(12) United States Patent
`Adjei et al.
`
`US006261539B1
`(10) Patent N0.:
`US 6,261,539 B1
`(45) Date of Patent:
`Jul. 17, 2001
`
`(54) MEDICINAL AEROSOL FORMULATION
`
`(76) Inventors: AkWete Adjei, 15 Tillman Ct.;
`Anthony J. Cutie, PO. Box 6725, both
`of Bndgewater’ NJ (Us) 08807
`
`5,674,472 * 10/1997 Akehurst et a1. .................... .. 424/45
`5,891,420 * 4/1999 Cutie ............. ..
`~~
`5916540 * 6/1999 Akehufst et a1~
`5,955,439 * 9/1999 Green ................................... .. 514/23
`FOREIGN PATENT DOCUMENTS
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`0518600 * 12/1992 (EP) _
`
`* cited by examiner
`
`(21) APPL NO; 09/209,228
`_
`(22) Flledi
`
`DBC- 10, 1998
`
`(51) Int. c1.7 ..
`(52) US. Cl. ................ ..
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—P. E. McQueeney
`(74) Attorney, Agent, or Firm—Frommer LaWrence &
`
`..... .. A61K 9/12
`424/46; 424/45
`
`Haug LLP
`(57)
`
`ABSTRACT
`
`(58) Field of Search ........................................ .. 424/45, 46
`
`(56)
`
`References Cited
`
`U-S~ PATENT DOCUMENTS
`
`_
`_
`_
`_
`_
`_
`This invention relates to a medicinal aerosol formulation and
`more particularly, to a medicinal aerosol formulation con
`taining a particulate drug, a propellant and a stabilizing
`agent comprising a Water addition.
`
`4,174,295 * 11/1979 Bargigia et a1. ................... .. 252/305
`5,225,183 * 7/1993 Purewal et a1. ...................... .. 424/45
`
`34 Claims, N0 Drawings
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`US 6,261,539 B1
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`1
`MEDICINAL AEROSOL FORMULATION
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`This invention relates to a medicinal aerosol formulation,
`and more particularly, to a medicinal aerosol formulation
`comprising a stabilizer comprising a Water addition.
`2. 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, includ
`ing such common local conditions as bronchial asthma and
`chronic obstructive pulmonary disease and some systemic
`conditions, including hormone replacement, pain
`management, cystic ?brosis, etc. Steroids, [32 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). The aerosol formulation can be
`presented as a liquid or a dry poWder. In order to assure
`proper particle siZe in a liquid aerosol, as a suspension,
`particles can be prepared in respirable siZe and then incor
`porated into the suspension formulation containing a pro
`pellant. Alternatively, formulations can be prepared in solu
`tion form in order to avoid the concern for proper particle
`siZe in the formulation. Solution formulations must never
`theless be dispensed in a manner that produces particles or
`droplets of respirable siZe.
`Once prepared an aerosol formulation is ?lled 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 pressuriZed dose discharged from the metered dose
`valve is reproducible. Rapid creaming, settling, or ?occu
`lation after agitation are common sources of dose irrepro
`ducibility in suspension formulations. This is especially true
`Where a binary aerosol formulation containing only medi
`cament and propellant, e.g. 1,1,1,2-tetra?uoroethane, 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 aerosol formulations often contain surfactants,
`Which serve as suspending aids to stabiliZe the suspension
`for a time suf?cient 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 par
`ticular drug and the propellant or class of propellant used in
`the formulation.
`It is sometimes dif?cult to dissolve sufficient quantities of
`conventional surfactants in hydro?uorocarbon (HFC) pro
`pellants such as HFC-134a and HFC-227. Cosolvents, such
`as ethanol, have been used to overcome this problem, as
`described in US. Pat. No. 5,225,183. An alternative
`approach that avoids cosolvents involves materials that are
`soluble in hydro?uorocarbon propellants and are said to be
`effective surfactants or dispersing aids in an aerosol formu
`lation. Among such materials are certain ?uorinated surfac
`tants and certain polyethyoXysurfactants.
`It is knoWn in the art that the presence of Water in
`conventional aerosol formulations often result in a number
`of potential problems, eg stability of the formulation,
`
`2
`erratic dose delivery, and, in some cases free radical reac
`tions in the propellant. Therefore, it has generally been
`accepted that these preparations should be maintained sub
`stantially free of Water. The rigorous exclusion of atmo
`spheric moisture during both the manufacture and storage of
`such formulations, referred to as “developed” or “nascent”
`formulation Water, increases the dif?culties of preparing
`satisfactory stable aerosols containing the drug and raises
`the overall cost of the ?nal product, especially When a
`moisture barrier, e.g. foil pouching, is included as a second
`ary package.
`An exception had been found for beclomethasone dipro
`pionate monohydrate. It has been reported that a formulation
`of this particular medicament combined With an amount of
`Water in addition to its Water of hydration is stable. In this
`regard, reference is made to US. Pat. No. 5,695,744.
`What has not been appreciated, hoWever, is that despite all
`efforts an amount of Water develops in medicinal aerosol
`formulations during processing of such formulations Which
`can not be eliminated and is alWays present (“developed” or
`“nascent” formulation Water). Most surprising and uneX
`pected is that such unstable formulations, containing nascent
`formulation Water, can be and are stabiliZed by the presence
`of a concentration of Water added in addition to the nascent
`or developed formulation Water Which stabiliZes such medi
`cament formulations, and Where such concentration of Water
`addition is much less than that required by the beclometha
`sone dipropionate monohydrate formulations reported in
`US. Pat. No. 5,696,744.
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`SUMMARY OF THE INVENTION
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`35
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`It has surprisingly been found that novel medicinal aero
`sol formulations 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.
`Stable medicinal aerosol formulations are obtained by the
`use of a Water addition.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`This invention involves a stable suspension aerosol for
`mulation suitable for pressuriZed delivery Which comprises
`(1) a particulate medicament or drug, (2) a suitable
`propellant, and (3) a stabiliZer comprising a Water addition.
`Asuitable medicament or drug is one Which is suitable for
`administration by inhalation, the inhalation being used for
`oral and nasal inhalation therapy. Therapeutic categories of
`drugs or medicaments include cardiovascular drugs,
`antiallergics, analgesics, brochodilators, antihistamines,
`antitussives, antifungals, antivirals, antibiotics, pain
`medicaments, antiin?ammatories, peptides, proteins and ste
`roids.
`Particularly suitable medicaments or drugs include
`albuterol (also knoWn as salbutamol), atropine, budesonide,
`cromolyn, epinephrine, ephedrine, fentanyl, ?unisolide,
`formoterol, ipratropium bromide, isoproterenol, pirbuterol,
`prednisolone, triamcinolone acetonide, salmeterol,
`amiloride, ?uticasone, ?uticasone esters, such as phosphate,
`monohydrate and furoate, (—)4-amino-3,5-dichloro-ot-[[[6
`(2-pyridinyl)ethoXy] heXyl] amino] methyl]benZene
`methanol. Also included are the suitable acid addition salts
`of the foregoing drugs, their hydrates and their other sol
`vates. In this regard, suitable acid addition salts include the
`salts obtained from inorganic acids, such as hydrochloric,
`hydrobromic, sulfuric, nitric, phosphoric and perchloric
`acids as Well as organic acids such as tartaric, citric, acetic,
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`US 6,261,539 B1
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`3
`succinic, maleic, fumaric and oxalic acids. Suitable phar
`maceutically acceptable solvates include solvates With
`ethylactate, alkanes, ethers, alcohols and Water.
`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 diam
`eter 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 particulate 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
`an aerosol, such as topically, or via oral or nasal inhalation,
`and cause its desired therapeutic effect, typically preferred
`With one dose, or through several doses. The particulate drug
`is administered as an aerosol from a conventional valve, e.g.,
`a metered dose valve.
`The term “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 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 2 parts by Weight based on 100 parts
`by Weight of the propellant.
`A suitable propellant is selected. A suitable propellant is
`any ?uorocarbon, e.g. a 1—4 hydrogen containing
`?urocarbon(, such as CHFZCHFZ, CF3CH2F, CHZFZCH3
`and CF3CHFCF3)), a per?uorocarbon, e.g. a 1—4 carbon
`per?uorocarbon, (such as CF3CF3, CF3CF2CF3); or any
`mixture of the foregoing, having a suf?cient vapor pressure
`to render them effective as propellants. Some typical suitable
`propellants include conventional chloro?uorocarbon (CFC)
`propellants such as mixtures of propellants 11, 12 and 114.
`Non-CFC propellants such as 1,1,1,2-tetra?uoroethane
`(Propellant 134a), 1,1,1,2,3,3,3-hepta?uoropropane
`(Propellant 227) or mixtures thereof are preferred. The
`propellant is preferably present in an amount suf?cient to
`propel a plurality of the selected doses of drug from an
`aerosol canister.
`A suitable stabiliZer is selected. A suitable stabiliZer is a
`“Water addition”. As used herein a “Water addition” is an
`amount of Water Which (1) is added, either initially With
`other components of the aerosol formulation, e.g. medica
`ment and propellant, or after the other components, e.g.
`medicament, propellant, are combined and processed, (2) is
`in addition to the Water Which is alWays present and Which
`develops during processing and/or storage of the aerosol
`formulation, i.e. “developed” or “nascent” formulation
`Water, and (3) is present in an amount Which stabiliZes the
`ordinarily unstable medicinal aerosol formulation having
`nascent formulation Water.
`An aerosol formulation preferably comprises the Water
`addition in an amount effective to stabiliZe the formulation
`relative to an identical formulation not containing the Water
`addition, i.e. containing only nascent formulation Water,
`such that the drug does not settle, cream or ?occulate after
`agitation so quickly as to prevent reproducible dosing of the
`drug. Reproducible dosing can be achieved if the formula
`tion retains a substantially uniform drug concentration for
`about tWo or three seconds after agitation.
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`The particular amount of the Water addition that consti
`tutes an effective amount is dependent upon the particular
`propellant and on the particular drug used in the formulation.
`It is therefore not practical to enumerate speci?c effective
`amounts for use With speci?c 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 Water addition must be
`present in a formulation in an amount in excess of the
`concentration of the nascent formulation Water. Such con
`centration of nascent formulation Water typically ranges up
`to 300 parts by Weight per one million parts by Weight of the
`total Weight of the aerosol formulation. Accordingly, the
`Water addition in excess of this nascent Water concentration
`typically ranges from about 300 parts by Weight to 2000
`parts by Weight per one million parts by Weight of the total
`aerosol formulation Weight. Most preferred is that the con
`centration of the Water addition is from 500 parts by Weight
`to 700 parts by Weight per one million parts by Weight of the
`total Weight of the medicinal aerosol formulation.
`It is to be emphasiZed that this is an amount Which
`exceeds the amount of nascent or developed formulation
`Water. It is also to be stressed that this amount of Water
`addition can be added and initially combined With the other
`components of the formulation, e.g. medicament, such as
`triamcinolone acetonide, and propellant, e.g. 1,1,1,2
`tetrahydro?uoroehtane, or added to the resultant formulation
`after these other components have been processed, e.g. prior
`to or subsequent to storage.
`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 US. Pat. No. 5,225,183, Which is
`incorporated by reference hereinto in its entirety.
`A most preferred formulation comprises the medicament,
`the propellant, the ethanol cosolvent and the Water addition,
`for example, triamcinolone acetonide, 1,1,1,2
`tetra?uoroethane, ethanol and the Water addition.
`Generally the formulations of the invention can be pre
`pared by combining
`the drug in an amount suf?cient to
`provide a plurality of therapeutically effective doses; (ii) the
`Water addition in an amount effective to stabiliZe each of the
`formulations; (iii) the propellant in an amount suf?cient to
`propel a plurality of doses 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. Bulk formulation can be
`transferred to smaller individual aerosol vials by using valve
`to valve transfer methods, pressure ?lling or by using
`conventional cold-?ll methods. It is not required that a
`stabiliZer used in a suspension aerosol formulation be
`soluble in the propellant. Those that are not suf?ciently
`soluble can be coated onto the drug particles in an appro
`priate amount and the coated particles can then be incorpo
`rated 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 been found, hoWever,
`that selection of appropriate valve assemblies for use With
`aerosol formulations is dependent upon the particular stabi
`liZer and other adjuvants used (if any), on the propellant, and
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`US 6,261,539 B1
`
`5
`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. 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 polyole?n (Union
`Carbide).
`Conventional aerosol canisters, coated or uncoated, anod
`iZed 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.
`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 sus
`ceptible 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 infec
`tion.
`What is claimed is:
`1. Amedicinal aerosol formulation, Which consists essen
`tially of:
`(a) a therapeutically effective amount of a particulate
`medicament;
`(b) a propellant; and
`(c) a stabiliZer consisting of Water, in addition to nascent
`Water present in formulation, in an amount ranging
`from about 300 parts by Weight to about 2000 parts by
`Weight to one million parts by total Weight of the
`formulation;
`Which is obtained by
`(a) either:
`i.) combining said medicament, propellant and Water;
`or
`ii) combining said medicament and propellant folloWed
`by the addition of Water; and
`(b) dispersing the medicament propellant and Water.
`2. The formulation as de?ned in claim 1, Wherein the
`medicament is selected form the group consisting of
`albuterol, atropine, budesonide, cromolyn, epinephrine,
`ephedrine, fentanyl, ?unisolide, formoterol, ipratropium
`bromide, isoproterenol, pirbuterol, prednisone, triamcino
`lone acetonide, salmeterol, amiloride, ?uticasone, (—)4
`amino-3,5-dichloro-ot-[[[6(2-pyridinyl)ethoxy] hexyl]
`amino] methyl]benZene-methanol and pharmaceutically
`acceptable esters and solvates of the foregoing.
`3. The formulation as de?ned in claim 2 Wherein the
`medicament is budesonide, formoterol or ?uticasone.
`4. The formulation in claim 1, Wherein the medicament is
`?uticasone.
`5. The formulation in claim 1, Wherein the medicament to
`are ?uticasone and an anticholinergic agent.
`6. The formulation as de?ned in claim 1, Wherein said
`propellant is selected from the group consisting of 1,1,1,2
`tetra?uoroethane, 1,1,1,2,3,3,3-hepta?uoropropane or a
`mixture thereof.
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`7. The formulation as de?ned in claim 1 Wherein said
`stabiliZer is present in an amount ranging from about 500
`parts by Weight to about 2000 parts Weight based on 1
`million parts by total Weight of the formulation.
`8. The formulation as de?ned in claim 7 Wherein said
`stabiliZer is present in an amount ranging from 500 parts by
`Weight to 700 parts by Weight to one million parts by total
`Weight of the formulation.
`9. A formulation according to claim 1 in an aerosol
`canister equipped With a metered dose valve.
`10. Amethod of treating in an animal a condition capable
`of treatment by oral or nasal inhalation, Which comprises,
`administering a formulation according to claim 1 to said
`animal by oral or nasal inhalation.
`11. Ametered dose inhaler containing a medicinal aerosol
`formulation, Wherein the medicinal aerosol formulation is as
`de?ned in claim 1.
`12. The metered dose inhaler as de?ned in claim 11,
`Wherein the medicament is ?uticasone or ?uticasone and an
`anticholinergic agent.
`13. The metered dose inhaler as de?ned in claim 11
`Wherein the medicament is selected from the group consist
`ing of albuterol, atropine, budesonide, cromolyn,
`epinephrine, ephedrine, fentanyl, ?unisolide, formoterol,
`ipratropium bromide, isoproterenol, pirbuterol, prednisone,
`triamcinolone acetonide, salmeterol, amiloride, ?uticasone,
`an ester of ?uticasone,(—)4-amino-3,5-dichloro-(x-[[[6(2
`pyridinyl)ethoxy] hexyl] amino] methyl]benZene-methanol
`and pharmaceutically acceptable hydrates, salts and solvates
`of the foregoing.
`14. The metered dose inhaler as de?ned in claim 13
`Wherein the propellant is selected from the group consisting
`of 1,1,1,2-tetra?uoroethane, 1,1,1,2,3,3,3
`hepta?uoropropane or a mixture thereof.
`15. The metered dose inhaler as de?ned in claim 14
`Wherein said medicament comprises triamcinolone
`acetonide.
`16. The metered dose inhaler as de?ned in claim 15
`Wherein said stabiliZer is present in an amount ranging from
`500 parts by Weight to 700 parts by Weight per one million
`parts by Weight of the medicinal aerosol formulation.
`17. A medicinal aerosol formulation, Which consists
`essentially of:
`(a) a therapeutically effective amount of a particulate
`medicament;
`(b) a propellant;
`(c) a cosolvent; and
`(d) a stabiliZer consisting of Water, in addition to nascent
`Water present in formulation, in an amount ranging
`from about 300 parts by Weight to about 2000 parts by
`Weight to one million parts by total Weight of the
`formulation;
`Which is obtained by
`(a) either:
`i.) combining said medicament, propellant, cosolvent
`and Water; or
`ii) combining said medicament, propellant, and cosol
`vent folloWed by the addition of Water; and
`(b) dispersing the medicament propellant, cosolvent and
`Water.
`18. The formulation as de?ned in claim 17 Wherein said
`medicament is selected from the group consisting of
`albuterol, atropine, budesonide, cromolyn, epinephrine,
`ephedrine, fentanyl, ?unisolide, formoterol, ipratropium
`bromide, isoproterenol, pirbuterol, prednisone, triamcino
`lone acetonide, salmeterol, amiloride, ?uticasone, (—)4
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`US 6,261,539 B1
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`7
`amino-3,5-dichloro-ot-[[[6(2-pyridinyl)ethoXy] heXyl]
`amino] methyl]benZene-methanol and pharmaceutically
`acceptable salts, esters, hydrates and solvates of the forego
`ing.
`19. The formulation as de?ned in claim 17 Wherein said
`medicament is selected from the group consisting of
`albuterol, atropine, budesonide, cromolyn, epinephrine,
`ephedrine, fentanyl, ?unisolide, formoterol, ipratropium
`bromide, isoproterenol, pirbuterol, prednisone, triamcino
`lone acetonide, salmeterol, amiloride, ?uticasone, (—)4
`amino-3,5-dichloro-ot-[[[6(2-pyridinyl)ethoXy] heXyl]
`amino] methyl]benZene-methanol and pharmaceutically
`acceptable esters and solvates of the foregoing.
`20. The formulation as de?ned in claim 17 Wherein said
`medicament comprises triamcinolone acetonide,
`budesonide, fomoterol, or ?uticasone.
`21. The formulation as de?ned in claim 17 Wherein said
`cosolvent is ethanol.
`22. The formulation as de?ned in claim 17 Wherein said
`stabiliZer is present in an amount ranging from about 500
`parts by Weight to about 2000 parts Weight based on 1
`million parts by total Weight of the formulation.
`23. The formulation as de?ned in claim 17 Wherein said
`stabiliZer is present in an amount ranging from 500 parts by
`Weight to 700 parts by Weight to one million parts by total
`Weight of the formulation.
`24. Amethod of treating in an animal a condition capable
`of treatment by oral or nasal inhalation, Which comprises,
`administering a formulation according to claim 17 to said
`animal by oral or nasal inhalation.
`25. A formulation according to claim 17 in an aerosol
`canister equipped With a metered dose valve.
`26. Ametered dose inhaler containing a medicinal aerosol
`formulation, Wherein the medicinal aerosol formulation is as
`de?ned in claim 17.
`27. The metered dose inhaler as de?ned in claim 26
`Wherein the drug is selected from the group consisting of
`albuterol, atropine, budesonide, cromolyn, epinephrine,
`ephedrine, fentanyl, ?unisolide, formoterol, ipratropium
`bromide, isoproterenol, pirbuterol, prednisone, triamcino
`lone acetonide, salmeterol, amiloride, ?uticasone, (—)4
`amino-3,5-dichloro-ot-[[[6(2-pyridinyl)ethoXy] heXyl]
`amino] methyl]benZene-methanol and pharmaceutically
`acceptable hydrates, salts and solvates of the foregoing.
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`28. The metered dose inhaler as de?ned in claim 27
`Wherein the propellant is selected from the group consisting
`of 1,1,1,2-tetra?uoroethane, 1,1,1,2,3,3,3
`hepta?uoropropane or a mixture thereof.
`29. The metered dose inhaler as de?ned in claim 28
`Wherein said medicament triamcinolone acetonide,
`budesonide, budesonide, or ?uticasone, and the cosolvent is
`ethanol.
`30. The metered dose inhaler as de?ned in claim 29
`Wherein said stabiliZer is present in an amount ranging from
`500 parts by Weight to 700 parts by Weight per one million
`parts by Weight of the medicinal aerosol formulation.
`31. A medicinal aerosol formulation, Which consists
`essentially of:
`(a) a therapeutically effective amount of a particulate
`medicament;
`(b) a propellant;
`(c) optionally, a cosolvent; and
`(d) a stabiliZer consisting of Water, in addition to nascent
`Water present in formulation, in an amount ranging
`from about 300 parts by Weight to about 2000 parts by
`Weight to one million parts by total Weight of the
`formulation.
`32. A medicinal aerosol formulation as de?ned in claim
`31, Wherein the medicament is selected from the group
`consisting of albuterol, atropine, budesonide, cromolyn,
`epinephrine, ephedrine, fentanyl, ?unisolide, formoterol,
`ipratropium bromide, isoproterenol, pirbuterol, prednisone,
`triamcinolone acetonide, salmeterol, amiloride, ?uticasone,
`(—)4-amino-3,5-dichloroot-[[[6(2-pyridinyl)ethoXy] heXyl]
`amino] methyl]benZene-methanol and pharmaceutically
`acceptable, salts, esters, hydrates and solvates of the fore
`going and the propellent is selected from the group consist
`ing of 1,1,1,2-tetra?uoroethane, 1,1,1,2,3,3,3
`hepta?uoropropane or a mixture thereof.
`33. The formulation as de?ned in claim 32 Wherein a
`cosolvent is present.
`34. The formulation as de?ned in claim 32, Wherein the
`medicament is triamcinolone acetonide, budesonide, for
`moterol or ?uticasone.
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1022, p. 5 of 5
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