
about 2 minutes. In yet still other
embodiments, substantially all of the nominal dosage can be delivered in less
than about 2 minutes. In a
preferred embodiment, substantially all of the nominal dosage can be delivered
in about 1.5 minutes. In a more
preferred embodiment, substantially all of the nominal dosage can be delivered
in less than about 1.5 minutes.
B. Cmax Blood Plasma Values
100367] The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein can deliver an inhalation mixture
comprising corticosteroid to the
subject in a manner wherein the active is delivered having an increased C~,,ax
blood plasma value of the
corticosteroid as compared to conventional inhalable corticosteroid
suspensions administered under the same
conditions. In one example, conventional budesonide suspensions administered
in a single dose using a Pari LC
Plusojet nebulizer in a 2.0 ml volume with an administration time of about 5
minutes display pharmacokinetic
profiles such that the Cm,,., blood plasma values ranges from about 556 zE 193
(pg/ml) to about 1114 593
(pg/ml) with nominal dosages of 500 gg to 1000 g, respectively. Using the
systems and methods described
herein, budesonide + SBE7-j3-CD inhalation solutions having nominal dosages of
60 g, 120 g, and 240 g
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delivered in a single dose using a Pari eFlow Inhaler in a 0.5 ml volume with
a delivery time of about 1.5
minutes had Cmax blood plasma values of about 227 1 89 (pg/ml), about 578
238 (pg/mi), and 1195 811
(pg/ml), respectively. FIG. 4 provides a graphic representation of the data
used to generate the aforementioned
Cm. blood plasma values.
[003681 In a second example, conventional budesonide suspensions (Pulmicort
RespulesF) administered twice
daily for seven days using a Pari LC Plus jet nebulizer in a 2.0 ml volume
with an administration time of about
4 minutes displayed pharmacokinetic profiles having mean C,,,,,, blood plasma
values of 319.6 :1: 185 pg/ml and
about 491.4 207 pg/ml with nominal dosages of 250 g and 500 g,
respectively. The same 250 g and 500
g Pulmicort Respules inhalation suspensions had geometric mean values for Cm.
blood plasma of 270.5
pg/mi and 451.6 pg/ml, respectively. Using the systems and methods described
herein, a 60 g CBIS inhalation
solution delivered twice daily for seven days using a Pari eFlow Inhaler in a
0.5 ml volume with a delivery
time of about 1.5 minutes had a minimum Cmax blood plasma value of about 186.4
pg/ml, a maximum C,,.
blood plasma value of about 779.4 pg/ml, and geometric mean C,,,a, values of
about 362.2 pg/ml. Likewise, a
120 g CBIS inhalation solution delivered twice daily for seven days using a
Pari eFlow Inhaler in a 0.5 ml
volume with a delivery time of about 1.5 minutes had a minimum Cmax blood
plasma value of about 169.8
pg/mi, a maximum Cma, blood plasma value of about 1160.4 pg/ml, and geometric
mean Cmax values of about
516.9 pg/ml. FIG. 5provides a graphic representation of the data upon which
the aforementioned Cm.. blood
plasma values were based.
1003691 Thus, the methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof provide the delivery of an inhalation mixture
comprising a nominal dosage of a
corticosteroid having an enhanced pharmacokinetic profile as compared to
conventional inhalable corticosteroid
suspensions comprising a nominal dosage of a corticosteroid administered under
the same conditions. More
specifically, in certain embodiments, the systems and methods described herein
provide at least about 1.5 fold
to about 14 fold increase in C,,... blood plasma values (as determined on an
individual basis) for a corticosteroid
normalized for dose of corticosteroid per microgram of corticosteroid
administered, as compared to
conventional inhalable corticosteroid therapies administered under the same
conditions. In certain
embodiments, the systems and methods described herein provide at least about
1.5 fold to about 13 fold, about
1.5 fold to about 12 fold, about 1.5 fold to about 10 fold, about 1.5 fold to
about 8 fold, about 1.5 fold to about
7.5 fold, about 1.5 fold to about 7 fold, about 1.5 fold to about 6.5 fold,
about 1.5 fold to about 6.25 fold, about
1.5 fold to about 6 fold, about 1.5 fold to about 5.75 fold, about 1.5 fold to
about 5.5 fold, about 1.5 fold to
about 5 fold, about 1.5 fold to about 4.75 fold, about 1.5 fold to about 4.5 -
fold, about 1.5 fold to about 4 fold
increase in Cma,, blood ptasma values (as determined on an individual basis)
for a corticosteroid normalized for
dose of corticosteroid per microgram of corticosteroid administered, as
compared to conventional inhalable
corticosteroid therapies administered under the same condition.
(003701 In other embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof described herein
provide at least a about 4 fold to about
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a 7 fold increase in Cmax blood plasma values for a corticosteroid taken
across a studied patient population,
normalized for dose of corticosteroid per microgram of corticosteroid
administered, as compared to
conventional inhalable corticosteroid therapies administered under the same
conditions, for example as
determined using the geometric mean across a studied patient population. In
certain embodiments, the systems
and methods described herein provide at least about 4 fold to about 7 fold,
about 4 fold to about 6.5 fold, about
4 fold to about 6.25 fold, about 4 fold to about 6 fold, about 4 fold to about
5.75 fold, about 4 fold to about 5.5
fold, about 4 fold to about 5 fold, about 5 fold to about 7 fold, about 5.5
fold to about 7 fold, about 6 fold to
about 7 fold increase in Cmax blood plasma values for a corticosteroid taken
across a studied patient population,
normalized for dose of corticosteroid per microgram of corticosteroid
administered, as compared to
conventional inhalable corticosteroid therapies administered under the same
conditions.
1003711 In some embodiments, the C,,,aY can be significantly greater than the
Cma.' blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid
administered at the same nominal
dosage under the same conditions. In certain embodiments, the C. can be from
about 1.5 fold (150%) to about
14 fold (1400%) the C,,,ax blood plasma values exhibited by conventional
inhalable suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In other
embodiments, the C,,. can be
from about 1.5 fold (150%) to about 12 fold (1200%) the Cmax blood plasma
values exhibited by conventional
inhalable suspensions comprising a corticosteroid at the same nominal dosage
under the same conditions. In
still other embodiments, the C,,,,,, can be from about 1.5 fold (150%) to
about 10 fold (1000%) the C,,,.. blood
plasma values exhibited by conventional inhalable suspensions comprising a
corticosteroid at the same noniinal
dosage under the same conditions. In one embodiment, the Cmax can be at least
about 12 fold (1200%) the C,,,a,
blood plasma values exhibited by conventional inhalable suspensions comprising
a corticosteroid at the same
nominal dosage under the same conditions. In cettain other embodiments, the
Cmax can be at least about 1000%
(10 fold) to about 1200% (12 fold) , about 1100 fo (11 fold) to about 1200%
(12 fold), or about 1150% (11.5
fold) to about 1200% (12 fold) greater than the Cmax blood plasma values
exhibited by conventional inhalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. In other
embodiments, the enhanced pharmacokinetic profile comprises a Cm. for the
aqueous inhalation mixture that is
greater than the Cm,, of the inhalable suspension comprising a corticosteroid,
administered at the same nominal
dosage under the same conditions. In one embodiment, the Cmax can be at least
about 1000% (10 fold) greater
than the Cma, blood plasma values exhibited by conventional inhalable
suspensions comprising a corticosteroid
at the same nominal dosage under the same conditions. In certain other
embodiments, the Cmax can be at least
about 900% (9 fold) to about 1000% (10 fold), about 925% (9.25 fold) to about
1000% (10 fold), or about
950% (9.5 fold) to about 1000% (10 fold) greater than the Cmax blood plasma
values exhibited by conventional
inhalable suspensions comprising a corticosteroid at the same nominal dosage
under the same conditions. In
another embodiment, the Cmax can be at least about 900% (9 fold) greater than
the C,,. blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid at
the same nominal dosage under
the same conditions. In certain other embodiments, the Cmax can be at least
about 800% (8 fold) to about 900%
(9 fold) , about 825% (8.25 fold) to about 900% (9 fold), or about 850% (8.5
fold) to about 900% (9 fold)
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greater than the Cm,,, blood plasma values exhibited by conventional inhalable
suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In still
another embodiment, the Cma" can
be at least about 800% (8 fold) greater than the Cm. blood plasma values
exhibited by conventional inhalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. ln certain other
embodiments, the Cmaõ can be at least about 700% (7 fold) to about 800% (8
fold) , about 725% (7.25 fold) to
about 800% (8 fold), or about 750% (7.5 fold) to about 800% (8 fold) greater
than the Cmaõ blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid at
the same nominal dosage under
the same conditions. In still yet another embodiment, the Cmaõ can be at least
about 700% (7 fold) greater than
the C,,,ax blood plasma values exhibited by conventional inhalable suspensions
comprising a corticosteroid at the
same nominal dosage under the same conditions. In certain other embodiments,
the Cm. can be at least about
600% (6 fold) to about 700% (7 fold), about 625% (6.25 fold) to about 700% (7
fold), or about 650% (6.5 fold)
to about 700% (7 fold) greater than the Cmax blood plasma values exhibited by
conventional inhalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. In one
embodiment, the C,,,aõ is at least about 600% (6 fold) greater than the Cm. of
the inhalable suspension
comprising a corticosteroid. In certain other embodiments, the Cm, can be at
least about 500% (5 fold) to about
600%
(6 fold) , about 525% (5.25 fold) to about 600% (6 fold), or about 550% (5.5
fold) to. about 600% (6 fold)
greater than the C,n,x blood plasma values exhibited by conventional inhalable
suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In
another embodiment, the C,,. is at
least about 500% (5 fold) greater than the. Cmaõ of the inhalable suspension
comprising a corticosteroid. In
certain other embodiments, the C,,,a, can be at least about 400% (4 fold) to
about 500% (5 fold) , about 425%
(4.25 fold) to about 500% (5 fold), or about 450% (4.5 fold) to about 500% (5
fold) greater than the C,n. blood
plasma values exhibited by conventional inhalable suspensions comprising a
corticosteroid at the same nominal
dosage under the same conditions. In yet another embodiment, the C,,. is at
least about 400% (4 fold) greater
than the Cn,aõ of the inhalable suspension comprising a corticosteroid. In
certain other embodiments, the Cm..'
can be at least about 300% (3 fold) to about 400% (4 fold), about 325% (3.25
fold) to about 400% (4 fold), or
about 350% (3.5 fold) to about 400% (4 fold) greater than the Cblood plasma
values exhibited by
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In still another embodiment, the Cm.õ is at least about 300% (3
fold) greater than the Cma7e of the
inhalable suspension comprising a corticosteroid. In certain other
embodiments, the C,,,aõ can be at least about
200% (2 fold) to about 300% (3 fold), about 225% (2.25 fold) to about 300% (3
fold), or about 250% (2.5 fold)
to about 300% (3 fold) greater than the C,,,,,,. blood plasma values exhibited
by conventional inhalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. In yet still
another embodiment, the C,,,a., is at least about 200% (2 fold) greater than
the Cmaõ of the inhalable suspension
comprising a corticosteroid. In certain other embodiments, the C,,,,,., can be
at about 150% (1.5 fold) to about
200% (2 fold) greater than the Cm,,, blood plasma values exhibited by
conventional inhalable suspensions
comprising a corticosteroid at the same nominal dosage under the same
conditions. In another embodiment, the
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C,,. is at least about 150% (1.5 fold) greater than the C,,~ of the inhalable
suspension comprising a
corticosteroid.
1003721 In other embodiments, the C,,. can be substantially equivalent to the
C,,,a, blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid
wherein the aqueous inhalation
mixture comprising a corticosteroid is administered at a lower nominal dosage
under the same conditions. In
one embodiment, the nominal dosage can be about 1:1.5 (i.e., 1.5 fold enhanced
pharmacokinetic profile) to
about 1:10 (i.e., 10 fold enhanced pharmacokinetic profile) the nominal dosage
of the conventional inhalable
suspensions comprising a corticosteroid. In another embodiment, the nominal
dosage of the aqueous inhalation
mixture comprising a corticosteroid can be about 1:1.5 to about 1:9 of the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In yet another embodiment,
the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to
about 1:8 the nominal dosage of
the conventional inhalable suspensions comprising a corticosteroid. In still
another embodiment, the nominal
dosage of the aqueous inhalation mixture comprising a corticosteroid can be
about 1:1.5 to about 1:7 the
nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In an additional
embodiment, the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about
1:1.5 to about 1:6 the nominal dosage of the conventional inhalable
suspensions comprising a corticosteroid. In
another embodiment, the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid can be
about 1:2 to about 1:5 the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In still another embodiment, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:2 to about 1:4 the nominal dosage of the
conventional inhalable suspensions
comprising a corticosteroid. In still yet other embodiments, the nominal
dosage of the aqueous inhalation
mixture comprising a corticosteroid can be about 1:2 to about 1:3 the nominal
dosage of the conventional
inhalable suspensions comprising a corticosteroid. In certain embodiments, the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid can be about 1:2 the nominal
dosage of the conventional
inhalable suspensions comprising a corticosteroid. In certain other
embodiments, the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:3 the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In other certain
embodiments, the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:4 the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In still other embodiments,
the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:5 the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In yet still other
embodiments, the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:6 the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In still yet other
embodiments, the nominal dosage of the
aqueous inhalation mixture comprising a corticosteroid can be about 1:7 the
nominal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In other embodiments, the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid can be about 1:8 the nominal
dosage of the conventional
inhalable suspensions comprising a corticosteroid. In still other embodiments,
the nominal dosage of the
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aqueous inhalation mixture comprising a corticosteroid can be about 1:9 the
norninal dosage of the conventional
inhalable suspensions comprising a corticosteroid. In yet still other
embodiments, the nominal dosage of the
aqueous inhalation mixture comprising a cordcosteroid can be about 1:10 the
nominal dosage of the
conventional inhalable suspensions comprising a corticosteroid.
C. AUCs0 ,S,) Blood Plasma Values
[00373] The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein can deliver of an inhalation mixture
comprising a corticosteroid to the
subject in a manner wherein the active is delivered having an increased
AUCt,,.,q blood plasma value of the
corticosteroid as compared to conventional inhalable corticosteroid
suspensions administered under the same
conditions. For example, conventional budesonide suspensions administered in a
single dose using a Pari LC
Plus jet nebulizer in a 2.0 ml volume with an administration time of about 5
minutes display pharmacokinetic
profiles such that the AUC(ias,) blood plasma values ranges from about 739 f
220 (pg/h/ml) to about 1989 t 379
(pg/h/ml) with nominal dosages of 500 pg to 1000 g, respectfully. Using the
systems and methods described
herein, budesonide + SBE7-0-CD inhalation solutions having nominal dosages of
60 g, 120 g, and 240 g
delivered in a single dose using a Pari eFlow Inhaler in a 0.5 ml volume with
a delivery time of about 1.5
minutes had AUCt1,,,q blood plasma values of about 179 75 (pg/h/ml), about
569 1213 (pg/h/ml), and 1] 83 ~:
328 (pg/h/ml), respectively. FIG. 4 provides a graphic representation of the
data used to generate the
aforementioned AUC(bSi) blood plasma values. =
[00374] [n a second example, conventional budesonide suspensions (Pulmicort
Respules) administered twice
daily for seven days using a Pari LC Plus jet nebulizer in a 2.0 ml volume
with an administration time of about
4 minutes displayed phannacokinetic profiles having mean AUC(iaz,) blood
plasma values of 361.1 212 pg/ml
and about 811.1 J: 328 pg/mi with nominal dosages of 250 g and 500 g,
respectively. The same 250 g and
500 pg Pulmicort Respules inhalation suspensions had geometric mean values
for AUCtuS,, blood plasma of
302.6 pg/ml and 735.1 pg/ml, respectively. Using the systems and methods
described herein, a 60 g CBIS
inhalation solution delivered twice daily for seven days using a Pari eFlow
Inhaler in a 0.5 ml volume with a
delivery time of about 1.5 minutes had a minimum AUC(ust) blood plasma value
of about 106.4 pg/ml, a
maximum AUCtLg? blood plasma value of about 463.1 pg/ml, and geometric mean
AUCt,as,? values of about
293.7 pg/ml. Likewise, a 120 g CBIS inhalation solution delivered twice daily
for seven days using a Pari
eFlow Inhaler in a 0.5 ml volume with a delivery time of about 1.5 minutes
had a minimum AUC (usl) blood
plasma value of about 168.2 pg/ml, a maximum AUC(,aSQ blood plasma value of
about 1496.7 pg/ml, and
geometric mean AUC(,as,) values of about 621.4 pg/ml. FIG. 5 provides a
graphic representation of the data
upon which the aforementioned AUCtusq blood plasma values were based.
[00375] Thus, the methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof provide the delivery of an inhalation mixture
comprising a corticosteroid having an
enhanced pharmacokinetic profile as compared to conventional inhalable
corticosteroid suspensions
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administered under the same conditions. More specifically, the systems and
methods described herein provide
at least about 1.5 fold to about 10 fold increase in AUC(I.st) blood plasma
values for a corticosteroid (as
determined on an individual basis), normalized for dose of corticosteroid per
microgram of corticosteroid
administered, as compared to conventional inhalable corticosteroid therapies
administered under the same
conditions. In certain embodiments, the systems and methods described herein
provide at least about 1.5 fold to
about 10 fold, about 1.5 fold to about 9.5 fold, about 1.5 fold to about 9
fold, about 1.5 fold to about 8.5 fold,
about 1.5 fold to about 8 fold, about 1.5 fold to about 7.75 fold, about 1.5
fold to about 7.5 fold, about 1.5 fold
to about 7.25 fold, about 1.5 fold to about 7 fold, about 1.5 fold to about
6.75 fold, about 1.5 fold to about 6.5
fold, about 1.5 fold to about 6 fold, about 1.5 fold to about 5.75 fold, about
1.5 fold to about 5.5 fold, about 1.5
fold to about 5 fold, about 1.5 fold to about 4.75 fold, about 1.5 fold to
about 4.5 fold, about 1.5 fold to about 4
fold increase in AUC(,,st) blood plasma values (as determined on an individual
basis) for a corticosteroid
normalized for dose of corticosteroid per microgram of corticosteroid
administered; as compared to
conventional inhalable corticosteroid therapies administered under the same
condition.
[00376) In other embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof described herein
provide at least a about 4 fold to about
a 6 fold increase in AUC(uS,) blood plasma values for a corticosteroid taken
across a studied patient population,
normalized for dose of corticosteroid per microgram of corticosteroid
administered, as compared to
conventional inhalable corticosteroid therapies administered under the same
conditions, for example as
determined using the geometric mean across a studied patient population. In
certain embodiments, the systems
and methods described herein provide at least about 4 fold to about 6 fold,
about 4 fold to about 5.75 fold, about
4 fold to about 5.5 fold, about 4 fold to about 5.25 fold, about 4 fold to
about 5 fold, about 4.5 fold to about 6
fold, about 4.75 fold to about 6 fold, about 5 fold to about 6 fold, about 5.5
fold to about 6 fold increase in
AUCtt,st, blood plasma values for a corticosteroid taken across a studied
patient population, normalized for dose
of corticosteroid per microgram of corticosteroid administered, as compared to
conventional inhalable
corticosteroid therapies administered under the same conditions.
[003771 In some embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof can provide a
AUC(w,) that is significantly greater than
the AUC(t,st) blood plasma values exhibited by conventional inhalable
suspensions comprising a corticosteroid
administered at the same nominal dosage under the same conditions. In certain
embodiments, the AUC(i,si) can
be from about 1.5 fold (150%) to about 10 fold (1000%) the AUCtusq blood
plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In one embodiment, the AUCtus,l can be at least about 1000% (10
fold) greater than the
AUC(j,sgblood plasma values exhibited by conventional inhalable suspensions
comprising a corticosteroid at the
same nominal dosage under the same conditions. In certain other embodiments,
the AUC(,as,) can be at least
about 900% (9 fold) to about 1000% (10 fold) , about 925% (9.25 fold) to about
1000% (10 fold), or about
950% (9.5 fold) to about 1000% (10 fold) greater than the AUCt,,,SQ blood
plasma values exhibited by
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conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In another embodiment, the AUC(It) can be at least about 900% (9
fold) greater than the AUC(bs,)
blood plasma values exhibited by conventional inhalable suspensions comprising
a corticosteroid at the same
nominal dosage under the same conditions. In certain other embodiments, the
AUCt%sq can be at least about
800% (8 fold) to about 900% (9 fold) , about 825% (8.25 fold) to about 900% (9
fold), or about 850% (8.5 fold)
to about 900% (9 fold) greater than the AUCtt.,, blood plasma values exhibited
by conventional inhalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. In still another
embodiment, the AUC(hSq can be at least about 800% (8 fold) greater than the
AUC(ust) blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid at
the same nominal dosage under
the same conditions. In certain other embodiments, the AUC(wt) can be at least
about 700% (7 fold) to about
800% (8 fold) , about 725% (7.25 fold) to about 800% (8 fold), or about 750%
(7.5 fold) to about 800% (8 fold)
greater than the AUC(I.,) blood plasma values exhibited by conventional
inhalable suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In still
yet another embodiment, the
AUCtL~,q can be at least about 700% (7 fold) greater than the AUC(us,) blood
plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In certain other embodiments, the AUCt%,,I can be at least about
600% (6 fold) to about 700% (7
fold) , about 625% (6.25 fold) to about 700% (7 fold), or about 650% (6.5
fold) to about 700% (7 fold) greater
than the AUCp,,,y blood plasma values exhibited by conventional inhalable
suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In one
embodiment, the AUC(%s,) is at
least about 600% (6 fold) greater than the AUC(it) of the inhalable suspension
comprising a corticosteroid. In
certain other embodiments, the AUC(t,s,) can be at least about 500% (5 fold)
to about 600% (6 fold) , about
525% (5.25 fold) to about 600% (6 fold), or about 550% (5.5 fold) to about
600% (6 fdld) greater than the
AUC(ust) blood plasma values exhibited by conventional inhalable suspensions
comprising a corticosteroid at
the same nominal dosage under the same conditions. In another embodiment, the
AUC(us,) is at least about
500% (5 fold) greater than the AUC(la,,) of the inhalable suspension
comprising a corticosteroid. In certain other
embodiments, the AUC(i,sq can be at least about 400% (4 fold) to about 500% (5
fold), about 425% (4.25 fold)
to about 500% (5 fold), or about 450% (4.5 fold) to about 500% (5 fold)
greater than the AUCtusp blood plasma
values exhibited by conventional inhalable suspensions comprising a
corticosteroid at the same nominal dosage
under the same conditions. In yet another embodiment, the AUC(,as,) is at
least about 400% (4 fold) greater than
the AUC(uõ) of the inhalable suspension comprising a corticosteroid. In
certain other embodiments, the
AUC(la,,) can be at least about 300% (3 fold) to about 400% (4 fold) , about
325% (3.25 fold) to about 400% (4
fold), or about 350% (3.5 fold) to about 400% (4 fold) greater than the AUCp.q
blood plasma values exhibited
by conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In still another embodiment, the AUCtiq is at least about 300% (3
fold) greater than the AUCtusq of
the inhalable suspension comprising a corticosteroid. In certain other
embodiments, the AUCti,s,7 can be at least
about 200% (2 fold) to about 300% (3 fold) , about 225% (2.25 fold) to about
300% (3 fold), or about 250%
(2.5 fold) to about 300% (3 fold) greater than the AUCt,,,q blood plasma
values exhibited by conventional
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inhalable suspensions comprising a corticosteroid at the same nominal dosage
under the same conditions. In yet
still another embodiment, the AUC(as,) is at least about 200% (2 fold) greater
than the AUC(,,s,) of the inhalable
suspension comprising a corticosteroid. In certain other embodiments, the
AUCttas,l can be at about 150% (1.5
fold) to about 200% (2 fold) greater than the AUC(ast) blood plasma values
exhibited by conventional inbalable
suspensions comprising a corticosteroid at the same nominal dosage under the
same conditions. In another
embodiment, the AUC(iazt) is at least about 150% (1.5 fold) greater than the
AUCtkõq of the inhalable suspension
comprising a corticosteroid.
1003781 In some embodiments, the AUCtwtt can be substantially equal to the
AUCthstl blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid
wherein the aqueous inhalation
mixture is administered at a lower nominal dosage under the same conditions.
In one embodiment, the nominal
dosage can be about 1:1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to
about 1:10 (i.e., 10 fold enhanced
pharmacokinetic profile) the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In another embodiment, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the
conventional inhalable suspensions
comprising a corticosteroid. In yet another embodiment, the nominal dosage of
the aqueous inhalation mixture
comprising a corticosteroid can be about 1:1.5 to about 1:8 the nominal dosage
of the conventional inhalable
suspensions comprising a corticosteroid. In still another embodiment, the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:7
the nominal dosage of the
conventional inhalable suspensions comprising a corticosteroid. In an
additional embodiment, the nominal
dosage of the aqueous inhalation mixture comprising a corticosteroid can be
about 1;1.5 to about 1:6 the
nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In another embodiment,
the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2 to about 1:5
the nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In still another
embodiment, the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2
to about 1:4 the nominal dosage of the conventional inhalable suspensions
comprising a corticosteroid. In still
yet other embodiments,'the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid can
be about 1:2 to about 1:3 the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In certain embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:2 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In certain other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:3 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In other certain embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:4 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:5 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:6 the nominal dosage of the conventional
inhalable suspensions comprising a
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corticosteroid. In still yet other embodiments, the nomiinal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:7 the nominal dosage of the conventional
inhalable* suspensions comprising a
corticosteroid. In other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:8 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
cordcosteroid can be about 1:9 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:10 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid.
D. AiICo_ea Blood Plasma Values
1003791 The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein can deliver a corticosteroid to the
subject in a manner wherein the
active is delivered having an increased AUCt" blood plasma value of the
corticosteroid as compared to
conventional inhalable corticosteroid suspensions administered under the same
conditions. For example,
conventional budesonide suspensions administered in a single dose using a Pari
LC Pluso jet nebulizer in a 2.0
ml volume with an administration time of about 5 minutes display
phannacokinetic profiles such that the
AUCto..4 blood plasma values ranges from about 867 216 (pg/h/ml) to about
2083 394 (pg/h/ml) with
nominal dosages of 500 g to 1000 g, respectfully. Using the systems and
methods described herein,
budesonide + SBE7-13-CD inhalation solutions having nominal dosages of 60 g,
120 g, and 240 g delivered
in a single dose using a Pari eFlow Inhaler in a 0.5 ml volume with a
delivery time of about 1.5 minutes had
AUCto_.4 blood plasma values were about 262 125 (pg/h/ml), about 679 f 201
(pg/h/ml), and 1365 f 313
(pg/h/ml), respectively. FIG. 4 provides a graphic representation of the data
used to generate the
aforementioned AUC(IaSQ blood plasma values.
J003801 In a second example, conventional budesonide suspensions (Pulmicort
Respules ) administered twice
daily for seven days using a Pari LC Plus jet nebulizer in a 2.0 ml volume
with an administration time of about
4 minutes displayed pharmacokinetic profiles having mean AUCto_ 3 blood plasma
values of 472.3 :1- 239 pg/ml
and about 945.7 t 363 pg/mi with nominal dosages of 250 }tg and 500 pg,
respectively. The same 250 g and
500 g Pulmicort Respules inhalation suspensions had geometric mean values
for AUC{o_c4 blood plasma of
413.0 pg/ml and 874.6 pg/mi, respectively. Using the systems and methods
described herein, a 60 g CBIS
inhalation solution delivered twice daily for seven days using a Pari eFlow
Inhaler in a 0.5 ml volume with a
delivery time of about 1.5 minutes had a minimum AUCto.,4 blood plasma value
of about 156.5 pg/rnl, a
maximum AUCto.,4 blood plasma value of about 748.5 pg/ml, and geometric mean
AUC(o_,~ values of about
396.1 pg/ml. Likewise, a 120 g CBIS inhalation solution delivered twice daily
for seven days using a Pari
eFlow Inhaler in a 0.5 ml volume with a delivery time of about 1.5 minutes
had a.minimum AUCto.,4 blood
plasma value of about 221.4 pg/ml, a maximum AUCto_.4 blood plasma value of
about 1863.7 pg/ml, and
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geometric mean AUCto.,,q values of about 752.2 pg/ml. FIG. 5provides a graphic
representation of the data
upon which the aforementioned AUCco.,q blood plasma values were based.
[00381) Thus, the methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein provide the delivery of a
corticosteroid having an enhanced
pharmacokinetic profile as compared to conventional inhalable corticosteroid
suspensions administered under
the same conditions. More specifically, the systems and methods described
herein provide at least about 1.5
fold to about 10 fold increase in AUCto_4 blood plasma values for a
corticosteroid (as determined on an
individual basis), normalized for dose of corticosteroid per microgram of
corticosteroid administered, as
compared to conventional inhalable corticosteroid therapies administered under
the same conditions. In certain
embodiments, the systems and methods described herein provide at least about
1.5 fold to about 10 fold, about
1.5 fold to about 9.5 fold, about 1.5 fold to about 9 fold, about 1.5 fold to
about 8.5 fold, about 1.5 fold to about
8 fold, about 1.5 fold to about 7.75 fold, about 1.5 fold to about 7.5 fold,
about 1.5 fold to about 7.25 fold, about
1.5 fold to about 7 fold, about 1.5 fold to about 6.75 fold, about 1.5 fold to
about 6.5 fold, about 1.5 fold to
about 6 fold, about 1.5 fold to about 5.75 fold, about 1.5 fold to about 5.5
fold, about 1.5 fold to about 5 fold,
about 1.5 fold to about 4.75 fold, about 1.5 fold to about 4.5 fold, about 1.5
fold to about 4 fold increase in
AUCt" blood plasma values (as determined on an individual basis) for a
corticosteroid normalized for dose of
corticosteroid per microgram of corticosteroid administered, as compared to
conventional inhalable
corticosteroid therapies administered under the same condition.
[00382] In other embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof described herein
provide at least a about 4 fold to about
a 6 fold increase in AUCto_,j blood plasma values for a corticosteroid taken
across a studied patient population,
normalized for dose of corticosteroid per microgram of corticosteroid
administered, as compared to
conventional inhalable corticosteroid therapies administered under the same
conditions, for example as
determined using the geometric mean across a studied patient population. In
certain embodiments, the systems
and methods described herein provide at least about 4 fold to about 6 fold,
about 4 fold to about 5.75 fold, about
4 fold to about 5.5 fold, about 4 fold to about 5.25 fold, about 4 fold to
about 5 fold, about 4.5 fold to about 6
fold, about 4.75 fold to about 6 fold, about 5 fold to about 6 fold, or about
5.5 fold to about 6 fold increase in
AUCto_.4 blood plasma values for a corticosteroid taken across a studied
patient population, normalized for dose
of corticosteroid per microgram of corticosteroid administered, as compared to
conventional inhalable
corticosteroid therapies administered under the same conditions.
(00383] In some embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof can provide a AUCto-
.4 that is significantly greater than
the AUCto..4 blood plasma values exhibited by conventional inhalable
suspensions comprising a corticosteroid
administered at the same nominal dosage under the same conditions. In certain
embodiments, the AUCto..4 can
be from about 1.5 fold (150%) to about 10 fold (1000%) the AUC(o.,4 blood
plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
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conditions. In one embodiment, the AUCto-0 can be at least about 1000% (10
fold) greater than the AUC(o-.)
blood plasma values exhibited by conventional inhalable suspensions comprising
a corticosteroid at the same
nominal dosage under the same conditions. In certain other embodiments, the
AUCto-.j can be at least about
900% (9 fold) to about 1000% (10 fold), about 925% (9.25 fold) to about 1000%
(10 fold), or about 950% (9.5
fold) to about 1000% (10 fold) greater than the AUC(o,~4 blood plasma values
exhibited by conventional
inhalable suspensions comprising a corticosteroid at the same nominal dosage
under the same conditions. In
another embodiment, the AUCto..4 can be at least about 900% (9 fold) greater
than the AUCto.,4 blood plasma
values exhibited by conventional inhalable suspensions comprising a
corticosteroid at the same nominal dosage
under the same conditions. In certain other embodiments, the AUC(o..,4 can be
at least about 800% (8 fold) to
about 900% (9 fold) , about 825% (8.25 fold) to about 900% (9 fold), or about
850% (8.5 fold) to about 900%
(9 fold) greater than the AUCt" blood plasma values exhibited by conventional
inhalable suspensions
comprising a corticosteroid at the same nominal dosage under the same
conditions, In still another
embodiment, the AUC(o-.4 can be at least about 800% (8 fold) greater than the
AUCt" blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid at
the same nominal dosage under
the same conditions. In certain other embodiments, the AUC(o..4 can be at
least about 700% (7 fold) to about
800% (8 fold), about 725% (7.25 fold) to about 800% (8 fold), or about 750%
(7.5 fold) to about 800% (8 fold)
greater than the AUCto..4 blood plasma values exhibited by conventionai
inhalable suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In still
yet another embodiment, the
AUCto-q can be at least about 700% (7 fold) greater than the AUC(a.,.) blood
plasma values exhibited by =
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In certain other embodiments, the AUCto.,4 can be at least about
600% (6 fold) to about 700% (7
fold), about 625% (6.25 fold) to about 700% (7 fold), or about 650% (6.5 fold)
to about 700% (7 fold) greater
than the AUC(0.,4 blood plasma values exhibited by conventional inhalable
suspensions comprising a
corticosteroid at the same nominal dosage under the same conditions. In one
embodiment, the AUC'~,q is at
least about 600% (6 fold) greater than the AUC(o.,4 of the inhalable
suspension comprising a corticosteroid. In
certain other embodiments, the AUC(o.,~ can be at least about 500% (5 fold) to
about 600% (6 fold) , about
525% (5.25 fold) to about 600% (6 fold), or about 550% (5.5 fold) to about
600% (6 fold) greater than the
AUC(" blood plasma values exhibited by conventional inhalable suspensions
comprising a corticosteroid at
the same nominal dosage under the same conditions. In another embodiment, the
AUCt" is at least about
500% (5 fold) greater than the AUCto.,~ of the inhalable suspension comprising
a corticosteroid. In certain
other embodiments, the AUC(a.,.) can be at least about 400% (4 fold) to about
500% (5 fold) , about 425% (4.25
fold) to about 500% (5 fold), or about 450% (4.5 fold) to about 500% (5 fold)
greater than the AUCta,~) blood
plasma values exhibited by conventional inhalabte suspensions comprising a
corticosteroid at the same nominal
dosage under the same conditions. In yet another embodiment, the AUC(o..~ is
at least about 400% (4 fold)
greater than the AUCto-,.) of the inhalable suspension comprising a
corticosteroid. In certain other
embodiments, the AUC(o.,q can be at least about 300% (3 fold) to about 400% (4
fold), about 325% (3.25 fold)
to about 400% (4 fold), or about 350% (3.5 fold) to about 400% (4 fold)
greater than the AUCto..q blood plasma
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values exhibited by conventional inhalable suspensions comprising a
corticosteroid at the same nominal dosage
under the same conditions. In still another embodiment, the AUCto.,4 is at
least about 300% (3 fold) greater
than the AUCto.,q of the inhalable suspension comprising a corticosteroid. In
certain other embodiments, the
AUC(a.4 can be at least about 200% (2 fold) to about 300% {3 fold) , about
225% (2.25 fold) to about 300% (3
fold), or about 250% (2.5 fold) to about 300% (3 fold) greater than the
AUCto..q blood plasma values exhibited
by conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In yet still another embodiment, the AUCto.., is at least about
200% (2 fold) greater than the AUCto_
.4 of the inhalable suspension comprising a corticosteroid. In certain other
embodiments, the AUCt" can be at
about 150% (1.5 fold) to about 200% (2 fold) greater than the AUCt" blood
plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid at the same
nominal dosage under the same
conditions. In another embodiment, the AUCto..4 is at least about 150% (1.5
fold) greater than the AUCt" of
the inhalable suspension comprising a corticosteroid.
1003841 In some embodiments, the AUCco_,~ can be substantially equal to the
AUC(" blood plasma values
exhibited by conventional inhalable suspensions comprising a corticosteroid
wherein the aqueous inhalation
mixture is administered at a lower nominal dosage under the same conditions.
In one embodiment, the nominal
dosage can be about 1:1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to
about 1:10 (i.e., 10 fold enhanced
pharmacokinetic profile) the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In another embodiment, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the
conventional inhalable suspensions
comprising a cotticosteroid. In yet another embodiment, the nominal dosage of
the aqueous inhalation mixture
comprising a corticosteroid can be about 1:1.5 to about 1:8 the nominal dosage
of the conventional inhalable
suspensions comprising a corticosteroid. In still another embodiment, the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:7
the nominal dosage of the
conventional inhalable suspensions comprising a corticosteroid. In an
additional embodiment, the nominal
dosage of the aqueous inhalation mixture comprising a corticosteroid can be
about 1:1.5 to about 1:6 the
nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In another embodiment,
the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2 to about 1:5
the nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In still another
embodiment, the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2
to about 1:4 the nominal dosage of the conventional inhalable suspensions
comprising a corticosteroid. In still
yet other embodiments, the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid can
be about 1:2 to about 1:3 the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In certain embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:2 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In certain other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:3 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In other certain embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
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a corticosteroid can be about 1:4 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid, In still other embodiments, the nominal dosage of the aqueous
inbalation mixture comprising a
corticosteroid can be about 1:5 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:6 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still yet other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:7 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:8 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:9 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:10 the nominal dosage of the conventional
inhalable suspensions comprising a
corti costeroi d.
E. Decreased TSlood Plasma Values
[003851 The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof described herein can deliver a corticosteroid to the
subject in a manner wherein the
active is delivered having a decreased Tma, blood plasma value of the
corticosteroid as compared to
conventional inhalable corticosteroid suspensions administered at the same
dose under the same conditions. In
one example, conventional budesonide suspensions administered in a single dose
using a Pari LC Plus jet
nebulizer in a 2.0 ml volume with an administration time of about 5 minutes
display pharmacokinetic profiles
such that the Tm,x blood plasma values ranges from about 0.24 f 0.25 (h) to
about 0.23 0.24 (h) with nominal
dosages of 500 g to 1000 g, respectfully. Using the systems and methods
described herein, budesonide +
SBE7-0-CD inhalation solutions having nominal dosages of 60 g, 120 g, and
240 g delivered in a single
dose using a Pari eFlow lnhaler in a 0.5 ml volume with a delivery time of
about 1.5 minutes had T,,,a,; blood
plasma values of about 0.11=L 0.09 (h), 0.11-+ 0.09 (h), and 0.21f 0.24 (h),
respectively.
[003861 In a second example, conventional budesonide suspensions (Pulmicort
Respulese) administered twice
daily for seven days using a Pari LC Plus jet nebulizer in a 2.0 ml volume
with an administration time of about
4 minutes displayed pharmacokinetic profiles having mean Tn,,,, blood plasma
values of 0.22 0.22 (h) with
nominal dosage of 250 g budesonide, with a minimum T,,,a,, blood plasma value
of about 0.08 (h) and a
maximum T,,. blood plasma value of about 0.75 (h), and mean T. blood plasma
values of about 0.19 f 0.19
(h) with nominal dosage of 500 g budesonide, with a minimum Tm~ blood plasma
value of about 0.08 (h) and
a maximum T. blood plasma value of about 0.75 (h). Using the systems and
methods described herein, a 60
g CBIS inhalation solution delivered twice daily for seven days using a Pari
eFlow Inhaler in a 0.5 ml
volume with a delivery time of about 1.5 minutes had a minimum T,,,ax blood
plasma value of about 0.08 (h), a
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maximum T,,,,x blood plasma value of about 0.25 (h), and mean T,,,,x values of
about 0.11 (h). Likewise, a 120
g CBIS inhalation solution delivered twice daily for seven days using a Pari
eFlow Inhaler in a 0.5 ml
volume with a delivery time of about 1.5 minutes had a minimum T,,,ax blood
plasma value of about 0.08 (h), a
maximum Tma,, blood plasma value of about 0.50 (h), and mean T,,.x values of
about 0.14 (h). FIG. 5 provides a
graphic representation of the data upon which the aforementioned T,,. blood
plasma values were based.
1003871 Thus, the methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof can provide a Tmax that is significantly less than the
T. blood plasma values exhibited
by conventional inhalable suspensions comprising a corticosteroid administered
at the same nominal dosage
under the same conditions. In some embodiments, the TmIx can be at least about
1.5 fold to about 10 fold less
than the T. blood plasma values exhibited by conventional inhalable
suspensions comprising a corticosteroid
administered at the same nominal dosage under the same conditions. In certain
embodiments, the T,,,,,,, can be at
least about 8 fold less than the Tm,, blood plasma values exhibited by
conventional inhalable suspensions
comprising a corticosteroid administered at the same nominal dosage under the
same conditions. In certain
other embodiments, the Tmax can be at least about 6 fold less than the T,,.
blood plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid administered at
the same nominal dosage under
the same conditions. In one such embodiment, the Tm. can be at least about 4
fold less than the Tm,,, blood
plasma values exhibited by conventional inhalable suspensions comprising a
corticosteroid administered at the
same nominal dosage under the same conditions. In another embodiment, the
T,,,,., can be at least about 3 fold
less than the Tmax blood plasma values exhibited by conventional inhalable
suspensions comprising a
corticosteroid administered at the same nominal dosage under the same
conditions. In still another
embodiment, the T.,,, can be at least about 2 fold faster than the Tma~ blood
plasma values exhibited by
conventional inhalable suspensions comprising a corticosteroid administered at
the same nominal dosage under
the same conditions. In yet still another embodiment, the Tma, can be at least
about 1.5 fold faster than the T,,,,,
blood plasma values exhibited by conventional inhalable suspensions comprising
a corticosteroid administered
at the same nominal dosage under the same conditions.
1003881 In some embodiments, the Tmax can be less than the Tmax blood plasma
values exhibited by
conventional inhalable suspensions comprising a corticosteroid wherein the
aqueous inhalation mixture is
administered at a lower nominal dosage under the same conditions. In one
embodiment, the nominal dosage
can be about 1:1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to about
1:10 (i.e., 10 fold enhanced
pharmacokinetic profile) the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In another embodiment, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the
conventional inhalable suspensions
comprising a corticosteroid. In yet another embodiment, the nominal dosage of
the aqueous inhalation mixture
comprising a corticosteroid can be about 1:1.5 to about 1:8 the nominal dosage
of the conventional inhalable
suspensions comprising a corticosteroid. In still another embodiment, the
nominal dosage of the aqueous
inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:7
the nominal dosage of the
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conventional inhalable suspensions comprising a corticosteroid. In an
additional embodiment, the nominal
dosage of the aqueous inhalation mixture comprising a corticosteroid can be
about 1:1.5 to about 1:6 the
nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In another embodiment,
the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2 to about 1:5
the nominal dosage of the conventional inhalable suspensions comprising a
corticosteroid. In still another
embodiment, the nominal dosage of the aqueous inhalation mixture comprising a
corticosteroid can be about 1:2
to about 1:4 the nominal dosage of the conventional inhalable suspensions
comprising a corticosteroid. In still
yet other embodiments, the nominal dosage of the aqueous inhalation mixture
comprising a corticosteroid can
be about 1:2 to about 1:3 the nominal dosage of the conventional inhalable
suspensions comprising a
corticosteroid. In certain embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:2 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In certain other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:3 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In other certain embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:4 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:5 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:6 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still yet other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising
a corticosteroid can be about 1:7 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:8 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In still other embodiments, the nominal dosage of the aqueous
inhalation mixture comprising a
corticosteroid can be about 1:9 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid. In yet still other embodiments, the nominal dosage of the
aqueous inhalation mixture comprising =
a corticosteroid can be about 1:10 the nominal dosage of the conventional
inhalable suspensions comprising a
corticosteroid.
XIII. DOSAGES FOR USE IN METHODS AND SYSTEMS FOR TREATMENT
[00389] The methods and systems for the treatment or prophylaxis of a
bronchoconstrictive disorder in a
patient in need thereof can deliver an aqueous inhalation mixture comprising a
corticosteroid, e.g., budesonide,
and a solubility enhancer to the subject in a manner wherein the active is
delivered in accordance with good
medical practice, taking into account the clinical condition of the individual
patient, the site and method of
administration, scheduling of administration, and other factors known to
medical practitioners. In human
therapy, the methods described herein can deliver corticosteroid solutions,
e.g., a budesonide solution, that
maintain a therapeutically effective amount of the corticosteroid, e.g.,
budesonide, at the site of action which
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reduces or mitigates symptoms related to bronchoconstrictive disorders. In
other embodiments the aqueous
inhalation mixture comprises a corticosteroid and a solubility enhancer,
wherein the inhalation mixture is
substantially free of pharmaceutically active agents other than a
corticosteroid.
1003901 In other embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof described herein can
deliver an aqueous inhalation
mixture comprising a corticosteroid, e.g., budesonide, a solvent, and a
solubility enhancer to the subject in a
manner wherein the active is delivered in accordance with good medical
practice, taking into account the
clinical condition of the individual patient, the site and method of
administration, scheduling of administration,
and other factors known to medical practitioners. In human therapy, the
methods described herein can deliver
corticosteroid solutions, e.g., a budesonide solution, that maintain a
therapeutically effective amount of the
corticosteroid, e.g., budesonide, at the site of action which reduces or
mitigates symptoms related to
bronchoconstrictive disorders. In other embodiments the aqueous inhalation
mixture comprises a corticosteroid,
a solvent, and a solubility enhancer, wherein the inhalation mixture is
substantially free of pharmaceutically
active agents other than a corticosteroid.
[003911 In various embodiments of the methods =and systems described herein
above in Section XiI, the
methods and systems for the treatment or prophylaxis of a bronchoconstrictive
disorder in a patient in need
thereof described herein can deliver an aqueous inhalation mixture comprising
a therapeutically effective
amount of a corticosteroid administered to a subject via an inhalation
nebulizer at a nominat dosage in the range
of about 15 g/dose to less than about 250 pg/dose, or from about 25 g/dose
to about 240 g/dose, or from
about 200 g/dose to about 240 g/dose, or from about 125 g/dose to about 200
g/dose, or from about 150
g/dose to about 200 g/dose, or from about 100 pg/dose to about 150 g/dose,
or from about 100 pg/dose to
about 125 g/dose, or from about 50 g/dose to about 125 g/dose, or from
about 60 g/dose to about 125
g/dose, or from about 25 jig/dose to about 50 g/dose. In a preferred
embodiment, the corticosteroid is
budesonide administered to a subject via an inhalation nebulizer at a nominal
dosage in the range of about 25
jig/dose to about 240 g/dose. In one embodiment, the aqueous inhalation
mixture comprises a corticosteroid,
such as budesonide, wherein the aqueous inhalation mixture is administered
according to the methods and
systems described herein with a nominal dosage of the corticosteroid of about
60 g/dose to less than about 250
g/dose. In another embodiment, the aqueous inhalation mixture comprises a
corticosteroid, such as
budesonide, wherein the aqueous inhalation mixture is administered according
to the methods and systems
described herein with a nominal dosage of the corticosteroid of less than
about 250 g/dose. In still another
embodiment, the aqueous inhalation mixture comprises a corticosteroid, such as
budesonide, wherein the
aqueous inhalation mixture is administered according to the methods and
systems described herein with a
nominal dosage of the corticosteroid of about 240 g/dose. In yet another
embodiment, the aqueous inhalation
mixture comprises a corticosteroid, such as budesonide, wherein the aqueous
inhalation mixture is administered
according to the methods and systems described herein with a nominal dosage of
the corticosteroid of about 125
jig/dose. In still another embodiment, the aqueous inhalation mixture
comprises a corticosteroid, such as
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budesonide, wherein the aqueous inhalation mixture is administered according
to the methods and systems
described herein with a nominal dosage of the corticosteroid of about 120
g/dose. In yet still another
embodiment, the aqueous inhalation mixture comprises a corticosteroid, such as
budesonide, wherein the
aqueous inhalation mixture is administered according to the methods and
systems described herein with a
nominal dosage of the corticosteroid of about 60 g/dose. In still another
embodiment, the aqueous inhalation
mixture comprises a corticosteroid, such as budesonide, wherein the aqueous
inhalation mixture is administered
according to the methods and systems described herein with a nominal dosage of
the corticosteroid of about 40
g/dose. In certain embodiments, the aqueous inhalation mixture comprises a
single corticosteroid and is
substantially free of pharmaceutically active agents other than the
corticosteroid.
(003921 In certain embodiments, the methods and systems for the treatment or
prophylaxis of a
bronchoconstrictive disorder in a patient in need thereof can deliver an
aqueous inhalation mixture comprising a
therapeutically effective amount of a corticosteroid administered to a subject
via an inhalation nebulizer at a
nominal dosage in the range of about 25 g/dose to less than about 100 g/dose
wherein the the corticosteroid
is selected group of corticosteroids in the foregoing paragraph not including
the betamethasone. In one such
embodiment, the aqueous inhalation mixture comprises a corticosteroid, such as
budesonide, wherein the
aqueous inhalation mixture is administered according to the methods and
systems described herein with a
nominal dosage of the corticosteroid of less than about 100 g/dose. In
another embodiment, the aqueous
inhalation mixture comprises a corticosteroid, such as budesonide, wherein the
aqueous inhalation mixture is
administered according to the methods and systems described herein with a
nominal dosage of the
corticosteroid of about 60 g/dose. In still another embodiment, the aqueous
inhalation mixture comprises a
corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is
administered according to the
methods and systems described herein with a nominal dosage of the
corticosteroid of about 40 g/dose. In
certain embodiments, the aqueous inhalation mixture comprises a single
corticosteroid and is substantially free
of pharmaceutically active agents other than the corticosteroid.
1003931 In some embodiments of the inhalable compositions or aqueous
inhalation mixtures described herein,
the inhalable composition or aqueous inhalation mixture comprises a solvent.
In certain embodiments, the
solvent is selected from the group comprising water, aqueous alcohol,
propylene glycol, or aqueous organic
solvent. In preferred embodiments, the solvent is water.
1003941 In some embodiments of the systems and methods described herein, a
corticosteroid-containing
aqueous inhalation mixture is employed which further comprises a solubility
enhancer. In some embodiments,
the solubility enhancer can have a concentration (w/v) ranging from about
0.001% to about 25%. In other
embodiments, the solubility enhancer can have a concentration (w/v) ranging
from about 0.01 !o to about 20%.
In still other embodiments, the solubility enhancer can have a concentration
(w/v) ranging from about 0.1 % to
about 15%. In yet other embodiments, the solubility enhancer can have a
concentration (w/v) ranging from
about 1% to about 10%. In a preferred embodiment, the solubility enhancer can
have a concentration (w/v)
ranging from about 2% to about 10% when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,
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e.g. SBE7-,6-CD (Captisol ). In one embodiment, the solubility enhancer can
have a concentration (w/v) of
about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin
derivative, e.g. SBE7-(3-CD
(Captisol ). In another embodiment, the solubility enhancer can have a
concentration (w/v) of about 5% when
the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-
13-CD (Captisol ). In yet another
embodiment, the solubility enhancer can have a concentration (w/v) about 7%
when the solubility enhancer is a
cyclodextrin or cyclodextrin derivative,e.g. SBE7-0-CD (Captisol ). In still
yet another embodiment, the
solubility enhancer can have a concentration (w/v) of about 10% when the
solubility enhancer is a cyclodextrin
or cyclodextrin derivative, e.g. SBE7-0-CD (Captisol ).
[003951 In certain embodiments, the aqueous inhalation mixture comprises a
solubility enhancer selected from
the group consisting of propylene glycol, non-ionic surfactants, tyloxapol,
polysorbate 80, vitamin E-TPGS,
macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched
lecithin, phosphatidylcholine
fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC),
dipalmitoyl phosphatidylcholine
(DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-0-CD, SBEl-('i-CD, SBE4-0-CD, SBE7-(3-CD (Captisol ), SBE--~-CD,
dimethyl (3-CD,
hydroxypropyl-(.3-cyclodextrin, 2-HP-0-CD, hydroxyethyl-a-cyclodextrin,
hydroxypropyl--,~-cyclodextrin,
hydroxyethyl-y-cyclodextrin, dihydroxypropyl-(3-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-0-
cyclodextrin, diglucosyl-/3-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-/3-
cyclodextrin, maltosyl-j-
cyclodextrin, maltotriosyl-R-cyclodextrin, maltotriosyl-,y-cyclodextrin,
dimaltosyl-(3-cyclodextrin, methyl-(.i-
cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate,
vinyl pyrrolidone, sodium lauryl
sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain
embodiments, the solubility
enhancer is SBE7-(3-CD (Captisoi ).
(00396] In certain other embodiments, the inhalable compositions of the
present invention comprise a solubility
enhancer selected from the group consisting of cyclodextrins and derivatives
thereof, SAE-CD derivatives,
SBE-a-CD, SBE-0-CD, SBEi-/3-CD, SBE4-(3-CD, SBE7-Q-CD (Captisol ), SBE-y-CD,
dimethyl Q-CD,
hydroxypropyl-(3-cyclodextrin, 2-HP-/3-CD, hydroxyethyl-f3-cyclodextrin,
hydroxypropyl- t-cyclodextrin,
hydroxyethyl- y-cyclodextrin, dihydroxypropyl-f.3-cyclodextrin, glucosyl-cr-
cyclodextrin, glucosyl-/3-
cyclodextrin, diglucosyl-/3-cyclodextrin, maltosyl-c~-cyclodextrin, maltosyl-
,Q-cyclodextrin, maltosyl-,y-
cyclodextrin, maltotriosyl-(3-cyclodextrin, maltotriosyl-y-cyclodextrin,
dimaltosyl-0-cyclodextrin, methyl-;6-
cyclodextrin. In certain embodiments, the solubility enhancer is SBE7-(3-CD
(Captisol ).
1003971 In addition to aqueous inhalation mixtures or inhalable composition
comprising a corticosteroid and a
solubility enhancer, it is contemplated herein that aqueous inhalation
mixtures or compositions formulated by
methods which provide enhanced solubility are likewise suitable for use in the
presently disclosed invention.
Thus, in the context of the present invention, a "solubility enhancer"
includes aqueous inhalation mixtures
formulated by methods which provide enhanced solubility with or without a
chemical agent acting as a
solubility enhancer. Such methods include, e.g., the preparation of
supercritical fluids. In accordance with such
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methods, corticosteroid compositions, such as budesonide, are fabricated into
particles with narrow particle size
distribution (usually less than 200 nanometers spread) with a mean particle
hydrodynamic radius in the range of
50 nanometers to 700 nanometers. The nano-sized corticosteroid particles, such
as budesonide particles, are
fabricated using Supercritical Fluids (SCF) processes including Rapid
Expansion of Supercritical Solutions
(RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as
well as any other techniques
involving supercritical fluids. The use of SCF processes to form particles is
reviewed in Palakodaty, S., et al.,
Pharmaceutical Research 16:976-985 (1999) and described in Bandi et al., Eur.
J. Pharm. Sci. 23:159-168
(2004), U.S. Patent No. 6,576,264 and U.S. Patent Application No. 2003/009 1 5
1 3, each of which is specifically
incorporated by reference herein.
[003981 In another aspect, the aqueous inhalation mixture comprising a
corticosteroid is administered
according to the methods and systems described herein not more than twice a
day (b.i.d). In still another aspect,
the aqueous inhalation mixture comprises a corticosteroid, such as budesonide,
wherein the aqueous inhalation
mixture is administered according to the methods and systems described herein
twice a day. In yet another
aspect, the aqueous inhalation mixture comprises a corticosteroid, such as
budesonide, wherein the aqueous
inhalation mixture is administered according to the methods and systems
described herein not more than once a
day. In still another embodiment, the aqueous inhalation mixture comprises a
corticosteroid, such as
budesonide, wherein the aqueous inhalation mixture is administered according
to the methods and systems
described herein not more than once a day in the evening.
[003991 In certain embodiments, the methods and systems described herein can
further include administering
aqueous inhalation mixtures comprising a corticosteroid in combination with
one or more active agents. In
some embodiments, the corticosteroid, e.g., budesonide, can be administered in
combination with one or more
other drugs one or more active agents selected from the group consisting of:
(a) a B2-adrenoreceptor agonist;
(b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as
a steroid; (d) a topical anesthetic;
or (e) an anti-cholinergic agent; either simultaneously with, prior to or
subsequent to the inhalable composition
provided herein.
[00400) Examples of combinations of active agents which can be used in the
methods and systems of the
present invention are provided below.
[004011 B2-Adrenoreceptor agonists for use in combination with the
compositions provided herein include, but
are not limited to, Albuterol (a-3-(((l, 1-dimethylethyl) amino) methyl)-4-
hydroxy-1, 3-benzenedimethanol);
Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-
hydroxyethyl)-1, 3-phenyleneester);
Bitolterol (4-methylbenzoic acid4-(2-((1, 1-dimethylethyl) amino)-1-
hydroxyethyl)-I, 2-phenyleneester);
Broxaterol (3-bromo-alpha-(((1, 1-dimethylethyl) amino) methyl)-5-
isoxazolemethanol); Isoproterenol (4-(1-
hydroxy-2-((I-methylethyl-) amino) ethyl)-1, 2-benzene-diol); Trirnetoquinol
(1, 2, 3, 4-tetrahydro-l-((3, 4-,5-
trimethoxyphenyl)-methyl)-6, 7-isoquinolinediol); Clenbuterol (4-amino-3, 5-
dichloro-alpha-(((1,1-
diemthylethyl) amino) methyl) benzenemethanol); Fenoterol (5-(1-hydroxy-2-((2-
(4-hydroxyphenyl)-1-
rnethylethyl) amino) ethyl)-1,3-benzenediol); Formoterol (2-hydroxy-5-((l RS)-
1-hydroxy-2-(((1 RS)-2-(p-
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methoxyphenyl)-1-methylethyl) amino) ethyl)formanilide); (R, R)-Formoterol;
Desformoterol ((R, R) or (S,S)-
3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl) amino) methyl)
benzenemethanol);
Hexoprenaline (4,4'-(1, 6-hexane-diyl)-bis (imino(1-hydroxy-2, 1-ethanediyl)))
bis-1, 2-benzenediol);
Isoetharine (4-(I-hydroxy-2-((1-methylethyl) amino) butyl)-1, 2-benzenediol);
Isoprenaline (4-(1-hydroxy-2-
((I-methylethyl) amino) ethyl)-1, 2-benzenediol); Meta-proterenol (5-(1-
hydroxy-2-((1-methylethyl)
amino)ethyl)-1, 3-benzened- iol); Picumeterol (4-amino-3,5-dichloro-cx-(((6-(2-
(2-pyridinyl) ethoxy)hexyl)-
amino) methyl) benzenemethanol); Pirbuterol (cL-6-(((1,1-dimethylethyl)-amino)
methyl)-3-hydroxy-2,6-
pyridinemethanol); Procaterol (((R*,S*)-(+-)-8-hydroxy-5-(I-hydroxy-2-((1-
methylethyl) amino)butyl)-2 (IH)-
quinolin-one); Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)
amino)-propyl)-3, 7-dihydro-1,3-
dimethyl-lH-purine- 2,6-dione) ; Rimiterol(4-(hydroxy-2-piperidinylmethyl)-1,
2-benzenediol); Salbutamol ((+-
)-alphal-(((1,1-dimethylethyl) amino) methyl)-4-hydroxy-l,3-b-
enzenedimethanol); (R)-Salbutamol;
Salmeterol((+-)-4-hydroxy-a-1-(((6-(4-phenylbutoxy)hexyl)- amino) methyl)-I, 3-
benzenedimethanol); (R)-
Salmeterol; Terbutaline (5-(2-((1, 1-dimethylethyl) amino)-1-hydroxyethyl)-1,
3-benzenediol); Tulobuterol (2-
chloro-cr-(((1, 1-dimethylethyl) amino) methyl) benzenemethanol); and TA-2005
(8-hydroxy-5-((IR)-1-hydroxy-
2-(N-((1R)-2-(4-methoxyphenyl)-I-methylethyl) amino) ethyl) carbostyri l
hydrochloride).
[00402) Dopamine (D2) receptor agonists include, but are not limited to,
Apomorphine ( (r)- 5,6, 6a, 7-
tetrahydro-6-methyi-4H-dibenzo (de,glquinotine-I0, II-dioi); Bromocriptine (
(5'. atpha.)-2-bromo-I2'-
hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)ergotaman-3', 6', 18-trione);
Cabergoline ((8-#)-N-(3-
(dimethylamino) propyl)-N-((ethylamino) carbony-1)-6-(2-propenyl) ergoline-8-
carboxamide); Lisuride (N'-
((8-a-)-9, i 0-didehydro-6- methylergolin-8-yl) -N, N-diethylurea); Pergolide
((8-(.3 )-8-((methylthio) methyl)-6-
propylergoline); Levodopa (3-hydroxy-L-tryrosine); Pramipexole ((s)-4, 5, 6, 7-
tetrahydro-N6-prop-yl-2, 6-
benzothiazolediamine); Quinpirole hydrochloride (trans-(-)-4aR-4, 4a, 5, 6, 7,
8, 8a, 9-octahydro-5-propyl-lH-
pyrazolo [3,4-g] quinoline hydrochloride); Ropinirole (4-(2- (dipropylamino)
ethyl)-1, 3-dihydro-2H-indol-2-
one); and Talipexole (5, 6, 7, 8-tetrahydro-6-(2-propenyl)-4H-thia-zolo [4,5-
d] azepin-2-amine). Other
dopamine D2 receptor agonists for use herein are disclosed in International
Patent Application Publication No.
WO 99/36095, the relevant disclosure of which is hereby incorporated by
reference.
[00403) Anti-cholinergic agents for use herein include, but are not limited
to, ipratropium bromide, oxitropium
bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna
extract, scopolamine, scopolamine
methobromide, homatropine methobromide, hyoscyamine, isopriopramide,
orphenadrine, benzalkonium
chloride, tiotropium bromide and glycopyrronium bromide.
j004041 Other active ingredients for use herein in combination therapy,
include, but are not limited to, IL-5
inhibitors such as those disclosed in U. S. Patents No. 5,668,110, No.
5,683,983, No. 5,677,280, No. 6,071,910
and No. 5,654,276, each of which is incorporated by reference herein; anti-
sense modulators of IL-5 such as
those disclosed in U. S. Pat. No. 6,136,603, the relevant disclosure of which
is hereby incorporated by
reference; milrinone (1, 6-dihydro-2-methyl-6-oxo-[3, 4'-bipyridine]-5-
carbonitrile); milrinone lactate; tryptase
inhibitors such as those disclosed in U. S. Pat. No. 5,525,623, which is
incorporated by reference herein;
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tachykinin receptor antagonists such as those disclosed in U. S. Patents No.
5,691,336, No. 5,877,191, No.
5,929,094, No. 5,750,549 and No. 5,780,467, each bf which is incorporated by
reference herein; leukotriene
receptor antagonists such as montelukast sodium (Singular, R-(E)]-1-[[[1-[3-[2-
(7-chloro-2-quinolinyl)-
ethenyl]-phenyl]-3-[2-(I-hydroxy-l-methylethyl)-phenyl]-propyl]-thio]-
methyl]cyclopro-paneacetic acid,
monosodium salt), 5-lypoxygenase inhibitors such as zileuton (Zyflo , Abbott
Laboratories, 'Abbott Park, IL),
and anti-IgE antibodies such as Xolair (recombinant humanized anti-IgE
monoclonal antibody (CGP 51901;
IGE 025A; rhuMAb-E25), Genentech, Inc. , South San Francisco, CA), and topical
anesthetics such as
lidocaine, N-arylamide, aminoalkylbenzoate, prilocaine, etidocaine (U. S.
Patents No. 5,510,339, No.
5,631,267, and No. 5,837,713, the relevant disclosures of which are hereby
incorporated by reference).
XIV. Methods of Use of Agueous Inhalation Mixtures comprisinQ a Corticosteroid
[00405] The methods and systems described herein above in Section XII herein
can deliver an aqueous
inhalable mixture comprising a corticosteroid, e.g. budesonide, to a subject
in therapeutically effective amount
for the treatment of a subject that has had or is anticipating a
bronchoconstrictive disorder selected from the
group consisting of asthma, pediatric asthma, bronchial asthma, allergic
asthma, intrinsic asthma, chronic
obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or a
combination of any of the above.
In one embodiment, the bronchoconstrictive disorder is pediatric asthma. In
another embodiment, the
bronchoconstrictive disorder is bronchial asthma. In still another embodiment,
the bronchoconstrictive disorder
is chronic obstructive pulmonary disease (COPD).
[004061 Actual dosage levels of the aqueous inhalation mixtures comprising a
corticosteroid described herein
may be varied to obtain an amount of active ingredient that is effective to
obtain a desired local therapeutic
response for a particular composition and method of administration. The
selected dosage level therefore
depends upon the desired therapeutic effect, on the desired duration of
treatment, and other factors.
XV. Pharmacokinetic Analysis
(00407) Any standard pharmacokinetic protocol can be used to determine blood
plasma concentration profile in
humans following administration of an aqueous inhalation solution. comprising
a corticosteroid, such as a
budesonide, and a solubility enhancer by the systems and methods described
herein, and thereby establish
whether that formulation meets the pharmacokinetic criteria set out herein.
For example, but in no way limiting
the type of a randomized single-dose crossover study can be perfonned using a
group of healthy adult human
subjects. The number of subjects should be sufficient to provide adequate
control of variation in a statistical
analysis, and is typically about 8 or greater, although for certain purposes a
smaller group can suffice. For
example, subject receives administration at time zero a single dose (e.g., 240
g) of a test inhalation mixture
comprising a corticosteroid, such as a budesonide, and a solubility enhancer.
Blood samples are collected from
each subject prior to administration (e.g., 15 minutes) and at several
intervals after administration. For the
present purpose it is typically preferred to take several samples within the
first hour and to sample less
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frequently thereafter. Illustratively, blood samples could be collected at 5,
10, 20, 30, 45, and 60 minutes after
administration, and then at 2, 4, 8, and 12 hours after administration. If the
same subjects are to be used for
study of a second test formulation, a period of at least 10 days should elapse
before administration of the second
formulation. Plasma is separated from the blood samples by centrifugation and
the separated plasma is
analyzed for a corticosteroid, such as a budesonide, by a validated high
performance liquid
chromatography/tandem weight spectrometry (LC/APCI-MS/MS) procedure such as,
for example, Ramu et al.,
Journal of Chromatography B, 751:49-59 (2001). In other embodiments, data from
a single subject may be
indicative of an enhanced pharmacokinetic profile. In still other embodiments,
appropriate in vitro models may
be 'used to demonstrate enhanced pharmacokinetic profiles.
1004081 Any aqueous inhalable mixture giving the desired pharmacokinetic
profile is suitable for
administration according to the present systems and methods. Exemplary types
of inhalable mixtures giving
such profiles are solutions comprising a corticosteroid, such as a budesonide,
and a solubility enhancer.
EXAMPLES
[00409] The following ingredients, processes and procedures for practicing the
compositions, systems and
methods disclosed herein correspond to that described above. The procedures
below describe specific
embodiments of inethods of delivery of an aqueous inhalation mixture
comprising budesonide as described
herein and pharmacokinetic profiles thereof. Methods, materials, or excipients
which are not specifically
described in the following examples are within the scope of the invention and
will be apparent to those skilled
in the art with reference to the disclosure herein.
Examale 1
[00410] Multiple aqueous inhalation mixtures were prepared by discharging the
contents of one or more
containers of commercially available Pulmicort Respules (1000 g budesonide
per 2 mL of the suspension),
and 82.5 mg (corrected for water content) of Captisolo (CyDex, Inc., Lenexa,
KS, USA) was added per mL of
Pulmicort Respules (dispensed volume was 2.1 mL) and vortexed for 5-10
minutes. In addition to budesonide
and water, the Pulmicort Respules also contain the following ingredients which
are believed to be inactive:
citric acid, sodium citrate, sodium chloride, disodium EDTA, and polysorbate
80.
Example 2
(00411] As an alternative method of preparation to Example 1, multiple aqueous
inhalation mixtures are
prepared by weighing approximately 200 mg amounts of CAPTISOL (CyDex, Inc.,
Lenexa, KS, USA)
(corrected for water content) into 2-dram amber vials. Into each vial
containing the weighed amount of
CAPTISOL, the contents of two Pulmicort Respules containers (0.5 mg/2 mL) are
emptied by gently
squeezing the deforrriable plastic container to the last possible drop. The
Pulmicort Respules are previously
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swirled to re-suspend the budesonide particles. The vials are screw capped,
mixed vigorously by vortex and
then foil wrapped. The material can be kept refrigerated until use.
Example 3
[004121 Table I provides exemplary formulations of aqueous inhalation mixtures
comprising budesonide and a
solubility enhancer which are used in the methods and systems described
herein. As indicated by the following
example, the aqueous inhalation mixtures can further comprise excipients,
e.g., antioxidants, stabilizing agents,
and preservatives. The amount of the various excipients to be used in the
aqueous inhalation mixture will be
relative to the dosage to be administered and will be readily ascertained by a
person having ordinary skill in the
art.
Table I
Starting Material 1% DM-,Q-CD 5% DM-j3-CD 7% DM-j3-CD 5% DM-P-CD 5% DM-ig-CD
(mg)
Budesonide 0.024 0.024 0.024 0.006 0.012
Di methyl-if3-CD 1.0 5.0 7.0 5.0 5.0
Citric Acid 0.045 0.045 0.045 0.045 0.045
Sodium Chloride 0.850 0.850 0.850 0.850 0.850
Disodium edetate 0.05 0.05 0.05 0.05 0.05
Water Ad 100.0 Ad 100.0 Ad 100.0 Ad 100.0 Ad 100.0
Example 4
[004131 Table 2 provides exemplary formulations of aqueous inhalation mixtures
comprising budesonide and a
solubility enhancer which are used in the methods and systems described
herein. As indicated by the following
example, the aqueous inhalation mixtures can further comprise excipients,
e.g., antioxidants, stabilizing agents,
and preservatives. The amount of the various excipients to be used in the
aqueous inhalation mixture will be
relative to the dosage to be administered and will be readily ascertained by a
person having ordinary skill in the
art.
Table 2
Starting Material (mg) 1% HP-l4-CD 5% HP-13-CD 7% HP-#-CD 5% HP-fl-CD 5% HP-13-
CD
Budesonide 0.024 0.024 0.024 0.006 0.012
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HP-0-CD 1.0 5.0 0.7 5.0 5.0
Citric Acid 0.045 0.045 0.045 0.045 0.045
Sodium Chloride 0.850 0.850 0.850 0.850 0.850
Disodium edetate 0.05 0.05 0.05 0.05 0.05
Water Ad 100.0 Ad 100.0 Ad 100.0 Ad 100.0 Ad 100.0
Example 5
[004141 Set forth in Table 3 are doses of aqueous inhalation mixtures
comprising budesonide and Pulmicort
Respules , and the nebulizer devices used for the delivery to the lung of said
doses. Administrations A-C were
prepared by diluting the aqueous inhalation mixtures prepared as described in
Example 1 with 0.9% (w/w)
saline in the following manner: Administration A was diluted at a 25:75 ratio
with 0.9% (w/w) saline;
Administration B was diluted at a 50:50 ratio with 0.9% (w/w) saline; and
Administration C was not diluted.
The budesonide + SBE7-a-CD (Captisol') inhalation solutions were delivered
using a Pari eFlow Inhaler'$' in a
0.5 ml volume with a delivery time of about 1.5 minutes. The Pari eFlow
Inhaler was fitted with a size 30
mesh membrane and a small size aerosol chamber. The Pulmicort Respules were
administered using a Pari LC
Plus jet nebulizer in a 2.0 ml volume with an administration time of about 5
minutes.
Table 3
Study No. Admin. Dose Inhaler
1 A 60 g 99mTc-DTPA labeled budesonide + SBE7-(3-CD Pari eFlow inhaler
inhalation solution
2 B 120 Ftg 99mTc-DTPA labeled budesonide + SBE7-p- Pari eFlow inhaler
CD inhalation solution
3 C 240 g 99mTc-DTPA labeled budesonide + SBE7-/3- Pari eFlow inhaler
CD inhalation solution
4 D 500 i.cg budesonide suspension Pari LC Plus jet
(Pulmicort Respules ') nebulizer
E 1000 g budesonide suspension Pari LC Plus jet
(Pulmicort Respules ) nebulizer
Example 6
1004151 Clinical evaluation was conducted by performing gamma scintigraph
analysis on subjects before and
after administration of the dosage form by nebulization. The purpose of the
study is to determine, by gamma
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scintigraphy, the intra-pulmonary deposition of radiolabeled budesonide
following nebulization of a budesonide
suspension or a solution with a solubility enhancer.
1004161 Set forth in Table 4 is a summary of the data related to percent lung
deposition for Administrations A
to C as delivered by the methods described in Example 5. Percent lung
deposition is the mean value for all
subjects evaluated and was deten,nined by quantification of scintigraphy data
taken for each Administration.
Figure 1 shows percentage of total lung deposition and oropharyngeal
deposition of an inhalable composition
comprising budesonide. Figure 2 shows total lung deposition of budesonide from
scintigrapgy data.
Table 4
Target Dose True nominal Dose Corrected Lung Dose Percent Lung
Admin (pg) (pg) ( g) Deposition
A 60 60.69 f 1.95 21.72 :L 4.81 35.7
B 120 121.16 ~ 4.29 49.26 10.13 40.6
C 240 234.85 ~ 2.74 88.13 14.93 37.5
Example 7
1004171 Set forth in Table 5 is the summary of the pharmacokinetic profiles
for budesonide following a single
dose delivery of Administrations A to E as set forth in Example 5. Eight (8)
healthy males were used in this
clinical study and the values presented below are the mean values for each of
the pharmacokinetic parameters
measured during the clinical study. FIG. 4 provides a graphic representation
of the data used to generate the
pharmacokinetic profiles for Administrations A to E.
Table 5
C.x AYJC(last) AUC(aINF)
Administration (pg/ml) T,,,,X (h) (pg/mUh) (pg/ml/h) T%u (h)
Admin A(60 g BUD- Mean 227.6 0.11 179.17 262.93 1.24
SBE7-9-CD, Pari eFlow) SD 89.67 0.09 75.47 125.14 0.59
Admin B (120 g BUD- Mean 578.2 0.11 569.68 679.85 2.08
SBE7-0-CD, Pari eFlow) SD 238.69 0.09 213.22 201.53 0.93
Admin C(240 g BUD- Mean 1195.33 0.21 1183.45 1365.27 2.81
SBE7-(3-CD, Pari eFlow) SD 811.61 0.24 328.57 313.04 0.57
Admin D (500 g BUD, Mean 556.74 0.24 739.99 867.56 2.18
Pari LC Plus) SD 193.63 0.25 220.09 216.95 1.1
Admin E(1000 g BUD, Mean 1114.83 0.23 1989.93 2083.5 2.33
Pari LC Plus) SD 593.16 0.24 379.46 394.37 0.66
Example S
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[004181 Table 6 provides the doses for the study medications used in the
clinical study set forth in Example 8
(described in detail below). The study medications comprised two test
formulations of inhaled Captisol-
Enabled Budesonide Inhalation Solution (CBIS) (Treatments A and B) and two
reference formulations of
inhaled budesonide suspensions (Pulmicort Respules) (Treatments C and D), and
the nebulizer devices used
for the delivery to the lung of said study medications.
Table 6
Treatment Dose Inhaler
A 60 g CBIS (60 pg Budesonide, 2% Captisol ) Pari eFlow inhaler
B 120 g CBIS (120 g Budesonide, 4% Captisol(D) Pari eFlow inhaler
C 250 g Pulmicort Respules (250 g Budesonide Pari LC Plus jet nebulizer
suspension)
D 500 g Pulmicort Respules (500 g Budesonide Pari LC Plus jet nebulizer
suspension)
[004191 Individual components of the test and reference formulations are
detailed in Table 7.
Table 7
Treatment Treatment B Treatment C Treatment D
A Test Reference Reference
Component Ingredient 60 g CBIS 120 g CBIS 250 pg PR 500 g PR
Active Approx Approx
Ingredient Budesonide 60 g! 120 g/ 250 g/2mL 500 g/2mL
0.5 mL 0.5 mL
Solubilizing
Agent Captisol 2% 4% None None
Chelating
Agent EDTA 0.01% 0.01% 0.01% 0.01%
Isotonicity NaCf 0.85 % 0.85% 0.85% 0.85%
Buffer(s) Na Citrate 0.05 % 0.05% 0.05% 0.05%
Citric Acid 0.03% 0.03% 0.03% 0.03%
Examule 9
[00420) Set forth in Table 8 is the summary of the pharmacokinetic profiles
for budesonide following a single-
centre, double-blind, multiple dose, parallel group, placebo controlled, two
period crossover study involving
Administrations A to D as set forth in Example 8. Forty-eight (48) healthy
male volunteers were used in this
clinical study. Each subject that qualified for the study was randomized to
receive one of the following
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treatments: Treatment A (60 g CBIS solution), Treatment B (120 g CBIS
solution), Treatment C (250 g
Pulmicort Respule Respule suspension (250 g Pulmicort)), Treatment D (500 g
Pulmicort Respule
suspension (500 g Pulmicort)). The Subjects received Treatment A, B, C or D
twice daily for seven days.
Each subject received active drug and placebo crossed over two study periods.
Table 8 provides the values for
each of the pharmacokinetic parameters measured in the study for the
administration of Treatments A-D during
the clinical study.
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Table 8
Dose Summary Cmax Tmax AUC(,ast) AUC(a,Nn 0/2
Statistic (pg/ml) (h) (pg/ml.h) (pg/ml.h) (h)
Treatment A N 12 12 12 12 12
(60 ug CBI S)
Mean 402.001 0.117 310.861 424.875 2.4860
SD 192.549 0.058 95.652 157.589 2.9550
Min 186.370 0.08 106.380 156.520 0.7000
Median 378.730 0.08 317.000 409.780 1.6800
Max 779.340 0.25 463.070 748.450 11.7200
CV (0/-) 47.898 NIA 30.800 37.100 118.9000
Geo. Mean 362.202 N/A 293.699 396.119 1.8370
Treatment B N 11 11 11 11 11
(120 g CBIS)
Mean 625.337 0.14 726.658 860.632 2.4270
SD 357.439 0.13 417.236 464.844 0.9530
Min 169.800 0.08 168.220 221.420 1.5000
Median 735.280 0.08 576.370 740.700 1.9800
Max 1160.440 0.50 1496.720 1863.680 4.4000
CV (%) 57.159 N/A 57.400 54.000 39.3000
Geo. Mean 516.991 N/A 621.429 752.164 2.2840
Treatment C N 11 11 11 11 11
(250 g Pulmicort)
Mean 319.673 0.22 361.162 472.314 2.0230
SD 185.337 0.22 212.378 239.042 0.9370
Min 107.450 0.08 78.570 148.720 0.9100
Median 231.560 0.08 318.120 425.030 1.7600
Max 574.720 0.75 803.030 920.020 4.3200
CV (%) ' 57.977 N/A 58.800 . 50.600 46.3000
Geo. Mean 270.563 N/A 302.632 413.000 1.8600
Treatment D N 12 12 12 12 12
(500 g Pulmicort)
Mean 491.398 0.186 811.145 945.718 2.4930
SD 207.942 0.193 328.022 363.252 0.7700
Min 199.390 0.08 236.220 381.480 1.2100
Median 474.310 0.08 856.320 952.860 2.4600
Max 963.250 0.75 1224.800 1454.800 3.6600
CV (%) 42.316 N/A 40.400 38.400 30.9000
Geo. Mean 451.661 N/A 735.111 874.697 2.3720
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Example 10
[004211 The aqueous inhalation mixtures set forth in Examples 3 and 4 are
delivered to a patient population
according the methods set forth in Example 5. Pulmicort Respules'o is likewise
administered according the
methods set forth in Example 5. The pharmacokinetic profile of the aqueous
inhalation solutions will exhibit
enhanced pharmacokinetic parameters as compared to the pharmacokinetic profile
of the Pulmicort Respules .
For example, the aqueous inhalation solutions will display greater C,,,,,,
AUCtj,s,', AUCto.,j values and/or lower
T,,,a,, values as compared to Pulmicort Respules . Likewise, the aqueous
inhalation solutions will display equal
Cmaõ, AUCt,,s,t, and AUCIa_.4 values as compared to Pulmicort Respules if
administered at a lower dosage.
Example 11
(00422] The aqueous inhalation mixtures set forth in Examples I and 2 are
delivered to a patient population
according the methods set forth in Example 5. Pulmicort Respulesat a nominal
dosages ranging from 1000
g/dose up to 2500 g/dose, are administered according the methods set forth in
Example 5. The
pharmacokinetic profile of the aqueous inhalation solutions will exhibit
enhanced pharmacokinetic parameters
as compared to the pharmacokinetic profile of the Pulmicort Respules . For
example, the aqueous inhalation
solutions will display substantially equal C,,,,,,, AUCt,astl, AUCto_ ~ values
as the Pulmicort Respules even
though the nominal dosages to be administered are substantially lower.
Example 12
(004231 Preparation and use of an aqueous inhalation mixture containing a
corticosteroid, a solubility enhancer
and albuterol sulfate or levalbuterol HCI (Xopenex).
(004241 A citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately
62.5 mg of citric acid is
dissolved in and brought to volume with water in one 100 ml volumetric flask.
Approximately 87.7 mg of
sodium citrate is dissolved in and brought to volume with water in another 100
mL volumetric flask. In a
beaker, the sodium citrate solution is added to the citric acid solution until
the pH is approximately 4.5.
[004251 Approximately 10.4 mg of budesonide and 1247 mg of Captisol '(CyDex
Inc.) are ground together
with a mortar and pestle and transferred to a 10 mL flask. Buffer solution is
added, and the mixture is vortexed,
sonicated and an additional 1.4 mg budesonide is added. After shaking
overnight, the solution is filtered
through a 0.22 m Durapore Millex-GV Millipore syringe filter unit. The
resulting budesonide concentration is
about I mg/mi. Approximately 0.5 ml of the budesonide solution is added to a
unit dose of either Proventil
(2.5 mg/3 mL) or Xopenex (1.25 mg/3 mL) thereby forming a clear aqueous
inhalation mixture suitable for
use in an inhalation nebulizer as described in Example 5.
Example 13
[004261 Preparation and use of an aqueous inhalation mixture containing a
corticosteroid, a solubility enhancer,
and formoterol (FORADIL ; (formoterol fumarate inhalation powder)).
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[00427) The contents of one capsule containing 12 g of formoterol fumarate
blended with 25 mg of lactose is
emptied into a via] to which is added 3 mL of 3 mM citrate buffer (pH 4.5)
prepared as described in Example
12. The contents of the via] are vortexed to dissolve the solids present. The
budesonide concentrate is prepared
as described in Example 9 to provide a concentration of 1 mg/mL.
[004281 Approximately I ml of the budesonide solution is added to the
formoterol fumarate buffered solution.
The combination is a clear aqueous inhalation mixture suitable for use in an
inhalation nebulizer as described in
Example 5.
Example 14
[004291 The aqueous inhalation mixtures set forth in Examples 12 and 13 are
delivered to a patient population
according the methods set forth in Example 5. Pulmicort Re'spules is likewise
administered according the
methods set forth in Example 5. The pharmacokinetic profile of the aqueous
inhalation mixtures will exhibit
enhanced pharmacokinetic parameters as compared to the pharmacokinetic profile
of the Pulmicort Respules .
For example, the aqueous inhalation solutions will display,greater C,,,a,,
AUC(,d5t), AUCto_,4 values and/or lower
T,,,. values as compared to Pulmicort Respules if administered at the same
nominal dosage. Likewise, the
aqueous inhalation solutions will display equal C,,,a,,, AUC(us,), and
AUCto.o~ values as compared to Pulmicort
Respules if administered at a lower nominal dosage.
Example 15
[004301 Using traditional cascade impactor for in vitro testing of particle
sizes, the following deposition
characteristics are observed for both a budesonide solution and a Pulmicort
Respule suspension. The
budesonide solution was nebulized using a PARI eFlow device. The Pulmicort
Respule suspension was
nebulized using a PARI LC Plus nebulizer. These results are further
transformed in pulmonary deposition
efficiencies are shown in Table 9, using different definitions of pulmonary
deposition as function of the stage
range (Stage 3-7, Stage 4-7, Stage 5-7). Table 10 shows that dependent on the
stage range used for pulmonary
deposition (stage 3-7, stage 4-7, stage 5-7) the ratio of pulmonary deposition
(expressed as the ratio of
eFlow/Pari LC plus depositions) ranges from 1.2, 1.9 to 3.8 for stage 3-7,
stage 4-7 or stage 5-7, respectively.
Fine particle fraction is defined as particle sizes less than 4.7 m (Bosco AP
et a1., In Vitro Estimation of In
Vivo Jet Nebulizer Efficiency Using Actual and Simulated Tidal Breathing
Patterns, Journal of Aerosol
Medicine 18(4): 427-38 (2005); herein incorporated by reference in its
entirety).
Table 9
Stage Number Size Stage Deposition
eFLOW with Budesonide Solution Pari LC Plus with Pulmicort
m % %
3 5.36 5 32
4 3.3 20 28
2.08 40 13
6 1.36 24 4
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7 0.95 5 l
Filter <0.95 3
Table 10
Stage Range Size Range % Pulmonary be osition
m eFLOW with Budesonide Solution Pari LC Plus with Pulmicort Ratio
Stage 3-7 5.36-0.98 94 78 1.2
Stage 4-7 3.3-0.98 89 46 1.9
Stage 5-7 2.08-0.98 69 18 3.8
-filter=0.98 m
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