CA2320129C - Suspension aerosol formulations - Google Patents

Abstract

A metered dose aerosol canister, equipped with a metering valve, containing a medicinal aerosol formulation suitable fox inhalation comprising a therapeutically effective amount of a drug in suspension and a proellant selected from the group consisting of HFC 134a, HFC 227 and mixtures thereof, the formulation being further characterized in that it is free of surfactant, includes 5 to 15 percent ethanol, and said drug is albuterol sulfate.

Description

SUSPENSION AEROSOL FORMI:fLATIONS
The present application is a division of applica-tion n° 2,126,244 filed on December 11, 1992.
BACKGROUND OF THE INVENTION
Field of the Invention The invention as broadly disclosed hereinafter relates to pharmaceutical aerosol formulations. In another aspect this invention relates to pharmaceutical suspension aerosol formulations wherein the propellant comprises HFC
134a or HFC 227. In another aspect, it relates to pharmaceutical suspension aerosol formulations containing pirbuterol. In another aspect, it relates to pharmaceutical suspension aerosol formulations containing albuterol sul f ate .
Description of the Related Art Pharmaceutical suspension aerosol formulations currently use a mixture of liquid chlorofluorocarbons as the propellant,.
Fluorotrichioromethane, dichlorodiflu,oromethane and dichlorotetrafluoroethane are the most commonly used propellants in aerosol formulations for administration by inhalation.
Chlorofluorocarbons (CFCs), however, have been implicated in the destruction of the ozone layer and their production is being phased out.
Hydrofluorocarbon 134a (HFC 134a, 1,1,1,2-tetraf luoroethane) and hydrof luorocax-bon 227 (HFC 227 , 1,1,1,2,3,3,3-heptafluoropropane) are: viewed as being more ozone friendly than many chlorol:luorocarbon propellants; furthermore, they have .low toxicity and vapor pressures suitable for. use in aerosols.

la 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,-Expedit: ROBIC/BREVETS 4eme 514 B45 8705; 09!20!00 16:24; JetFax #716; Page WO 93/11747 PCTIUS9t/lflSB7 , .
Z ..
butane, propellant is4~, prapel~.aret 1i, propellant 125, ar propellant 15~a.
European Patent Offioe Publioation 0 384 371 (Heiskel) describes solution aerosols in which i,l,l,Z,3,3,3-heptafluoropropane or its mixture with propane, butane, isobutane, dia~ethyl ether, or l,i-ditluaroethane serves as the propellant. fihe Appiioation does not, however, disolose suspension aerosols or pha~ceutf.cai aerosol formulationx.
~opean Patent llppiication 89.31zz7o.5 (Pux~awal et al..) discloses, inter alia,.aerosol formulations comprising a ~aedicamcnt, 1,1,1,3-tetrafluoxaethane, n surface active agsnt, and at least Qne compound having higher paiar~.ty than !,!,!,z-tetras fluoroethane .
.U.6. Pat. No. x,$68,691 (Porush et al..) discloses aerosol formulations comprising a med~.cament, a halaqDtlated lowex alkanQ propellant, and a t~osolve~t which assists ire dissolving the medicament in the 10 propellant. The che~ai.r~l formula for the propellant given in Col. 2, limes s~lb, generically embraces HFC
134a and HFC z27. Examples pI cosolvants disclosed include ethanol and diethyl ether.
U.8. Pat. HD. 3,014,8A4 (This! et aZ~) discxasea aerosol. foL'mulations comprising a hicror~ised medicamexit, a halogeaated lower alkane propellant and a aurfaee-active agent to assist in the suspensia>n of the medioament in the propellant. The chemical formula fp~-the propellant given is ~l. 4, lines 19-za, generically embraces HFC 134a and HFC 22~.
patent Application yip 9p~01454 (Greanlenf et al.) disalases aerosol co~tpositfons having HFC 134a as the propellant and comprising a medicament coated with a nvn-perfluorinated surface active dispers~.nc~ agent-This appiioation describes control ~ormulationc containing only HFC 134a and o..sss paroent by weight of a drug.

Expedit: ROBICIBREUETS 4eme 514 S45 8705; 09!20/00 18:24; J tFa~ #718; Page WO 93//1747 PG'f'1~592/111587 Albuteroi sulfate is a relatively saaoctive betar2 adrenergic bronchodil.atar. It is availarile~ in a variety of dosage forms including tablets, syrups end formulations suitable tar inhalation. For example, s v~NToI.,IN"' Inhalation Aerosol (eomm:rcially available from Allen & Hansburys) is a metered dose aerosol unit containing a mivrocrystailine suspension of albuterc~l (free base) in propellant (a miacture o!
trichloro~aonofluQromethane and dichlorodifluoromethane) lo with oleic acid. VENTOLIN R4TOCAPb"" for Inhalation (aammeraially available from Allen & Iiansburxs) aQntain a mixture of mior8fihe aibuterol sulfate with laatr~~
arid are intended far use with a apeøially designed device for inhaling powder. VENTDLIM"' solution for 15 Inhalation (aomme4tcialiy available from Allen &
Hansbyxys) is an aqueous solution of aibutero3. sulfate intended for use with a nebulizer.
pi.rbuterol acetate is a relatively aslectiv!
beta-2 adrenergio broncbodilatar. MAXAIR~' lnhalar ao (commerci$11y available from 3M Pharmaceuticals, St. Paul, MH) is a aetered doses aerosol unit containing a fine-partials suspension c~f pirbuterol acetate in the propellant mixture of trichloramanofluoromathane and d~.ahlorvdifluoromathane~, with sorbitan triole~xte.
,~,~ummar~ of tb ~ I rm~y~ t~ l nn This invention provides a phar~aaoeuticai suspension fcrraulation suitable far aerosol admiaistxatian, consisting essentially of a so therapeutically effective amount of a drug and a propellant scleated from the group consisting of 8FC
13~a, HFC 229,, and a mixture.thareof, said formulation being further aharaate~i~ed in that it exhibits substantially nn growth in partiole 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.

Expedit: ROBICIBREVETS 4eme 514 B45 8705; 09120100 iB:25; l~tFa~ #718; Page WQ 9$/11747 PCT/US92/lp5$7 . , , This invention also provides are s~sxosol canister containing a formulation as dsscribed a~sove ixv an amount sufficient to provide a plurality of therapeutically sffoctive doses of the drug. Also provided is a method of preparing a formulation as described above, comprising the steps oi~: (l) combining an amount of the drug sufficient to p~r8vid~ a, plurality of thsrapsutically effective doses and a propellant seleoted from the group consisting of WFC
to l3aa, HFc a~~, and a mixture thereof, in an amount cuffioient to propel from all aero9ol canister a plurality of therapeutically effective dasee of the drug; and (ii) dispersing the drug in the pFopellant, This invention further provides a method of treating a mammal having a condition capable of treatment lay inhalation, comprising the step of administer~.ng by inhalation a formulation as described abo~re to the mammal.
In anothex aspeot, this invention provides ~0 suspension aerosol fo~nulationv comprising a therapeutically effective aiaount of aicronized albuterol sulfate and HFC z27 as eubgtantially the only propellant. This invention also pxovides suspension aerosol forxaulations oomprising a therapeutically effective aaount of micranizsd albuterol sulfate, from about O, ~. to t ~s p~os~t by weight off' ethari0l, and HFC ~2? as substantially the only propellant. This invention also provides suspension aerosol formulations comprising a therapeutically effective amount of 3o micronized albuterai su~.fate, from about 5 to 15 percent by wsiQht of ethanol, from about o.05 to about Q.5 percent by wsi$ht of a surfactant s~electsd from the group consisting of oleic acid and sorbitan trioleats, and IiFC 227 as substantially the only propellant.
In another aspect this inventiols prowidss suspension aerosol formu7.ttiohs compr.isir~q a therapeutical~.y effective amount of micronizad pirbuterol acetate and a propellant comprising HFC 2~7, the formulation being further characterized in that it is substantially free of perfluorinated surfactant. This invention also provides suspension aerosol formulations comprising a therapeutically effective amount of micronized pirbuterol acetate, about 0.1 to about: 12 percent by weight of ethanol, and a propellant comprising HFC 227. This invention also provides suspension aerosol formulations comprising a therapeutically effective amount of micronized pirbuterol acetate, about 5 to about 12 percent by weight of ethanol, about 0.05 to about 0.5 percent by weight of oleic acid, and a propellant comprising HFC 227.
The invention as broadly disclosed also provides a method for inducing bronchodil<~tion in a mammal, comprising administering to the mammal a formulation as described above by inhalation.
The invention as claimed hE=_reinafter is however directed exclusively to a metered close aerosol canister equipped with a metering valve, and containing a medicinal aerosol formulation suitable for inhalation, said formulation comprising a therapeutically effective amount of a drug in suspension and a propellant selected form the group consisting of HFC 134a, HFC 227 and mixtures thereof;
the formulation being further characterized in that it is free of surfactant, it includes 5 to 15 percent ethanol, and said drug is albuterol sulfate.
Detailed Descrit~tion of the Invention The term "suspension aerosol formulation" as used herein refers to a formulation ~.n which the drug is in particulate form and is substantially insoluble 3o in the propellant.
Amounts expressed herein in terms of percent refer to percent by weight based on t:he total weight of the formulation.

5a 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 addii~ional 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 _____.~ ~.,~r, that the drug can be administered as an Expedit: ROBICIBREUETS 4eme 514 845 8705; 09120100 18:28; )~tFax #718; Page WO 93111747 PCfIUS92/10587 , .

aerosol (e. g., topioally or by oral or nasal inhalation) and cause its desired therapeutic effect with one dose, or legs preferably several doses, tram a c4nventiorral valve, e.g., a metered dose valve.
"7lmaunt" as used herein refers to quantity ar to concentration a3 appropriate to the context. The antaunt of a drug th~xt constitutes a tharapautically effective amount varies according to factors such as the potency, efficacy, cold the like, of the particular lo drug, on the route of administration of the ~ornaulation, and ~,n the device used to administer the formulation. A therapeutically effective amount of a particular drug can be selected by those of ordinary skill in the art with clue consideration of such factors. riazticularly in formulations of the invention intended for oral inhalation into the 7.t~ngs~, the drug is preferably micronizld, i.a., about so percent or more of the particles have a diameter of less than about 14 microns, in order to actors that the part~.ales ~o can be intxaled into the lungs.
The pazt.icular amount of drug that will romaain suspardad in a for~nul.ation Qf the invention for a time sufficient to allow reproducible dosing of the drug depends to soma extent on the nature of tbs particular drug, e.g., it: d:nsity,~and on the particular propellant used in the formulat~.on, c~nerally, however, it has been found that when chug concentzationa of less than abort 0.i pelrcent are used in a formulation of the invant3.on the drug flocculates ao to some degree but generally does not settle or cream to the extent that the suspension becomes unsuitable for a:a as an aerosol farmulaticn, e.g., in a metered dose inhaler. Therefore ~t$ regards drug concentration such formulations are acceptably homog~eous.
3s when drug concentrations greater titan about o.i parawnt but less than about o.5 percent era used in a forasalativn of the invention it is sometimes seen that the drug flocculates cans~iderabiy in the Expedit: ROBICIBREUETS 4eme 514 845 8705; 09120/00 16:28; J Fex #716; Page WO 93/I 17x7 PGT/US9?J 1 DS87 farmulatian and trierslore might have an increased tendency to cream or settle. As disauassd below in connection with the propellant component of the formulations of the invention, iri thaae instar~aes it is preferable to select the propellant in a manner that aairimizss creaming and settling of.the drug in order to assure that the formulation is acceptably homogeneous as regards drug concentration. E
As drug concentration increases, e.g., beyond k about D.5 percent, the tendency of the drug to flQCS~ulate generally increases also. Iiowavar, the Yalume occupied by the f loeculated ~lrl,tg alaQ inCreaBe$
and the flaaculated drug begins to occupy substant~.elly all of the volume of the farmuiatibri. zn such instances the flocculated drug often shows a laser tendency to cream ar settle. As~ragards drug concentration such foxmulatians are acoeptably homogeneous.
Generally the concentration of the drug irt a l ~0 formulation of the invention is preferably less trim about o.1 peroent, more preferably less than about o.0e percent, and host preferabllr less than about 0.05 I
percent. Aaeordingly, it is preferred< aaoording to this invention that the drug have a potency eu~ fat concentrations less than about 0.l percent, more prefarnbly lass than ablaut o, o8 percent, ~d ~poct grsfarably less than about o.05 percent, are therapeutically effective. Preferred drugs for use in the formulations of the invention tharetare include f formoterol, salneteral, and pharmaaeutiaally aacapta~ble salts thereof, particularly formoterol fumarata. other drugs that can bye formulated. acaarding to this iriverition inchide albuterpl, beclomethasone c diprapiana~te, cromalyn, pirbuterol, and pharmaoeutiGally acceptab3.e salts arid aofvatss thereof, E
p$rticularly albuterol sulfate,, disodium cromogiycste, and pirbuterol acetate.

Expedit: ROBIC16REVETS 4eme 514 S45 9705; 09120100 19:28; JretFax #718; Page WQ 93111747 PGT/US9~11t1587 g _ The propellant in a formulation of thn invention can be HFC 134a, liF'c a2~, or a mixture thereof ix~ any proportion. The propellant is pre:ant in an amount sufficient to propel a plurality or doses s from a metered dose inhaler. The density of xi!c 134a differs from the density of IiFC Z~7. Therefore the density Qf the propellant can be ad3usted within limits by using mixtures of HFC 134a and HfC Z27 in order to aarommodate the density of the drug. It is sometimes to preferred that the propellant be selected such that the propellant density is as closely matched as poaibla to the drug density iri order to ~ainimize tendencies for the drag to s~ttla or cream, particularly when drug t concentration is greater than o.1 percent yr when the 15 drug concentration is between about o.1 percent and about o.5 percent.
The pirbutarol acetate formulations of the inventfor~ contain a therapeutically effective amount of pirbuteroi acetate. preferably, the pirbuteroi acetate 20 constitutes about 0.~ to about 1.0 percent by Weight, more preferably about o.45 to about 0.9 percent by weight, of the aerosol formulai~ion. preferably the pirbuterol acetate is miaronised.
Ethanol can optionally be included in a 25 p~.Fbuteroi acetate aerosol formulation of the .invention. When ethanol is pxs:ant it aonstitutQC frox~
about o.1 t4 about 1~ percent by waiQht, preferably from about 5 to about 1z p~aent by weight of the aerosol formulation. In another aspect of this 3o invention $thanai preferab3y oonstitutes from about z to about s percent by weight of the formulation. Oleic said can optionally be included in a pirbuteroi acetate fr~rmulation of the invention that inoludes ethanol.
When oleic acid ~.s present it constitutes about 0.01 to 35 about 0.s peraant riy weight of the f~armulation.
Typically the propellant constitutes the remainder of the weight of the formulation once the pirbuterol acetate arid the optional ethanol and olsia Expedit: R08ICIBREUETS 4eme 514 845 8705; 09120/00 16:27; ,/~tFax #716; Page WU 931 1 ~a~ PCf/~,J59Z/ 10587 g acid are accounted for. Accordingly tbs propellant is generally pz~esent in $n amount of at least about percent by weight based an the total weight Qf the farmulatios~. The propellant its a pirbutarol acetate 5 formulatiar~ of the invention compriacs tlPc a27, preferably as substantially the only propell$nt.

Ho~,rever, one or mora,othsr propellants such as propellant 142b (1-chlero-1,1-difluoroethana), 8FC

134x, and the like can be used, preferably in o pirbuterol acetate formulations of the invention captaining ethanol.

preferred pirbuterol acetate formulations of the invention eathibft substantially no growth in particle size ox change in crystal morphology of the 15 pirbutex~ol acetate over a prolonged period, are substantially and readily radispersible, and upon radispar:ion do not flocculate so quic7cly as to prevent reproduaibia dosing of pirbuterol acetate.

The albutarol r~ulfate formulations at the 20 invdntion contain a therapeuti.oa7.ly effeativQ amount of mioronized albuterQl aul#~ate. preferably microniz~ed albuterol sulfate oanstitutas about 0.3 tc about 0.5 peraant by weight, more preferably from about 0.35 to about 0.42 percent by weight of the ae~xosol 25 farmulat3on.

Ethanol can dptiona~ily ba included in such an albuterol sulfate tpsamlation of the invention. When ethanol is prssesnt it constitutes fxom about 0.1 to l about 20 percent by weight, preferably from about 5 to 3D about 15 percent by wei.gbt of the fora~u~.atian.

surfactant selected from the group consi:tang of oleic acid and sorbitan txieleate rarr also optionally be included in the for~uu~.atic~n when the toxmulation also includes ethanol. When a surtaatant is present it 33 constitutes about o.o~. tc about 0.5 percent by weight of the aerosol formulation. Albuterol sulfate formulations Qf the invention triat do not contain l I
l L

Expedit: ROBICIBREVETS 4eme 514 845 9705; 09120!00 18:27; lletFa~ #718; Page 15!38 W~ 93111747 PGTIL.rS9x/1b587 ethanol are preferably substantially f>raa of p~rfli3orinated surfactant.
certain preferred albuterol sulfate sucpsrision aerosol formulation~t of the invention comprise HFC 227 ,ae substantially the only propellant.
Typically th,e propellent o4nstitutas the remainder of the weight of the formulation once the albutsrol sulfate and the optional surfactant and/or Methanol are accounted for. Accordingly the propellant is generally present in an amount of at iee$it about 73 percent by weight based on the total weight of the formulation.
preferred albuterol sulfate formulations of the #.uvention exhibit substax~tially no grQr"tth in particle s~,ae or change in crystal morphaloc~y of the albuterol sulfate over a prolonged period, a.re substantially and readily redispersible, and t~por~
redispsrsion do not fiocaulate so quickly us to prevent repxoducibls dosing of ellaoterQl sulfate.
Generally the formulatiQnsv of the invention 2o ~eari be prepared by combining (1) t#~e drug in an amount sufficient to provide a plurality of therapeutically effective doses; and (ii) the prope~.la~t~ in an amount sufficient to propel a plurality of .closes from an aerosol oanister; and disper8ing the drug in the Z5 propellant. The dr>xg can be dis~persad using a conventional mixer or homogenizer, by shaking, or by ultrasonic energy. $u1x formulation can be tran~sferrec~
to smaller individual aerosol vials by using valve to valve transfer methods or by using conventional cold-3a rill metl~~oc~s.
the p~.rbuta.TOl aC6tate CuspensiQn atrosol formulations of this invention can be prepared by coiabining trie pirbraterol ncstat~ 4x~d the px~c~pellartt and then dispersing the pirbutsrol acetate fn the 35 propellant using a conventiaaal mixer or homQgenizer.
pirbuterol acetate, however, is somewhat soluble in ethax~o~, alone. Accordingly, when oleic acid and/or ethanol are inc~.uded in the formulation, it is Expedit: ROBICIBREUETS 4eme 514 845 8705; 09!20!00 16:27; ;~atFax #716; Page WO 93111 ~~i7 P~'1'/US92/ l 0587 li -preferred that the pirbutarol 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 di:parsed in thg mixture.

The albutsral s~ilfate suspension aerosol formulations of this invention ca~ri he prepared by combining the albuterol sulfate and the prapallant.and dis~pessinq the albuteral sulfate in the propellant using a conventional mixer or riomaganizar. tr~hen a to surfactant and/or ethanol are included in the formulation, they rah b$ added to the propellant along w~.th the albuterol sulfate.

Aerosol caniatars equipped with conventional valves, preferably metered doss valves, can bs used to is daliv*r the formulations of the invention. It has been found, however, that selection of appropriate valve assQmbliss for use with eeraaal tQrmulations is dependent upon the partioulat sztrf~xCtants or adjuvants l us~ad (if any), on tho propellant, and on the particular ac drug being used. Conventional neoprene and buts valve rubbers used in metered dose valves for delivering conventional CFC formulstions often have leas than optimal valve delivery characterisrtics and sass of operation when used witty formulations containing Hf'C

85 134a or HFc z27. Moreover, conyantivnal CFC
I L

j formulations generally contain a surfactant in part as a lubricant for the valve stem. Sarae gQrmulat~.ons of the invention, however, do not contain a surfactant ay a lubricant. Therefore aertafx~ formulations of tb 30 invention are pxeferat~ly d.ispe~esed via a valve aarsembiy wherein the diaphragm is fashioned by extrusion, injection mblding or cantpression holding from a thermoplastic alastomaric matex3al such as FLEXOMER"' DFDA i139 NT7 polyolafin, XO~tER"' DFDA 1138 NT

3s polyol~fin, F~C.E?co' dEPb 893 NT palyalafin, FLEXOMER"' GERS io85 t~ polyolt~in, FLE7tt~MER'" DFDA 1163 NT7 polyolef in, fI.EXO~R"' 1491 NT7 polyolaf in, FI~Sxo~ 902o irr7 paiyalsfin, FLEXOH~'" so42 t~rr Expedit: ROBICIBREVETS 4eme 5i4 845 8705; 09120100 18:28; JI~tFa~ #718; Page WD 9x11 I747 PGTIUS~2/I0~587 - s.a -polyolefin (ilnion Carbide) , c-FLEX"' thermoplastic elastomer R7o-401, c-hLEX"' thermoplastic ela:tourer 870-051, C-FLEX"' thermoplastic elastom:r R7o-o41, C->FLEXa' thsr~aoplastic alastomer R~o-085, t-FLT thermoplastic alastomar R7a--OG3, or C-FLEX"' thermoplastic elaatomer R~0-0~6 (Concept Polyaar Technologies), or a blend of two or more thereof.
Conventional aerosol caniators, e.g., those of a~.uminum, glass, stainless steel, or polyethylene is terephthalate, can be used to contain a formulation of trig in~rention.
Tl~~a formulations of the invention can be delivered to thn lung by oral inhalation in order to effect bronchodilativn or in order to treat a condition z5 eusaeptible of treatment by inhalation, e.g., asthma, chronic obstructive pulmonary disease. The formulations of the invention can alro be delivered by nasal inhalation is order to treat, e.g., allergic ~rhini.tie. rhinitis~ or diabetes, or they can be as delivered vi,a~topicai (e.$., buccal) administration in archer to treat, e.g., angina or local infaation.
The fol~.owing Examples are provided to illustrate the invention. A1~. parts and percentages are by weight unless otherwiso indicated.
Formulations in HFC 134a For each of the nicronized drug substar~oes A-G set forth below, formulations were prepared at drug concentrations of O.pi7 percent, O.o39 percent, o.oe3 percent. 0~41 percent, and 1.6 percent by weight based on the total. weight of the formulation (corresponding to O.zo mg/mL, 0.5o mglmL. 1.0 mglmL, 5.o mglMi, and 2a ~3lm.L. x~espective~.y) . The formulations vats prepared 3S by dispa~W ng microni~ad d~ue~ Z.n HOC 134a in a oaalad i5 mL clear PET vial using uitrasonZC energy.

Expedit: ROBIOIBREVETS 4eme 314 845 8705; 09120100 iB:2B; II~tFex #7i8;Page iBl3B
WO 93/1177 PCf/rIS4111DS87 Drugsa A Beoiomethasone dipr~opionate ~3 Albuterol C Albuterol sulfate D Formoterol famerete E Disadiuaa oromoglycate F Pirbuterol sestets For each drug the lowest concentration formulation (0.017 percent by weight) was well to dispersed and easily redisp~srsible after Standing.
Hone of the formulations at this concentration showed any tendency to flocculate rapidly. As drug concentration increased to 0.41 percent visible flocs Started to appear, different drugs having a greater or is lesser tendency to flocculate. The increase in flocculation with increasing aancentration resulted in an increasing zate of sedimentation ox creaming (depending on the partia~ttiar drug involved) of suspended drug.
2o As drug concentration was further increased the fcrmu~.ations ~loccxulated but maintained a state of greater homogeneity as the flocculated drug began to occupy more of the formulation volume.
using tie lapse photography 10 and 30 25 sacarids after agitation the formulations were assess~ad as follaras:
Co,~gysltrat3.oss t.t1 ~g A H C D ~ g 30 0.417 + + + + + +
0.039 + + + 3 + +
0.083 3. 3 + ? 3 Dal 4 ~ ~ ~ -1.b3 -E + ~ + - +
35 + l visue~lly acceptable torinulation ~ vi$ually unacceptable tox~aula~tian ? = border line aCOOpt~tble formulation Expedit: ROBICIBREVETS 4eme 514 845 8705; 09120100 18:28; ll~tFa~ #716; Page WO 93/117x7 PCT/US92I10587 T?aese results show that aaah of the drug subst$r~ces evaluated can be formulated in HFC 134a alone. The formulations retain homogeneity after shaking to form aat~isgaatory formulations for use with s a metered Base inha~.er, Formulations of low concentration were pa~~ticularly homogenous.
For7~ul8tions of intexmedf~te concentration were of varying degrees of aaoept~tbility.
At the high concentration of 1.6 percent the to drugs with dsnaity close to the propellant density (bec~.omethasona dipropionate and albutsrol) formed particularly homogenous auapsnsions due to the rlocculated drug occupying aubstantialiy all of the tor~xuiation volume. Thud suspenaians would be ss axpeated to form sati*tactary formulations for use with a motored dose inhaler.
~c;aua~l ~ s Formulatiarrs its #~lPc 227 20 Farmulationi of disodium cromog~.xcate (pSCG) tvere prepared at ooncantrations of O.Oib percent, 0.035 percent, 0.0'74 ~aercant, 0.35 percent, and i.4 ,perasat by weight based an the we~.ght of the formulation with HFC 23? as the propellant fn a si~nila.x manner to these 25 prepared in Example 1 (again correspond~.ng tQ O.ZO, 0_50, 1.0, 5.0, and 20 mg/mL. r~pgotivvly).
Formulations were particularly homogenous at concentrations of 0.015 percent, 0.035 percent, and 0.070 percent lay weight. At 0.35 percent and 1.4 30 percent the formulations exhibited more rapid f~.occulation and :alimentation.
These results ahow,that di:odium aromoglyaata can be fo~u~.ated in 8FC 227 with na surfactant or other adjuva~tir, Expedit: ROBICIBREVETS 4eme 514 845 8705; 09120/00 18:29; ll~tFax #718; Page Cnar~~a~Cgtiye Exd'a5n1 a Farmulati,ons with cFCs Albutarol sulfate was fox~aulated in two _ propslla:zt mixes A and $, with no surfactant or adjuvant.
Propellant mix A: Prapsllant 1l 54 Propellant 114 14.25 Propellant 12 80.75 to propellant mix H: Propellant 11 a5~
propellant 1~.4 25~
Propellant ~,2 504 For each prcpeilant mix the range of drug aancentrations used in rxaa~ple 1 was seed.
The formulations at 0.20 mq/mlr, 0.50 zng/mL, and 1.o mg/mL were acceptably homogenous. The formulations at 5.0 mg/mzr and 20 mg/mL exhibited ~o relatively rapid flocculation. Notably, all these coaparative forraulatiana exhibited more caxirrg of drug on the walls of the co~taiiier than their HFC t34a GQUntsrp~4~'ts of Exa~le 1.
Formulation of >?ormoterol Fumarate with Mixtures of HFC 72~ and HFC i34a Formoterol tumarate was formulated as set forth in Ex~uaple 1 at concentrations of 0.015 percent, 0.038 percent, 0.076 percent, 0.3$ percent, and 1.5 percent (0.20, 0.50, 1..0, 5.0, and 20 zag/mL, xespectively) in a izi mixture tW/i~1) of HFC 134a and #IFC 22' .
?'base formulations of formoter47. fumarate show reduced flocculation arid a slower sedimentation rate than the corresponct.~ng formu~.ations at Example 1 above in~'oZying I3FC 134t~ along.

Expedit: ROBICIBREVETS 4eme 514 B45 8705; 09120100 18:29; llatFax #718; Page WO 93/117A7 PC.TItJSg311058'7 , .

The formulations were photographed using time lapse photography at l0 and 30 necarsds past agitation axrd Were assessed as follows:
~a C~naentration (~1 ~,ss~~m~nt 0.015 +
0.038 +
o.o?s o.3a 1o i.s +
Those results show that the ~tse of HF~ 227 in combination with HFC is4a spa a propellant affQxds formvterol fusaarate suspensions with reduced is flQGCUlation and greater homogeneity aamparad with corresponding formulations with EiFC 134a nlorxe as the propellant.
F?r:le 4 2o Formulations of BeQio~methasone p~.pxopianats (BDg) BDP formulations ware prepared at 0.070 percent by weight (i.o mg/mL) in 8FC z27 and at 0.38 percent by weight (5.o mg/mL) in a Z:i mixtuxe of HhC

2 ~ 7 and Iir'C 13 4 x .
The formulation at 0.0?o percent in HFC 22i was fairly well dispersed. Flocculation occurred at about to seconds after shaking and then areaning about 30 seconds after shaking.
The foriaulation at 0.38 percent in ~iFC
34 134a/xFC 2Z? invo~.ved a drug with a density closely matched to the propellant density, Although flocculation was rapid (small flQCs were visible almost immediately after shavlcing) the flocs nei~thar settled nor creamed.
35 The results show that it is poss~,blo to density match the drug to the propellant m~.x such that only the flocculat.ipn charaeteristics of the formulations influence homogeneity.

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~~~la salmateral Foxsrulations in HFC 134x arid HFC 227 formulations of se~lmeterol true bare at o.D2 percent by weight and D.os percent Dy weight ware prepared in HFC 134a and in Hla'C Zz7 by placing the drug and 5 mL of glees beads into a 15 mL glass vial, crimping on a continuous valve, end adding th~
appropriate amattr~t of propellant. The formulations were shaken ors a paint gh~er for iD min in order to lo disperse the drug. The dxug was seen to cream in both propellants, more so in HFC 227 than in HFC 134x.
Floaoulatiah was also apparent. However, the formulations were deemed suitable fvr use in connection with a matured dace inhaler.
Exam 1~6_ Formotaral Forxxul.stions in 8FC 227 A fQx~ntulation containing 4.01 percent by weight of farmoteroi fuaarate in 8PC 2z7 was prøparud 2D in an arrosal aanistex~ equipped with a 5D pL
SpRI~YMtsEH"' pracsure-fill metered dose valve. The formulation was prepared by plaQing 14 mc~ formoteroi famerete and 3D mL of glass beads ~,n a ~.2o inL (4 dunce) glass vial, crimping crn continuous valve, and adding 1D0 q of HFC X27. '1'he vial wlxs then sh$JCen on a paint shaker, chilled, and the contents transrarred to 10 mI.
vials fitted with the metered doss valve. The suspension was acceptably stable to settling and crsam~.ng. valve delivery was measured through the lf.i(a 3o c~f tl~e formulations. The results are shown in the Table below.
s$H~ ER (microctrams ~tl Nil~B per s ~o~-llo x,60-163 173--177 vial. ~1 3.0 4.7 4,2 4.8 3.1 vial #Z 2.7 4.1 4..1 4.1 3.6 135138 148-1~1 vial #3 ~.i 5.1 4.8 4.8 4.D

Expedit: ROBICIBREVETS 4eme 514 845 8705; 09120100 1B:30; llatFax #7i6;Page W~ 93111747 PCT/U$9Z/lOSB'1 Farsaoteral Formulations in HFC ~.34a P. torawlation aoni~airlir~g o _ fla scant by freight fo~pt~o~, aerate in HFC l3da Was prepared and tested us~.ng a 50 ~tL SPR.AYMIBERt" pxo~~ux~-f ill metered dose valve. Test methods acrd results are set forth below.
SOSpE?1SION AEROSOL pJIRTICLE SIZE hNxILYSI$
The particle siz~ distribution of drug in the aerosol suspension is assayed by Malvern Mastarsizsr'°
particle Size Analyser using a suspending asdium et 0.01 perce~at sorbitan trioleate in haptan~a.
is using a primed canneator, shots are tired via an in action Adapter into the Malvern sample cell containing the susprnding mddiun. When a suitable level of obscurat~on (in tk~e xange 8,5 - 9) is achieved, analysis by laser diffraction is then 2G performed.
The results below show the percsntage by Weight of particle: having particle sire below 10.'7 ~cm, below 5. p7 Vim, and below 1.95 Vim. The "initial"
entrie$ represent the average of three independent 2 5 (lete»miri~itians, and the "Z 5 ° C° , "CYC ° , and "HfiC"
entries represent a single determination after one maritb under the ~dicated storage c~and~.tians.

Expedit: ROBIClBREVETS 4eme 514 845 9705; 09!20100 18:30; J tFe~ #718; Page WQ 9311747 PGT/~3593110587 .
- i~ -Unit _ Llnit 1.._ ~articla ~ za L~ ~ ~ s Percent by waiaht Initial 99.6 93.4 33.3 98.0 92.6 30.5 i4 ~~~'c , 1 Month 99.8 93.6 36.3 99.9 94.8 31~

18 1 Month99.$ 9Z.9 3fi.1 99.8 92.5 32.5 1 Month 99.8 93.1 33.'~ 99.7 92.4 34.9 3p ------_-----~.._....-~~~~ _--.-..

25Ci 6dmples at a3C -stored CYC: sample: batwaan ayclad 1SG anCt 37C, one cycle 25 par diy, twalva each temparaturc boors at EI3Cs sa~ctples in a highhumidity aahinat at stoxed appraximataly 0C and percent relative humidity VALVE DELIVERY
35 This teat ig aarr~.ed out at 2o°C using 30 individual canisters. Each canister is primed by firing 10 successive shots just prior to the determination. The weight in mg of one shat tram each of the 3o canistarc is measured. The auaregs weight of 40 the 3o doses is calaulatad and recorded as the xaean.
Al:o shown below l: the number of individual dose weights differing by more than 7.5 percent and by more than 15 percent from the mean weight.

Expedit: ROBICIBREVETS 4eme 514 845 8705; 09120100 18:30; IotFu #718; Page WO 93111747 PGT/US92/1OS87 . . . .
- zo -.
Mdr~n Valve > ~ . 51; from > 1~% from Deliverv lmrrl mean mean 59.1 O p THROOGH TrIFE DELIVERY
Delivery of d~~uq ex valve is determined by firing ten shots through a stainless steel, cfarcular adapter IaQSS under liquid. Ths aerosol canister to be examined is primed prior to use. The canister is 1Q shaken and alloWid to stand for 13 seconds betWeon shots. The s~asapie solutions ars as~aaysd by IipI~~, The above tesi~ was carried out on shots 6-15, ~~s-5h, arid 9i-loo of the canister.

Expedit: ROBICIBREVETS 4eme 514 845 8705; 09!20100 18:30; l~tFa~ #718; Page WO 93/11747 PCT/U592l10587 chats Throuar~ Lifer »eliv~y ~(~~g Ir, do:paa ?nitia~.
Uxylt l '~ . 19 9 . i$ $ . ??
Zl;tlt 2 b.5°~ 9.20 11.77 Dnit 3 x.17 8.99 7.53 1~."f~~ h ~!?~'.S,l snit 1 ~.o~ s.o9 s.~?
Unit Z 8.99 9.71 7.7?
1 Month lCYC1 UIlit 1 8.58 7.8fi 6.82 i5 Unit 2 5.12 9.29 x.75 ~Qrith.. . l HHC 1 Unit l s.s3 ?.s8 ?.?s Unit 2 9.83 9.27 8.80 25pC: samples stor~ad at 25°C
CYC: samples ay ~sleCt ?setween 15°C arid 37~C. orie Cycle per day, tw:lve hours at each tes~psrature Htic: samples stored in a high humidity cabinet at approximately 40°C and 85 percent relative h~idity TWIN STAGE IMPINGER
Glass impinger apparatus A ~BPi98 Apparidix xviic) is used. Ta detenaine the de~pasftian crf the emitted dose, the apparatus is assembled as t~ascrihed.
The oral adapter is attached to the throatpiect of the 4o apparatsss, and a suitable pump is connected to the outlet of the aggaratus. The air flow through the apparatus is 60 t 5 liters par~minute measured at the inlet o~ the throat. The canister to be examined is Expedit: R08ICIBREVETS 4eme 514 B45 8705; 09!20100 18:31; JI~tFax #718; Page WO 93/i17~i7 E~C?IUSl2I14587 , .
- zz -primed prior to uce, shakers, and a1.14wed tv stand fQr 15 seconds between shots. Ten shots are then fire. via the adapter lets the appara~tua fxom the vanis~ter, The appar8tus is then dis:aantled and each stage washed with the appropriate a~oour~t of methanol.
The washings are assayed by HPhC to give the aonte~rt of the drag lotted at each stage and also the material b$ la~c~e , Material valve ~ stemj 9azance Ceiivery ~s~t~ ~e ~ ~tst~ r ~ ~ ~maa is Unit ~,zs.o 37.5 36.5 s3.~ 59.9 Unit 2 24.7 35.3 4D.0 81.0 59.7 ~Jnit3 28.5 3s.7 34.8 80.9 59.3 mon th,( 25!

~0 Unit 1 5Z.5 23.9 23.6 80,5 SB.B

U~~t 2 52.4 16.7 31.3 ?6.z 5z.0 ~;I~ol7th~(CY~

Unit ~,15.8 53.s X9.7 70.9 57.~

25 Oait ~ 24.6 47,6 Z7.8 82.6 60.0 1 ~ (t~tc1 Mon t7n,it1 ,~ 37 . 29 . O $Z 59 . 6 33. 9 0 .

Lllll'G2 15. 3 60 . 24 . 3 81. 60. 7 ~ 4 z5c: sa~apies stored x5C
at 35 CYC: :simples Cycled and Cycle between 37C, 15C floe per dax, twelve hours at each temperature Hl3c: samples stored a high at in hu~eiaity aabindt ~m~ a5 pcrcen t relative t~ ably 4oc and 4o al - .
h Y

Expedit: ROBICIBREUETS 4eme 514 845 8705; 08/20100 iB:3l; ll~tFa~ #716; Page WQ 93!11747 _ 23 _ Exam A 1.3s g portion of micrcmizac~ pirbuterol acetate, 15.o g of ethanol and 3o mL of glassy beads were placed in a loo mL (a ounce) glass aerosol vial.
The vial wa$ sealed with a continuous valve, pressure filled with approximately ?.33 g of 13PC 227 and there shaxen on a paint shaker fQr 10 minutes. The resulting formulation cQntaj,ne~t 0.9 percent by weight of l0 pirnuterol acetate and 10.p peroent by weight of ettxanol. The dispersion was trap:ferred into 18 mL
aerosol. vials which were sealed with 25 ~I. Spraymiser"
Aelrt~sol Valves (available from Nlatechnic En9ineerinq Ltd.).
This formulation was tested far its ability td deliver a oonsistent dose throughout the ~iife~ of the aerosol by determining the amount of p~.xb~terol acetate delivered per shot for shots e, 2, ion., x.02, 201, 202, 301 and 3Q2. T'he amount dali.vered par shot was dete~p~ed using the assay described below. The results are showc~ in the ,tile below.
A firihg d~.ek was piacmd in a loo aL beaker arid submerged in about 30 mL of diiuent (S5 part:
methanol/ 45 parts O.i percent phosphoric acid, v/v).
The Vial was shaken, inserted into the fixing disk, and actuated. The valve asld valve stets were rinsed i~ito the beaker with additional diluent. The ssolution in the beaker,was quantitatively transferred to a 100 mL
vQlumetaria flask which was then brought to volume with ~ additional diluent. The amount of pirbuterol acetate irr the :solution was detsra~insd using high perlormamce liquid ahxamatography.

Expedit: ROBIC/BREVETS 4eme 514 845 8705; 09120100 16:31; i~tFa~ #716; Page wo rcrlus~=nos8~
93nm~~ , .

-a4 -~g Pirbuterol Aaetata of chats Vial 1 Vial 2 Vial 3 .
615.4 379.3 3b0.1 2 378.7 361.0 3Z2.~.

101 404.0 380.4 374.7 1.02 352.0 389.1 337.9 201 37b.8 380.5 337.5 ~0~ 3'71.5 357.8 328. fi 30l 288.2 408.8 361.1 302 193.4 364.5 341.0 Examula 9 A I1.7 g portion of pirbuterQl acetate was placed in a beaker than chilled in a dry ica/trichiorofluoroaethane bath. A portion of ~rreohilled aFC a27 was added to ~tha b~sakQr and tt~o res~lt~,ng slurry W~is mixed at high sped ~tith a VIRTIS"' ~ode~. 45 mixer for $t least 3 minutes. The diepersad ccnoentrata was than trar~farred to a glass bottle and e~o~xc~h prechilled HFC ~2~ was added to bring the total not content weicJht to 130o q. The resulting formulation rantained o.9 parcant by weight of pirbutarol acetate.
Tns formulation was transferred tc * cold fillirrq system and filled into 10 mh aluminum aerosol vials which ware than asaled with 25 ~sL valves. The foxzaulation was deemed to lie suitable far use ia1 cr~nnection with a met*rød dose inhaler.
~xam~ple 10 A 11.7 g portion of micrani~ed pirbuterol acetate, 3.0 g of oleic aoi.d ans7 so g of ethanol ware planed in a beaker and hamoganizad for at least 3 Expedit: ROBICIBREUETS 4eme 514 845 8705; 09!20100 18:32; J tFax #716; Page ~Vb 93111747 PCTJU59211t158T

minutes. The resulting slurry was transferred to a tared glass bottle and enough ethanol was added to bring the total weight of the concentrate to 144. g.
The concentrate was chilled then placed alone with 1155 g of prechilled HFC 227 into a prschilled cald fi.~.~.ing system. The formulation was filled into ~.o mL ait~minum aerosol vials which were then sealed w~.th ~5 ~L
Spraymiss~' valves. The resulting formulation contained 0.90 percent by weight of pirbuterol acetate, a.a3 percent by weight of oleic acid and 10,4 percent by weight of ethanol. The formulation Was deemed to be suitable for uae in connection with a metered dose inhals~.
In ~tamples 11-1~ below, r~spirable fraction l5 is determined using the test method described below.
~~asoi.rable Fraction In this assay the, respirabls fraction (the percent by weight of particles having an aerodynamio 2Q ps'xx'tiole size of less than 4.'7 mir,~rons) of iGhe aerosol suspensio7i is detex7ti~,ned usi7~g an Alxderson Cascade lmpaator (available from Anderson sampler Ina,;
Atl$nta, GA).
The aerosai vial to be tested is prim~d five tiass. The valve and valve stem axe than cleaned with methanol and dried with compressed aix. Ths aerosol vial end a aleaa, dry actuator are coupled to the glass throat attached to the top of the 3~apactor using an appropriate firing adaptor. The calibrated vacuum pump 30 (~8.3 L/min) attached to the caacads impactor is turned on. A total of 20 sprays is delivered into the Qascade impactor by repeatedly shaking the v~.al, seating it ire t~#e actuator and immediately delivering a 6irigls spray.
The time between sprays is approximately 3o seoonds.
35 Th~a casa~xde impaator is dicaceambled and each component is rinsed separately with dilusnt (55 paxts methanol mixed with 48 parts of 0.1 percent aqueous phosphoric acid, v/v). Each solution is analyzed for pirbuteroi Expedit: ROBICIBREUETS 4eme 514 845 8705; 09120!00 18:32; j~tFax #7lB;Page W093/11'7A7 ~y~$~l/1~~7 - 2b -as:etate content using high perfoxnance liquid chromatography. The respirable fraction is calculated as follows:
% respl.rable ~ drya recovered from dates 3-7 X 100 total drug - drug recovered from recovexed actuator and valve i0 A 1.35 g potion of micronized pirbuterol acetate and as mL of glass beads were plaaed'in a 120 aiL (~ ounce) glass r~erQSOl vial. The vial was sealed with n continu~aus valve, preaur~ fflled with approximately 150 g of ~gc 227 and then shaken for at is !.east 10 minutes on an ~xutomatio shaker. The resulting formulation contained 0.9 percent by weight of pirbuterol acetate. The vial wxs then charged with 150 psi nitrogen to aid in product transfer to smaller' vials. The fornulatian was transferred to to ml, ~0 aluminum a~r~~sol vial0 e~ealed with cantinucus valves by using a valve to valve transfer button. The vials were then chilled in dry ice then the continuous valves were removed and the vials se$ied with 2s ~L :neterinq valves, using the method c~esarxbed above, the 25 ~respirabie. fraction was datormir~ed in duplicate for two separate vials. Valuef~ of 59.1. percent and 5A.8 percent were obtained for vial 1. values of 5~.9 percent and 49.3 percent were obtained for vial a.
~o A i.35 g portion of micraniaed pirbuterol acetate, 15.0 g bf ethanol and a5 mL of glass beads were placed in a l20 ~tl. (4 ounce) glass aerosol vial.
The vial was sealed with t~ oontinuous valve, pressure 35 filled with approximately 134 g of I;FC 227 and then shaken on an automatic shaker for at least to minutes.
The resulting formu~.atiori contained 0.9 percent by weight ox girl~uterol acetate and 10 percent by weight Expedit: ROBICIBREUETS 4eme 514 845 8705; 09120!00 18:32; htFax ~716;Page we aam~4~ ~crms9zmase~
of ethanol. Individual 10 mL aerosol vials were fillat~
arid aea~.ed with ~s ~cl, metering valves using the m*thod described in E~tsmple 11. Using' the fast method described above, the respirable traction was determined in dupliaata for two separate vials. Values of 3~.9 percent and 3~.5 percent were obtained for vial 1.
Values of 31.1 percent and 31.3 percent wars obtaia~d for vial 2.
In Examples 13-14 below r*spirabla frs,ction is determined using the test method described a~bovs but using a dilusnt of 45 parts by volume snathanol and 55 parts by volutbs o! 0.1 psz~cont aqusous phosphoric acid.
A 0 . f10 g portioli bf micrdnf Zed albuterol ssulfata and 35 aL or glass beads waxa pla,aed in a 120 mL (4 ounce) glass aerosol vial. fibs vial ws~s sea3ed with a continuous valve and than pressure filled with approximately 3.50 g of HFC X27 The vial was shaken to disperse the albutsrol sulfate. The resulting formulation contained 0.4 pcrcent by weight of albuterol sulfate. The formulation was trap:tarred to ~.o mI~ aIu=ainum aexoaol vials seai~l with cQntinuo~zs valves by using a valve to valve txansfer button. '~.'he vials w*ra chilled in dry iae then the aantinuons valves ware removed and the vials ware saxlaci with a5 ~rL metering valves. tTsing the method described abov:, the respirabla fraction was determined in duplicate fox two separate vials. Values of f~9.3 percent and ro.r 3D percent were obtained for vial 1. Values of 6~.0 percent and 63.o percent were obtained for vial Example id A 0.60 g portion of micrQnixed aibuteroi s~ttlfate, O~'75 c~ o.f px~lc aca,.d, ~~.5 c~ of etha~~i arid 25 mL of glass beads wee p~.aced iri a 1zo ~a~. (4 ounce) glass aerosol vial. The vial was sealed with a continuous valve and then pressure filled with Expedit: ROBICIBREVETS 4eme 514 B45 8705; 09120100 16:33; J tFax #716; Page WO 93/11747 PLT/US92/10587 ' - 2s approximately zzs q of liFC zz7 ~e vial was abaken to disperse the albutarol sr~~.~ate. The resulting farnulation contained 0.40 percent by Weight of aihuteroi sulfates, 0.50 pwreant by weight of oleic acid and 15.0 percent by weight of ethanci. Tndividuai aerosol vials were filled and fitted with 25 ~L
metering vaivea using the method described in Example 13. Using the test method described above, the respirable traction was determined in duplicate for twa to separate v~.als. Values of a8.0 percent xnd 22.0 percent were obtained for vial 1. Values of 2~.1 percent and 2s.s percent ware obtained for vial 2.
Ex~ly iS
tr suspensfdn ae~cQe41 foraulatian containing 0.3'7 per~ssnt by weight of albutero~. sulfate, 0.10 percent toy weight of sorbitaa trialeate (co~uneraialiy available~t~ndex the trade designation span Bay, s.gs percent by weight of ethanol and es.58 perce!Ot by 2o weight of 8FC 22~ ~,ras prepared. The forraulatfon was deemed to be suitable for use in conneatian with a metered do:e inha7.er.
m~7~!e . 1 s A 4.5 g portion of eth$r~ol was placed in a 12s luL (4 Qunce) glass aerosol vi$1. The vial was sealed with a continuous valve then pressure filled with 147 g of BFC 227. portions (approximately 225 mg) of micrpniaeci pirbuterol acetate were we~.ghed into 6 3o se~sarate ~.5 mh glass aerosol vials. A s mz, portion of glass )seeds was added to each vial and the vials were sealed with c.~ntinuous valves, Each vial was then pressure filled w~.tb approximately 19.8 g of the sthanol/l3FC 22~ solution. The resulting formulatian 38 contained 3 percent by weight of ~thanoi s~rid o.9 percent by weight of pirbuterol acetate. The vial: were then shaken in a pai.~nt shaker for 15 mfnt~tes. The vials were ooo,ied in dry ice, the continuous valves were Expedit: ROBIClBREVETS 4eme 514 845 8705; 09120100 18:33; l~tFax #718; Page wo ~~ri m~~ rc~rnus~rioss~
_ 29 _ x~e~nov$d and the contents poured into xsegarata 15 mL
aluminium aerosol vials. '~.'~ie aluloinum Vials ware s~2tled with 25 ~CI~ naives oqttfpped with diaphragms ~abx'icated from C-Flex R-9o-o51 and tanks seals fabricated from DB218. using the test method described above, the respirable fraction was determined for two separate vials. Values of 58.8 and 52.8% were obta~,ned. using the Mast method described above, the ability of the formulation to deliver a can:i:tent dos~a throughout tt~e "life" of the aerosol was determined. The results are Shown is the table below. The values are tde average for the indicated shots.
~sg pirbuterol h~etate/sl~ot -~., .-i5 shot ~ ~ Vial 1 vial Z

1 ~ 2 2'79.4 304.6 loi i~ 102 197.1 329, 2D1 & Zo2 294.9 478.1 301 i 302 295.8 294.x.

2D .&01 & 402 269.6 350.3 ~ *, a 1~
using the general aethod of Example 16, 6 25 v~.a~.s~ of a formulation containing s percent by weight of ethanol and o.~ percent by weight of pirbuterol acetate wer~ prepared. using the method described above, the respirable fractit~n was determined fvr two separate vials. Values of 4g:2% and 43.5% were 3Q obtained. tTSing the method described above, the ability of the formulation to deliver a consistent dose throughout the ~lifa" of the aerosol Was determined.
The results are shown in the Tt~ble below.

Expedit: ROBIC/BREUETS 4eme 514 845 8705; 09120100 1B:33; J tFa~c #718; Page Wb 93/y1747 ~'CT/US92/10387 - 3v -~q Pirl~uteral Acetate/~hot shot ~ vial ~ vial 2 1 & 2 263.9 288.5 jai ~ ion ~ss.s ~3z~.~

s 20~ & 202 300.6 387.2 301 & 302 330.7 3Dfi.B

4b1 & 402 3a.a.$ 27D,3 f'

Claims

WHAT IS CLAIMED IS:

1. A metered dose aerosol canister equipped with a metering valve, and containing a medicinal aerosol formulation suitable for inhalation, said formulation comprising a therapeutically effective amount of a drug in suspension and a propellant selected form the group consisting of HFC 134a, HFC 227 and mixtures thereof, the formulation being further characterized in that it is free of surfactant, it includes 5 to 15 percent ethanol, and said drug is albuterol sulfate.