Note: Descriptions are shown in the official language in which they were submitted.
CA 02396796 2009-01-19
1
STABILIZED MEDICINAL AEROSOL PARTICULATE FORMULATIONS
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to a medicinal aerosol formulation, and more
particularly, to a medicinal aerosol formulation comprising a protective
colloid
stabilizer.
Description of the Related Art
Delivery of drugs to the lung by way of inhalation is an important
means of treating a variety of conditions, including such common local
conditions as
cystic fibrosis, pneumonia, bronchial asthma and chronic obstructive pulmonary
disease and some systemic conditions including pain management, immune
deficiency, hormonal therapy, erythropoiesis, diabetes, etc. Steroids, ¾2
agonists,
anti-cholinergic agents, proteins and polypeptides are among the drugs that
are
administered to the lung for such purposes. Such drugs are commonly
administered
to the lung in the form of an aerosol of particles of respirable size (less
than about 10
pm in diameter). In order to assure proper particle size in the aerosol,
particles can
be prepared in respirable size and then incorporated into a colloidal
dispersion
containing either a propellant, as a pressurized metered dose inhaler (MIDI),
or air
such as is the case with a dry powder inhaler (DPI). Alternatively,
formulations can
be prepared in solution or emulsion form in order to avoid the concern for
proper
particle size in the formulation. Solution formulations must nevertheless be
dispensed in a manner that produces particles or droplets of respirable size.
For MIDI preparations, once prepared, the aerosol formulation is filled
into an aerosol canister equipped with a metered dose valve. In the hands of
the
patient the formulation is dispensed via an actuator adapted to direct the
dose from
the valve to the patient.
It is important that an aerosol formulation be stable such that the
delivered dose discharged from the metered dose valve is reproducible. Rapid
creaming, settling, or flocculation after agitation are common sources of dose
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
2
irreproducibility in suspension formulations. This is especially true where a
binary
aerosol formulation containing only medicament and propellant, e.g. 1,1,1,2-
tetrafluoroethane, is employed or where such formulation contains small
amounts of
surfactant as well. Sticking of the valve also can cause dose
irreproducibility. In
order to overcome these problems, MDI aerosol formulations often contain
surfactants, which serve as suspending aids to stabilize the suspension for a
time
sufficient to allow for reproducible dosing. Certain surfactants also function
as
lubricants to lubricate the valve to assure smooth actuation. Myriad materials
are
known and disclosed for use as dispersing aids in aerosol formulations.
Suitability
of materials, however, is dependent on the particular drug and the propellant
or class
of propellant used in the formulation.
It is sometimes difficult to dissolve sufficient quantities of
conventional surfactants in hydrofluorocarbon (HFC) propellants such as HFC-
134a
and HFC-227. Cosolvents, such as ethanol, have been used to overcome this
problem, as described in U.S. Patent No. 5,225,183. An alternative approach
that
avoids cosolvents involves materials that are soluble or homogeneously
dispersible
in hydrofluorocarbon propellants and are said to be effective surfactants or
dispersing aids in an aerosol formulation. Among such materials are certain
fluorinated surfactants and certain polyethyoxysurfactants.
Medicaments which are relatively small molecules are much more
predictable in terms of their aerosol formulation characteristics than
macromolecules. The macromolecules, such as peptides or proteins, which range
in
molecular size from about 1K Dalton to about 150 K Daltons in molecular size
are
very unpredictable and present unique problems in forming aerosol formulations
thereof which are stable and provide reproducible dosage.
Most peptide and protein drugs, such as hormones, e.g. insulin,
amylin, etc., enzymes, antinfectives, are quite variable in their amino acid
composition and three-dimensional structure. Consequently their surface
activity is
highly variable, and importantly, no model is yet available that explains
differences
in protein surface activity based on their most basic and structural
properties, such as
molecular weight, adsorptivity, solubility, partition coefficient and
isoelectric pH.
Hemoglobin, for example, has far higher affinity for solid surfaces than does
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
3
albumin, yet the molecular weights of these two proteins are very similar.
Fundamentally, the diversity in surface activity of peptides and proteins
originates in
the linear sequence of amino acids that uniquely characterizes each type of
protein.
The amino acid side chains often vary dramatically in that some carry no
charge at
any pH, yet exhibit considerable polar character (serene, threonine). Other
amino
acids are ionizable and vary from fairly acidic (aspartic and glutamic acid
are fully
negatively charged at the physiological pH of 7.4) to basic functionalities,
such as
the imidazole group in histidine (which carries a partial positive charge at
pH 7.4),
and the still more basic amino groups in lysine and arginine that carry full
positive
charges at pH 7.4. Another group of amino acids, somewhat hydrocarbon-like in
character, appear to demonstrate generally a much lower solubility profile in
water
(tryptophan, phenylalanine, isoluecine, etc.) than many of the other amino
acids
found in biological systems. It is noteworthy that the hydrophobicity of these
water-
hating amino acids varies greatly with their specific structure in the
protein. For
example, the single methyl group side chain in alanine contributes only 0.5
kcal/mole to the free energy of transfer from water to an organic phase,
whereas the
double-ringed indole group in tryptophan contributes 3.4 kcal. The variety of
amino
acid side chains, together with the many different types of chemical
interactions that
result in solution and at surfaces, should be expected to have a considerable
impact
on aerosol formulation stability as well as transport of these peptide and
protein
biotherapeutic agents across biologic membranes.
The diverse character of the amino acid side chains, together with the
complexity of various combinations of amino acids present in each particular
protein, means that physicochemical properties of the proteins, their
intermolecular
as well as intramolecular reactivity, and also their ability to interact with
surfaces
should be highly variable. Due to their large size, and correspondingly due to
the
large numbers of charged amino acid side chains, proteins have many charges
distributed over their exterior surface. This could lead to very large
variances in
aerosol formulation stability and lung uptake of these compounds. Peptide and
protein drugs also generally have multiple ionization sites and therefore they
often
demonstrate pH-dependent solubility profiles. Importantly, the hydrophilic
nature of
these compounds provides excellent conditions for high aqueous solubility.
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
4
Consequently, most peptide and protein drugs present extremely low lipid
solubility
characteristics, the latter possibly being one reason why dispersions of these
drugs in
hydrofluorocarbon propellants would be physically and chemically stable across
a
wide range of storage conditions. An aerosol medicament formulation comprising
peptide and protein drugs in carrier or formulation media within which they
are
virtually insoluble is needed to reduce hydrolytic and chemical deactivation
usually
typical of aqueous solutions.
The combination of a large surface area, thin absorptive carrier, and
extensive vasculature constitutes a favorable absorptive environment for
proteins
and peptides when delivered by the pulmonary route. Studies show that
intratracheal (i.t.) administration of peptides is rapid and quantifiable;
however the
resultant distribution is often localized in central airways. Administration
by
aerosol, for example, depending on particle size distribution, may be used to
give
more uniform distribution with greater alveolar penetration. Drug absorption
from
the airways is dependent upon the site of deposition, the method of drug
delivery,
the type of solute presentation and composition of the formulation. Therefore,
formulation and device characteristics will have a dramatic impact upon the
rate and
extent of peptide absorption from the lung. Studies show that absorption rates
following aerosol delivery of small molecular weight compounds can be roughly
twice that of i.t. delivery. What is desired is to present peptides and
proteins as
hydrophobic dispersions via a multi dose inhalation device ("pMDI") in order
to
have greater penetration of the drug particles to the peripheral lung where
absorption
should be significantly greater than it is for centrally deposited drug as is
the case
with aqueous instillations.
The realty that insulin can be absorbed from the lung into the
bloodstream has been demonstrated by a number of scientists. A 1990 review
article
[Lung, supplement pp. 677-684] demonstrated from multiple studies that
aerosolized
insulin delivered into the lung yielded a half-life of 15-25 minutes but
results were
quite variable. Comprehensive studies also have demonstrated that aerosolized
insulin given peripherally into the lung of rabbits produced bioavailability
of over
50.7 percent in contrast to 5.6 percent bioavailability seen for liquid
insulin dripped
into the central airways. These studies therefore support the contention that
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
aerosolized insulin must be delivered peripherally into the lung for maximum
efficiency and that inadvertent central disposition of inhaled aerosolized
insulin will
produce an effect ten times lower than that desired. Such variations in dosing
of ten-
fold are clearly unacceptable if aerosolized insulin should become an
effective
5 means of treating diabetes. Thus, there is need for effective, high
precision aerosol
devices to achieve the tolerances required for aerosolizing insulin to human
subjects.
This concept for using aerosolized insulin in diabetes management would also
apply
to amylin and glucagon, partner hormones to insulin in the regulation of
plasma
glucose concentrations, which until now, must be administered by subcutaneous
injection (s.c.).
Dry powder presentations of peptide and protein drugs possess
unique opportunities in formulations, which do not occur in liquid
presentations
such as pMDIs and nebulized solutions. Dry powder aerosols of peptide and
protein
drugs, because of improved solid state stability, are attractive from the
formulation
standpoint since many of the undesirable solution and liquid state interactive
effects
are circumvented. In this regard, reference is made to Rubsamen et al., US
Patent
No. 5,672,581 and Patton et al. in US Patent No. 5,775,320.
Both the Rubsamen and Patton approaches are therapeutically
feasible although their complexity and presumed inherent costs limit their
applicability to the management of a chronic disease like diabetes mellitus.
Thus, it
is a problem to use an expensive, complicated device such as the portable,
electronically based portable nebulizer to routinely deliver hypoglycemics to
patients that need them. It is further a problem to use large, bulky,
difficult to clean
a dry powder aerosol device like the Patton device to deliver the
hypoglycemics to
the body via lung. Thus, the primary objective in formulating a peptide or
protein
drug as a dry powder inhalation aerosol (DPI) is to enable the drug, and in
some
cases, added excipients, to form an aerocolloid which is chemically and
physical
stable and can remain in suspension until the drug particle reaches the
alveolar or
other absorption sites. Once at the absorption site, the drug particles should
be
efficiently trapped at the deposition site, dissolve rapidly in the epithelial
lining
fluids, and be absorbed quickly across the biomembrane thereby limiting
possible
deactivation by metabolizing enzymes in the airways.
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
6
Spray drying is a process used to prepare medicament particles for
drug formulations. Spray drying constitutes a single step process which
transforms
a solution or suspension into fine powder. Generally, spray drying produces
spherical particles, which are often hollow thus resulting in a powder with
low bulk
density compared to the initial material. Powder characteristics of spray
dried
materials (i.e., particle size distribution, bulk density, porosity, moisture
content,
dispersibility, etc.) are generally good in many regards, but particles
manufactured
by this process demonstrate poor flow characteristics. Furthermore, a
requirement
for heat during particle formation by this process makes spray drying less
desirable
for heat sensitive compounds such as peptide and protein drugs. Thus, it is a
problem that most dry powder aerosols demonstrate adhesion and poor
flowability
through device hardware to the extent that accuracy of dose delivery becomes a
problem to the patient.
Another problem associated with peptide and protein formulations as
dry powder aerosols is that of packaging the material as agglomerates in a
device
such that during aerolization, the agglomerates are broken up, and the
individual
particles released prior to entry into the airways. Preparation of robust
agglomerates
of micron or sub-micron sized particles is a reasonably straightforward task
which
can be achieved by conventional granulation, with or without polymeric
binders.
However, the requirement that upon entering the airways, the agglomerates
should
break up into primary particles, probably rules out a simple, conventional
approach
to granulation since the interparticle forces could be too large to allow
easy, efficient
and prompt deagglomeration. The total adhesive force between two unlike
particles
or total cohesive force between two like particles can be considered as being
constituted from a sum of one or more attractive forces. Many of these forces
are
known to be responsible for formation of adhesive units between dry powder and
excipient particles in formulations. Therefore the aim of any manipulation of
inter-
particle forces will be to produce agglomerates of between say, 50 and 200 m
diameter, which are robust enough to withstand flow, storage and packing in
the
delivery device, but which can be de-agglomerated rapidly and completely by
the
shear stresses in the inspired air stream. This problem which is quite common
in
peptide and protein aerosol formulations may be avoided completely in liquid
CA 02396796 2003-10-14
WO 01/60420 PCTIUS01/0011
7
formulations within which the drug is insoluble, is presented as a colloidal
dispersion, and is sterically protected against self-association. Hence it is
a desire to
formulate peptide and protein drugs as loose, flocculated colloids in non-
aqueous
media, like hydrofluorocarbons, which rapidly and easily break up into
discrete
particles upon aerolization to the airways. Additionally, it is desired to
present
peptide and protein drugs in formulation systems within which the drug
particles are
perpetually in random motion, thus eliminating aggregate formation of the
individual drug particles.
Other non-injectable diabetes therapies have been proposed, some
demonstrating that a biotherapeutic response could be produced following nasal
administration of insulin when formulated with detergents and other membrane
penetrants, as indicated in Moses et al., Diabetes, Vol. 32, November 1983;
and
Salzman et al., New England Journal of Medicine, Vol. 312, No. 17. Significant
inter-subject variability and irritation of nasal membranes to varying degrees
is
observed. Since diabetes is a chronic disease which must be continuously
treated by
the administration of insulin, and since mucosal irritation tends to increase
with
repeated exposures to membrane penetration enhancers, efforts at developing a
non-
invasive nasally administered insulin have not been commercialized.
Accordingly, a
safe, reproducible, effective, non-invasive delivery means for peptide and
protein
drugs via lung as pMDIs is desired and needed.
SUMMARY OF THE IIWENTION
It has surprisingly been found that novel and stable medicinal aerosol
formulations of macromolecular medicaments can be obtained without the use of
either cosolvents, such as ethanol, or surfactants, such as sorbitan trioleate
which are
added to a binary aerosol formulation of small molecule medicaments. Stable
medicinal aerosol formulations are obtained by the use of a protective colloid
stabilizer.
CA 02396796 2011-01-06
7a
DETAILED DESCRIPTION OF THE INVENTION
Reference is made to U. S. Patent 6,136,294.
In accordance with one aspect of the invention, there is provided a
medicinal aerosol particulate formulation, which comprises:
(a) particles of a protein or peptide medicament having a molecular
size ranging from about 1K Dalton to about 150K Daltons;
(b) a fluid carrier for containing said medicament; and
(c) particles of a stabilizer, wherein the stabilizer is selected from
the group consisting of:
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group; or phenyl, unsubstituted or substituted
with a halogen, an alkyl of 1 to 6 carbon atoms, an alkoxy
of 1 to 6 carbon atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic acid of the amino acid of formula (I), (II) or
(III) with an
aliphatic straight or branched chain alcohol of from 1 to 6 carbon atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v).
In accordance with another aspect of the invention, there is provided a
method of preparing a stable medicinal aerosol formulation of the invention,
which
comprises:
CA 02396796 2011-01-06
7b
(a) combining (i) said medicament in an amount sufficient to
provide a plurality of therapeutically effective doses, (ii) said fluid
carrier in an amount
sufficient to propel a plurality of said therapeutically effective doses; and
(iii) said
stabilizer in an amount effective to stabilize the formulation; and
(b) dispersing components (i), (ii) and (iii).
In accordance with still another aspect of the invention, there is
provided a method of stabilizing a suspension aerosol particulate formulation
comprising a propellant and particles of a protein medicament, which
comprises,
incorporating into the formulation particles of a stabilizer, wherein the
stabilizer is
selected from the group consisting of-
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group; or phenyl, unsubstituted or substituted
with a halogen, an alkyl of I to 6 carbon atoms, an alkoxy
of 1 to 6 carbon atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic group of the amino acid of formula (I), (II)
or (III)
with an aliphatic straight or branched chain alcohol of from 1 to 6 carbon
atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v);
to prevent settling, creaming, or flocculation of the formulation for a time
sufficient to
allow reproducible dosing of the drug after agitation of the formulation.
CA 02396796 2011-01-06
7c
In accordance with yet another aspect of the invention, there is
provided a metered dose inhaler containing a medicinal aerosol formulation,
the
formulation comprising:
(a) particles of a protein or peptide medicament in a therapeutically
effective amount;
(b) a propellant; and
(c) particles of a suitable stabilizer, wherein said stabilizer is
selected from the group consisting of:
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group; or phenyl, unsubstituted or substituted
with a halogen, an alkyl of 1 to 6 carbon atoms, an alkoxy
of 1 to 6 carbon atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic group of the amino acid of formula (I), (II)
or (III)
with an aliphatic straight or branched chain alcohol of from 1 to 6 carbon
atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v).
In accordance with a further aspect of the invention, there is provided
a medicinal aerosol particulate formulation, which comprises:
(a) particles of a protein or peptide medicament having a molecular
size ranging from about I K Dalton to about 150 K Daltons, which is selected
from the
group consisting of an insulin, an insulin analog, an immunomodulating
protein, a
thrombolytic, an antitrypsin, an anti-protease, a hormone, a growth factor, an
enzyme, a
CA 02396796 2011-01-06
7d
nucleic acid, an immunoglobulin, an antibiotic, an antiinfective, a
hematopoietic factor,
a vaccine, a vasoactive peptide, an antisense agent, an oligonucleotide, and a
mixture of
any of the foregoing medicaments;
(b) a non-chlorofluorohydrocarbon fluid propellant carrier for
containing said medicament; and
(c) particles of a stabilizer, wherein said stabilizer is selected from
the group consisting of-
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group; or phenyl, unsubstituted or substituted
with a halogen, an alkyl of 1 to 6 carbon atoms, an alkoxy
of I to 6 carbon atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic group of the amino acid of formula (I), (II)
or (III)
with an aliphatic straight or branched chain alcohol of from I to 6 carbon
atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v).
In accordance with a yet further aspect of the invention, there is
provided a method of preparing a stable medicinal aerosol particulate
formulation as
defined herein, which comprises:
(a) combining (a) said medicament in an amount to provide a
plurality of therapeutic doses, (b) said fluid carrier in an amount to propel
said plurality
of doses and (c) said stabilizer to stabilize the formulation; and
(b) dispersing components (a), (b) and (c).
CA 02396796 2011-01-06
7e
In accordance with another aspect of the invention, there is provided a
method of stabilizing a suspension aerosol particulate formulation comprising
a non-
chlorofluorohydrocarbon propellant and particles of a protein or peptide
medicament
which is selected from the group consisting of an insulin, an insulin analog,
an
immunomodulating protein, a thrombolytic, an antitrypsin, an anti-protease, a
hormone,
a growth factor, an enzyme, a nucleic acid, an immunoglobulin, an antibiotic,
an
antiinfective, a hematopoietic factor, a vaccine, a vasoactive peptide, an
antisense
agent, an oligonucleotide, and a mixture of any of the foregoing medicaments;
said
method comprising: incorporating into the formulation particles of a
stabilizer, wherein
said stabilizer is selected from the group consisting of-
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group; or phenyl, unsubstituted or substituted
with a halogen, an alkyl of 1 to 6 carbon atoms, an alkoxy
of 1 to 6 carbon atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic group of the amino acid of formula (I), (II)
or (III)
with an aliphatic straight or branched chain alcohol of from 1 to 6 carbon
atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v);
to prevent settling, creaming, or flocculation of the formulation for a time
sufficient to
allow reproducible dosing of the drug after agitation of the formulation.
CA 02396796 2011-01-06
7f
In accordance with still another aspect of the invention, there is
provided a metered dose inhaler containing a medicinal aerosol particulate
formulation,
the formulation which consists essentially of.
(a) particles of a protein or peptide medicament which is selected
from the group consisting of an insulin, an insulin analog, an
immunomodulating
protein, a thrombolytic, an antitrypsin, an anti-protease, a hormone, a growth
factor, an
enzyme, a nucleic acid, an immunoglobulin, an antibiotic, an antiinfective, a
hematopoietic factor, a vaccine, a vasoactive peptide, an antisense agent, an
oligonucleotide, and a mixture of any of the foregoing medicaments;
(b) a non-chlorofluorohydrocarbon propellant; and
(c) particles of a stabilizer, wherein said stabilizer is selected from
the group consisting of
(i) an amide of a carboxylic acid group of an amino acid, the amino acid is
selected
from the group consisting of
a) a monoamino carboxylic acid of formula H2N-R-COOH (I),
b) a monoamino dicarboxylic acid of formula H2N-R(COOH) 2 (II),
and
c) a diamino carboxylic acid of formula (H2N) 2-RCOOH (III),
wherein R is:
a straight or branched alkyl radical of from 1 to 22 carbon
atoms, which is unsubstituted or mono or poly-substituted
with sulfide, oxide, hydroxyl, amide or sulfate; a
heterocyclic group;
or phenyl, unsubstituted or substituted with a halogen, an
alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon
atoms, a hydroxyl, or a nitro;
(ii) an ester of the carboxylic group of the amino acid of formula (I), (II)
or (III)
with an aliphatic straight or branched chain alcohol of from 1 to 6 carbon
atoms;
(iii) an ether of said amide (i) or said ester (ii);
(iv) salts of any of (i) to (iii);
(v) hydrates and semi-hydrates of any of (i) to (iv); and
(vi) mixtures of any of (i) to (v).
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
8
This invention involves a stable suspension aerosol formulation
suitable for pressurized delivery which comprises (1) a particulate
macromolecular
medicament or drug, (2) a suitable propellant, and (3) a suitable stabilizer.
A suitable macromolecular medicament or drug is one which is
suitable for administration by inhalation, the inhalation being used for oral
and nasal
inhalation therapy. A stable, colloidal dispersion of a medicament in a fluid,
e.g. air,
hydrocarbon gases, chlorofluorocarbon (CFC) propellants or non-CFC
propellants,
such as tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227) is
described.
A stabilizer of a polyionic species, such as an amino acid and a small
molecule peptide, as inactive formulation components which trigger loss of
adhesive
bond strength between the medicament particles is employed. An electret or
sterially stabilized aerocolloid particles of the selected medicaments is thus
formed.
Electrets are the electrostatic equivalent of permanent magnets but can be
susceptible to breakdown in the presence of moisture, such as that present in
air or at
ambient humidity conditions of the respiratory tract. Accordingly the present
invention applies to dry powder aerosols, portable nebulizer systems, as well
pressurized metered dose inhaler formulations.
The resultant aerocolloid is chemically and physically stable and can
remain in suspension until the selected medicament or drug particles reach the
alveolar or other absorption sites in the airways of a patient, e.g. human,
animal,
being treated. Once at the absorption site, the drug particles should be
efficiently
trapped at the deposition site as a result of moisture in the ambient,
dissolve rapidly
in the epithelial lining fluids, and be absorbed quickly across the
biomembranes of
the patient, thereby limiting possible deactivation by metabolizing enzymes in
the
airways.
A suitable medicament to which the subject invention is directed is
one that forms a stable hydrophobic dispersion suitable for delivery to a
patient, e.g.,
human or animal. Typically, the medicament includes a peptide, polypeptide, or
protein biotherapeutic ranging from 0.5 K Dalton to 150 K Dalton in molecular
size.
In particular, the peptide, polypeptide, or protein biotherapeutic medicament
includes diabetic aids; insulins and insulin analogs; amylin; glucagon;
surfactants;
CA 02396796 2011-01-06
9
immunomodulating peptides such as cytokines, chemokines, lymphokines
interleukins such as taxol, interleukin-1, interleukin-2, and interferons;
erythropoetins; thrombolytics and heparin; anti-proteases, antitrypsins and
amiloride; rhDNase; antibiotics and other antiinfectives; hormones and growth
factors such as parathyroid hormones, LH-RH and GnRH analogs; nucleic acids;
DDAVP; calcitonins; cyclosporine; ribavirin; enzymes; heparins; hematopoietic
factors; cyclosporins; vaccines; immunoglobulins; vasoactive peptides;
antisense
agents; genes, oligonucleotides, and nucleotide analogs.
The term diabetic aid includes natural, synthetic, semi-synthetic and
recombinant medicaments such as activin, glucagon, insulin, somatostatin,
proinsulin, amylin, and the like.
The term "insulin" shall be interpreted to encompass natural extracted
human insulin, recombinantly produced human insulin, insulin extracted from
bovine and/or porcine sources, recombinantly produced porcine and bovine
insulin
and mixtures of any of these insulin products. The term is intended to
encompass
the polypeptide normally used in the treatment of diabetics in a substantially
purified
form but encompasses the use of the term in its commercially available
pharmaceutical form, which includes additional excipients. The insulin is
preferably
recombinantly produced and may be dehydrated (completely dried) or in
solution.
The terms "insulin analog," "monomeric insulin" and the like are
used interchangeably herein and are intended to encompass any form of
"insulin" as
defined above wherein one or more of the amino acids within the polypeptide
chain
has been replaced with an alternative amino acid and/or wherein one or more of
the
amino acids has been deleted or wherein one or more additional amino acids has
been added to the polypeptide chain orwamino acid sequences which act as
insulin in
decreasing blood glucose levels. In general, the "insulin analogs" of the
present
invention include "insulin lispro analogs," as disclosed in U.S. Pat. No.
5,547,929,
insulin analogs including LysPro insulin and humalog insulin, and other "super
insulin analogs", wherein the ability of the insulin analog to affect serum
glucose
levels is substantially enhanced as compared with conventional insulin as well
as
hepatoselective insulin analogs which are more active in the liver than in
adipose
tissue. Preferred analogs are monomeric
CA 02396796 2003-10-14
WO 01/60420 PCTIUS01/00117
insulin analogs, which are insulin-like compounds used for the same general
purpose
as insulin such as insulin lispro i.e., compounds which are administered to
reduce
blood glucose levels.
The term "amylin" includes natural human amylin, bovine, porcine,
5 rat, rabbit amylin, as well as synthetic, semi-synthetic or recombinant
amylin or
amylin analogs including pramlintide and other amylin agonists as disclosed in
U.S.
Pat. No. 5,686,411, and U.S. Pat. No. 5,854,215.
The term "immunomodulating proteins" include cytokines,
10 chemokines, lymphokines complement components, immune system accessory and
adhesion molecules and their receptors of human or non-human animal
specificity.
Useful examples include GM-CSF, IL-2, IL-12, OX40, OX40L (gp34),
lymphotactin, CD40, CD40L. Useful examples include interleukins for example
interleukins 1 to 15, interferons alpha, beta or gamma, tumour necrosis
factor,
granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony
stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF),
chemokines such as neutrophil activating protein (NAP), macrophage
chemoattractant and activating factor (MCAF), RANTES, macrophage
inflammatory peptides MIP-la and MIP-lb, complement components and their
receptors, or an accessory molecule such as B7.1, B7.2, ICAM-1, 2 or 3 and
cytokine receptors. OX40 and OX40-ligand (gp34) are further useful examples of
immunomodulatory proteins. Immunomodulatory proteins can for various purposes
be of human or non-human animal specificity and can be represented for present
purposes, as the case may be and as may be convenient, by extracellular
domains
and other fragments with the binding activity of the naturally occurring
proteins, and
muteins thereof, and their fusion proteins with other polypeptide sequences,
e.g.
with immunoglobulin heavy chain constant domains. Where nucleotide sequences
encoding more than one immunomodulating protein are inserted, they can for
example comprise more than one cytokine or a combination of cytokines and
accessory/adhesion molecules.
The term "interferon" or "IFN" as used herein means the family of
highly homologous species-specific proteins that inhibit viral replication and
cellular
CA 02396796 2003-10-14
WO 01/60420 PCT/USO1/0011
11
proliferation and modulate immune response. Interferons are grouped into three
classes based on their cellular origin and antigenicity, alpha-interferon
(leukocytes),
beta-interferon (fibroblasts) and gamma-interferon (immunocompetent cells).
Recombinant forms and analogs of each group have been developed and are
commercially available. Subtypes in each group are based on
antigenic/structural
characteristics. At least 24 interferon alphas (grouped into subtypes A
through H)
having distinct amino acid sequences have been identified by isolating and
sequencing DNA encoding these peptides. See also Viscomi, 1996 Biotherapy
10:59-86.
The terms "alpha.-interferon", "alpha interferon", "interferon alpha", "human
leukocyte interferon" and IFN are used interchangeably herein to describe
members
of this group. Both naturally occurring and recombinant alpha interferon,
including
consensus interferon such as that described in U.S. Pat. No. 4,897,471,
may be used in the
practice of the invention. Human leukocyte interferon prepared in this manner
contains a mixture of human leukocyte interferons having different amino acid
sequences. Purified natural human alpha inteferons and mixtures.thereof which
may
be used in the practice of the invention include but are not limited to
Sumiferon*
RTM interferon alpha-nI available from Sumitomo, Japan; Welfferong interferon
alpha-nl (Ins) available from Glaxo-Wellcome Ltd., London, Great Britain; and
AlferoifRTM interferon alpha n3 available from the Purdue Frederick Co.,
Norwalk, Conn.
The term "erythropoietin" applies to synthetic, semi-synthetic,
recombinant, natural, human, monkey, or other animal or microbiological
isolated
polypeptide products having part or all of the primary structural conformation
(i.e.,
continuous sequence of amino acid residues) and one or more of the biological
properties (e.g., immunological properties and in vivo and in vitro biological
activity) of naturally-occurring erythropoietin, including allelic variants
thereof.
These polypeptides are also uniquely characterized by being the product of
procaryotic or eucaryotic host expression (e.g., by bacterial, yeast and
mammalian
cells in culture) of exogenous DNA sequences obtained by genomic or cDNA
cloning or by gene synthesis. Products of microbial expression in vertebrate
(e.g.,
* trade-mark
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
12
mammalian and avian) cells may be further characterized by freedom from
association with human proteins or other contaminants which may be associated
with erythropoietin in its natural mammalian cellular environment or in
extracellular
fluids such as plasma or urine. The products of typical yeast (e.g.,
Saccaromyces
cerevisiae) or procaryote (e.g., E. coli) host cells are free of association
with any
mammalian proteins. Depending upon the host employed, polypeptides of the
invention may be glycosylated with mammalian or other eucaryotic carbohydrates
or
may be nonglycosylated. Polypeptides of the invention may also include an
initial
methionine amino acid residue (at position -1). Novel glycoprotein products of
the
invention include those having a primary structural conformation sufficiently
duplicative of that of a naturally-occurring (e.g., human) erythropoietin to
allow
possession of one or more of the biological properties thereof and having an
average
carbohydrate composition which differs from that of naturally-occurring (e.g.,
human) erythropoietin.
The terms "heparins" and "thrombolytics" include anti-clotting
factors such as heparin, low molecular weight heparin, tissue plasminogen
activator
(TPA), urokinase (Abbokinase) and other factors used to control clots.
The terms "anti-proteases" and "protease-inhibitors" are used
interchangeably and apply to synthetic, semi-synthetic, recombinant, naturally-
occurring or non-naturally occurring, soluble or immobilized agents reactive
with
receptors, or act as antibodies, enzymes or nucleic acids. These include
receptors
which modulate a humoral immune response, receptors which modulate a cellular
immune response (e.g., T-cell receptors) and receptors which modulate a
neurological response (e.g., glutamate receptor, glycine receptor, gamma-amino
butyric acid (GABA) receptor). These include the cytokine receptors
(implicated in
arthritis, septic shock, transplant rejection, autoimmune disease and
inflammatory
diseases), the major histocompatibility (MHC) Class I and II receptors
associated
with presenting antigen to cytotoxic T-cell receptors and/or T-helper cell
receptors
(implicated in autoimmune diseases) and the thrombin receptor (implicated in
coagulation, cardiovascular disease). The list also includes antibodies which
recognize self-antigens such as those antibodies implicated in autoimmune
disorders
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
13
and antibodies which recognize viral (e.g., HIV, herpes simplex virus) and/or
microbial antigens.
The terms "hormones" and "growth factors" include hormone
releasing hormones such as growth hormone, thyroid hormone, thyroid releasing
hormone (TRH), gonadotropin-releasing hormone (GnRH), leuteininzing hormone,
leuteininzing hormone-releasing hormone (LHRH, including the superagonists and
antagonists such as leuprolide, deltirelix, gosorelin, nafarelin, danazol,
etc.) sourced
from natural, human, porcine, bovine, ovine, synthetic, semi-synthetic, or
recombinant sources. These also include somatostatin analogs such as
octreotide
(Sandostatin). Other agents in this category of biotherapeutics include
medicaments
for uterine contraction (e.g., oxytocin), diuresis (e.g., vasopressin),
neutropenia (e.g.,
GCSF), respiratory disorders (e.g., superoxide dismutase), RDS (e.g.,
surfactants,
optionally including apoproteins), and the like.
The term "enzymes" include recombinant deoxyribonuclease such as
DNAse (Genentech) from Corporation, proteases (e.g., serine proteases such as
trypsin and thrombin), polymerases (e.g., RNA polymerases, DNA polymerases),
reverse transcriptases and kinases, enzymes implicated in arthritis,
osteoporosis,
inflammatory diseases, diabetes, allergies, organ transplant rejection,
oncogene
activation (e.g., dihydrofolate reductase), signal transduction, self-cycle
regulation,
transcription, DNA replication and repair.
The term "nucleic acids" includes any segment of DNA or RNA
containing natural or non-naturally occurring nucleosides, or other proteinoid
agents
capable of specifically binding to other nucleic acids or oligonucleotides via
complementary hydrogen-bonding and also are capable of binding to non-nucleic
acid ligates. In this regard, reference is made to Bock, L., et al., Nature
355:564-566
(1992) which reports inhibition of the thrombin-catalyzed conversion of
fibrinogen
to fibrin using aptamer DNA.
Examples of biological molecules for which lead molecules can be
synthesized and selected in accordance with the invention include, but are not
limited to, agonists and antagonists for cell membrane receptors,
neurotransmitters,
toxins and venoms, viral epitopes, hormones, opiates, steroids, peptides,
enzyme
substrates and inhibitors, cofactors, drugs, lectins, sugars,
oligonucleotides, nucleic
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
14
acids, oligosaccharides, lipids, proteins, and analogs of any of the foregoing
molecules.
The term "analog" refers to a molecule, which shares a common
functional activity with the molecule to which it is deemed to be an analog
and
typically shares common structural features as well.
The term "recombinant" refers to any type of cloned biotherapeutic
expressed in procaryotic cells or genetically engineered molecule, or
combinatorial
library of molecules which may be further processed into another state to form
a
second combinatorial library, especially molecules that contain protecting
groups
which enhance the physicochemical, pharmacological, and clinical safety of the
biotherapeutic agent.
The term "vaccines" refers to therapeutic compositions for
stimulating humoral and cellular immune responses, either isolated, or through
an
antigen presenting cell, such as an activated dendritic cell, that is able to
activate T-
cells to produce a multivalent cellular immune response against a selected
antigen.
The potent antigen presenting cell is stimulated by exposing the cell in vitro
to a
polypeptide complex. The polypeptide complex may comprise a dendritic cell-
binding protein and a polypeptide antigen, but preferably, the polypeptide
antigen is
either a tissue-specific tumor antigen or an oncogene gene product. However,
it is
appreciated that other antigens, such as viral antigens can be used in such
combination to produce immunostimulatory responses. In another preferred
embodiment, the dendritic cell-binding protein that forms part of the
immunostimulatory polypeptide complex is GM-CSF. In a further preferred
embodiment, the polypeptide antigen that forms part of the complex is the
tumor-
specific antigen prostatic acid phosphatase. In still other preferred
embodiments, the
polypeptide antigen may be any one of the oncogene product peptide antigens.
The
polypeptide complex may also contain, between the dendritic cell-binding
protein
and the polypeptide antigen, a linker peptide. The polypeptide complex may
comprise a dendritic cell-binding protein covalently linked to a polypeptide
antigen,
such polypeptide complex being preferably formed from a dendritic cell binding
protein, preferably GM-CSF, and a polypeptide antigen. The polypeptide antigen
is
preferably a tissue-specific tumor antigen such as prostatic acid phosphatase
(PAP),
CA 02396796 2007-11-23
or an oncogene product, such as Her2, p21RAS, and p53; however, other
embodiments, such as viral antigens, are also within the contemplation of the
invention.
The teen "immunoglobulins" encompasses polypeptide
oligonucleotides involved in host defense mechanisms such as coding and
encoding
by one or more gene vectors, conjugating various binding moieties of nucleic
acids
in host defense cells, or coupling expressed vectors to aid in the treatment
of a
human or animal subject. The medicaments included in this class of
polypeptides
include IgG, IgE, IgM, IgD, either individually or in a combination with one
another.
In a suitable embodiment, the medicament is selected from the group
consisting of an insulin, an insulin analog, an amylin, glucagons, LH-RH,
deltirex,
leuprolide, gosorelin, nafarelin, octreotide, somatostatin, a calcitonin,
parathyroid
hormone, TRH, growth hormone-releasing hormone, G-CSF, G-SF, a cytokine,
rhDNAse, a heparin, an antibiotic, albumin, ovalbumin, aminloride, DDAVP, VIP,
a
cyclosporine, an erythropoietin, an interferon, IgG, IgE, IgM, IgA, IgD, an
interleukin, IRAP, papain, peroxidase, serration peptidase, catalase, a-l-
antitrypsin, a
gene; a vector, an amiloride, a rhDNAse, an oligonucleotide, ribavirin or a
mixture of
a any of the foregoing medicaments.
For purposes of the formulations of this invention, which are
intended for inhalation into the lungs, the medicament or drug is preferably
micronized whereby a therapeutically effective amount or fraction (e.g.,
ninety
percent or more) of the drug is particulate. Typically, the particles have a
diameter
of less than about 10 microns, and preferably less than about 5 microns, in
order that
the particles can be inhaled into the respiratory tract and/or lungs.
The selected medicament or drug is present in the inventive
formulations in a therapeutically effective amount, that is, an amount such
that the
drug can be administered as a dispersion, aerosol, via oral or nasal
inhalation, and
cause its desired therapeutic effect, typically preferred with one
.dose , or through
several doses. The drug is typically administered as an aerosol from a
conventional
valve, e.g., a metered dose valve, through an aerosol adapter also known as an
actuator.
CA 02396796 2007-11-23
15 a
The term "amount" as used herein refers to a quantity or to a
concentration as appropriate to the context. The amount of a drug that
constitutes a
therapeutically effective amount varies according to factors such as the
potency of
the particular drug, the route of administration of the formulation, and the
mechanical system used to administer the formulation. A therapeutically
effective
amount of a particular drug can be selected by those of ordinary skill in the
art with
due consideration of such factors. Generally a therapeutically effective
amount will
be from about 0.001 parts by weight to about 5 parts by weight based on 100
parts
by weight of the fluid or propellant selected.
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
16
A suitable fluid includes air, a hydrocarbon such as n-butane,
propane, isopentane, etc. or a propellant. A suitable propellant is any
fluorocarbon,
e.g. a 1-6 hydrogen containing flurocarbon (such as CHF2CHF2, CF3CH2F,
CH2F2CH3 and CF3CHFCF3), a perfluorocarbon, e.g. a 1-4 carbon perfluorocarbon,
(such as CF3CF3, CF3CF2CF3); or any mixture of the foregoing, having a
sufficient
vapor pressure to render them effective as propellants. Some typical suitable
propellants include conventional chlorofluorocarbon (CFC) propellants such as
propellants 11, 12 and 114 or a mixture thereof. Non-CFC propellants such as
1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane
(Propellant 227) or a mixture thereof are preferred. The fluid or propellant
is
preferably present in an amount sufficient to propel a plurality of the
selected doses
of drug from an aerosol canister when such is employed.
A suitable stabilizer is selected. A suitable stabilizer includes (1) an
amino acid selected from (a) a monoamino carboxylic acid of the formula, H2N-R-
COOH (1), (b) a monoamino dicarboxylic acid of the formula, H2N-R(COOH)2 (II)
and (c) a diamino monocarboxylic acid of the formula (H2N)2-R COOH (III),
where
R is a straight or branched alkyl radical of from 1 to 22 carbon atoms, which
can be
mono or poly-substituted with moieties such as sulfide (-S-), oxide (-0-),
hydroxyl
(-OH), amide (-NH), sulfate (-S04); aryl of the formula
where X is hydrogen, halogen (F, Cl, BR, I), alkyl of 1 to 6 carbon atoms,
alkoxy of
1 to 6 carbon atoms, hydroxy and nitro; and heterocyclic, such as thienyl,
furyl,
pyranyl, imidazolyl, pyrrolyl, thizolyl, oxazolyl, pyridyl, and pyrimidinyl
compounds; (2) a derivative of the amino acid selected from (a) acid addition
salts
of the amino group, obtained from inorganic acids, such as hydrochloric,
hydrobromic, sulfuric, nitric, phosphoric, and perchloric acids, as well as
organic
acids, such as tartaric, citric, acetic, succinic, maleic, fumaric, oxalic
acids; (b)
amides of the carboxylic acid group, e.g., glutamine, di-peptides, e.g. salts
and esters
of oxidized and unoxidized L-cysteinylglycine, gamma-L-glutamyl-L-cysteine, N-
acetyl-L-cysteine-glycine, either conjugated, unconjugated or polymeric forms
of L-
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
17
Gly-L-Glu and L-Val-L-Thr, L-aspartyl-L-phenylalanine, muramyl dipeptides,
nutrients such as L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-
tyrosine, L-
tyrosyl-L-arginine, N-Cbz-L-Leu-L-Leu-OCH and its salts or esters, glycyl-
glycine,
N-acetyl-L-aspartate-L-glutamate (NAAG), etc.; and tripeptides, e.g. oxidized
and
unoxidized gamma-L-glutamyl-L-cysteinylglycine; muramyl tripeptides, etc.
(c) esters of the carboxylic acid group obtained from aliphatic straight or
branched
chain alcohols of from 1 to 6 carbon atoms, e.g. L-aspartyl-L-phenylalanine
methylester (Aspartame@), (3) an ether of any of the foregoing; (4) a hydrate
or
semi-hydrate of any of the foregoing and (5) a mixture of the amino acid and
the
derivative of the amino acid.
Suitable amino acids of the formula I include glycine, alanine, valine,
leucine, isoleucine, leucylalanine, methionine, threonine, isovaline,
phenylalanine,
tyrosine, serine, cysteine, N-acetyl-L-cysteine, histidine, tryptophan,
proline, and
hydroxyproline, e.g. trans-4-hydroxy proline. Compounds of the formula II
include,
aspartic acid, and glutamic acid, compounds of the formula (III) include
arginine,
glutamine, lysine, hydroxylysine, ornithine, asparagine, and citrulline.
A fluid or aerosol formulation preferably comprises the protective
colloid stabilizer in an amount effective to stabilize the formulation
relative to an
identical formulation not containing the stabilizer, such that the drug does
not settle,
cream or flocculate after agitation so quickly as to prevent reproducible
dosing of
the drug. Reproducible dosing can be achieved if the formulation retains a
substantially uniform drug concentration for about fifteen seconds to about
five
minutes after agitation.
For optimal functional and therapeutic performance of the aerosol
formulation, either as a dry powder or as an aerosol suspension, the
stabilizer is
present either as a coarse carrier (e.g., 20-90 m) or as a finely micronized
powder,
< 10 pm in diameter. In either case, reproducible drug dosimetry is obtained
without the need to qualify the inspiratory maneuver of the patient.
Accordingly,
excellent dose uniformity is obtained at tidal flows of up to 2 liters, or at
inspiratory
flow rates of as low as 15 liters per minute to about 90 liters per minute.
The particular amount of stabilizer that constitutes an effective
amount is dependent upon the particular stabilizer, the particular propellant,
and on
CA 02396796 2003-10-14
WO 01/60420 PCT/US01/00117
18
the particular drug used in the formulation. It is therefore not practical to
enumerate
specific effective amounts for use with specific formulations of the
invention, but
such amounts can readily be determined by those skilled in the art with due
consideration of the factors set forth above. Generally, however, the
stabilizer can
be present in a formulation in an amount from about 0.001 parts per million to
about
200,000 parts per million, more preferably about 1 part per million to about
10,000
parts per million, most preferably from about 10 parts per million to about
5,000
parts per million of the total formulation.
It has surprisingly been found that the formulation of the invention is
stable without the necessity of employing a cosolvent, such as ethanol, or
surfactants. However, further components, such as conventional lubricants or
surfactants, cosolvents, ethanol, etc., can also be present in an aerosol
formulation of
the invention in suitable amounts readily determined by those skilled in the
art. In
this regard, reference is made to U.S. Patent No. 5,225,183.
Generally the formulations of the invention can be prepared by
combining (i) the drug in an amount sufficient to provide a plurality of
therapeutically effective doses; (ii) the stabilizer in an amount effective to
stabilize
each of the formulations; (iii) the fluid or propellant in an amount
sufficient to
propel a plurality of doses, e.g. from an aerosol canister; and (iv) any
further
optional components e.g. ethanol as a cosolvent; and dispersing the
components.
The components can be dispersed using a conventional mixer or homogenizer, by
shaking, or by ultrasonic energy. The components can also be dispersed using a
bead mill or a microfluidizer. Bulk formulations can be transferred to smaller
individual aerosol vials by using valve to valve transfer methods, pressure
filling or
by using conventional cold-fill methods. It is not required that a stabilizer
used in a
suspension aerosol formulation be soluble in the propellant. Those that are
not
sufficiently soluble can be coated onto the drug particles in an appropriate
amount
and the coated particles can then be incorporated in a formulation as
described
above.
Aerosol canisters equipped with conventional valves, preferably
metered dose valves, can be used to deliver the formulations of the invention.
It has
CA 02396796 2002-07-22
WO 01/60420 PCT/US01/00117
19
been found, however, that selection of appropriate valve assemblies for use
with
aerosol formulations is dependent upon the particular stabilizer and other
adjuvants
used (if any), on the propellant, and on the particular drug being used.
Conventional
neoprene and bung valve rubbers used in metered dose valves for delivering
conventional CFC formulations often have less than optimal valve delivery
characteristics and ease of operation when used with formulations containing
HFC-
134a or HFC-227. Therefore certain formulations of the invention are
preferably
dispensed via a valve assembly wherein the diaphragm is made of a nitrile
rubber
such as DB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDM
rubber such as VistalonTM (Exxon), RoyaleneTM (UniRoyal), bunaEP (Bayer). Also
suitable are diaphragms fashioned by extrusion, injection molding or
compression
molding from a thermoplastic elastomeric material such as FLEXOMERTM GERS
1085 NT polyolefin (Union Carbide).
Conventional aerosol canisters, coated or uncoated, anodized or
unanodized, e.g., those of aluminum, glass, stainless steel, polyethylene
terephthalate, and coated canisters or cans with epon, epoxy, etc., can be
used to
contain a formulation of the invention.
Conventional nebulizer systems can be employed with the
formulations of this invention, as well as by powder aerosols.
The formulation of the invention can be delivered to the respiratory
tract and/or lung by oral inhalation in order to effect bronchodilation or in
order to
treat a condition susceptible of treatment by inhalation, e.g., asthma,
chronic
obstructive pulmonary disease. The formulations of the invention can also be
delivered by nasal inhalation in order to treat, e.g., allergic rhinitis,
rhinitis, (local) or
diabetes (systemic), or they can be delivered via topical (e.g., buccal)
administration
in order to treat, e.g., angina or local infection.
