Note: Descriptions are shown in the official language in which they were submitted.
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ALBUTEROL INHALATION SOLUTION, SYSTEM, KIT AND METHOD FOR RELIEVING
SYMPTOMS OF PEDIATRIC ASTHMA
II. FIELD OF THE INVENTION
The present invention relates to an albuterol inhalation solution, system, kit
and
method for relieving symptoms associated with asthma in children.
M. BACKGROUND OF INVENTION
Asthma is a pulmonary disease marked by (1) labored breathing; (2) wheezing;
and
(3) coughing. Asthma is characterized by: (1) airway inflammation; (2) airway
hyperrespunsiveness; and (3) airway obstruction (or airway narrowing) that is
partially dr
completely reversible, either spontaneously or with treatment. Common symptoms
of asthma
include wheezing, shortness of breath, tightness in the chest and a persistent
cough. The
severity of the symptoms vary widely from patient to patient, and even from
one episode
(attack) to the next.
A key condition of asthma is chronic inflammation of the linings of the lungs.
This
inflammation is associated with an increase in airway sensitivity
(hyperresponsiveness) to
stimuli such as allergens, irritants, cold air and viruses. When exposed to
these triggers, the
linings undergo an allergic reaction, causing spasms that constrict the
airways. This
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bronchoconstriction, in combination with edema and the release of thickened
secretions,
reduces movement of air through the lungs, resulting in the symptoms commonly
associated
with asthma.
Asthma is the most common chronic lung disease in children. Asthma prevalence
in
children has reportedly increased in the United States by 160%. Asthma
hospitalization rates
are also higher in young children due, in part, to difficulties in using
currently available drug
delivery devices and failure to use optimal doses of asthma therapies.
Despite progress in emergency and critical care medicine, the pediatric
mortality rate
from asthma ranges from 0.2 to 0.4 per 100,00 population, depending on age.
Pediatric
asthma ranks as the 7th leading cause of death among children ages 10 to 14
years.
Approximately 0.05% of known children with asthma die annually from the
disease.
Short-acting inhaled beta-agonists, such as albuterol, are the first choice
treatment for
relieving symptoms of acute asthma in children. Albuterol is currently
available as a 2.5 mg
unit dose (0.083%) inhalation solution for use in nebulizers. Although this
dose has been
approved for use by adults, the FDA has recently expanded labeling guidelines
to include this
amount of albuterol for use by pediatric asthmatic patients as young as 2
years old. However,
when administered on a regular basis to a child, the 2.5 mg formulation may
provide more
albuterol than needed, thereby increasing the risk of adverse drug effects.
In the recently revised guidelines for asthma treatment, the National
Institutes of
Health recommended that pediatric patients use the lowest beta-agonist doses
needed to
control symptoms. However, using lower doses of albuterol in patients under
age 12 to
reduce the risk of side effects necessitates dilution of currently available
asthma medications.
This poses several problems because parents, care givers, teachers and others
typically do not
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have adequate experience diluting these medications, resulting in
contamination or
inappropriate dosing, among other problems.
Also, antimicrobial preservatives, such as benzalkonium chloride (BAC), are
often
present in inhalation solutions used to treat asthma and chronic obstructive
pulmonary disease
(COPD). The presence of BAC in these solutions generally does not affect the
short-term
(single dose) bronchodilator response. However, case reports suggest that
repeated use of
asthma treatments with BAC may result in paradoxic bronchoconstriction. When
inhaled by
asthmatic subjects, BAC may also cause dose-dependent bronchoconstriction.
Despite these
side effects, many commercially available albuterol inhalation solutions
contain BAC.
There is, therefore, a need for an improved albuterol inhalation solution,
system, kit
and method for relieving symptoms associated with pediatric asthma.
IV. SUMMARY OF THE INVENTION
One object of the present invention is to provide an albuterol inhalation
solution for
the relief of bronchospasm in children with asthma. Another object of the
present invention
is to provide a prepackaged, sterile, premixed, premeasured, reduced-dosage
albuterol
inhalation solution for the relief of bronchospasm in patients 2 to 12 years
of age with
asthma.
It is yet another object of the present invention to provide an antimicrobial
preservative-free albuterol inhalation solution to relieve bronchospasm in a
pediatric patient
with asthma.
A further object of the present invention is to provide a method of
administering an
albuterol inhalation formulation for relief of bronchospasm associated with
pediatric asthma.
An additional object of the present invention is to provide a kit or system
for relief of
bronchospasm in a pediatric patient with asthma.
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A further object of the present invention is to provide a process for making
an
inhalation solution for relief of bronchospasm in a pediatric patient with
asthma.
Another object of the invention includes a device for use in relieving
bronchospasm in
a pediatric patient with asthma.
Other objects, features and advantages of the present invention will be
apparent to
those of ordinary skill in the art in view of the following detailed
description of the invention
and accompanying drawings.
V. BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1-4 depict a non-limiting example of administering the inhalation
solution of
the present invention by a nebulizer.
Figure 5 depicts a non-limiting example of a unified prepackaged kit or system
of the
present invention.
Figure 6 depicts a non-limiting example of one or more pre-filled containers
comprising the inhalation system of the present invention.
Figure 7 depicts a non-limiting example of a label utilized in the present
invention.
VI. DETAILED DESCRIPTION OF THE INVENTION
Albuterol
The present invention relies on the bronchodilation effects of albuterol to
provide
relief from symptoms associated with pediatric asthma. As used herein, the
term "albuterol"
includes, but is not limited to, any form of albuterol which is capable of
producing a desired
bronchodilation effect in pediatric patients, including, but not limited to,
all tautomeric forms,
enantomeric forms, stereoisomers, anhydrides, acid addition salts, base salts,
solvates,
analogues and derivatives of albuterol.
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In the present invention, acceptable salts of albuterol may include, but are
not limited
to, hydrochloride, sulfate, maleate, tartrate, citrate and the like. These and
other acceptable
salts are described in U.S. Patent No. 3,644,353.
In the present invention, the preferred salt of albuterol is sulfate. In an
alternative
embodiment, the inhalation solution of the present invention comprises the
sulfate salt of
racemic albuterol. Albuterol sulfate is a relatively selective beta-2-
adrenergic bronchodilator
with an empirical formula of C13H21NO3. The chemical name for albuterol
sulfate is a1-
[(tert-
butylamino)methyl]-4-hydroxy-m-xylene-a, a'-diol sulfate (2:1)(salt), and its
established
chemical structure is as follows:
LOCH'
LHOHCHaNHCCH3J.HaSO4 ..
In the present invention, the albuterol may be provided in a variety of
pharmaceutically acceptable vehicles, including, but not limited to, water or
other aqueous
solutions comprising a pharmaceutically acceptable amount of an osmotic agent.
In one alternative embodiment, the inhalation solution of the present
invention
comprises a therapeutically effective pediatric amount of albuterol. As used
herein the phrase
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"therapeutically effective pediatric amount of albuterol" means a safe and
tolerable amount of
albuterol for pediatric patients, as based on industry and/or regulatory
standards. Such
amount being sufficient to effectively induce bronchodilation and/or provide
relief of
bronchospasm in children.
In the inhalation solution of the present invention, a therapeutically
effective pediatric
amount of albuterol may include about 0.63 mg or about 1.25 mg albuterol.
Here, the
potency of the albuterol is equivalent to about 0.75 mg and about 1.50 mg of
albuterol
sulfate, respectively. In an alternative embodiment, a therapeutically
effective pediatric
amount of albuterol may include from about 0.63 mg to about 1.25 mg of
albuterol. In
another alternative embodiment, such pediatric amount comprises no more than
about 1.25
mg of albuterol, or it comprises 1.25 mg of albuterol or less.
In another alternative embodiment of the present invention, a therapeutically
effective
pediatric amount of albuterol may include from about 0.08 mg to about 1.90 mg
albuterol,
including the following intermediate amounts of albuterol: about 0.08 mg to
about 0.20 mg;
about 0.21 mg to about 0.50 mg; about 0.51 mg to about 0.60 mg; about 0.61 mg
to about
0.70 mg; about 0.71 mg to about 0.80 mg; about 0.81 mg to about 0.90 mg; about
0.91 mg to
about 1.0 mg; about 1.01 mg to about 1.05 mg; about 1.06 mg to about 1.10 mg;
about 1.11
mg to about 1.15 mg; about 1.16 mg to about 1.20 mg; about 1.21 mg to about
1.25 mg;
about 1.26 mg to about 1.30 mg; about 1.31 mg to about 1.35 mg; about 1.36 mg
to about
1.40 mg; about 1.41 mg to about 1.45 mg; about 1.46 mg to about 1.50 mg; about
1.51 mg to
about 1.55 mg; about 1.56 mg to about 1.60 mg; about 1.61 mg to about 1.65 mg;
about 1.66
mg to about 1.70 mg; about 1.71 mg to about 1.75 mg; about 1.76 mg to about
1.80 mg;
about 1.81 mg to about 1.85 mg; about 1.86 mg to about 1.90 mg.
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In another alternative embodiment of the present invention, a therapeutically
effective
pediatric amount of albuterol may include from about 0.1 mg to about 2.5 mg
albuterol
sulfate, including the following intermediate amounts of albuterol sulfate:
about 0.1 mg to
about 0.2 mg; about 0.3 mg to about 0.4 mg; about 0.5 mg to about 0.6 mg;
about 0.7 mg to
about 0.8 mg; about 0.9 mg to about 1.00 mg; about 1.01 mg to about 1.20 mg;
about 1.21
mg to about 1.40 mg; about 1.41 mg to about 1.60 mg; about 1.61 mg to about
1.80 mg;
about 1.81 mg to about 2.00 mg; about 2.01 mg to about 2.20 mg; about 2.21 mg
to about
2.40 mg; about 2.41 mg to about 2.50 mg.
In another alternative embodiment of the present invention, a therapeutically
effective
pediatric amount of albuterol may include from about 0.002 % to about 0.075 %
by weight
albuterol, including the following intermediate amounts of albuterol: about
0.002 wt % to
about 0.010 wt %; about 0.011 wt % to about 0.020 wt %; about 0.021 wt % to
about 0.030
wt %; about 0.031 wt % to about 0.040 wt %; about 0.041 wt % to about 0.050 wt
%; about
0.051 wt % to about 0.060 wt %; about 0.061 wt % to about 0.070 wt %; about
0.071 wt % to
about 0.075 wt %.
In another alternative embodiment of the present invention, a therapeutically
effective
pediatric amount of albuterol may include from about 0.003 % to about 0.1 % by
weight
albuterol sulfate in solution, including the following intermediate amounts of
albuterol
sulfate: about 0.003 wt % to about 0.010 wt %; about 0.011 wt % to about 0.020
wt %; about
0.021 wt % to about 0.030 wt %; about 0.031 wt % to about 0.040 wt %; about
0.041 wt % to
about 0.050 wt %; about 0.051 wt % to about 0.060 wt %; about 0.061 wt % to
about 0.070
wt %; about 0.071 wt % to about 0.080 wt %; about 0.081 wt % to about 0.090 wt
%; about
0.091 wt % to about 0. 10 wt %.
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Most pharmaceutical inhalation solutions contain an antimicrobial preservative
such
as BAC or EDTA. One problem with BAC-containing solutions is that the BAC may
cause
paradoxic bronchoconstriction if the solution is administered repeatedly over
short intervals.
Another problem is that, when inhaled by asthmatic patients, the BAC can cause
dose-
dependent bronchoconstriction. The inhalation solution of the present
invention may be
provided without BAC, thereby making it more suitable for pediatric patents,
especially in an
emergency situation where the inhalation solution is administered repeatedly
over a short
period of time. Also, administering a BAC-free inhalation solution to a
pediatric patient
reduces the concomitant liability of adverse effects associated with BAC. It
also reduces the
toxicity and other side effects associated with BAC.
The inhalation solution of the present invention may also be provided in
sterile, unit
dose treatments, thus eliminating the need to include BAC in the solution.
Moreover, as
shown in Table 1, in its sterile form the formulation of the present invention
(which
comprises a therapeutically effective pediatric amount of albuterol) provides
a stable
pediatric inhalation solution such that the formulation can be stored (e.g.,
on a shelf) for long
periods of time.
Table 1
Stability Data
0.021 wt % Albuterol 0.042 wt % Albuterol
Assay* pH Osmolality Assay* pH Osmolality
( O g) )
Time zero 98 3.5 289 100 3.5 291
25 C/35%RH 12 months 99 3.5 289 100 3.5 291
24 months 101 3.5 294 100 3.5 292
40 C/15%RH 3 months 99 3.6 290 100 3.6 291
6.5 months 96 3.5 290 99 3.5 292
* as percent of label claim (0.021 wt % and 0.042 wt % albuterol,
respectively).
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Another benefit of a sterile inhalation solution is that it reduces the
possibility of
introducing contaminants into the patient when administered, thereby reducing
the chance of
an opportunistic infection in the patient.
As stated, the compositions provided herein are stable. For example, the
compositions provided herein are stored between about 15 C and about 30 C, and
remain
stable for a relatively long period of time. In one embodiment, the
compositions are stored at
25 C.
In another embodiment, the stability of the compositions provided herein may
contain
greater than 80%, 85%, 90% or 95% of the initial amount of active ingredient,
i.e., Albuterol,
at a given temperature for a long period of time. Thus, for example, a
composition that is
stable for 30 days at 25 C would have greater than 80%, 85%, 90% or 95% of the
initial
amount of active ingredient present in the composition at 30 days following
storage at 25 C.
In another embodiment, the compositions herein are stable during long term
storage,
in that the compositions are suitable for administration to a subject in need
thereof when the
compositions have been stored for a length of time (i.e., shelf-life) for a
period greater than 1,
2 or 3 years at 25 C. In other embodiments herein, using Arrhenius Kinetics,
>80% or >85%
or >90% or >95% estimated bronchodilating agent remains after such storage,
for example.
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Other indications of the stability of the present compositions can be shown in
terms of
by-products or degradation products present over time, as shown in Table 2
below.
TABLE 2
Degradation products/related compounds Range at 6 to Range in drug
as % of albuterol 18 25months at substance
5-2-((1,1-Dimethylethyl)amino-l-hydroxyethyl)-2- ND-0.012%
hydroxybenzaldehyde w/w
2 Bis-(2-hydroxy0-5-(2-tertbutylamino-l-hydroxyethyl) phenylmethyl 0.09 -
0.174%
ether w/w
3 2-tert-butylamino-l-(4-hydroxy-3-methoxymethylphenyl)-ethanol 0.01-0.12%
w/w
4 Tert-butylamino-3-chloro-4-hydroxy-5-hydroxymethylacetophenone ND - 0.0002%
w/w
Tert-butylamino-4-hydroxy-5-hydroxymethylacetophenone ND - 0.002%
w/w
6 1-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol 0.0009-
0.036% w/w
7 1-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ND
ethanol
ND - 0.06%
8 Any other unknown
by peak area
9 Total 0.1-0.38%
ND=none detected
In one embodiment, the compositions produced herein are at least substantially
clear,
based on color measurement tests set forth by the America Public Health
Association
("A-PHA"). For example, the APHA color results for compositions herein at upto
24 months
at 25 C may range from less than 10 units, or preferably 0 to 5 units, most
preferably 0 units
as based on APHA standards.
In one embodiment, the process of the present invention provides compositions
having an albuterol content of about 0.021% or 0.042% per vial. In another
alternative
embodiment, the process of the present invention provides compositions having
an albuterol
content of about 0.0197% to about 0.0218%w/v, about 0.0201% to about 0.0214%
w/v, about
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0.0394% to about 0.0436% w/v and about 0.0403% to about 0.0428% w/v per vial.
In yet
another alternative embodiment, the process of the present invention provides
an average fill
volume of about 2.80 ml to about 3.30 ml into each vial.
In another alternative embodiment, the process of the present invention
provides
compositions that may contain minimal amounts of contaminants including, but
not limited to
the following:
TABLE 3
1. Volatiles
acetone none detected to about NMT 0.2 mcg/ml
ethyl acetate none detected to about NMT 0.3 mcg/ml
n-heptane none detected to about NMT 0.1 mcg/ml or less
n-propyl acetate none detected to about NMT 0.3 mcg/ml
toluene none detected to about NMT 0.lmcg/ml
2-butanone none detected to about NMT 0.3mcg/ml
unknowns
2. Leachables
Irganox 129 none detect to about NMT 0.02mcg/ml
Extractable 1 none detected (signal/noise NMT 3)
Extractable 2 none detected (signal/noise NMT 3)
unknowns none detected (signal/noise NMT 3)
In another alternative embodiment, such compositions may also contain minimal
amounts of particulate matter, including, but not limited to the following:
about NMT 1000 to
5000 particles, preferably about NMT 3800 particles/vial >2mm; about NMT 10 to
about 100
particles, preferably about 80 particles/vial >l0mcm; or about NMT 1 to about
5 particles,
preferably about NMT 3 particles/vial >25mcm.
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Adherence to asthma medication therapy and prevention of asthma medication
error
are considerable problems. These problems can be significantly reduced by
providing
asthmatic patients a prepackaged, premixed, premeasured amount of albuterol.
Providing
albuterol in this fashion makes asthma therapy simple because it increases
convenience and
eliminates confusion in preparing appropriate dosages. These advantages are
especially
significant in the treatment of pediatric asthma, where treatments often come
in multiple
dosage units and must be diluted to specific concentrations suitable for
treating a pediatric
patient. This poses several problems. For instance, asthma treatments
requiring
administration of a single dose unit from multiple dosage units sometimes lack
proper mixing
or diluting instructions, or the instructions for preparing and using the
asthma treatment may
be hard to follow or can be easily lost. Of even greater importance is
haphazard diluting or
mixing of asthma medications, which can result in administering the wrong
dosage. This
could be especially harmful for pediatric patients, who often are less
tolerant to higher
dosages of albuterol. Incorrect mixing can also result in treatment failure
such that additional
medical attention is required, thereby increasing the time, expense, and
personnel costs
associated with therapy.
The present invention overcomes the aforementioned problems by providing
therapeutically effective pediatric amounts of albuterol in prepackaged,
premixed,
premeasured and/or unit dose amounts. In one embodiment, the present invention
comprises
one or more prefilled containers. The one or more containers each comprising a
single unit
dose of an aqueous solution comprising a therapeutically effective pediatric
amount of
albuterol for the relief of bronchospasm associated with pediatric asthma.
Providing the
inhalation solution in such a manner eliminates the need to dilute or mix
asthma medications
to obtain proper dosages for treatment. Also, no special pharmacy compounding
is required,
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and the chance of medication errors are reduced. Further, there is a lower
risk of cross-
contamination, and less waste of medication when providing an inhalation
solution in a
premixed, ready to use form.
Other features of the present invention include improved user compliance and
quality
of life as compared to conventional treatments for relieving bronchospasm in
children. While
the level of compliance of any asthma treatment depends in part on the
motivation and skill
of the individual dispensing the treatment, compliance nevertheless may be
improved by
controllable factors such as the ease with which the treatment may be
administered, as well as
the desirability of receiving the treatment.
The present invention provides a convenient, fast and reliable treatment for
relieving
bronchospasm in children, and clearly represents an improvement over
traditional asthma
treatments. Also, the present invention is designed to facilitate user
compliance by providing
one or more dispensing containers comprising a premixed, premeasured
inhalation solution
comprising a single unit dose of a therapeutically effective pediatric amount
of albuterol for
the relief of bronchospasm in children. Said containers may be utilized in a
method of
relieving such bronchospasm, or the containers may be incorporated in a system
and/or kit for
treating the same.
In one alternative embodiment, the formulation of the present invention is a
sterile,
premixed, premeasured, BAC-free inhalation solution comprising a single unit
dose of a
therapeutically effective pediatric amount of albuterol in a single container.
Each unit dose
container comprises either 0.75 mg/3 ml of albuterol sulfate (equivalent to
0.63 mg of
albuterol) or 1.50 mg/3 ml of albuterol sulfate (equivalent to 1.25 mg of
albuterol) in a sterile,
aqueous solution. Sodium chloride may be added to adjust the isotonicity of
the solution and
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sulfuric acid may be added to adjust pH of the solution to about 3.5. The
inhalation solution
of the present invention may or may not include a chelating agent, such as
EDTA.
In another alternative embodiment, the inhalation solution of the present
invention
may be supplied as a 3 ml, sterile, BAC-free, nebulizer solution comprising
from about 0.75
mg/3 ml to about 1.50 mg/3 ml of albuterol sulfate (equivalent to about 0.63
mg to about 1.25
mg of albuterol, respectively). The nebulizer solution is contained in a unit-
dose, low-density
polyethylene (LDPE) container. Each unit-dose container may be disposed in a
foil pouch,
and each foil pouch may contain 5 or more unit-dose containers. Each foil
pouch containing
the unit dose container may be disposed in a shelf carton.
The present invention provides an albuterol inhalation solution for relieving
bronchospasm in a pediatric patient with asthma, including, but not limited
to, allergic
(extrinsic) asthma, non-allergic (intrinsic) asthma, occupational asthma and
aspirin sensitive
asthma. The present invention also provides an albuterol inhalation solution
for relieving
bronchospasm associated with different classes of pediatric asthma including,
but not limited
to, severe persistent asthma, moderate persistent asthma, mild persistent
asthma and mild
intermittent asthma. Some characteristics associated with the different
classes of asthma are
shown in Table 2. The information in this table is presented for illustrative
purposes only. It
is not intended to limit the scope of the invention.
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Table 4
Type of Asthma Description
Severe Persistent = Continual symptoms during the day;
= Frequent symptoms at night;
= 60% of lower predicted values for DEV; and
>60% or lower of personal best PEF, and more than 30% PEF variability.
Moderate Persistent = Some symptoms every day;
= Nighttime symptoms five or more nights a month; and
>60% and <80% of PEF or FEVI and greater than 30% FEVI variability.
Mild Persistent = Daytime symptoms 3-6 days a week;
= Symptoms at night 3-4 times a month; and
80% or higher PEF or FEVI and PEF variability of 20-30%.
Mild Intermittent = Daytime symptoms 2 or fewer times a week;
= Nighttime symptoms 2 or fewer times a month; and
80% or higher PEF or FEVI and PEF variability <20%.
In the present invention, a therapeutically effective pediatric amount of
albuterol is
administered to induce bronchodilation and/or provide relief of bronchospasm
in pediatric
patients with asthma. Such amount of albuterol may be administered to a
pediatric patient
after the onset of bronchospasm to reduce breathing difficulties resulting
from asthma. In
another embodiment, the albuterol may be administered prophylactically, that
is, to prevent
or to reduce the extent of bronchospasm.
The quantity of albuterol to be administered will be determined on an
individual basis,
and will be based at least in part on consideration of the patient's size, the
severity of the
symptoms to be treated and the results sought. The actual dosage (quantity of
albuterol
administered at a time) and the number of administrations per day will depend
on the mode of
administration, such as inhaler, nebulizer or oral administration. For
example, about 0.63 mg
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to about 1.25 mg of albuterol given by nebulization one or more times per day
would be
adequate to produce the desired bronchodilation effect in most children.
In an alternative embodiment, the inhalation solution of the present invention
provides
relief of bronchospasm in patients 2 to 12 years of age. For example, a 0.63
mg unit dose of
albuterol inhalation solution is effective for children ages 10 years and
younger, children
weighing < 40 kg or children with less severe asthma. A 1.25 mg unit dose of
albuterol is
effective for prolonged use in children ages 11-12 years, children weighing >
40 kg or in
children with more severe asthma.
Further, the albuterol inhalation solution of the present invention may be
administered
together with one or more other drugs. For example, an antiasthmatic drug such
as
theophylline or terbutaline, or an antihistamine or analgesic such as aspirin,
acetaminophen or
ibuprofen, may be administered with or in dose temporal proximity to
administration of a
therapeutically effective pediatric amount of albuterol. The albuterol and the
one or more
drugs may be administered in one formulation or as two separate entities.
According to the
present invention, a therapeutically effective pediatric amount of albuterol,
alone or in
combination with another drug(s), may be administered to a pediatric
individual periodically
as necessary to reduce symptoms of asthma.
In an alternative embodiment of the present invention, relief of severe
persistent
asthma may include administration of a therapeutically effective pediatric
amount of
albuterol for quick relief of symptoms and a high dose of inhaled
corticosteroids using a
spacer or holding chamber with a face mask. If needed, oral corticosteroids
(2mg/kg/day)
may be administered. Oral corticosteroid should be reduced to the lowest daily
or alternate-
day dose that stabilizes symptoms.
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For moderate persistent asthma, treatment may include administering
therapeutically
effective pediatric amounts of albuterol for quick relief of symptoms and an
inhaled
corticosteroid at a mid-level dose, delivered using a spacer or holding
chamber with a
facemask. As symptom control is achieved, the inhaled corticosteroid dose may
be lowered,
and either inhaled nedocromil or theophylline may be added.
For mild persistent asthma, treatment may include administering
therapeutically
effective pediatric amount(s) of the present formulation for quick relief of
symptoms and
daily anti-inflammatory medication such as low-dose inhaled corticosteroid
using a spacer or
holding chamber with a facemask or a trial of cromolyn by nebulizer or
nedocromily by MDI.
For mild intermittent asthma, aside from administering a therapeutically
effective pediatric
amount of albuterol, no daily drug therapy is ordinarily required.
In another alternative embodiment, the inhalation solution of the present
invention
may be administered by nebulizer, such nebulizer including, but not limited
to, a jet
nebulizer, ultrasonic nebulizer and breath-actuated nebulizer. Preferably, the
nebulizer is a
jet nebulizer connected to an air compressor with adequate air flow. The
nebulizer being
equipped with a mouthpiece or suitable face mask.
In an alternative embodiment, the system and/or kit of the present invention
comprises an inhalation solution comprising a therapeutically effective
pediatric amount of
albuterol in a prepackaged, premeasured, premixed and/or single unit dose form
for the relief
of bronchospasm in children. The inhalation solution may be sterile and/or
antimicrobial
preservative-free.
In another embodiment, the present invention provides a system and/or kit for
organizing and storing one or more prefilled dispensing containers, each
container
comprising a premixed, premeasured inhalation solution comprising a single
unit dose of a
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therapeutically effective pediatric amount of albuterol. Such system and/or
kit may provide
such containers in prepackaged form. The one or more containers may be
comprised of
plastic including, but not limited to, a semi-permeable plastic such as, for
example, LDPE.
The container may also comprise a Twist-F1exTM top, such top comprising an
easy-to-grip
tab-like handle such that the container may be opened, for example, by
twisting off the tab by
hand. The Twist-FlexTM top is advantageous in that it allows for easy
dispensing of the
solution, prevents spillage and eliminates the need to open the container by
cutting off the
top, or the like, thereby reducing cross-contamination. One or more of the
semi-permeable
single unit dose containers may be disposed in a sealed aluminum foil pouch,
such that the
foil provides a protective barrier against environmental contaminants and
light. Such a
barrier improves the shelf-life and stability of the inhalation solution.
In another alternative embodiment, the present invention comprises a
prepackaged
inhalation system and/or kit suitable for pediatric patients suffering from
asthma. Such
prepackaged system and/or kit comprising: (a) one or more single unit dosages
of a
therapeutically effective pediatric amount of albuterol; (b) administration
instructions for the
use of said unit dose as an asthma treatment for pediatrics; and (c) a
dispensing container
prefilled with the one or more single unit doses of albuterol.
In another alternative embodiment, the prepackaged inhalation system and/or
kit of
the present invention provides one or more premixed, premeasured, single unit
dose vials
comprising a therapeutically effective pediatric amount of albuterol for the
relief of
bronchospasm associated with pediatric asthma, and instructions for using the
same.
The prepackaged inhalation system and/or kit may be provided in one of any
number
of forms, including, but not limited to, a box containing one or more
prepackaged, unit dose
vials or a box containing individual packages or pouches comprising one or
more unit dose
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vials. For example, an embodiment of a unified prepackaged system and/or kit
for relieving
bronchospasm in children is depicted in Figure 5. Specifically, Figure 5
depicts a support
package, box, carton or container (10) comprising one or more prepackaged, pre-
filled
dispensing containers (21 - 25). Each container comprising a premixed,
premeasured
inhalation solution. The inhalation solution comprising a unit dose of a
therapeutically
effective pediatric amount of albuterol for relieving bronchospasm in a child
suffering from
asthma. The inhalation solution may be provided in sterile and/or
antimicrobial preservative-
free form.
Support package, box, carton or container (10) may incorporate one or more
labels
(13) therein. One or more labels (13) may comprise indicia (14) indicating
that the inhalation
solution can be used to relieve bronchospasm in children. The label may also
comprise
indicia (15) which provides instructions for using the inhalation solution to
relieve
bronchospasm in children. As used herein "indicia" includes, but is not
limited to, wording,
pictures, drawings, symbols and/or shapes. A non-limiting example of the
indicia that may
appear on the one or more labels (13) is shown in Figure 7. The one or more
labels may be
positioned on one or more surfaces of the support package, box, carton or
container (10) or a
separate sheet, or any combination thereof. Support package (10) may also
incorporate lid
(16) to enclose the packaging material therein.
The system and/or kit of the present invention may also include a label and/or
instructions designed to facilitate user compliance. For example, in an
embodiment, a system
and/or kit of the present invention comprises packaging material containing
one or more
prepackaged vials comprising a sterile, premixed, premeasured, unit dose of an
inhalation
solution comprising a therapeutic effective pediatric amount of albuterol. The
packaging
material may further comprise a label indicating that each vial can be used
with each
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nebulizer treatment for the relief of bronchospasm associated with pediatric
asthma. Such
instructions may also include instructions on dosage for each nebulizer
treatment, as well as
instructions for administration, such as by nebulizer. The instructions may be
positioned on
one or more surfaces of the packaging material, or the instructions may be
provided on a
separate sheet, or any combination thereof.
In an alternative embodiment, the present invention is directed to a
prepackaged therapeutic system and/a kit for inducing bronchodilation in a
child suffering
from asthma, the prepackaged therapeutic system comprising:
(a) one or more dispensing containers; the one or more containers each
prefilled with about 3 ml of a sterile, benzalkonium chloride-free,
premixed, premeasured aqueous inhalation solution comprising a unit
dose of a therapeutically effective pediatric amount of racemic
albuterol; wherein the dosage of racemic albuterol is about 0.63 or
about 1.25 mg; the inhalation solution in each of the one or more
containers is suitable for nebulization in a nebulizer; wherein the
inhalation solution in each of the one or more containers has a long
shelf life;
(b) indicia comprising indication, adverse reaction, dosage and
administration data pertaining to the inhalation solution in each of the
one or more containers;
(c) wherein the indication data comprises data that the inhalation solution
in each of the one or more containers is indicated for the relief of
bronchospasm in patients 2 to 12 years of age with asthma; and
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(d) wherein the adverse reaction data comprises data indicating that otitis
media and skin-appendage infection might occur after administering
the inhalation solution in the one or more containers.
In another alternative embodiment, the prepackaged therapeutic system of the
present
invention comprises data that the dosage for patients 2 to 12 years of age is
0.63 mg or 1.25
mg of albuterol administered 3 to 4 times daily by nebulization over 5 to 15
minutes. Also,
the adverse reaction data may include a list of one or more preprinted adverse
events that may
occur after administering the inhalation solution in each of the one or more
containers, the
adverse events comprising asthma exacerbation, allergic reaction,
gastroenteritis, flu
syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or
nausea.
In another alternative embodiment, the prepackaged therapeutic system and/a
kit is adapted to induce bronchodilation in a child suffering from asthma, the
prepackaged
therapeutic system may comprise:
(a) one or more dispensing containers; the one or more containers each
prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-free,
premixed,
premeasured aqueous inhalation solution consisting essentially of a unit dose
of a
therapeutically effective pediatric amount of racemic albuterol; wherein the
dosage of
racemic albuterol is about 0.63 or about 1.25 mg; wherein the racemic
albuterol is in the form
of an acid addition salt; wherein the acid addition salt is albuterol sulfate;
the inhalation
solution in each of the one or more containers is suitable for nebulization in
a nebulizer;
wherein the inhalation solution in each of the one or more containers has a
long shelf life;
(b) indicia comprising indication, adverse reaction, and dosage and
administration data pertaining to the inhalation solution in each of the one
or more containers;
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(c) wherein the indication data comprises data that the inhalation solution
in each of the one or more containers is indicated for the relief of
bronchospasm in patients 2
to 12 years of age with asthma;
(d) wherein the adverse reaction data comprises a list of preprinted adverse
events that may occur after administering the inhalation solution in each of
the one or more
containers; the adverse events comprising otitis media, skin-appendage
infection, asthma
exacerbation, allergic reaction, gastroenteritis, flu syndrome,
lymphadenopathy, urticaria,
migraine, chest pain, bronchitis or nausea; and
(e) wherein the dosage and administration data comprises data that the
dosage for patients 2 to 12 years of age is 0.63 mg or 1.25 mg of albuterol
administered 3 to 4
times daily by nebulization over 5 to 15 minutes.
The present invention is also directed to a method of treating bronchospasm
associated with pediatric asthma, wherein albuterol is administered as a unit
dose from about
0.63 mg to about 1.25 mg of albuterol. Such unit dose may be in the form of a
nebulizer
solution.
In an alternative embodiment, the method of the present invention comprises
the step
of administering to a patient 2 to 12 years old in need thereof an inhalation
solution
comprising a therapeutically effective pediatric amount of albuterol. Such
solution may
comprise from about 0.63 mg to about 1.25 mg albuterol. Such solution may also
be
premixed, premeasured, antimicrobial preservative-free and/or sterile. Such
solution may
also be in a single unit dose vial.
In another alternative embodiment, the method of the present invention
comprises the
step of administering to a pediatric patient in need thereof an inhalation
solution comprising a
therapeutically effective pediatric amount of albuterol. The inhalation
solution being
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administered by nebulizer, more preferably a jet nebulizer connected to an air
compressor
with adequate air flow.
In yet another alternative embodiment, in reference to Figures 1-4, the method
of the
present invention comprises the steps: (i) placing an inhalation solution
comprising a
therapeutically effective pediatric amount of albuterol (1) into a nebulizer
cup (2) the
nebulizer may be powered by attachment to compressed gas cylinders or an
electrically
driven compressor; (ii) using a "T" adapter (3) to fit the cup lid (4) to a
mouthpiece (5) or
facemask (6); (iii) drawing the albuterol solution up by the velocity of a gas
jet and
fragmenting it into an aerosol; (iv) passing the aerosol through the
mouthpiece (5) or
facemask (6) to the pediatric patient (7) afflicted with bronchospasm; and (v)
the patient
continues breathing until no more mist is formed in the nebulizer chamber (8).
This may
occur in about 5-15 minutes.
In one alternative embodiment, the usual starting dosage for patients 2 to 12
years of
age is about 1.25 mg or about 0.63 mg of albuterol administered 3 or 4 times
daily, as needed
by nebulization. To administer these amounts of albuterol, the entire contents
of a one unit-
dose vial (e.g., 1.50 mg/3 ml or 0.75 mg/3 ml albuterol sulfate) may be used
by nebulization.
Preferably, the nebulizer flow rate is adjusted to deliver the albuterol
sulfate over 5 to 15
minutes. Patients 6 to 12 years of age with more severe asthma (baseline FEVI
less than 60%
predicated), weight >40kg or patients 11 to 12 years of age may achieve a
better initial
response with about a 1.25 mg dose.
Further, in an alternative embodiment, the method of the present invention
comprises
the steps: (i) preparing an inhalation solution comprising a therapeutically
effective pediatric
amount of albuterol solution by diluting one or more solutions comprising
albuterol; and (ii)
administering the inhalation solution to a pediatric patient in need thereof.
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In another alternative embodiment, the present invention is directed to a
method of inducing bronchodilation in a child suffering from asthma, said
method
comprising the step of:
(a) providing the child or prescriber a prepackaged therapeutic system
comprising:
one or more dispensing containers; the one or more containers each
prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-
free, premixed, premeasured aqueous inhalation solution comprising a
unit dose of a therapeutically effective pediatric amount of racemic
albuterol; wherein the dosage of racemic albuterol is about 0.63 or
about 1.25 mg; the inhalation solution in each of the one or more
containers is suitable for nebulization in a nebulizer; wherein the
inhalation solution in each of the one or more containers has a long
shelf life;
(b) providing the child or prescriber of the prepackaged therapeutic system
indication, adverse reaction, dosage and administration data pertaining
to the inhalation solution in each of the one or more containers;
(c) wherein the indication data informs the patient or prescriber that the
inhalation solution in each of the one or more containers is indicated
for the relief of bronchospasm in patients 2 to 12 years of age with
asthma; and
(d) wherein the adverse reaction data informs the patient or prescriber that
otitis media and skin-appendage infection might occur after
administering the inhalation solution in the one or more containers.
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In another alternative embodiment, the dosage and administration data informs
the patient or
prescriber that the dosage for children 2 to 12 years of age is 0.63 mg or
1.25 mg of albuterol
administered 3 to 4 times daily by nebulization over 5 to 15 minutes. Also, in
the adverse
reaction data may include a list of one or more preprinted adverse events that
may occur after
administering the inhalation solution in each of the one or more containers,
the adverse
events comprising asthma exacerbation, allergic reaction, gastroenteritis, flu
syndrome,
lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea.
In another embodiment, the method of the present invention is directed to
inducing bronchodilation in a child suffering from asthma. Such method may
comprise the
step of
(a) providing the child or prescriber a prepackaged therapeutic system
comprising:
one or more dispensing containers; the one or more containers each
prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-
free, premixed, premeasured aqueous inhalation solution consisting
essentially of a unit dose of a therapeutically effective pediatric amount
of racemic albuterol; wherein the dosage of racemic albuterol is about
0.63 or about 1.25 mg; wherein the racemic albuterol is in the form of
an acid addition salt; wherein the acid addition salt is albuterol sulfate;
the inhalation solution in each of the one or more containers is suitable
for nebulization in a nebulizer; wherein the inhalation solution in each
of the one or more containers has a long shelf life;
CA 02464660 2004-04-23
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(b) providing the child or prescriber of the prepackaged therapeutic system
indication, adverse reaction, dosage and administration data pertaining
to the inhalation solution in each of the one or more containers;
(c) wherein the indication data informs the patient or prescriber that the
inhalation solution in each of the one or more containers is indicated
for the relief of bronchospasm in patients 2 to 12 years of age with
asthma;
(d) wherein the adverse reaction data informs the patient or prescriber that
otitis media, skin-appendage infection, asthma exacerbation, allergic
reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria,
migraine, chest pain, bronchitis or nausea might occur after
administering the inhalation solution in the one or more containers; and
(e) wherein the dosage and administration data comprises data that
informs the patient or prescriber that the dosage for patients 2 to 12
years of age is 0.63 mg or 1.25 mg of albuterol administered 3 to 4
times daily by nebulization over 5 to 15 minutes.
The present invention also provides a process for making a sterile, premixed,
premeasured, and/or BAC-free inhalation solution comprising a single unit dose
of a
therapeutically effective pediatric amount of albuterol. In such an
embodiment, the method
of the present invention comprises one or more of the following steps: (i)
adding at least a
therapeutically effective pediatric amount of albuterol in a vehicle, such as
water; (ii)
optionally sterilizing the solution and sealing the container. An osmotic
adjusting agent may
be added to adjust the isotonicity of the solution. In one embodiment of the
present
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invention, the solution of the present invention is isotonic. Isotonicity may
be achieved by
adding an osmotic adjusting agent to adjust the isotonicity of the solution
from about 280 to
about 320 mOsm/kg. In addition, an acid (e.g., sulfuric acid) may be added to
adjust the pH
of the solution to a level ranging from about 3.0 to about 4.0, preferably
about 3.5.
In another embodiment, a process for making an inhalation solution of the
present
invention comprises one or more of the following steps: (i) adding at least a
therapeutically
effective pediatric amount of albuterol in a vehicle such as water; (ii)
placing the mixture in a
container, and sterilizing the mixture by steam sterilization, or any other
sterilizing means
known in the art. Each mixture being filled into a vial, and then packaged,
stored and/or used
directly. Here, the resulting mixture is stable, and after sterilization, it
can be dispersed, if
necessary, into multiple mixtures each containing a unit dose of a
therapeutically effective
pediatric amount of albuterol.
Osmotic adjusting agents which may be used include, but are not limited to,
sodium
chloride, potassium chloride, zinc chloride, calcium chloride and mixtures
thereof. Other
osmotic adjusting agents may also include, but are not limited to, mannitol,
glycerol, and
dextrose and mixture thereof. In an alternative embodiment, the present
invention may
comprise about 0.4 to about 1.0 weight percent ionic salt. Preferably, the
present invention
comprises about 0.9 weight percent of an osmotic adjusting agent.
In an alternative embodiment, the inhalation solution of the present invention
may be
prepared as follows: (i) fitting a high density polyethylene (HDPE) or
stainless steel
formulation tank with a bottom drain and peristaltic recirculation system (for
HDPE) or tri-
blender (for stainless steel) for mixing; (ii) filling the tank with
approximately 90% of the
required amount of Purified Water USP at a temperature of between 18 C to 25
C; while
mixing, (iii) adding sulfuric acid, Sodium Chloride USP, and at least a
therapeutically
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effective pediatric amount of Albuterol Sulfate USP to the tank; (iv) continue
mixing until all
chemical components are dissolved; (v) adding Purified Water USP to adjust the
final
volume, if necessary, thus producing an albuterol mixture.
From the formulation tank, the albuterol mixture is pumped through sanitary
delivery
lines directly into a form-fill-seal (FFS) machine. The albuterol mixture
passes through a 0.2
micron sterilizing cartridge filter, to the filling nozzles within the sterile
air shower
compartment, and subsequently into formed vials of low density polyethylene
(LDPE). The
albuterol mixture being sterile filled into the vials such that each vial
contains a single unit
dose of a therapeutically effective amount of albuterol. The filled vials are
then sealed. The
machine may form, fill and seal the vials in a continuous operation under
aseptic conditions,
thus producing a sterile product. For example, cards of five filled vials
(Figure 6) are
overwrapped into a protective laminated foil pouch using an autowrapper
machine. Five or
twelve such pouches may then be packaged in a shelf carton, thus forming a
prepackaged
therapeutic system for relieving bronchospasm in children suffering from
asthma. An
appropriate label and instructions may be added in the shelf carton.
The present invention is also directed to a method of forming a unit-dose
nebulizer
solution comprising the step of. (i) preparing an admixture containing a
therapeutically
effective pediatric amount of albuterol in a pharmaceutically acceptable
vehicle.
In an alternative embodiment, the present invention also comprises a device
for use in
the relief of bronchospasm associated with pediatric asthma. Such device may
take the form
of a label, written instructions or any other form incorporating indicia
thereon. The device
may comprise indicia which indicates that a patient suffering from
bronchospasm can be
treated with at least one prepackaged, sterile, premixed, premeasured and/or
antimicrobial
preservative-free inhalation solution comprising a unit dose of a
therapeutically effective
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pediatric amount of albuterol in a single vial. The inhalation solution being
suitable for
nebulization in a nebulizer. The device also comprising indicia which provides
instructions
for utilizing the inhalation solution to relieve said bronchospasm in the
patient.
Examples
Patients were randomized to receive a nebulizer solution comprising either
0.63 mg/3
ml or 1.25 mg/3 ml of albuterol sulfate, or a placebo. The inhalation solution
was
administered via a Pari LC P1usTM nebulizer and a Pari PRONEBTM compressor.
Both of
these products are commercially available.
In this study, qualifying children ages 6 to 12 were randomized to receive 1
of the
following three treatments twice daily (TD) for 4 weeks, each in 3.0 ml,
volume: (1) 1.25 mg
albuterol sulfate inhalation solution; (2) 9.63 mg albuterol sulfate
inhalation solution; or (3)
placebo (saline). Each patient was provided with a personal compressor-driven
PARI LC
PLUSTM nebulizer, by Pari Respirator Equipment, Inc., Richmond, VA, for the
duration of
the study.
A screening visit was followed by a 2-week placebo run-in phase to confirm the
need
for regular symptomatic beta-agonist therapy, and to give patients experience
with daily
diaries and peak flow measurements, as well as to demonstrate compliance. The
4-week
study period began with the initial dose, to be taken in the morning,
administered at the study
site. Pre-dose pulmonary function tests and pulmonary function tests 30
minutes after the
end of nebulization and hourly thereafter for 6 hours were performed.
After 11 days, patients returned for exchange of study medication and diaries
and
pulmonary function tests before and 30 minutes after the morning dosing. After
completing
28 days of treatment, patients returned to the test site for a repeat of the 6-
hour evaluation of
safety and efficacy following administration of study medication. Diary cards
were used to
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record asthma symptoms, night awakenings, peak flow measurements, supplemental
albuterol
use, change in medication and adverse events. The safety profiles of each unit
dose and
placebo were determined by collecting vital signs (heart rate, blood pressure,
respiration rate,
and body temperature) as well as electrocardiograms.
Patients
A total of 349 children (220 males and 129 females) were initially randomized,
and
288 completed the double-blind 4-week treatment period. Demographic and other
baseline
characteristics were comparable between the three treatment groups. To be
eligible for
enrollment, patients had to meet the criteria described in Table 3 below.
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Table 5
Inclusion/Exclusion Criteria
Design Element Description
Inclusion Criteria = Documented history (26 months) of moderately severe
persistent asthma
confirmed by a physician and requiring daily asthma medication.
= Generally good health apart from asthma.
= FEVI between 50% and 80% of predicted values at baseline and at the
beginning of the double-blind treatment phase.
= At least 15% reversibility in FEVI following the administration of inhaled
nebulized albuterol at the screening visit.
= Symptomatic asthma requiring the use of beta-agonists on at least 6 of the
14 days of observation during the placebo-controlled run-in-period.
= Willingness of patient and caregiver to provide informed consent.
Exclusion Criteria = Severe asthma or any serious medical condition.
= Use of prescription medication for which albuterol sulfate is
contraindicated.
= Known hypersensitivity to albuterol of similar agents.
= Active pulmonary disease other than bronchial asthma.
= Upper respiratory tract infection within 4 weeks of the start of the placebo
phase.
= Any other chronic condition that could have interfered with successful
completion of the study or confounded its interpretation.
= Acute use of corticosteroids or other treatments which might interfere with
the study within 4 weeks of the screening visit.
= Inability or unwillingness to perform the requirements of the protocol.
Interventions
Patients meeting the inclusion criteria and on regularly prescribed asthma
medications
were permitted to continue on those medications during the course of the study
if the doses
remained stable. Patients were required to withhold their morning dose before
each study
visit and during the entire study session. After the patient completed the
study session, the
regularly scheduled dosing resumed for that day. All medication used to treat
chronic
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conditions, including immunotherapy, had to be initiated at least 30 days
prior to the start of
the study, and the dosing regimen had to be stabilized by the initial visit.
Racemic albuterol
delivered by a chlorofluorocarbon (CFC) MDI or nebulizer was used on an as-
needed basis as
the rescue medication.
Efficacy Results
The primary efficacy endpoint was the area under the percent change from pre-
dose
FEV, versus time curve for the initial closing visit (Day 1) and the final
closing visit (Day
28). Compared to placebo, both unit doses of albuterol produced significant
improvement in
FEV, following both the initial dose and the dose given at visit 4 after 4
weeks of TD
treatment. The mean percent change from baseline in the area under the 6-hour
curve for
FEV 1 for both active treatment regimens compared with placebo, is shown in
Table 4 (for
Day 1) and Table 5 (for Day 28).
Table 6
% Change from Pre-Dose FEVI
Intent-to-Treat Population
Day 1
-------- - --------
0O.to 7.25 0.50 0.75 110 1.50 200 240 0.00 0.50 4.00 MO SA4
Hours from Pre-Base
I*ftaal ut'M.b3 0404
Figure 3. Percent change i1 FEV, time course after treatment on Day 1.
Table 7
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% Change from Pre-Dose FEVI
Intent-to-Treat Population
Day 28
ao Day 28
m
t
^iw-- .---------
-
G 00 4195 0.50 0.75 #.G) t.50 200 250 3,63 2.50 400 5.00 000
Hours from Pre-Dose
7rtatma4t --c- AI iral0.i tm4G
.r-*= pl*tnka
Figure 4. Percent change n FEVI time course after treatment on Day 28.
The onset of a 15% increase in FEVI over baseline for both doses of AccuNeb
was
seen at 30 minutes. The mean time to speak effect was approximately 30 to 60
minutes for
both doses on day 1 and after 4 weeks of treatment. The mean duration of
effect, as
measured by a >15% increase from baseline in FEVI was approximately 2.5 hours
for both
doses on day 1 and approximately 2 hours for both doses after 4 weeks of
treatment. In some
patients, the duration of effect was as long as 6 hours.
Subgroup analysis was performed to determine whether the overall efficacy of
AccuNeb was consistent across all age, weight and disease severity groups. In
all age groups,
weight categories and disease severity groups, the 1.25 mg dose provided a
statistically
significant improvement over placebo on both Day 1 and Day 28. However, at the
lower
0.63 mg dose, children 11 to 12 years of age, children heavier than 40 kg and
children with
more severe disease (classified as an FEVI <60% of predicted) did not have a
statistically
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significant improvement in FEV1 over placebo at Day 29. As a result, older
children, heavier
children or children with more severe disease may have a better response at
the 1.25 mg dose.
Safety/Tolerability
Adverse reaction information to the albuterol solution used in the study was
derived
from the 4-week controlled clinical trial described above. Adverse events were
reported in
>1% of patients receiving the present solution, more frequently than adverse
events reported
by patients receiving placebo, as shown in Table 6. In the study, there was
one case of ST
segment depression in the 1.25 mg treatment group, but no clinically relevant
laboratory
abnormalities related to administration were observed.
Table 8
Adverse Event Reports
(ADVERSE EVENTS WITH AN INCIDENCE OF 0.1% OF PATIENTS RECEIVING THE PRESENT
ALBUTEROL SOLUTION AND GREATER THAN PLACEBO (EXPRESSED AS % OF TREATMENT
GROUP))
1.25 mg AccuNeb 0.63 mg AccuNeb Placebo
(N=115) (N=117) (N=117)
Asthma Exacerbation 13 11.1 8.5
Otitis Media 4.3 0.9 0
Allergic Reaction 0.9 3.4 1.7
Gastroenteritis 0.9 3.4 0.9
Cold Symptoma 0 3.4 1.7
Fly Syndrome 2.6 2.6 1,7
Lymphadenopathy 2.6 0.9 1.7
Skin/Appendage injection 1.7 0 0
Urticaria 1.7 0.9 0
Migrane 0.9 1.7 0
Chest Pain 0.9 1.7 0
Bronchitis 0.9 1.7 0.9
Nausea 1.7 0.9 0.9
The figures and attachments herein are presented for illustrative proposes
only. They
are not intended to limit the scope of the invention. Further, it should be
understood that
various changes and modifications to the presently preferred embodiment
described herein
34
CA 02464660 2004-04-23
WO 03/037317 PCT/US02/33352
will be apparent to those skilled in the art. Such changes and modifications
can be made
without departing from the spirit and scope of the present invention and
without diminishing
its attendant advantages. It is therefore intended that such changes and
modifications be
covered by the appended claims.
Also, the invention may suitably comprise, consist of or consist essentially
of the
elements described herein. Further, the invention described herein suitably
may be practiced
in the absence of any element which is not specifically disclosed herein.
