1
`
`3M COMPANY 2002
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`

`FOR THE PURPOSES OF INFORJVIATION ONLY
`
`Codes used to identify Slates party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Aualriu
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Canada
`Central African Republic
`(‘ongo
`Swiuerland
`(‘file d‘Ivoin:
`(‘amcroon
`Czechoslovakia
`Cu-¢:l1 Republic
`Germany
`Denmark
`Spain
`Finland
`
`Framze
`Gabon
`United Kingdom
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Democratic People‘: Republic
`of Korea
`Republic of Korea
`Kzwiklislan
`Liechtenstein
`Sri lanka
`Luxembourg
`Monaco
`Madagascar
`Mali
`Mongolia
`
`2
`
`Mauritania
`Malawi
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovak Republic
`Senegal
`Soviet Union
`(Iliad
`Togo
`Ukraine
`United States of America
`Viel Nam
`
`AT
`AU
`BB
`BE
`BF
`B6
`BJ
`BR
`CA
`CF
`CG
`CH
`Cl
`CM
`CS
`CZ
`DE
`DK
`
`3F
`
`l
`
`

`

`W0 93/ 1 1 743
`
`PCT/EP92/02808
`
`MEDl§;AMENT§
`
`This invention relates to aerosol formulations of use for the administration of
`
`medicaments by inhalation.
`
`The use of aerosols to administer medicaments has been known for several decades.
`
`Such aerosols generally comprise the medicament, one or more chlorofluorocarbon
`
`propellants and either a surfactant or a solvent, such as ethanol. The most commonly
`
`used aerosol propellants for medicaments have been propellant
`
`1 l
`
`(CCl3F) and/or
`
`propellant 114 (CFZCICFZCI) with propellant 12 (CCIZF1). However these propellants are
`
`now believed to provoke the degradation of stratospheric ozone and there is thus a need
`
`to provide aerosol fonnulations for medicaments which employ .so called "ozone-friendly"
`
`propellants.
`
`A class of propellants which are believed to have minimal ozone-depleting effects in
`
`comparison
`
`to
`
`conventional
`
`chlorofluorocarbons
`
`comprise
`
`fluorocarbons
`
`and
`
`hydrogen-containing
`
`chlorofluorocarbons,
`
`and
`
`a
`
`number of medicinal
`
`aerosol
`
`formulations using such propellant systems are disclosed in, for example, EP 0372777,
`
`W091/04011, W091/11173, W091/11495 and WO9l/ 14422. These applications are all
`
`concerned with the preparation of pressurised aerosols for
`
`the administration of
`
`medicamentsand seek to overcome the problems associated with the use of the new class
`
`of propellants, in particular the problems of stability associated with the pharmaceutical
`
`formulations prepared. The applications all propose the addition of one or more, of
`
`adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and
`
`nonéfluorinated surfactants, carboxylic acids, polyethoxylates etc) and even conventional
`
`chlorofluorocarbon propellants in small amounts intended to minimise potential ozone
`
`damage.
`
`Thus, for example EP 0372777 requires the use of l,l,l,2-tetrafluoroethane in
`
`combination with both a cosolvent having greater polarity than 1, 1,1,2-tetrafluoroethane
`
`(e.g. an alcohol or a lower alkane) and a surfactant
`
`in order to achieve a stable
`
`formulation of a medicament powder.
`
`In‘ particular it is_noted in the specification at page
`
`3
`
`

`

`W0 93/U743
`
`PCI'/EP92/02808
`
`3, line 7 that "it has been found that the use ofpropellant 134a (1,1,1,2-tetrafluoroethane)
`and drug as a binary mixture or in combination with a conventional surfactant such as
`sorbitan trioleate does not provide formulations having suitable properties for use with
`pressurised inhalers". Surfactants are generally recognised by those skilled in the art to be
`essential components of aerosol formulations, required not only to reduce aggregation of
`the medicament but also to lubricate the valve employed, thereby ensuring consistent
`
`reproducibility ofvalve actuation and accuracy of dose dispensed. Whilst WO91ll 1 173,
`"W091/11495 and W091/14422 are concerned with formulations comprising an
`
`admixture of dmg and surfactant, W091/04011 discloses medicinal aerosol formulations
`in which the particulate medicaments are pre-coated with surfactant prior to dispersal in
`
`I, 1, 1,2-tetrafluoroethane.
`We have now surprisingly found that, in contradistinction to these teachings, it is in
`fact possible to obtain satisfactory dispersions of certain medicaments in fluorocarbon or.
`hydrogen-containing chlorofluorocarbon propellants such as 1,1,1,_2-tetrafluoroethane
`without recourse to the use of any surfactant or cosolvent in the composition, or the
`
`in the propellant. More
`necessity to pre-treat the medicament prior to dispersal
`particularly, satisfactory dispersions may be formed where themedicament is selected
`from salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and
`
`physiologically acceptable salts and solvates thereof.
`There is thus provided in one aspect of the invention a pharmaceutical aerosol
`formulation which.comprises particulate medicament selected from the group consisting
`
`of salmeterol,
`salbutamol,
`fluticasone propionate, beclomethasone dipropionate and
`physiologically acceptable salts and solvates (for example hydrates) thereof and a
`fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is
`
`substantially free of surfactant. By “substantially free of surfactant" is meant formulations
`which contain no- significant amounts of surfactant, for example less than 0.000l% by
`
`weight ofthe medicament.
`In an alternative embodiment the present invention provides a pharmaceutical aerosol
`
`formulation as hereinbefore defined with the proviso that when said formulation consists
`
`4
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`W0 93/1 1743
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`PCT/EP92/02808
`
`essentially of salbutamol and 1,l,1,2—tetrafluoroethane in a weight ratio of 0.05218, said
`
`salbutamol is present in the form of a physiologically acceptable salt.
`
`The particle size of the particulate (e.g. micronised) medicament should be such as to
`permit inhalation of substantially all of the medicament into the lungs upon administration
`of the aerosol formulation and will thus be less than 100 microns, desirably less than 20
`
`microns, and preferably in the range l-10 microns, e.g. l-5 microns.
`Suitable pharmaceutically acceptable salts of the medicaments of use in the
`
`fomiulations of the present invention include acid addition salts such as for example
`
`sulphates, hydrochlorides and xinafoates (1-hydroxy-2—naphthoate), amine salts or alkali
`metal salts (eg. sodium). Salmeterol will preferably be in the fonn of its xinafoate salt
`
`and salbutamol will preferably be in the form of its sulphate salt.
`
`The finalaerosol formula'tion desirably contains 0.005-l0% w/w, preferably 0.005 -
`
`5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the
`
`formulation.
`
`-The propellants
`
`for use in‘ the invention may be any
`
`fluorocarbon or
`
`hydrogen-containing chlorofluorocarbon or mixtures thereof having a sufficient vapours .
`
`pressure to render them effective as propellants. Preferably the propellant will be a
`non-solvent
`for
`the medicament.
`Suitable
`propellants
`include,» for
`example,
`Cmhydrogen-containing chlorofluorocarbons such as CHZCIF, CClF2CHC1F, CF,CHClF,
`CHFZCCIFZ,
`CHCIFCHF2,
`CF3CH2Cl
`and
`CCIFZCH3;
`Cmhydrogen-containing
`fluorocarbons
`such as CI-IFZCHFZ, CFSCHZF,
`CHFECH3 and CF3CHFCF3;
`and
`
`perfluorocarbons such as CF3CF3 and CF3CF2CF3.
`
`Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons
`
`are employed they may be mixtures of the above identified compounds or mixtures,
`
`preferably binary mixtures, with other fluorocarbons or hydrogen-containing chloro-
`
`fluorocarbons for example CHCIFZ, CHEF: and CF3CH3. Preferably a single fluorocarbon
`
`or hydrogen-containing chlorofluorocarbon is employed as the propellant. Particularly
`
`preferred as propellants are Cmhydrogen-containing fluorocarbons such as
`
`l,1,l,2-
`
`tetrafluo'roethane(CF3CH,F) and’ 1, 1, 1,2,3 ,3,3-heptafluoro-n-propane (CF,CHFCF3).
`
`5
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`

`

`W0 93/11743
`
`PCI‘/EP92/02808
`
`It is desirable that the formulations of the invention contain no components which
`may provoke the degradation of stratospheric ozone.
`In particular it is desirable that the
`formulations are substantially free of chlorofluorocarbons such as CCl3F, CCl1F2 and
`
`CF3CCl3.
`The propellant may additionally contain a volatile adjuvant such as a saturated
`hydrocarbon for example propane, n-butane,
`isobutane, pentane and isopentane or a
`dialkyl ether for example dimethyl ether.
`In general, up to 50% w/w of the propellant
`may comprise a volatile hydrocarbon,
`for example 1
`to 30% w/w.
`However,
`formulations which are substantially free of volatile adjuvants are preferred.
`It is further desirable that the formulations of the invention are substantially free of
`liquid components of higher polarity than the propellant employed- Polarity may be
`determined for example, by the method described in European Patent Application
`Publication No. 0327777.
`In particular formulations which are substantially free of
`alcohols such as ethanol are preferable. As used herein "substantially free" means less
`than 1% w/w based upon the fluorocarbon or hydrogen-containing chlorofluorocarbon, in
`
`particular less than 0.5% for example 0.1% or less.
`A particularly preferred embodiment of the invention provides a phannaceutical
`aerosol formulation consisting essentially of one or more particulate medicament selected
`from the group consisting of
`salmeterol,
`salbutamol,
`fluticasone propionate,
`beclomethasone dipropionate and physiologically acceptable salts and solvates thereof,
`and one or more fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
`It will be appreciated by those skilled in the art that the aerosol formulations
`according to the invention may , if desired, contain a combination of two or more active
`ingredients. Aerosol compositions containing two active ingredients (in a conventional
`propellant system) are known, for example, for the treatment ofrespiratory disorders such
`as asthma. Accordingly the present invention fiirther provides aerosol formulations in
`accordance with the invention which contain two or more particulate medicaments.
`Medicaments may be selected from suitable combinations of the medicaments mentioned
`hereinbefore or may be selected from any other suitable drug useful in inhalation therapy
`and which may be presented in a form which is substantially completely insoluble in the
`
`6
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`W0 93/ 1 1 743
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`PC!"/ EP92/02808
`
`selected propellant. Appropriate medicaments may thus be selected from, for example,
`
`analgesics, e.g. codeine, dihydromorphine, ergotamine,
`
`fentanyl or morphine; angina]
`
`preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil;
`
`antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides,
`
`tetracyclines
`
`and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. flunisolide,
`
`budesonide,
`
`tipredane or
`
`triamcinolone
`
`acetonide;
`
`antitussives,
`
`e.g.
`
`noscapine;
`
`bronchodilators,
`
`e.g.
`
`ephedrine,
`
`adrenaline,
`
`fenoterol,
`
`formoterol,
`
`isoprenaline,
`
`metaproterenol,
`
`phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,
`
`terbutaline,
`
`isoetharine,
`
`tulobuterol,
`
`orciprenaline,
`
`or
`
`(-)-4-amino-3,5-dichloro-
`
`0t-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;.
`
`diuretics,
`
`e.g.
`
`amiloride; anticholinergics e.g.
`
`ipratropium, atropine or oxitropium; hormones, e.g.
`
`cortisone, hydrocortisone or prednisolone; - xanthines
`
`e.g.
`
`aminophylline,
`
`choline
`
`theophyllinate,
`
`lysine theophyllinate’ or
`
`theophylline; and. therapeutic proteins and
`
`peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where
`
`appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or
`
`amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as soivates
`
`(e.g. hydrates) to optimise the activityand/or stability of the medicament and/or to
`
`minimise the solubility of the medicament in the propellant.
`
`Particularly preferred aerosol fonnulations contain salbutamol (e.g. as the free base
`
`or the sulphate salt) or salmeterol (e.g.t as the xinafoate salt).'in combination with an
`
`antiinflammatory steroid such as a beclomethasone ester (e.g. the diproprionate) or a
`
`- fluticasone ester (e.g. the propionate) or an antiallergic such as cromoglycate (e.g. the
`
`sodium salt). Combinations of salmeterol‘ and fluticasone propionate or beclomethasone .
`
`dipropionate, or salbutamol and fluticasone propionate or beclomethasone dipropionate
`
`are preferred, especially salmeterol xinafoate and fluticasone propionate or salbutamol and
`
`beclomethasone dipropionate.
`
`The formulations of the invention may be prepared by dispersal of the medicament in
`
`.the selected propellant in an appropriate ‘container, e.g. with the aid of sonication. The
`
`7
`
`

`

`W0 93/1 1743
`
`PC17EP92/02808
`
`process is desirably carried out under anhydrous conditions to obviate any adverse effects
`
`ofmoisture on suspension stability.
`The formulations according to the invention form weakly flocculated suspensions on
`standing but, surprisingly, these suspensions have been found to be easily redispersed by
`mild agitation to provide suspensions with excellent delivery characteristics suitable for
`use in pressurised inhalers, even afier prolonged storage. Minimising and preferably
`avoiding the use of formulation excipients e.g. surfactants, cosolvents etc in the aerosol
`formulations according to.the invention is also advantageous since the formulations may
`be substantially taste and odour free,
`less irritant and less toxic than conventional,
`
`formulations.
`
`The chemical and physical stability and the pharmaceutical acceptability of the _
`aerosol formulations according to the invention may be determined by techniques well ‘
`known to those skilled in the art. Thus, for example, the chemical stability of the
`components may be detemrined by HPLC assay, for example, after prolonged storage of
`the product-- Physical stability data may be gained fi'om other conventional analytical
`techniques such as, for example, by leak testing, by valve delivery assay (average shot.
`weights per actuation), by close reproducibility assay (active ingredient per actuation) and
`
`-
`
`spray distribution analysis.
`The particle size distribution ofthe aerosol formulations according to the invention is
`particularly impressive and may be measured by conventional techniques; for example by
`cascade impaction or by the "Twin Impinger" analytical process. As used herein reference
`to the "Twin Impinger" assay means "Determination ofthe deposition of the emitted dose.
`in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988,
`pages A204-207, Appendix XVII C. Such techniques’ enable the "respirable fraction" of
`the aerosol formulations to be calculated. As. used herein reference to "respirable
`
`fraction" means the amount of active ingredient collected in the lower impingement
`
`. chamber per actuation expressed as a percentage of the total. amount of active ingredient
`delivered per actuation using the twin impinger method described above.
`The
`formulations according to the invention have been found to have a respirable fraction of
`
`8
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`

`

`W0 93/ 11743
`
`PCT/EP92/02808
`
`20% or more by weight of the medicament, preferably 25 to 70%, for example 30 to
`
`60%.
`
`Optionally, the medicament may be surface-modified prior to its dispersion in the
`
`propellant by treatment with a substantially non-polar
`
`liquid medium which is a
`
`non-solvent for the medicament. There is thus provided in a further aspect of the
`
`invention an aerosol formulation comprising particulate, surface-modified medicament, as
`
`defined herein, and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant,
`
`which formulation is substantially free of surfactant. By "surface-modified medicament“
`
`is meant’ particles of medicament selected from the group consisting of salmeterol,
`
`salbutamol,
`
`fluticasone propionate, beclomethasone dipropionate and physiologically
`
`acceptable salts and solvates thereof which have been surface-modified by admixture with
`
`a substantially non-polar non-solvent liquid, followed by removal of the liquid. The
`
`substantially non-polar non-solvent
`
`liquid medium is
`
`conveniently an aliphatic
`
`hydrocarbon, e.g. a lower alkane, which is sufficiently volatile to permit
`
`its ready
`
`evaporation,
`
`e.g. at ambient
`
`temperature and pressure, after
`
`slurrying with the
`
`medicament. The use of isopentane as liquid medium is particularly advantageous in this
`
`respect.
`
`The medicament
`
`is desirably slurried with the liquid medium under anhydrous
`
`conditions to obviate any adverse effects of moisture on suspension stability. The slurry
`
`may advantageously be sonicated to maximise the surface-modifying effect of the
`
`treatment. The liquid may be removed by any convenient means for example by
`
`evaporation or by filtration followed by evaporation, provided that following treatment
`
`the medicament is substantially free of the liquid. The formulations of the invention will
`
`be substantially free of the non-solvent non-polar liquid. Surface-modified medicament
`
`‘prepared by the above-described process comprises a further aspect of the present
`
`invention.
`
`The fonnulations according to the invention may be filled into canisters suitable for
`
`delivering pharmaceutical aerosol formulations. Canisters generally comprise a container
`
`,
`
`T capable of [withstanding the vapour pressure of the propellant used such as a plastic or
`
`plastic-coated glass bottle or preferably a metal can, for example an aluminium can which
`
`9
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`

`

`W0 93/11743
`
`PCI'IEP92/02808
`
`lacquer-coated and/or plastic-coated, which container is
`may optionally be anodised,
`The metering valves are designed to deliver a metered
`closed with a metering valve.
`amount of the formulation per actuation and incorporate a gasket to prevent leakage of
`propellant through the valve. The gasket may comprise any suitable elastomeric material
`such as
`for example
`low density polyethylene,
`chlorobutyl, black and white
`butadiene-acrylonitrile rubbers, butyl
`rubber and neoprene.
`Suitable valves are
`commercially available from manufacturers well known in the aerosol
`industry, for
`example, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e-g. BK300,
`.“"‘),.
`BK3 56) and 3M-Neotechnic Ltd, UK (e.g. Sprayrniser
`Conventional bulk manufacturing methods and machinery well known to those skilled.
`in the art of pharmaceutical aerosol manufacture-may be employed for the preparation of
`large scale batches for the commercial production of filled canisters. Thus, for example,
`in one bulk manufacturing method a metering valve is crimped onto an aluminium can to
`form an empty canister. The particulate medicament is. added to a charge vessel and
`liquified propellant is pressure filled through the charge vessel into a manufacturing
`vessel. The drug suspension is mixed before recirculation to a filling machine and an.
`aliquot of the drug suspension is then filled through the metering valve into the canister.
`Typically,
`in batches prepared for pharmaceutical use,
`each filled . canister.
`is
`check-weighed-, coded with a batch number and packed into a tray for storage before
`
`release testing.
`Each filled canister is conveniently.fitted into a suitable channelling device prior to
`
`use to form a metered dose inhaler for administration of the medicament into the lungs or
`nasal cavity of a patient. Suitable channelling devices comprise for example a valve
`actuator and a cylindrical or cone-like passage.through which medicament maybe
`delivered from the filled canister via the metering valve to the nose or mouth of a patient
`eg. a mouthpiece actuator. Metered dose inhalers are designed to deliver a fixed unit
`dosage of medicament per actuation or "puff", for example in the range of IO to 5000
`
`microgram medicament per puff.
`Administration of medicament may be indicated for the treatment of mild, moderate
`
`30
`
`or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated
`
`10
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`

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`W0 93/1 1 743
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`PCT/EP92/02808
`
`that the precise dose administered will depend on the age and condition of the patient, the
`
`particular particulate medicament used and the frequency of administration and will
`
`ultimately be at
`
`the discretion of the attendant physician. When combinations of
`
`medicaments are employed the dose of each component of the combination will in general
`
`be that employed for each component when used alone. Typically, administration may be
`
`one or .more times, for example from 1 to 8 times per day, giving for example 1,2,3 or 4
`
`pufifs each time.
`
`Suitable daily doses, may be, for example in the range 50 to 200 microgram of
`
`salmeterol, 100. to 1000 microgram of salbutamol, 50 to 2000 microgram of fluticasone
`
`propionate or 100 to 2000‘microgram of beclomethasone dipropionate, depending on the
`
`severity of the disease.
`
`Thus, for example, each valve actuation may deliver 25 microgram salmeterol, 100
`
`microgram salbutamol, 25, 50, 125 or 250 microgram fluticasone propionate or 50, 100,
`
`200 or 250 microgram beclomethasone dipropionate. Typically each filled canister for
`
`a
`
`use in a metered dose inhaler contains 100, 160 or 240 metereddoses or puffs of
`
`medicament.
`
`The filled canisters and metered dose inhalers described -herein comprise fiirther
`
`i aspects ofthe present invention.
`
`A still fiuther aspect of the present
`
`invention comprises a method of treating
`
`respiratory disorders such as, for example,easthma, which comprises administration by
`
`inhalation of an effective amount of a formulation as herein described.
`
`The following non-limitative Examples serve to illustrate the invention.
`
`Example 1
`
`Micronised salmeterol xinafoate (24mg) was weighed into a clean, dry, plastic-coated
`
`glass bottle and l,l,.1,2—tetrafluoroethane (l8.2g) was added from a vacuum flask. The
`
`bottle was quickly sealed with a blank aluminium ferrule. «The resulting aerosol contained
`
`0.132% ‘"/W salmeterol xinafoate.
`
`11
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`

`W0 93/11743
`
`PC!‘IEP92/02808
`
`Examplez
`Micronised salmeterol xinafoate (38.28g) and 1,l,1,2-tetrafluoroethane (36.36kg)
`were added to a pressure vessel and mixed with a high shear mixer for 20 minutes.
`Aliquots (l8.2g) ofthe suspension were filled into aluminium cans closed with a metering
`valve, filling under pressure through the valve using conventional filling equipment. The
`resulting inhalers contained 9.57mg salmeterol xinafoate and delivered 25 microgram
`
`salmeterol (39.9 microgram salt) per actuation.
`
`Example3
`Micronised fluticasone propionate (24mg) was weighed into a clean, dry,
`plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (l8.2g) was added from a
`vacuum flask. The bottle was quickly sealed with a blank aluminium fenule. The
`
`resulting aerosol contained 0.132% "’/W fluticasone propionate.
`
`Examples 4 and 5
`Micronised fluticasone propionate (66mg or 6.6mg) was weighed directly into each
`. of 100 open aluminium cans and a metering valve was then crimped into place on each
`can. 1,1,l,2-Tetrafluoroethane (18.2g) was then added to each canister under pressure,
`through'the valve, and each filled canister shaken to disperse the drug. The resulting
`inhalers contained 66 or 6.6mg fluticasone propionate and delivered 250 "or 25 microgram
`
`fluticasone propionate per actuation (Examples 4 and 5 respectively).
`
`Example 6
`Micronised salbutamol (24mg) was weighedinto a clean, dry, plastic-coated glass
`bottle and 1,l,1,2-tetrafluoroethane (18.2g) was added fi'om a vacuum flask. The bottle
`was quickly sealed with a blank aluminium ferrule. The resulting aerosol contained
`
`0.132% “’/wsalbutamol.
`
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`PCT/ EP92/02808
`
`Examples 7 and 8
`
`Micronised salbutamol (24mg or 48mg) was weighed directly into each of 3 open
`
`aluminium cans.
`
`1, l, 1,2-Tetrafluoroethane (18.2g) was added to each can from a vacuum
`
`flask and a metering valve was then crimped into place. Each filled canister was then
`
`shaken in an ultrasonic bath for 8 minutes. The resulting inhalers contained 24mg or
`
`48mg salbutamol and .delivered 100 or 200 microgram salbutamol per actuation
`
`(Examples 7 and 8 respectively).
`
`Example 9
`
`Micronised salbutamol
`
`sulphate
`
`(3I.7mg) was weighed into a
`
`clean,
`
`dry,-
`
`plastic-coated glass bottle and .1,l,1,2-tetrafluoroethane (l8.2g) was added from a
`
`vacuum flask. The bottle was quickly sealed with a _blank aluminium ferrule. The
`
`resulting aerosol contained 0.174% "’/W salbutamol sulphate.
`
`Example 10
`
`Micronised salbutamol sulphate (31.7mg) was weighed directly into each of 4 open
`
`aluminium scans. 1,l,1,2-Tetrafluoroethane (18.2g-) was added to each can from a vacuum
`
`flask and a metering valve was then crimped- into place. Each filled canister was then
`
`shaken in an ultrasonic bath for 5 minutes. The resulting inhalers contained 3l.7mg
`
`salbutamol sulphate and delivered 100 microgram salbutamol per actuation.
`
`Example 1 l
`
`Isopentane (25ml) was added to rnicronised salmeterol xinafoate (0.5g) to form a
`
`slurry, which was sonicated for 3 minutes. The resulting suspension was dried by
`
`evaporating the isopentane at ambient temperature to yield surface-modified salmeterol
`
`xinafoate. Samples of this product (1 l.6mg) were weighed into aluminium aerosol cans
`
`and l, 1,1,2-tetrafluoroethane (18.2g - 99.95% w/w of total fill weight) was added to each
`
`can, whereafier suitable metering valves were crimped onto the cans, which were then -
`
`each sonicated for 5 minutes. The resulting aerosols contained salmeterol in an amount
`
`equivalent to 240 .actuations at 25 microgram per actuation.
`
`13
`
`

`

`W0 93/11743
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`PCT/EP92/02808
`
`Example 12
`Micronised beclomethasone dipropionate monohydrate (68 mg) was weighed into a
`clean, dry, plastic-coated glass bottle and l,l,1,2-tetrafluoroethane (to 18.2g) was added
`from a vacuum flask. The bottle was quickly sealed with a metering valve. The resulting
`aerosol dispensed 250 microgram beclomethasone dipropionate (as the monohydrate) per
`
`75.8mg actuation.
`
`Example 13
`Micronised salmeterol xinafoate-(9.57mg) is weighed directly into an aluminium can
`and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4g) added from a vacuum flask. A
`metering. valve is crimped into place and the filled canister sonicated-for five’minutes. The
`aerosol delivers 25 microgram salmeterol per actuation.
`
`Example l4
`Micronised fluticasone propionate (l3.3mg) is weighed "directly into an. aluminium can
`and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 2l.4g) added from a vacuum flask, A
`metering valve is crimped into place and the filled canister sonicated for five minutes. The
`aerosol delivers 50 microgram fluticasone propionate per actuation.
`
`Example 15
`Micronised salbutamol sulphate (29mg) was weighed directly into an aluminium can
`and 1,1,l,2,3,3,3—heptafluoro-n-propane (to 2l.4g) added from a vacuum flask. A
`metering valve was crimped into place and the filled canister sonicated for five minutes.
`The aerosol delivered 100 microgram salbutamol per actuation.
`
`—
`
`Example 16
`Micronised beclomethasone diproprionate monohydrate (62mg) was weighed directly
`into an aluminium can and l,1,1,2,3,3,3-heptafluoro-n-propane (to 2l.4g) added from a
`vacuum flask- A metering valve was crimped into place and the filled canister sonicated -
`
`14
`
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`

`W0 93/1 1743
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`PCT/E P92/02808
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`for five minutes. The aerosol delivered 250 microgram beclomethasone diproprionate per
`
`actuation.
`
`Example 17
`
`Salmeterol xinafoate
`
`Fluticasone propionate
`
`1, 1, 1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.066
`
`to 100
`
`36.25 microgram
`
`50 microgram
`
`to 75.8mg
`
`Micronised medicaments were weighed into an aluminium can, 1,1,-1,2-tetrafluoroethane
`
`(1 8.2g) was added from a vacuum flask and a metering valve was crimped into place.
`
`Example 18
`
`Salmeterol xinafoate
`
`Fluticasone propionate
`
`1, 1, 1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.165
`
`to 100
`
`36.25 microgram
`
`125 microgram
`
`to 75.8mg
`
`Micronised medicaments were weighed into an aluminium can, 1,1,1,2-tetrafluoroethane
`
`(18.2g) was added from a vacuum flask and a metering valve was crimped into place.
`
`Examgle 19
`
`Salmeterol xinafoate
`
`Fluticasone propionate
`
`1,1, 1,2-Tetrafluoroethane
`
`Example 20
`
`Salmeterol xinafoate
`
`Fluticasone propionate
`
`1, 1,1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.132
`
`to 100
`
`36.25 microgram
`
`100 microgram
`
`to 75.8mg
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.330
`
`to 100
`
`36.25 microgram
`
`250 microgram
`
`to 75.8mg
`
`15
`
`

`

`W0 93/11743
`
`PC1'IEP92/02808
`
`Example 2]
`
`Salbutamol *
`
`Fluticasone propionate
`
`I, 1, 1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.132
`
`0.132
`
`to 100
`
`lOO microgram
`
`100 microgram
`
`to 75.8mg
`
`*
`
`as free base or an equivalent weight of salt e.g. sulphate
`
`Example 22
`
`Salbutamol *
`
`Fluticasone propionate
`
`1, 1, 1,2—Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.264
`
`0.330
`
`to 100
`
`200 microgram
`
`250 microgram
`
`to 75_8mg
`
`*
`
`as free base or an equivalent weight of salt e.g. sulphate
`
`Example 23
`
`Salmeterol xinafoate
`
`Beclomethasone dipropionate
`
`1,1, 1,2-Tetrafluoroethane
`
`Example 24
`
`Salmeterol xinafoate
`
`Fluticasone propionate
`
`1, 1, 1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.066
`
`to 100
`
`36.25 microgram
`
`50 microgram
`
`to 75.8mg
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.048
`
`0.264
`
`to 100
`
`36.25 microgram
`
`200 microgram
`
`to 75.8mg
`
`16
`
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`W0 93/ 1 1 743
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`PCT/E P92/02808
`
`Example 25
`
`Salbutamol *
`
`Beclomethasone dipropionate
`
`1,1,1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.132
`
`0.066
`
`to 100
`
`lOO microgram
`
`50 microgram
`
`to 75.8mg
`
`*
`
`as free base or an equivalent weight of salt e.g. sulphate
`
`Example 26
`
`Salbutamol *
`
`Beclomethasone dipropionate
`
`1, l, 1,2-Tetrafluoroethane
`
`Per Inhaler % w/w
`
`Per Actuation
`
`0.264
`
`0.264
`
`to 100
`
`200 microgram
`
`200 microgram
`
`to 75.8mg
`
`*
`
`as fi'ee base or an equivalent weight of salt e.g. sulphate
`
`In Examples 19 to 26 micronised medicaments are weighed into aluminium cans,
`
`l,l,1,i2-tetrafluoroethane (l8.2g) is added from a vacuum flask, and metering valves are
`
`cfimped into place.
`
`17
`
`

`

`W0 93/11743
`
`PCI‘/EP92/02808
`
`LAIM
`
`A pharmaceutical aerosol formulation which comprises particulate medicament
`1.
`selected from the group consisting of salmeterol, salbutamol, fluticasone propionate,
`
`beclomethasone dipropionate and physiologically acceptable salts and solvates thereof and
`a fluorocarbon or hydrogen—containing chlorofluorocarbon propellant, which fonnulation
`
`is substantially free of surfactant.
`
`«
`
`A pharmaceutical aerosol formulation which comprises particulate medicament
`2.
`selected from the group consisting of salmeterol‘, salbutamol, fluticasone propionate,
`beclomethasone dipropionate and physiologically acceptable salts and solvates thereof and"
`a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, ,which formulation
`is substantially fi'ee of surfactant and with the proviso that when said formulation consists
`373
`‘essentially of salbutamol and 1 1 I 2-tetrafluoroethane in a weight ratio of 0'.05:l8,. said
`
`salbutamol is present in the form of a physiologically acceptable salt.
`
`A pharmaceutical aerosol fonnulation consisting essentially of one or more
`3.
`particulate medicament selected from the group’ consisting of salmeterol, salbutamol; .
`fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts
`and ‘solvates
`thereof,
`and one or more fluorocarbon or hydrogen-‘containing
`
`chlorofluorocarbon propellant.
`
`. 4.
`
`A fonnulation as claimed in any one of claims 1 to 3 wherein the medicament is
`
`salmeterol xinafoate
`
`5.
`
`A fonnulation as claimed in any one of claims 1 to 3 wherein the medicament is
`
`salbutamol sulphate.
`
`6.
`
`A -formulation as claimed. in any one of claims 1 to 3 wherein the medicament is
`
`fluticasone propionate.
`
`18
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`W0 93/ 1 1 743
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`PCT/ EP92/02808
`
`7.
`
`A fonnulation as claimed in any one of claims 1 to 3 wherein the medicament is
`
`beclomethasone dipropionate or a physiologically acceptable solvate thereof.
`
`8.
`
`A formulation as claimed in one of claims 1 to 7 wherein the propellant comprises
`
`1, 1, 1,2—tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.
`
`9.
`
`A formulation as claimed in one of claims 1 to 8 wherein the propellant comprises
`
`1, 1, 1,2-tetrafluoroethane.
`
`10.
`
`A formulation as claimed in any one of claims I to 9 wherein the medicament is
`
`present in an amount of 0.005 to 10% w/w based on the total weight of the formulation.
`
`ll.
`
`A formulation as claimed in any one of claims 1 to 10 which contains two or more
`
`particulate medicaments.
`
`12.
`
`A fonnulation as claimed in Claim 11 which contains salbutamol or salmeterol or
`
`a physiologically acceptable salt thereof in combination with an antiinflammatory ‘steroid
`
`or an antiallergic.
`
`13.
`
`A fonnulation as claimed in Claim 12 which contains salmet