U.S. patent application number 10/820817 was filed with the patent office on 2004-10-07 for suspension aerosol formulations.
This patent application is currently assigned to 3M COMPANY. Invention is credited to Jinks, Philip A., Moris, Robert A., Oliver, Martin J., Schultz, David W., Schultz, Robert K..
Application Number | 20040197273 10/820817 |
Document ID | / |
Family ID | 27420051 |
Filed Date | 2004-10-07 |
United States Patent
Application |
20040197273 |
Kind Code |
A1 |
Schultz, Robert K. ; et
al. |
October 7, 2004 |
Suspension aerosol formulations
Abstract
A pharmaceutical suspension aerosol formulation containing
HFA-227 as a propellant.
Inventors: |
Schultz, Robert K.;
(Shoreview, MN) ; Schultz, David W.; (Pine
Springs, MN) ; Oliver, Martin J.; (Loughborough,
GB) ; Moris, Robert A.; (Lino Lakes, MN) ;
Jinks, Philip A.; (Mount Sorrel, GB) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
3M COMPANY
|
Family ID: |
27420051 |
Appl. No.: |
10/820817 |
Filed: |
April 9, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10820817 |
Apr 9, 2004 |
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08455280 |
May 31, 1995 |
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6743413 |
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08455280 |
May 31, 1995 |
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07878039 |
May 4, 1992 |
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07878039 |
May 4, 1992 |
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07809791 |
Dec 18, 1991 |
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07878039 |
May 4, 1992 |
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07810401 |
Dec 18, 1991 |
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Current U.S.
Class: |
424/45 ;
128/200.23 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 31/137 20130101; A61K 9/124 20130101; A61P 11/00 20180101;
A61K 9/008 20130101 |
Class at
Publication: |
424/045 ;
128/200.23 |
International
Class: |
A61L 009/04; A61M
011/00 |
Claims
What is claimed is:
1. A process for preparing a metered dose inhaler comprising a
container closed with a metering valve, said metered dose inhaler
containing a pharmaceutical composition suitable for inhalation by
a patient, comprising the steps of: preparing a pharmaceutical
suspension formulation consisting essentially of a therapeutically
effective amount of one or more particulate drugs sufficient to
provide a plurality of therapeutically effective doses of the drug
and a propellant selected from the group consisting of HFC 134a,
HFC 227, and a mixture thereof; and providing said particulate drug
and said propellant in said metered dose inhaler.
2. The process of claim 1, wherein said metering valve contains a
surfactant as a lubricant for the metering valve.
3. The process of claim 2, wherein said metering valve comprises a
valve stem and said valve stem contains a surfactant as a lubricant
for the valve stem.
4. The process of claim 2, wherein a pharmaceutical suspension is
first prepared in bulk outside of said metered dose inhaler and
then transferred to said metered dose inhaler equipped with said
metering valve using a valve to valve transfer method.
5. The process of claim 3, wherein a pharmaceutical suspension is
first prepared in bulk outside of said metered dose inhaler and
then transferred to said metered dose inhaler equipped with said
metering valve using a valve to valve transfer method.
6. The process of claim 2, wherein said pharmaceutical suspension
is provided in a first container and is then transferred into said
metered dose inhaler through said metering valve.
7. The process of claim 1, wherein said pharmaceutical suspension
is prepared in said metered dose inhaler.
8. The process of claim 1, wherein said pharmaceutical suspension
formulation contains a single drug.
9. The process of claim 2, wherein said pharmaceutical suspension
formulation contains a single drug.
10. The process of claim 3, wherein said pharmaceutical suspension
formulation contains a single drug.
11. A metered dose inhaler prepared by a process according to claim
1.
12. A metered dose inhaler prepared by a process according to claim
2.
13. A metered dose inhaler prepared by a process according to claim
3.
14. A metered dose inhaler prepared by a process according to claim
4.
15. A metered dose inhaler prepared by a process according to claim
5.
16. A metered dose inhaler prepared by a process according to claim
6.
17. A metered dose inhaler prepared by a process according to claim
7.
18. A metered dose inhaler prepared by a process according to claim
8.
19. A metered dose inhaler prepared by a process according to claim
9.
20. A metered dose inhaler prepared by a process according to claim
10.
Description
SUSPENSION AEROSOL FORMULATIONS
[0001] This application is a Rule 53(b) divisional of U.S.
application Ser. No. 08/455,280 filed on May 31, 1995; which is a
Rule 60 divisional of U.S. application Ser. No. 07/878,039, filed
May 4, 1992; which is a CIP of U.S. application Ser. Nos.
07/809,791 and 07/810,401, both filed Dec. 18, 1991. The entire
contents of each of these applications is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to pharmaceutical aerosol
formulations. In another aspect this invention relates to
pharmaceutical suspension aerosol formulations wherein the
propellant comprises HFC 134a or HFC 227. In another aspect, it
relates to pharmaceutical suspension aerosol formulations
containing pirbuterol. In another aspect, it relates to
pharmaceutical suspension aerosol formulations containing albuterol
sulfate.
[0004] 2. Description of the Related Art
[0005] Pharmaceutical suspension aerosol formulations currently use
a mixture of liquid chlorofluorocarbons as the propellant.
Fluarotrichloromethane, dichlorodifluoromethane and
dichlorotetrafluoroethane are the most commonly used propellants in
aerosol formulations for administration by inhalation.
[0006] Chlorofluorocarbons (CFCs), however, have been implicated in
the destruction of the ozone layer and their production is being
phased out. Hydrofluorocarbon 134a (HFC 134a,
1,1,1,2-tetrafluoroethane) and hydrofluorocarbon 227 (HFC 227,
1,1,1,2,3,3,3-heptafluoropropane) are viewed as being more ozone
friendly than many chlorofluorocarbon propellants; furthermore,
they have low toxicity and vapor pressures suitable for use in
aerosols.
[0007] Patent Applications WO 91/11495 and WO 91/11496 (both by
Weil) describe pharmaceutical suspension aerosol formulations
comprising a medicinal agent, optionally a surfactant, and a
propellant mixture containing 1,1,1,2,3,3,3-heptafluoropropane and
one or more additional components, e.g., pentane, butane,
propellant 134a, propellant 11, propellant 125, or propellant
152a.
[0008] European Patent Office Publication 0 384 371 (Heiskel)
describes solution aerosols in which
1,1,1,2,3,3,3-heptafluoropropane or its mixture with propane,
butane, isobutane, dimethyl ether, or 1,1-difluoroethane serves as
the propellant. The application does not, however, disclose
suspension aerosols or pharmaceutical aerosol formulations.
[0009] European Patent Application 89.312270.5 (Purewal et al.)
discloses, inter alia, aerosol formulations comprising a
medicament, 1,1,1,2tetrafluoroethane, a surface active agent, and
at least one compound having higher polarity than
1,1,1,2tetrafluoroethane.
[0010] U.S. Pat. No. 2,868,691 (Porush et al.) discloses aerosol
formulations comprising a medicament, a halogenated lower alkane
propellant, and a cosolvent which assists in dissolving the
medicament in the propellant. The chemical formula for the
propellant given in Col. 2, lines 6-16, generically embraces HFC
134a and HFC 227. Examples of cosolvents disclosed include ethanol
and diethyl ether.
[0011] U.S. Pat. No. 3,014,844 (Thiel et al.) discloses aerosol
formulations comprising a micronized medicament, a halogenated
lower alkane propellant and a surface-active agent to assist in the
suspension of the medicament in the propellant. The chemical
formula for the propellant given in Col. 4, lines 17-28,
generically embraces HFC 134a and HFC 227.
[0012] Patent Application WO 90/01454 (Greenleaf et al.) discloses
aerosol compositions having HFC 134a as the propellant and
comprising a medicament coated with a non-perfluorinated surface
active dispersing agent. This application describes control
formulations containing only HFC 134a and 0.866 percent by weight
of a drug.
[0013] Albuterol sulfate is a relatively selective beta-2
adrenergic bronchodilator. It is available in a variety of dosage
forms including tablets, syrups and formulations suitable for
inhalation. For example, VENTOLIN.TM. Inhalation Aerosol
(commercially available from Allen & Hansburys) is a metered
dose aerosol unit containing a microcrystalline suspension of
albuterol (free base) in propellant (a mixture of
trichloromonofluoromethane and dichlorodifluoromethaner with oleic
acid. VENTOLIN ROTOCAPS.TM. for Inhalation (commercially available
from Allen & Hansburys) contain a mixture of microfine
albuterol sulfate with lactose and are intended for use with a
specially designed device for inhaling powder. VENTOLIN.TM.
Solution for Inhalation (commercially available from Allen &
Hansburys) is an aqueous solution of albuterol sulfate intended for
use with a nebulizer.
[0014] Pirbuterol acetate is a relatively selective beta-2
adrenergic bronchodilator. MAXAIR.TM. Inhaler (commercially
available from 3M Pharmaceuticals, St. Paul, MLA) is a metered dose
aerosol unit containing a fine-particle suspension of pirbuterol
acetate in the propellant mixture of trichloromonofluoromethane and
dichlorodifluoromethane, with sorbitan trioleate.
SUMMARY OF THE INVENTION
[0015] This invention provides a pharmaceutical suspension
formulation suitable for aerosol administration, consisting
essentially of a therapeutically effective amount of a drug and a
propellant selected from the group consisting of HFC 134a, HFC 227,
and a mixture thereof, said formulation being further characterized
in that it exhibits substantially no growth in particle size or
change in crystal morphology of the drug over a prolonged period,
is substantially and readily redispersible, and upon redispersion
does not flocculate so quickly as to prevent reproducible dosing of
the drug.
[0016] This invention also provides an aerosol canister containing
a formulation as described above in an amount sufficient to provide
a plurality of therapeutically effective doses of the drug. Also
provided is a method of preparing a formulation as described above,
comprising the steps of: (i) combining an amount of the drug
sufficient to provide a plurality of therapeutically effective
doses and a propellant selected from the group consisting of HFC
134a, HFC 227, and a mixture thereof, in an amount sufficient to
propel from an aerosol canister a plurality of therapeutically
effective doses of the drug; and (ii) dispersing the drug in the
propellant. This invention further provides a method of treating a
mammal having a condition capable of treatment by inhalation,
comprising the step of administering by inhalation a formulation as
described above to the mammal.
[0017] In another aspect, this invention provides suspension
aerosol formulations comprising a therapeutically effective amount
of micronized albuterol sulfate and HFC 227 as substantially the
only propellant. This invention also provides suspension aerosol
formulations comprising a therapeutically effective amount of
micronized albuterol sulfate, from about 0.1 to about 15 percent by
weight of ethanol, and HFC 227. as substantially the only
propellant. This invention also provides suspension aerosol
formulations comprising a therapeutically effective amount of
micronized albuterol sulfate, from about 5 to 15 percent by weight
of ethanol, from about 0.05 to about 0.5 percent by weight of a
surfactant selected from the group consisting of oleic acid and
sorbitan trioleate, and HFC 227 as substantially the only
propellant.
[0018] In another aspect this invention provides suspension aerosol
formulations comprising a therapeutically effective amount of
micronized pirbuterol acetate and a propellant comprising HFC 227,
the formulation being further characterized in that it is
substantially free of perfluorinated surfactant. This invention
also provides suspension aerosol formulations comprising a
therapeutically effective amount of micronized pirbuterol acetate,
about 0.1 to about 12 percent by weight of ethanol, and a
propellant comprising HFC 227. This invention also provides
suspension aerosol formulations comprising a therapeutically
effective amount of micronized pirbuterol acetate, about 5 to about
12 percent by weight of ethanol, about 0.05 to about 0.5 percent by
weight of oleic acid, and a propellant comprising HFC 227.
[0019] This invention also provides a method for inducing
bronchodilation in a mammal, comprising administering to the mammal
a formulation as described above by inhalation.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The term "suspension aerosol formulation" as used herein
refers to a formulation in which the drug is in particulate form
and is substantially insoluble in the propellant.
[0021] Amounts expressed herein in terms of percent refer to
percent by weight based on the total weight of the formulation.
[0022] The formulations of the invention that consist essentially
of drug and a propellant contain drug and propellant in relative
amounts such that a formulation suitable for aerosol administration
is obtained without the need for additional components.
[0023] Such formulations preferably contain less than an effective
stabilizing amount of surfactant and more preferably are
substantially free of surfactant and other components.
[0024] The formulations of the invention contain a drug in a
therapeutically effective amount, that is, an amount such that the
drug can be administered as an aerosol (e.g., topically or by oral
or nasal inhalation) and cause its desired therapeutic effect with
one dose, or less preferably several doses, from a conventional
valve, e.g., a metered dose valve. "Amount" as used herein refers
to quantity or to 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, efficacy,
and the like, of the particular drug, on the route of
administration of the formulation, and on the device 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. Particularly in
formulations of the invention intended for oral inhalation into the
lungs, the drug is preferably micronized, i.e., about 90 percent or
more of the particles have a diameter of less than about 10
microns, in order to assure that the particles can be inhaled into
the lungs.
[0025] The particular amount of drug that will remain suspended in
a formulation of the invention for a time sufficient to allow
reproducible dosing of the drug depends to some extent on the
nature of the particular drug, e.g., its density, and on the
particular propellant used in the formulation. Generally, however,
it has been found that when drug concentrations of less than about
0.1 percent are used in a formulation of the invention the drug
flocculates to some degree but generally does not settle or cream
to the extent that the suspension becomes unsuitable for use as an
aerosol formulation, e.g., in a metered dose inhaler. Therefore as
regards drug concentration such formulations are acceptably
homogeneous.
[0026] When drug concentrations greater than about 0.1 percent but
less than about 0.5 percent are used in a formulation of the
invention it is sometimes seen that the drug flocculates
considerably in the formulation and therefore might have an
increased tendency to cream or settle. As discussed below in
connection with the propellant component of the formulations of the
invention, in these instances it is preferable to select the
propellant in a manner that minimizes creaming and settling of the
drug in order to assure that the formulation is acceptably
homogeneous as regards drug concentration.
[0027] As drug concentration increases, e.g., beyond about 0.5
percent, the tendency of the drug to flocculate generally increases
also. However, the volume occupied by the flocculated drug also
increases and the flocculated drug begins to occupy substantially
all of the volume of the formulation. In such instances the
flocculated drug often shows a lesser tendency to cream or settle.
As regards drug concentration such formulations are acceptably
homogeneous.
[0028] Generally the concentration of the drug in a formulation of
the invention is preferably less than about 0.1 percent, more
preferably less than about 0.08 percent, and most preferably less
than about 0.05 percent. Accordingly, it is preferred according to
this invention that the drug have a potency such that
concentrations less than about 0.1 percent, more preferably less
than about 0.08 percent, and most preferably less than about 0.05
percent, are therapeutically effective. Preferred drugs for use in
the formulations of the invention therefore include formoterol,
salmeterol, and pharmaceutically acceptable salts thereof,
particularly formoterol fumarate. Other drugs that can be
formulated according to this invention include albuterol,
beclomethasone dipropionate, cromolyn, pirbuterol, and
pharmaceutically acceptable salts and solvates thereof,
particularly albuterol sulfate, disodium cromoglycate, and
pirbuterol acetate.
[0029] The propellant in a formulation of the invention can be HFC
134.times., HFC 227, or a mixture thereof in any proportion. The
propellant is present in an amount sufficient to propel a plurality
of doses from a metered dose inhaler. The density of HFC 134a
differs from the density of HFC 227. Therefore the density of the
propellant can be adjusted within limits by using mixtures of HFC
134a and HFC 227 in order to accommodate the density of the drug.
It is sometimes preferred that the propellant be selected such that
the propellant density is as closely matched as possible to the
drug density in order to minimize tendencies for the drug to settle
or cream, particularly when drug concentration is greater than 0.1
percent or when the drug concentration is between about 0.1 percent
and about 0.5 percent.
[0030] The pirbuterol acetate formulations of the invention contain
a therapeutically effective amount of pirbuterol acetate.
Preferably, the pirbuterol acetate constitutes about 0.4 to about
1.0 percent by weight, more preferably about 0.45 to about 0.9
percent by weight, of the aerosol formulation. Preferably the
pirbuterol acetate is micronized.
[0031] Ethanol can optionally be included in a pirbuterol acetate
aerosol formulation of the invention. When ethanol is present it
constitutes from about 0.1 to about 12 percent by weight,
preferably from about 5 to about 12 percent by weight of the
aerosol formulation. In another aspect of this invention ethanol
preferably constitutes from about 2 to about 8 percent by weight of
the formulation. Oleic acid can optionally be included in a
pirbuterol acetate formulation of the invention that includes
ethanol. when oleic acid is present it constitutes about 0.01 to
about 0.5 percent by weight of the formulation.
[0032] Typically the propellant constitutes the remainder of the
weight of the formulation once the pirbuterol acetate and the
optional ethanol and oleic acid are accounted for. Accordingly the
propellant is generally present in an amount of at least about 85
percent by weight based on the total weight of the formulation. The
propellant in a pirbuterol acetate formulation of the invention
comprises HFC 227, preferably as substantially the only propellant.
However, one or more other propellants such as propellant 142b
(1-chloro-1,1-difluoroethane), HFC 134a, and the like can be used,
preferably in pirbuterol acetate formulations of the invention
containing ethanol.
[0033] Preferred pirbuterol acetate formulations of the invention
exhibit substantially no growth in particle size or change in
crystal morphology of the pirbuterol acetate over a prolonged
period, are substantially and readily redispersible, and upon
redispersion do not flocculate so quickly as to prevent
reproducible dosing of pirbuterol acetate.
[0034] The albuterol sulfate formulations of the invention contain
a therapeutically effective amount of micronized albuterol sulfate.
Preferably micronized albuterol sulfate constitutes about 0.2 to
about 0.5 percent by weight, more preferably from about 0.35 to
about 0.42 percent by weight of the aerosol formulation.
[0035] Ethanol can optionally be included in such an albuterol
sulfate formulation of the invention. When ethanol is present it
constitutes from about 0.1 to about 20 percent by weight,
preferably from about 5 to about 15 percent by weight of the
formulation. A surfactant selected from the group consisting of
oleic acid and sorbitan trioleate can also optionally be included
in the formulation when the formulation also includes ethanol. When
a surfactant is present it constitutes about 0.01 to about 0.5
percent by weight of the aerosol formulation. Albuterol sulfate
formulations of the invention that do not contain ethanol are
preferably substantially free of perfluorinated surfactant.
[0036] Certain preferred albuterol sulfate suspension aerosol
formulations of the invention comprise HFC 227 as substantially the
only propellant. Typically the propellant constitutes the remainder
of the weight of the formulation once the albuterol sulfate and the
optional surfactant and/or ethanol are accounted for. Accordingly
the propellant is generally present in an amount of at least about
75 percent by weight based on the total weight of the
formulation.
[0037] Preferred albuterol sulfate formulations of the invention
exhibit substantially no growth in particle size or change in
crystal morphology of the albuterol sulfate over a prolonged
period, are substantially and readily redispersible, and upon
redispersion do not flocculate so quickly as to prevent
reproducible dosing of albuterol sulfate.
[0038] 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; and (ii) the
propellant in an amount sufficient to propel a plurality of doses
from an aerosol canister; and dispersing the drug in the
propellant. The drug can be dispersed using a conventional mixer or
homogenizer, by shaking, or by ultrasonic energy. Bulk formulation
can be transferred to smaller individual aerosol vials by using
valve to valve transfer methods or by using conventional cold-fill
methods.
[0039] The pirbuterol acetate suspension aerosol formulations of
this invention can be prepared by combining the pirbuterol acetate
and the propellant and then dispersing the pirbuterol acetate in
the propellant using a conventional mixer or homogenizer.
Pirbuterol acetate, however, is somewhat soluble in ethanol alone.
Accordingly, when oleic acid and/or ethanol are included in the
formulation, it is preferred that the pirbuterol acetate be first
placed in an aerosol vial. A mixture of the propellant, oleic acid
and/or ethanol can then be added, and the pirbuterol acetate
dispersed in the mixture.
[0040] The albuterol sulfate suspension aerosol formulations of
this invention can be prepared by combining the albuterol sulfate
and the propellant and dispersing the albuterol sulfate in the
propellant using a conventional mixer or homogenizer. When a
surfactant and/or ethanol are included in the formulation, they can
be added to the propellant along with the albuterol sulfate.
[0041] Aerosol canisters equipped with conventional valves,
preferably metered dose valves, can be used to deliver the
formulations of the invention. It has been found, however, that
selection of appropriate valve assemblies for use with aerosol
formulations is dependent upon the particular surfactants or
adjuvants used (if any), on the propellant, and on the particular
drug being used. Conventional neoprene and buna 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. Moreover, conventional CFC formulations generally
contain a surfactant in part as a lubricant for the valve stem.
Some formulations of the invention, however, do not contain a
surfactant or a lubricant. Therefore certain formulations of the
invention are preferably dispensed via a valve assembly wherein the
diaphragm is fashioned by extrusion, injection molding or
compression molding from a' thermoplastic elastomeric material such
as FLEXOMER.TM. DFDA 1137 NT 7 polyolefin, FLEXOMER.TM. DFDA 1138
NT polyolefin, FLEXOMER.TM. DEFD 8923 NT polyolefin, FLEXOMER.TM.
GERS 1085 NT polyolefin, FLEXOMER.TM. DFDA 1163 NT7 polyolefin,
FLEXOMER.TM. 1491 NT7 polyolefin, FLEXOMER.TM. 9020 NT7 polyolefin,
FLEXOMER.TM. 9042 NT polyolefin (Union Carbide), C-FLEX.TM.
thermoplastic elastomer R70-001, C-FLEX.TM. thermoplastic elastomer
R70-051, C-FLEX.TM. thermoplastic elastomer R70-085, C-FLEX.TM.
thermoplastic elastomer R70-026 (Concept Polymer Technologies), or
a blend of two or more thereof.
[0042] Conventional aerosol canisters, e.g., those of aluminum,
glass, stainless steel, or polyethylene terephthalate, can be used
to contain a formulation of the invention.
[0043] The formulations of the invention can be delivered to the
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, or
diabetes, or they can be delivered via topical (e.g., buccal)
administration in order to treat e.g., angina or local
infection.
[0044] The following Examples are provided to illustrate the
invention. All parts and percentages are by weight unless otherwise
indicated.
EXAMPLE 1
Formulations in HFC 134a
[0045] For each of the micronized drug substances A-G set forth
below, formulations were prepared at drug concentrations of 0.017
percent, 0.039 percent, 0.083 percent,. 0.41 percent, and 1.6
percent by weight based on the total weight of the formulation
(corresponding to 0.20 mg/mL, 0.50 mg/mL , 1.0 mg/mL, 5.0 mg/mL,
and 20 mg/mL, respectively) . The formulations were prepared by
dispersing micronized drug in HFC 134a in a sealed 15 mL clear PET
vial using ultrasonic energy.
[0046] Drugs:
[0047] A Beclomethasone dipropionate
[0048] B Albuterol
[0049] C Albuterol sulfate
[0050] D Formoterol fumarate
[0051] E Disodium cromoglycate
[0052] F Pirbuterol acetate
[0053] For each drug the lowest concentration formulation (0.017
percent by weight) was well dispersed and easily redispersible
after standing. None of the formulations at this concentration
showed any tendency to flocculate rapidly. As drug concentration
increased to 0.41 percent visible flocs started to appear,
different drugs having a greater or lesser tendency to flocculate.
The increase in flocculation with increasing concentration resulted
in an increasing rate of sedimentation or creaming (depending on
the particular drug involved) of suspended drug.
[0054] As drug concentration was further increased the formulations
flocculated but maintained a state of greater homogeneity as the
flocculated drug began to occupy more of the formulation
volume.
[0055] Using time lapse photography 10 and 30 second& after
agitation the formulations were assessed as follows:
1 Drug Concentration (%) A B C D E F 0.017 + + + + + + 0.039 + + +
? + + 0.083 ? ? + ? ? ? 0.41 - - - - - ? 1.63 + + - + - + + =
visually acceptable formulation - = visually unacceptable
formulation ? = border line acceptable formulation
[0056] These results show that each of the drug substances
evaluated can be formulated in HFC 134a alone. The formulations
retain homogeneity after shaking to form satisfactory formulations
for use with a metered dose inhaler. Formulations of low
concentration were particularly homogenous. Formulations of
intermediate concentration were of varying degrees of
acceptability.
[0057] At the high concentration of 1.6 percent the drugs with
density close to the propellant density (beclomethasone
dipropionate and albuterol) formed particularly homogenous
suspensions due to the flocculated drug occupying substantially all
of the formulation volume. These suspensions would be expected to
form satisfactory formulations for use with a metered dose
inhaler.
EXAMPLE 2
Formulations in HFC 227
[0058] Formulations of disodium cromoglycate (DSCG) were prepared
at concentrations of 0.015 percent, 0.035 percent, 0.070 percent,
0.35 percent, and 1.4 percent by weight based on the weight of the
formulation with HFC 227 as the propellant in a similar manner to
those prepared in Example 1 (again corresponding to 0.20, 0.50,
1.0, 5.0, and 20 mg/mL, respectively).
[0059] Formulations were particularly homogenous at concentrations
of 0.015 percent, 0.035 percent, and 0.070 percent by weight. At
0.35 percent and 1.4 percent the formulations exhibited more rapid
5 flocculation and sedimentation.
[0060] These results show that disodium cromoglycate can be
formulated in HFC 227 with no surfactant or other adjuvant.
Comparative Example
Formulations with CFCs
[0061] Albuterol sulfate was formulated in two propellant mixes A
and B, with no surfactant or adjuvant.
2 Propellant mix A: Propellant 11 5% Propellant 114 14.25%
Propellant 12 80.75% Propellant mix B: Propellant 11 25% Propellant
114 25% Propellant 12 50%
[0062] For each propellant mix the range of drug concentrations
used in Example 1 was used. The formulations at 0.20 mg/mL, 0.50
mg/mL, and 1.0 mg/mL were acceptably homogenous. The formulations
at 5.0 mg/mL and 20 mg/mL exhibited relatively rapid flocculation.
Notably, all these comparative formulations exhibited more caking
of drug on the walls of the container than their HFC 134a
counterparts of Example 1.
EXAMPLE 3
Formulation of Formoterol Fumarate with Mixtures of HFC 227 and HFC
134a
[0063] Formoterol fumarate was formulated as set forth in Example 1
at concentrations of 0.015 percent, 0.038 percent, 0.076 percent,
0.38 percent, and 1.5 percent (0.20, 0.50, 1.0, 5.0, and 20 mg/mL,
respectively) in a 1:1 mixture (W/W) of HFC 134a and HFC 227.
[0064] These formulations of formoterol fumarate show reduced
flocculation and a slower sedimentation rate than the corresponding
formulations of Example 1 above involving HFC 134a alone.
[0065] The formulations were photographed using time lapse
photography at 10 and 30 seconds post agitation and were assessed
as follows:
3 Drug Concentration (%) Assessment 0.015 + 0.038 + 0.076 ? 0.38 ?
1.5 +
[0066] These results show that the use of HFC 227 in combination
with HFC 134a as a propellant affords formoterol fumarate
suspensions with reduced flocculation and greater homogeneity
compared with corresponding formulations with HFC 134a alone as the
propellant.
EXAMPLE 4
Formulations of Beclomethasone Dipropionate (BDP)
[0067] BDP formulations were prepared at 0.070 percent by weight
(1.0 mg/mL) in HFC 227 and at 0.38 percent by weight (5.0 mg/ML) in
a 1:1 mixture of HFC 227 and HFC 134a.
[0068] The formulation at 0.070 percent in HFC 227 was fairly well
dispersed. Flocculation occurred at about 10 seconds after shaking
and then creaming about 30 seconds after shaking.
[0069] The formulation at 0.38 percent in HFC 134a/HFC 227 involved
a drug with a density closely matched to the propellant density.
Although flocculation was rapid (small flocs were visible almost
immediately after shaking) the flocs neither settled nor
creamed.
[0070] The results show that it is possible to density match the
drug to the propellant mix such that only the flocculation
characteristics of the formulations influence homogeneity.
EXAMPLE 5
Salmeterol Formulations in HFC 134a and HFC 227
[0071] Formulations of salmeterol free base at 0.02 percent by
weight and 0.05 percent by weight were prepared in HFC 134a and in
HFC 227 by placing the drug and 5 mL of glass beads into a 15 mL
glass vial, crimping on a continuous valve, and adding the
appropriate amount of propellant. The formulations were shaken on a
paint shaker for 10 min in order to disperse the drug. The drug was
seen to cream in both propellants, more so in HFC 227 than in HFC
134a.
[0072] Flocculation was also apparent. However, the formulations
were deemed suitable for use in connection with a metered dose
inhaler.
EXAMPLE 6
Formoterol Formulations in HFC 227
[0073] A formulation containing 0.01 percent by weight of
formoterol fumarate in HFC 227 was prepared in an aerosol canister
equipped with a 50 .mu.L SPRAYMISER.TM. pressure-fill metered dose
valve. The formulation was prepared by placing 10 mg formoterol
fumarate and 30 mL of glass beads in a 120 mL (4 ounce) glass vial,
crimping on continuous valve, and adding 100 g of HFC 227. The vial
was then shaken on a paint shaker, chilled, and the contents
transferred to 10 mL vials fitted with the metered dose valve. The
suspension was acceptably stable to settling and creaming. Valve
delivery was measured through the life of the formulations. The
results are shown in the Table below.
4 SHOT NUMBER (micrograms per shot) 1-4 54-57 107-110 160-163
173-177 vial #1 3.0 4.7 4.2 4.8 3.1 vial #2 2.7 4.1 4.1 4.1 3.6
135-138 148-151 vial #3 4.1 5.1 4.8 4.8 4.0
EXAMPLE 7
Formoterol Formulations in HFC 134a
[0074] A formulation containing 0.02 percent by weight formoterol
fumarate in HFC 134a was prepared and tested using a 50 AL
SPRAYMISER.TM. pressure-fill metered dose valve. Test methods and
results are set forth below.
SUSPENSION AEROSOL PARTICLE SIZE ANALYSIS
[0075] The particle size distribution of drug in the aerosol
suspension is assayed by Malvern Mastersizer.TM. Particle Size
Analyser using a suspending medium of 0.01 percent sorbitan
trioleate in heptane.
[0076] Using a primed connector, shots are fired via an injection
adapter into the Malvern sample cell containing the suspending
medium. When a suitable level of obscuration (in the range 8.5-9)
is achieved, analysis by laser diffraction is then performed.
[0077] The results below show the percentage by weight of particles
having particle size below 10.7 .mu.m, below 5.07 .mu.m, and below
1.95 .mu.m. The "Initial" entries represent the average of three
independent determinations, and the "25.degree. C.", "CYC", and
"HHC" entries represent a single determination after one month
under the indicated storage conditions.
5 Unit 1 Unit 2 Particle <10.7 <5.07 <1.95 <10.7
<5.07 <1.95 Size (.mu.m) Percent by weight Initial 99.6 93.4
32.2 98.0 92.6 30.5 25.degree. C. 99.8 93.6 36.3 99.9 94.8 31.7 1
Month CYC 99.8 92.9 36.1 99.8 92.5 32.5 1 Month HHC 99.8 93.1 33.5
99.7 92.4 34.9 1 Month 25.degree. C.: samples stored at 25.degree.
C. CYC: samples cycled between 15.degree. C. and 37.degree. C., one
cycle per day, twelve hours at each temperature HHC: samples stored
in a high humidity cabinet at approximately 40.degree. C. and 85
percent relative humidity
VALVE DELIVERY
[0078] This test is carried out at 20.degree. C. using individual
canisters. Each canister is primed by firing 10 successive shots
just prior to the determination. The weight in mg of one shot from
each of the 30 canisters is measured. The average weight of the 30
doses is calculated and recorded as the mean. Also shown below is
the number of individual dose weights differing by more than 7.5
percent and by more than 15 percent from the mean weight. 1 Mean
Valve Delivery ( mg ) 59.1 > 7.5 % from mean 0 > 15 % from
mean 0
THROUGH LIFE DELIVERY
[0079] Delivery of drug ex valve is determined by firing ten shots
through a stainless steel, circular adapter boss under liquid. The
aerosol canister to be examined is primed prior to use. The
canister is shaken and allowed to stand for 15 seconds between
shots. The sample solutions are assayed by HPLC.
[0080] The above test was carried out on shots 6-15, 46-55, and
91-100 of the canister.
6 Shots 6-15 46-55 91-100 Through, Life Delivery (.mu.g/dose)
Initial Unit 1 7.19 9.18 8.77 Unit 2 6.55 9.20 11.77 Unit 3 7.17
8.99 7.53 1 Month (25.degree. C.) Unit 1 9.09 9.09 8.47 Unit 2 8.99
9.71 7.77 1 Month (CYC) Unit 1 8.58 7.86 6.82 Unit 2 9.12 9.29 7.75
1 Month (HHC) Unit 1 6.93 7.98 7.76 Unit 2 9.83 9.27 8.80
25.degree. C.: samples stored at 25.degree. C. CYC: samples cycled
between 15.degree. C. and 37.degree. C., one cycle per day, twelve
hours at each temperature HHC: samples stored in a high humidity
cabinet at approximately 40.degree. C. and 85 percent relative
humidity
TWIN STAGE IMPINGER
[0081] Glass impinger apparatus A (BP198 Appendix XV11C) is used.
To determine the deposition of the emitted dose, the apparatus is
assembled as described. The oral adapter is attached to the
throatpiece of the apparatus, and a suitable pump is connected to
the outlet of the apparatus. The air flow through the apparatus is
60.+-.5 liters per minute measured at the inlet of the throat. The
canister to be examined is primed prior to use, shaken, and allowed
to stand for 15 seconds between shots. Ten shots are then fired via
the adapter into the apparatus from the canister.
[0082] The apparatus is then dismantled and each stage washed with
the appropriate amount of methanol. The washings are assayed by
HPLC to give the content of the drug found at each stage and also
the material balance.
7 Material Valve % Stem/ Balance Delivery Adapter % Stage 1 % Stage
2 (%) (mg) Initial Unit 1 26.0 37.5 36.5 63.2 59.9 Unit 2 24.7 35.3
40.0 81.0 59.7 Unit 3 28.5 36.7 34.8 80.9 59.3 1 Month (25.degree.
C.) Unit 1 52.5 23.91 23.6 80.5 58.8 Unit 2 52.0 16.7 31.3 76.2
52.0 Month (CYC) Unit 1 16.8 53.6 29.7 70.9 57.9 Unit 2 24.6 47.6
27.8 82.6 60.0 1 Month (HHC) Unit 1 33.9 37.0 29.0 82.2 59.6 Unit 2
15.3 60.4 24.3 81.4 60.7 25.degree. C.: samples stored at
25.degree. C. CYC: samples cycled between 15.degree. C. and
37.degree. C., one cycle per day, twelve hours at each temperature
HHC: samples stored in a high humidity cabinet at approximately 400
C and 85 percent relative humidity
EXAMPLE 8
[0083] A 1.35 g portion of micronized pirbuterol acetate, 15.0 g of
ethanol and 30 mL of glass beads were placed in a 120 mL (4 ounce)
glass aerosol vial. The vial was sealed with a continuous valve,
pressure filled with approximately 133 g of HFC 227 and then shaken
on a paint shaker for 10 minutes. The resulting formulation
contained 0.9 percent by weight of pirbuterol acetate and 10.0
percent by weight of ethanol. The dispersion was transferred into
10 mL aerosol vials which were sealed with 25 AL Spraymiser.TM.
Aerosol Valves (available from Neotechnic Engineering Ltd.).
[0084] This formulation was tested for its ability to deliver a
consistent dose throughout the "life" of the aerosol by determining
the amount of pirbuterol acetate delivered per shot for shots 1, 2,
101, 102, 201,,202, 301 and 302. The amount delivered per shot was
determined using the assay described below. The results are shown
in the table below.
[0085] A firing disk was placed in a 100 mL beaker and submerged in
about 30 mL of diluent (55 parts methanol/45 parts 0.1 percent
phosphoric acid, v/v). The vial was shaken, inserted into the
firing disk, and actuated. The valve and valve stem were rinsed
into the beaker with additional diluent. The solution in the beaker
was quantitatively transferred to a 100 mL volumetric flask which
was then brought to volume with additional diluent. The amount of
pirbuterol acetate in the solution was determined using high
performance liquid chromatography.
8 .mu.g Pirbuterol Acetate # of shots Vial 1 Vial 2 Vial 3 1 415.4
379.3 360.1 2 378.7 361.0 322.1 101 404.0 380.4 374.7 102 352.0
389.1 337.9 201 376.8 380.6 337.5 202 371.5 357.8 328.6 301 288.2
408.8 361.1 302 193.4 364.5 341.0
EXAMPLE 9
[0086] A 11.7 g portion of pirbuterol acetate was placed in a
beaker then chilled in a dry ice/trichlorofluoromethane bath. A
portion of prechilled HFC 227 was added to the beaker and the
resulting slurry was mixed at high speed with a VIRTIS.TM. Model 45
mixer for at least 3 minutes. The dispersed concentrate was then
transferred to a glass bottle and enough prechilled HFC 227 was
added to bring the total net content weight to 1300 g. The
resulting formulation contained 0.9 percent by weight of pirbuterol
acetate. The formulation was transferred to a cold filling system
and filled into 10 mL aluminum aerosol vials which were then sealed
with 25 AL valves. The formulation was deemed to be suitable for
use in connection with a metered dose inhaler.
EXAMPLE 10
[0087] 11.7 g portion of micronized pirbuterol acetate, 3.0 g of
oleic acid and 60 g of ethanol were placed in a beaker and
homogenized for at least 3 minutes. The resulting slurry was
transferred to a tared glass bottle and enough ethanol was added to
bring the total weight of the concentrate to 144.7 g. The
concentrate was chilled then placed along with 1155 g of prechilled
HFC 227 into a prechilled cold filling system. The formulation was
filled into 10 mL aluminum aerosol vials which were then sealed
with 25 .mu.L Spraymiser.TM. valves. The resulting formulation
contained 0.90 percent by weight of pirbuterol acetate, 0.23
percent by weight of oleic acid and 10.0 percent by weight of
ethanol. The formulation was deemed to be suitable for use in
connection with a metered dose inhaler.
[0088] In Examples 11-12 below, respirable fraction is determined
using the test method described below.
Respirable Fraction
[0089] In this assay the respirable fraction (the percent by weight
of particles having an aerodynamic particle size of less than 4.7
microns) of the aerosol suspension is determined using an Anderson
Cascade Impactor (available from Anderson Sampler Inc,; Atlanta,
Ga.).
[0090] The aerosol vial to be tested is primed five times. The
valve and valve stem are then cleaned with methanol and dried with
compressed air. The aerosol vial and a clean, dry actuator are
coupled to the glass throat attached to the top of the impactor
using an appropriate firing adaptor. The calibrated vacuum pump
(28.3 L/min) attached to the cascade impactor is turned on. A total
of 20 sprays is delivered into the cascade impactor by repeatedly
shaking the vial, seating it in the actuator and immediately
delivering a single spray. The time between sprays is approximately
30 seconds. The cascade impactor is disassembled and each component
is rinsed separately with diluent (55 parts methanol mixed with 45
parts of 0.1 percent aqueous phosphoric acid, v/v). Each solution
is analyzed for pirbuterol acetate content using high performance
liquid chromatography. The respirable fraction is calculated as
follows: 2 % respirable = drug recovered from plates 3 - 7 total
drug - drug recovered from recovered actuator and valve .times.
100
EXAMPLE 11
[0091] A 1.35 g portion of micronized pirbuterol acetate and 25 mL
of glass beads were placed in a 120 mL (4 ounce) glass aerosol
vial. The vial was sealed with a continuous valve, pressure filled
with approximately 150 g of HFC 227 and then shaken for at least 10
minutes on an automatic shaker. The resulting formulation contained
0.9 percent by weight of pirbuterol acetate. The vial was then
charged with 150 psi nitrogen to aid in product transfer to smaller
vials. The formulation was transferred to 10 mL aluminum aerosol
vials sealed with continuous valves by using a valve to valve
transfer button. The vials were then chilled in dry ice then the
continuous valves were removed and the vials sealed with 25 .mu.L
metering valves. Using the method described above, the respirable
fraction was determined in duplicate for two separate vials. Values
of 59.1 percent and 54.8 percent were obtained for vial 1. Values
of 53.9 percent and 49.3 percent were obtained for vial 2.
EXAMPLE 12
[0092] A 1.35 g portion of micronized pirbuterol acetate, 15.0 g of
ethanol and 25 mL of glass beads were placed in a 120 mL (4 ounce)
glass aerosol vial. The vial was sealed with a continuous valve,
pressure filled with approximately 134 g of HFC 227 and then shaken
on an automatic shaker for at least 10 minutes. The resulting
formulation contained 0.9 percent by weight of pirbuterol acetate
and 10 percent by weight of ethanol. Individual 10 mL aerosol vials
were filled and sealed with 25 .mu.L metering valves using the
method described in Example 11. Using the test method described
above, the respirable fraction was determined in duplicate for two
separate vials. Values of 34.9 percent and 32.5 percent were
obtained for vial 1. Values of 31.7 percent and 31.3 percent were
obtained for vial 2.
[0093] In Examples 13-14 below respirable fraction is determined
using the test method described above but using a diluent of 45
parts by volume methanol and 55 parts by volume of 0.1 percent
aqueous phosphoric acid.
EXAMPLE 13
[0094] A 0.60 g portion of micronized albuterol sulfate and 25 mL
of glass beads were placed in a 120 mL (4 ounce) glass aerosol
vial. The vial was sealed with a continuous valve and then pressure
filled with approximately 150 g of HFC 227 The vial was shaken to
disperse the albuterol sulfate. The resulting formulation contained
0.4 percent by weight of albuterol sulfate. The formulation was
transferred to 10 mL aluminum aerosol vials sealed with continuous
valves by using a valve to valve transfer button. The vials were
chilled in dry ice then the continuous valves were removed and the
vials were sealed with 25 AL metering valves. Using the method
described above, the respirable fraction was determined in
duplicate for two separate vials. Values of 69.3 percent and 60.6
percent were obtained for vial 1. Values of 64.0 percent and 63.0
percent were obtained for vial 2.
EXAMPLE 14
[0095] A 0.60 g portion of micronized albuterol sulfate, 0.75 g of
oleic acid, 22.5 g of ethanol and 25 mL of glass beads were placed
in a 120 mL (4 ounce) glass aerosol vial. The vial was sealed with
a continuous valve and then pressure filled with approximately 126
g of HFC 227 The vial was shaken to disperse the albuterol sulfate.
The resulting formulation contained 0.40 percent by weight of
albuterol sulfate, 0.50 percent by weight of oleic acid and 15.0
percent by weight of ethanol. Individual aerosol vials were filled
and fitted with 25 .mu.L metering valves using the method described
in Example 13. Using the test method described above, the
respirable fraction was determined in duplicate for two separate
vials. Values of 28.0 percent and 22.0 percent were obtained for
vial 1. Values of 27.1 percent and 28.8 percent were obtained for
vial 2.
EXAMPLE 15
[0096] A suspension aerosol formulation containing 0.37 percent by
weight of albuterol sulfate, 0.10 percent by weight of sorbitan
trioleate (commercially available under the trade designation Span
85), 9.95 percent by weight of ethanol and 89.58 percent by weight
of HFC 227 was prepared. The formulation was deemed to be suitable
for use in connection with a metered dose inhaler.
EXAMPLE 16
[0097] A 4.5 g portion of ethanol was placed in a 125 mL (4 ounce)
glass aerosol vial. The vial was sealed with a continuous valve
then pressure filled with 147 g of HFC 227. Portions (approximately
225 mg) of micronized pirbuterol acetate were weighed into 6
separate 15 mL glass aerosol vials. A 5 mL portion of glass beads
was added to each vial and the vials were sealed with continuous
valves. Each vial was then pressure filled with approximately 19.8
g of the ethanol/HFC 227 solution. The resulting formulation
contained 3 percent by weight of ethanol and 0.9 percent by weight
of pirbuterol acetate. The vials were then shaken in a paint shaker
for 15 minutes. The vials were cooled in dry ice, the continuous
valves were removed and the contents poured into separate 15 mL
aluminum aerosol vials. The aluminum vials were sealed with 25 AL
valves equipped with diaphragms fabricated from C-Flex R-70-051 and
tanks seals fabricated from DB218. Using the test method described
above, the respirable fraction was determined for two separate
vials. Values of 59.8% and 52.8% were obtained. Using the test
method described above, the ability of the formulation to deliver a
consistent dose throughout the "life" of the aerosol was
determined. The results are shown in the table below. The values
are the average for the indicated shots.
9 Ag Pirbuterol Acetate/shot shot Vial 1 Vial 2 1 & 2 279.4
304.6 101 & 102 197.1 329.9 201 & 202 294.9 478.1 301 &
302 295.8 294.1 401 & 402 269.6 350.3
EXAMPLE 17
[0098] Using the general method of Example 16, 6 vials of a
formulation containing 5 percent by weight of ethanol and 0.9
percent by weight of pirbuterol acetate were prepared. Using the
method described above, the respirable fraction was determined for
two separate vials. Values of 48.2% and 43.5% were obtained. Using
the method described above, the ability of the formulation to
deliver a consistent dose throughout the "life" of the aerosol was
determined. The results are shown in the Table below.
10 Ag Pirbuterol Acetate/shot Shot # Vial 1 Vial 2 1 & 2 263.9
288.5 101 & 102 283.5 325.4 201 & 202 300.6 367.2 301 &
302 330.7 306.6 401 & 402 312.8 270.5
* * * * *