`Schultz et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,743,413 B1
`Jun. 1, 2004
`
`US006743413B1
`
`(54) SUSPENSION AEROSOL FORMULATIONS
`
`(75)
`
`Inventors: Robert K. Schultz, Shoreview, MN
`(US); David W. ‘Schultz, Pine Springs,
`MN (US); Mam“ J‘ Ohver’
`L°‘1g11b°1°‘1g11(GB); R°b°"A' M0115’
`Lmo Lakes» MN (US); Phlhl’ A- J“‘k5>
`M0111“ SOFFG1 (GB)
`
`.
`(73) Asslgneei 3M C0mPaI1y, St. Paul, MN (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 08/455,280
`
`_
`_
`Related U.S. Application Data
`
`(60) Division of application. No.‘ 07/878,039, filed ‘on ‘May 4,
`1992, which is a continuation—in—part of application No.
`07/809,791,
`on Dec. 18, 1991, now abandoned,
`is a continuation—in—part of application No. 07/810,401, filed
`°“ 136°" 18’ 1991’ “°“' "1"’“‘1°“°‘1"
`Int. Cl.7 ........................... .. A61L 9/04; A61K 9/00;
`A01N 25/02
`.......................................... .. 424/45, 424/43
`(52) U.s. Cl.
`(58) Field of Search .................................... .. 424/43-45
`
`(51)
`
`CA
`DE
`DE
`
`EP
`E13
`EP
`
`EP
`E13
`E1)
`EP
`EP
`EP
`EP
`E1’
`
`5,254,755 A
`5,270,305 A
`5,290,539 A
`2
`5,314,682 A
`5,348,730 A
`5,439,670 A
`5,474,759 A
`5,492,688 A
`5,508,023 A
`5,605,674 A
`
`10/1993 Li et al.
`12/1993 Palmer
`3/1994 Mafecki
`5:31: gt
`5/1994 Sweval et 51
`9/1994 Greenleaf et.al
`............. .. 424/45
`8/1995 Purewal et al.
`.
`424/45
`12/1995 Fassberg et al.
`
`424/45
`2/1996 Byron et al.
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`4/1996 Byron et al.
`2/1997 Purewal et al.
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`FOREIGN PATENT DOCUMENTS
`2075058
`3/2001
`27 03 119
`8/ 977
`2737132
`2 978
`
`0 039 369
`0 379 793 B1
`0 365 119 A2
`
`11/ 981
`1/ 990
`4/ 990
`
`............ .. C07J/5/00
`
`6/ 990
`0372777
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`0384371
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`0 403 301 B1
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`
`.......... .. A61K/9/72
`---------- -- A61K/9/72
`
`(56)
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`Primary Exami/1er—Thurman K. Page
`Assistant Exami/1er—Humera N. Sheikh
`
`(57)
`
`ABSTRACT
`.
`.
`.
`.
`.
`Pharmaceutical suspension aerosol formulations containing
`a therapeutically effective amount of a drug and HFC 134a,
`HFC 227, or a mixture thereof.
`
`24 Claims, N0 Drawings
`
`MYLAN EX 1001, Page 1
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`US 6,743,413 B1
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`
`EP
`GB
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`W0
`W0
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`
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`437 766
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`91/14422
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`MYLAN EX 1001, Page 2
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`
`
`US 6,743,413 B1
`Page 3
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`MYLAN EX 1001, Page 3
`
`MYLAN EX 1001, Page 3
`
`
`
`US 6,743,413 B1
`
`1
`SUSPENSION AEROSOL FORMULATIONS
`
`This is a division of application Ser. No. 07/878,039 filed
`May 4, 1992, now abandoned.
`This application is a continuation-in-part of commonly
`assigned, copending applications U.S. Ser. No. 07/809,791
`and U.S. Ser. No. 07/810,401, now abandoned both filed
`Dec. 18, 1991, and both incorporated herein by reference.
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`
`This invention relates to pharmaceutical aerosol formu-
`lations. In another aspect this invention relates to pharma-
`ceutical suspension aerosol formulations wherein the pro-
`pellant comprises HFC 134a or HFC 227. In another aspect,
`it relates to pharmaceutical suspension aerosol formulations
`containing pirbuterol. In another aspect, it relates to phar-
`maceutical suspension aerosol formulations containing
`albuterol sulfate.
`
`2. Description of the Related Art
`Pharmaceutical suspension aerosol formulations currently
`use a mixture of liquid chlorofluorocarbons as the propel-
`lant. Fluorotrichloromethane, dichlorodifluoromethane and
`dichlorotetrafluoroethane are the most commonly used pro-
`pellants in aerosol formulations for administration by inha-
`lation.
`
`Chlorofluorocarbons (CFCs), however, have been impli-
`cated in the destruction of the ozone layer and their produc-
`tion 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.
`
`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, propel-
`lant 11, propellant 125, or propellant 152a.
`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.
`European Patent Application 89.312270.5 (Purewal et al.)
`discloses,
`inter alia, aerosol formulations comprising a
`medicament, 1,1,1,2-tetrafluoroethane, a surface active
`agent, and at least one compound having higher polarity than
`1,1,1,2-tetrafluoroethane.
`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 dissolv-
`ing 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.
`U.S. Pat. No. 3,014,844 (Thiel et al.) discloses aerosol
`formulations comprising a micronized medicament, a halo-
`genated lower alkane propellant and a surface-active agent
`to assist in the suspension of the medicament in the propel-
`lant. The chemical formula for the propellant given in Col.
`4, lines 17-28, generically embraces HFC 134a and HFC
`227.
`
`2
`
`Patent Application WO 90/01454 (Greenleaf et al.) dis-
`closes aerosol compositions having HFC 134a as the pro-
`pellant 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.
`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 inha-
`lation. For example, VENTOLINTM 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
`
`dichlorodifluoromethane) with oleic acid. VENTOLIN
`ROTOCAPSTM 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. VENTOLINTM Solu-
`tion for Inhalation (commercially available from Allen &
`Hansburys)
`is an aqueous solution of albuterol sulfate
`intended for use with a nebulizer.
`
`Pirbuterol acetate is a relatively selective beta-2 adrener-
`gic bronchodilator. MAXAIRTM Inhaler (commercially
`available from 3M Pharmaceuticals, St. Paul, Minn) is a
`metered dose aerosol unit containing a fine-particle suspen-
`sion of pirbuterol acetate in the propellant mixture of
`trichloromonofluoromethane and dichlorodifluoromethane,
`with sorbitan trioleate.
`
`SUMMARY OF THE INVENTION
`
`This invention provides a pharmaceutical suspension for-
`mulation 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.
`This invention also provides an aerosol canister contain-
`ing 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:
`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 inhala-
`tion a formulation as described above to the mammal.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`this invention provides suspension
`In another aspect,
`aerosol formulations comprising a therapeutically effective
`amount of micronized albuterol sulfate and HFC 227 as
`
`60
`
`substantially the only propellant. This invention also pro-
`vides suspension aerosol formulations comprising a thera-
`peutically 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
`
`65
`
`MYLAN EX 1001, Page 4
`
`MYLAN EX 1001, Page 4
`
`
`
`US 6,743,413 B1
`
`3
`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.
`In another aspect this invention provides suspension aero-
`sol formulations comprising a therapeutically effective
`amount of micronized pirbuterol acetate and a propellant
`comprising HFC 227, the formulation being further charac-
`terized 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.
`This invention also provides a method for inducing bron-
`chodilation in a mammal, comprising administering to the
`mammal a formulation as described above by inhalation.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`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.
`Amounts expressed herein in terms of percent refer to
`percent by weight based on the total weight of the formu-
`lation.
`
`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. Such formulations preferably contain less than
`an effective stabilizing amount of surfactant and more
`preferably are substantially free of surfactant and other
`components.
`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 accord-
`ing 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. Atherapeutically effective amount of a particu-
`lar drug can be selected by those of ordinary skill in the art
`with due consideration of such factors. Particularly in for-
`mulations 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.
`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
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`4
`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.
`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 formula-
`tions 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 formula-
`tion is acceptably homogeneous as regards drug concentra-
`tion.
`
`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 floc-
`culated 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.
`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 phar-
`maceutically acceptable salts thereof, particularly formot-
`erol 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.
`The propellant in a formulation of the invention can be
`HFC 134a, 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 pro-
`pellant 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.
`The pirbuterol acetate formulations of the invention con-
`tain 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.
`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
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`US 6,743,413 B1
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`5
`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.
`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. Accord-
`ingly 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, pref-
`erably in pirbuterol acetate formulations of the invention
`containing ethanol.
`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 pro-
`longed period, are substantially and readily redispersible,
`and upon redispersion do not flocculate so quickly as to
`prevent reproducible dosing of pirbuterol acetate.
`The albuterol sulfate formulations of the invention con-
`
`tain 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.
`
`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. Asurfactant selected from the group consisting
`of oleic acid and sorbitan trioleate can also optionally be
`included in the formulation when the formulation also
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`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
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`40
`
`that do not contain ethanol are preferably substantially free
`of perfluorinated surfactant.
`Certain preferred albuterol sulfate suspension aerosol
`formulations of the invention comprise HFC 227 as sub-
`stantially the only propellant. Typically the propellant con-
`stitutes 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.
`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.
`Generally the formulations of the invention can be pre-
`pared by combining
`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.
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`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.
`
`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 homog-
`enizer. When a surfactant and/or ethanol are included in the
`formulation, they can be added to the propellant along with
`the albuterol sulfate.
`
`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 sur-
`factants 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 deliv-
`
`ering 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 elas-
`tomeric material such as FLEXOMERTM DFDA 1137 NT7
`
`polyolefin, FLEXOMERTM DFDA 1138 NT polyolefin,
`FLEXOMERTM DEFD 8923 NT polyolefin, FLEXOMERTM
`GERS 1085 NT polyolefin, FLEXOMERTM DFDA 1163
`NT7 polyolefin, FLEXOMERTM 1491 NT7 polyolefin,
`FLEXOMERTM 9020 NT7 polyolefin, FLEXOMERTM 9042
`NT polyolefin (Union Carbide), C-FLEXTM thermoplastic
`elastomer R70-001, C-FLEXTM thermoplastic elastomer
`R70-051, C-FLEXTM thermoplastic elastomer R70-041,
`C-FLEXTM thermoplastic elastomer R70-085, C-FLEXTM
`thermoplastic elastomer R70-003, or C-FLEXTM thermo-
`plastic elastomer R70-026 (Concept Polymer Technologies),
`or a blend of two or more thereof.
`
`Conventional aerosol canisters, e.g., those of aluminum,
`glass, stainless steel, or polyethylene terephthalate, can be
`used to contain a formulation of the invention.
`
`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 dis-
`ease. 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.
`
`The following Examples are provided to illustrate the
`invention. All parts and percentages are by weight unless
`otherwise indicated.
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`US 6,743,413 B1
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`7
`EXAMPLE 1
`
`Formulations in HFC 134a
`
`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.
`
`Drugs:
`
`Beclomethasone dipropionate
`Albuterol
`Albuterol sulfate
`Formoterol fumarate
`Disodium cromoglycate
`Pirbuterol acetate
`
`u1rnUOU:1>
`
`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
`conce