.1
`
`PCT/U392/10587
`U.S. PATENT APPLICATION
`\
`w
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`HM.
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`nccm1'| nu; pu; DATA**tt***at:ttttktstt$t*
`' VERIFIED
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`'
`
`fi*FORElGU/PCT APPL|CATIONS******fi*****
`VERIFIED
`
`INTELLECTUAL
`3!! OFFICE OF
`PROPERTY COUNSEL
`P.O. BOX 331327
`ST. PAUL. KN 55I33-31027
`
`‘
`
`'
`
`'
`
`ALBUTEROL SULFATE SUSPENSION AEROSOL FORHULATIONS
`
`This Is to canny thnt annuodhunto II a two ewy H-outta racer-as of thniuitnfl sun:
`hunt and Trauma-In Glues 0! tho appucatton :3 fund which Is Iuntinod anon.
`
`Iy authority av thn
`cnuussxcvu or umns no runnwuts
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`cu-tuymg Oflteor
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`MYLAN EX 1002, Page 1
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`MYLAN EX 1002, Page 1
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`01/
`
`U.
`s. DEPARDIENT or COHHI-ZRCE
`PATENT AND TRADE-MRK OFFICE
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`‘FEE at-:c“o‘a"n SHEET
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`MYLAN EX 1002, Page 2
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`MYLAN EX 1002, Page 2
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`L,<1o- c1>-/o/ IL
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`-1-
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`W7809791
`
`‘BUCKET NUMBER:
`
`47982USA9I
`
`ALBUTEROL SULFATE SUSPENSION AEROSOL FORIULAIIOIS
`
`This invention relates to suspension aerosol
`formulations suitable for the adninistration or
`-—
`
`hedicanents. In another aspect, ‘it relates to
`pharmaceutical suspension aerosol formulations containing
`
`albuterol sulrate and in"yet anotheraspect to aerosol
`formulations using 1,1,1,2,3,3,3-heptatluoropropane a the
`propellant.
`
`Albutergl sulfate is a relatively selective beta-
`
`,It,isl_.avai1able in a variety
`2 adrenergig bronchodilator.
`of dosage forms including tablets, syrups and rornulartions
`
`For example, vEnl'1'oLIll"" Inhalation
`suitable for inhalation.
`Aerosol (commercially available from Allen & Bansbnrys,
`
`Division ot Glaxo Inc. ; Research Triangle Park, NC} is at
`aetei-ed-dose aerosol ‘unit containing‘ a niorocryatalline
`suspension or albuterol (free base)
`in propellant (a
`mixture or trichloromonoiluoron-ethane and
`A ~
`
`dichloroditluaronethane) with oleic acid. VEN'l'0L1'.I
`
`ROTOCAPS“ for Inhalation (commercially available tron Allen
`I: Hansburys) contain a nixture or nicrotine albuterol
`
`sulfate with lactose and are intended for use with a_
`specially designed device for inhaling powder. Vfl'mI.IN“‘
`Solution for Inhalation (commercially available from Allen
`& Hansburys) is an aqueous solution or albuterol sulfate
`intended for use with a nebulizer.
`
`including
`chlorotluorocarbons,
`trichlorouonotluoronethane and diohloroditluorouethane,
`
`have been inplicated in the destruction of the ozone layer
`
`_
`_ __
`‘
`_
`and their production is being phased out.
`liydrotltforocarbon 227 (1.1,1,2,5,3,5-neptailuoropropane) is
`
`vieged as being less destructive to ozone than many
`
`'
`
`O
`*.""'-'~_'-:7 :4-w_.y-7.-. -_~-V:
`
`MYLAN EX 1002, Page 3
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`MYLAN EX 1002, Page 3
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`chlorotluorocarbon propellants; turtherlore, it has a low
`
`toxicity and a vapor pressure suitable for use in aerosols.
`
`Patent Applications.Ho 91/11495 and—W0-91/ll496- ~
`‘
`(both to Weir) describe pharmaceutical suspension aerosol
`formulations ccurising a medicinal agent, optionally a
`
`surtactant, and a propellant Iixture containing a partially
`":1do£1ha£.a loser alkane. The patent application
`specifically discloses an aerosol formulation containing
`
`(indicated in percentage by'weight) 9.3: salbutaaol, 632V
`Spanwéo, 50.0% pentane, 30.0% 1,1,1,2,3,3,3-
`heptatluoropropane and 49.5% 1,1,1,2-tetratluoroethane.
`
`The patent application does not, however, disclose or
`suggest the use of ethanol as a component in coabination
`
`with 1,1,1,2,3,3,3-heptatluoropropana.
`European Patent office Publication 0 384 371
`- (Heisxe1)'discloses solution aerosols in which
`
`1,1,1,2,3,3,3-heptatluoropropane in combination with at
`" 1east"one of propane, butane,
`isobutane, dimsthylether, and
`1,1-ditluoroethane serves as the propellant.
`rho
`application does not, however, disclose suspension aerosols
`
`or pharmaceutical aerosol formulations.
`
`_
`
`_ Patent.App1ication HO 91/02056 {Schultz et al.)
`H L
`'
`describes suspension aerosol formulations comprising a
`
`._nedicinal agent,'a member of a particular class of
`25 “‘perfluorinated"surtace-active dispersing aet, ad
`1,l,l,2,3,3,3-heptatluoropropane. Albuterol snltate is
`recited as a suitable medicinal agent. The patent
`. application does not, however, teach or suggest the use of
`ethanol in combination with l,l,l,2,3,3,3-
`heptafluoropropane.
`
`_
`
`'»
`
`-
`
`30
`
`SHHAEX_QE_IflE_IH!EEIIQH
`
`of micronized albuterol sul£ate;'£rom about 021 to about 15 ’
`
`MYLAN EX 1002, Page 4
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`.-*~.'»'2“,*
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`35
`
`This invention provides suspension aerosol
`formulations coaprisinq a therapeutically effective amount
`
`‘
`of micronized albuterol sultate and l,1,1,2,3,3,3-
`heptatluororopane as substantially the only propellant.
`1his_invention,a1so provides suspension aerosol
`formulations coaprising a therapeutically effective amount
`
`MYLAN EX 1002, Page 4
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`

`
`-3-
`
`percent by weight of ethanol, and l,l,l,2,3,3,3-
`
`heptatluoropropane as substantially the only propellant.
`”
`This invention also provides ‘suspension aerosol
`"T
`T
`formulations cenprising a therapeutically effective amount
`of mic:-onized albuterol sulfate,
`from about 5 to 15 percent
`
`by veight of ethanol,..froI about 0.05 to about‘o.5‘percerrt‘ ’
`by weight at a surfactant selected from the grow
`
`consisting of oleic acid and sorhitan trioleate, and
`1,1,1,2,3,73,3-heptafluoropropane as substantially the only
`propellant. This invention also provides a nethod for
`‘inducing bronchodilatien in a nannal, comprising the step
`of administering to the nasal a fornulation as described
`above by inhalation.
`
`RflAI
`
`_ _
`
`,
`
`-
`
`_ ______
`
`A
`
`All weight percentages recited herein are based
`
`on the total weight of the fornulation unless otherwise
`indicated.
`_
`h
`N ‘me tern"suspension aerosol‘ means that the
`albuterol sulfate is in particulate fern and the
`formulation is substantially free of dissolved albuterol
`‘ sulfate.
`_ J“ I ‘
`
`—
`Thewtera "nicronized'_'_neans that the albuterol-
`sulfate is in the tors of a fine powder, that is; over 90.-. _.
`percent of the particles will have a dianeter of less than
`I
`about 10 nicrons.
`‘
`The formulations of the invention contain a
`
`therapeutically effective anoont of nicronized annrterol
`sulfate. Preferably nicronized albuterol sulfate
`constitutes about 0.2 to about 0.5 percent by weight, more
`preferably from mine 0.35 to about o.42 percent by weight
`of the aerosol formulation.
`4
`Ethanol can optionally be included in a
`formulation of the invention. Ihen ethanol is pzaent it
`constitutes tron about 0.1 to about 20 percent by weight,
`preferably from about 5 to about 15 percent by weight of
`the formixlitiéif. {surfactant selected from the group
`
`consisting of oleic ‘acid and sorbita_n trioleate can also
`optionally‘ be included _in the formulation when the
`
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`MYLAN EX 1002, Page 5
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`MYLAN EX 1002, Page 5
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`_ ..
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`.....» ..—,.. 4-..- .-...r\4.'r..-vi.y~-,9\ta&Q4'4NraI-‘—IUv,¢'\£no-r-4ur\r» -
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`formulation also includes ethanol. when a surfactant is
`
`present it constitutes about 0,Ql_to_gbout o.5_percent by“-
`weight of-the aerosol forlulation.
`_
`_
`___M__U___w___
`suspension aerosol fornulations of the invention
`
`which do not contain ethanol are preferably substantially
`free of parfluorinated surfactant} -'
`"
`' "A‘‘’"
`The suspension aerosol formulations of the
`
`—-invention comprise 1,1,1,2,3,3,3-heptafluoropropane as
`substantially_the only propellant. The propellant is .
`present in an amount effective to propel the formulation
`from a aetered dose inhaler. Typically the propellant
`constitutes the remainder of the weight of the formulation
`
`—‘
`
`once the drug 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'veight '
`based on the total weight of the formulation.
`
`Preferred-formulations of the invention exhibit
`substantially no growth in particle size or change in
`crystal aorphology 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._ -
`The suspension aerosol formulations of this
`
`invention can be prepared by combining the drug and the
`propellant and then dispersing the_§rug in the propellant
`using a conventional mixer or honogenizer. when a
`surfactant and/or ethanol are included in the fornlation,
`
`they can be added to the propellant along with the drug.
`Bulk foraulation can be transferrd to smaller individual
`
`aerosol vials by using valve to valve transfer Iethods or
`by using conventional cold-fill mthods.
`In order to effect bronchodilation the
`
`formulations of the invention can he delivered to the lung
`
`by inhalation (e.g., oral or nasal) uing conventional
`
`inhalers (e.g., metered dose inhalers comprising an aerosol
`vial equipped with a metered dose valve).
`
`._ rho following examples sre—provided to-illustrate"’
`'
`the invention but should not be construed as limiting the
`
`MYLAN EX 1002, Page 6
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`MYLAN EX 1002, Page 6
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`

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`The respirahle fraction is deterninod using the
`invention.
`testenethod described below.
`-~-
`-“
`~— ‘
`‘"”“
`
`'
`
`&m
`
`_ _In this assag_the respirab1e_traction_1the__fl
`_____
`percent or particles having an aerodynamic particle size or
`
`less than 4.7 microns) or the aerosol suspension is
`determined using an_Anderson cascade Inpactor {available
`from Anderson sampler Inc.; Atlanta, GA).
`
`The aerosol—vial to he tested is primed five
`times. The valve an valve stem are then cleaned with
`
`methanol and dried with compressed air. The aerosol vial
`
`and a clean, df§”actuator are coupled to the glass throat
`attached to the top of the impactor using an appropriate
`' tiring adaptor} The eaiibrstaa vacuu pump (2813 t/min) ‘
`
`attached to the cascade inpactor is turned on. A total or
`20 sprays is delivered into the cascade impactor by
`repeatedly shaking the vial, seating it in the actuator nd
`immediately delivering a single spray. The time between
`
`sprays is approximately 39 seconds. The cascade impactor
`is disassembled an each ccuponent is rinsed separately
`
`with diluent (45 parts methanol mixed with 55 parts 0.1%
`phosphoric acid. v/v). Each solution is_analyzed for
`albitefal sulfate content using high prsssue liquid
`chromatography. The respirable fraction is calculated as_
`follows:
`‘-
`-
`-
`—_
`
`* respirable =dm X
`
`100
`
`total drug - drug recovered from recovered
`actuator and valve
`
`Ex§lD1§_1
`
`A 0.60 9 portion or nicronized albnterol sulfate
`and 25 mL of glass beads were placed in a 4 once glass
`aerosol vial. The vial was sealed with a cotinuous valve
`
`and then pressure filled with approximately 150 g or
`
`lpl,1,2,3,9,3-heptarluoropropane. The vial was shaken‘to
`disperse the albuterol sulfate. The‘resu1ting tornnlation
`contained‘DL4”perceht by veighE'o£ alhfiterol sulfate.
`The
`gformulation was transferred to 10 mL alumina: aerosol vials
`
`MYLAN EX 1002, Page 7
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`MYLAN EX 1002, Page 7
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`

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`sealed with continuous valves by using a yalve to valve
`button.
`‘The. vied; were ‘chilled in dry ice then
`‘ H
`" ‘"‘the_ "val§res were renewed"‘ A and the vials were
`
`_
`
`sealed with 25 pl. aetering valves. Using the nethod
`_ -.._5 - ducriI:ed'above.' the-reepirable traction was'd'ete3rn1n”ed' ‘is.
`dupil icate for two separate vials. Values of 69.3% and
`
`"
`
`
`
`
`
`
`<_
`
`6-‘
`
`60.6% were obtained for via1_~1.
`were obtained for v;ial-2.
`
`‘Values of 64.0% and-63.0%
`A
`7' W”
`
`'1o
`
`"
`
`
`' gang 2''
`A 0.60 9 portion of nicronized alhuterol sulfate,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.75 9 of oleic acid, 22.5 g ot ethanol and 25 at. or glass -
`beads were placed in a 4 ounce glass aerosol vial. The
`
`‘_ A ___‘_viz_:_l was sealed with a continuous valve andxhen pressure --— —
`15
`filled with approximately 126 g of 1,1,1,2,3,3,3-
`
`heptafluoropropane. The vial was shaken to—disperse—the—
`
`albuterol sulfate. The resulting toruulation contained
`0.40 percenthy weight of alhuterol sulfate, 0.50 percent
`
`by weight of oleic acid and 15.0 percent by weight of
`
`
`
`
`
`_
`
`__
`
`-
`
`
`
`20 . ethanol._ Individual aerosol _v:_lal_s_ _were_ti1led and_ fitted
`
`
`with‘ 25 pl. metering valwes using the method described in
`
`Example .1. Using the test method descrihed_ above, the
`
`
`;.<,;'~
`.,-= :
`respirable fraction was determined in duplicate for-two
`NI‘!
`separate vials. Value: at 28.0% and 22.0% were obtained
`’~" :
`
`
`25
`for vial 1. Values of 27.1% and 28.8% were obtained for
`
`33:‘ ‘
`vial 2.
`‘
`=-=:»-»Q:
`
`
`I
`
`
`
`
`
`30
`
`
`
`
`mimic;
`A suspension aerosol formulation containing 0.31
`percent by weight or albuterol sulfate, 0.10 percent by
`weight or sorbitan trioleate (colnercially available under
`the trade designation Span 85), 9.95 percent by weight of
`ethanol and 89.58 percent by weight of 1,1,1,2,3,3,3-
`m was prepared.
`
`
`
`.
`;:;
`:3’.
`
`
`
`air,___.
`
`
`
`
`
`MYLAN EX 1002, Page 8
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`

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`
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`A toraulation according to claim 4 wherein
`5.
`’
`said ethanol is pre5ent'ii an amount of about 5 to about 15
`percent by weight.
`
`-i‘
`
`'
`
`25
`
`30 ,
`
`’r‘
`
`A toramlation according to claim 5 further
`6:
`comprising from about 0.01 to about 0.5 percent by weight
`of a surtactant seleted tron the group consisting of oleic
`acid and sorbitan trioleate.
`
`A tornulation according to Claim 6 wherein
`7.
`said sufactant is oleic acid.
`
`
`
`A toraulation according to clain 6 wherein
`8.
`_%¥g‘
`9» 1
`--~—-~—
`"
`eaid_sur1actant is sorbitan trioleate.
`-
`-
`-— ~—~
`—
`
` .-
`
`.—
`—
`—
`- 9.
`-A_~rornulation according"to claim 1.’
`consisting essentially or about 01; to about_0;5 percent by
`weight of nicronized albterol sulfate and l,1,1,2,3,3,3-
`
`
`
`MYLAN EX 1002, Page 9
`
`HHA15 Is
`
`I5:
`
`479B2USA9l
`
`“ A‘ “'5‘
`
`1." TA §usS£n££bn aerosol toraulation comprising
`';"'
`a therapeutically ettective amount of nicronized alhuterol
`
`_
`
`_
`
`__ sulfate and 1,1,1,2,3,3,3-hepta;luoropropane'as
`substantially the only propellant.
`
`_
`
`‘H
`
`lo
`
`_
`
`A torlualation according to claim 1 wherein
`2.
`the nicronized albuterol sulfate is present in an amount or
`about 0.2 to about 0.5 percent by weight.
`
`— —
`
`-
`
`~
`15
`
`»
`
`-a*£ornu1ation‘accord1ng to Claim 1 wherein
`3.
`—
`said formulation is substantially free or pertluorinated
`
`surfactant.
`
`‘rv’
`
`“W““"”"
`
`V
`
`4.
`
`A tornulation according to claim 1 further
`
`comprising tron about 0.1 to about 20 percent by weight or
`ethano1._.__
`..
`'.
`-
`i
`-
`-
`~-
`-
`
`‘zo
`
`MYLAN EX 1002, Page 9
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`

`
`
`
`10
`
`15
`
`20'
`
`A
`
`
`
`
`
`'heptafluoropropane.
`
`‘
`
`'
`
`“
`
`’
`
`’
`
`' ‘“"' H"
`
`10.
`
`.ug. consisting essentially of about 0.35 to about 0.42 percent
`by weight of nicronized albuterol sulfate and
`_1,1,1,2,3,3,3-heptafluoropropane.
`
`formulation according to Clain 5
`A
`11.
`consisting-essentially of about 0.2 to about 0.5 percent by
`weight of nicronized albuterol sulfate, about 5 to about 15
`percent by weight of ethanol, and 1,1,1,2,3,3,3-
`heptafluoropropane.
`
`12. ‘A nethod for inducing bronchodilation in a
`usual comprising the step of administering by inhalation
`to the lung of the manual an anount of_a formulation
`according to clain 1 effective to induce honchodilation.
`
`A netbod of preparing a forlulation
`13.
`according to cla£n'1, comprising the steps of:
`(i)
`combining the nicronized albuterol sulfate
`_ with the propellant; and
`"-
`(ii) dispersing the albuterol sulfate in the
`propellant.
`
`
`
`
`A fornnlation according to clain 1 in an
`14.
`‘aerosol vial equipped with a metered-dose valve.
`
`'IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIE EIIIIIIIIIIIIIIIIHIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`ML‘x‘1”2
`
`
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`MYLAN EX 1002, Page 10
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`

`
`. “$751
`
`I DOCk3T'HUMER:
`
`47982USA9A
`
`53313391
`
`Pharmaceutical" suspension aurosol tor.-sulations
`comprising a therapeutically effective amount at albuterol
`
`sulfate and a propellant‘-cosprisinq 1,1,1,2,3,3,3-
`heptatluoropropane. The formulations optionally contain a
`surfactant and/or athanol. Also disclosed is 'a method of
`
`preparing said formulations and a nathod of inducing
`bronchodilation in a manual.
`_
`._
`
`MYLAN EX 1002, Page 11
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`MYLAN EX 1002, Page 11
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`

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