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`US008142763B2
`
`(12) United States Patent
`Lewis et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,142,763 B2
`*Mar.27,2012
`
`(54) PRESSURIZED METERED DOSE INHALERS
`(MDI) CONTAINING A SOLUTION
`COMPRISING IPRATROPIUM BROMIDE,
`HFA PROPELLANT, AND CO-SOLVENT AND
`COMPRISING A CONTAINER WITH A
`SPECIFIC INTERNAL SURFACE
`COMPOSITION AND/OR LINING
`
`(75)
`
`Inventors: David Lewis, Parma (IT); David
`Ganderton, Parma (IT); Brian Meakin,
`Bath (GB); Paolo Ventura, Parma (IT);
`Gaetano Brambilla, Parma (IT);
`Raffaella Garzia, Parma (IT)
`
`(73) Assignee: Chiesi Farmaceutici S.p.A., Parma (IT)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 666 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 12/023,315
`
`(22) Filed:
`
`Jan.31,2008
`
`(65)
`
`Prior Publication Data
`
`US 2008/0115782 Al
`
`May 22, 2008
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 09/831,888, filed as
`application No. PCT/EP99/09002 on Nov. 23, 1999,
`now Pat. No. 7,347,199.
`
`(30)
`
`Foreign Application Priority Data
`
`Nov. 25, 1998
`Jul. 30, 1999
`
`(IT) .................................. MI98A2559
`(IT) .................................. MI99Al 712
`
`(51)
`
`Int. Cl.
`A61K 9/00
`(2006.01)
`A61K 9/08
`(2006.01)
`A61K 9/12
`(2006.01)
`(52) U.S. Cl. ......................................................... 424/45
`(58) Field of Classification Search ..................... 424/45
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
`OTHER PUBLICATIONS
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`L. Harris et al., "Twenty-eight-day Double-blind Safety Study of an
`HFA- l 34a Inhalation Aerosol System in Healthy Subjects", J Pham.
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`P. Hoet et al.,
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`
`(Continued)
`James H. Alstrum-Acevedo
`Primary Examiner -
`Firm -Obion,
`(74) Attorney,
`Agent,
`or
`McClelland, Maier & Neustadt, L.L.P.
`ABSTRACT
`(57)
`The invention relates to pressurized metered dose inhalers
`(MDis) in which all or part of the internal surface is stainless
`steel, anodized aluminum, or lined with an inert organic coat(cid:173)
`ing and which contain a formulation which comprises iprat(cid:173)
`ropium bromide.
`21 Claims, No Drawings
`
`Spivak,
`
`Complex Ex. 1008
`
`1
`
`

`

`US 8,142,763 B2
`Page 2
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`8/1991
`WO 91/11173
`7 /1992
`WO 92/11236
`11/1992
`WO 92/20391
`4/1993
`WO 93/05765
`6/1993
`W093/11743
`6/1993
`W093/11747
`WO 93/18746
`9/1993
`WO 94/13282
`6/1994
`WO 94/14490
`7 /1994
`WO 94/21228
`9/1994
`WO 94/21229
`9/1994
`6/1995
`95/17195
`WO 95/17195
`6/1995
`WO 98/03533
`1/1996
`WO 96/18384
`6/1996
`WO 96/19198
`6/1996
`WO 96/19968
`7 /1996
`WO 96/19969
`7 /1996
`96/32099
`10/1996
`96/32345
`10/1996
`WO 96/32099
`10/1996
`WO 96/32150
`10/1996
`WO 96/32151
`10/1996
`WO 96/32345
`10/1996
`WO 97/47286
`12/1997
`WO 98/01147
`1/1998
`WO 98/05302
`2/1998
`WO 98/13031
`4/1998
`WO 98/24420
`6/1998
`WO 98/34595
`8/1998
`WO 98/34596
`8/1998
`WO 98/56349
`12/1998
`WO 91/12596
`3/1999
`WO 99/64014
`12/1999
`WO 99/65460
`12/1999
`WO 00/06121
`2/2000
`WO 00/07567
`2/2000
`WO 00/23065
`4/2000
`WO 00/30608
`6/2000
`WO 00/35458
`6/2000
`WO 00/53157
`9/2000
`WO 00/78286
`12/2000
`WO 01/47493
`7/2001
`
`OTHER PUBLICATIONS
`J. Daly, Jr., "Properties and toxicology ofCFR alternatives", Aerosol.
`Age. Feb. 1990. pp. 26-27, 40, 56 and 57.
`D. Sirobach, "Alternatives to CFCs" Part II, Aerosol Age, Jul. 1988,
`pp. 32-33, 42 and 43.
`Tsi-Zong Tzou et al., "Drug Form Selection inAlbuterol-Containing
`Metered-Dose Inhaler Formulations and its impact on Chemical and
`Physical Stability", Journal of Pharmaceutical Sciences, 1997, vol.
`86, No. 12, pp. 1352-1357.
`M.J. Kontny et al. "Issues Surrounding MDI Formulation Develop(cid:173)
`ment with Non-CFR Propellants", Journal of Aerosol Medicine, vol.
`4, No. 3, pp. 181-187, 1991.
`LP. Tansey, "Changing to CFC-Free Inhalers: The Technical and
`Clinical Challenges", The Pharmaceutical Journal, 1997, vol. 259,
`pp. 896-898.
`D. Tiwari et al, Compatibility Evaluation of Metered-Dose Inhaler
`Valve Elastomers with Teirafluoroethane (P134a), a Non-CFC Pro(cid:173)
`pellant, Drug Development and Industrial Pharmacy, 1998, vol. 24,
`No. 4, p. 345-354.
`Handbook of Pharmaceutical Excipients, 3rd Ed., Kibbe Editor, pp.
`7-9, 220-222, 234-235 and 560-561, 1994.
`L.I. Harrison et al., "Pharrnacokinetics and dose Proportionality of
`Beclomethasone From Three Strengths of a CFC-Free
`Beclomethasone
`Dipropionate
`metered-Dose
`Inhaler",
`Biopharmaceutics & Drug Disposition, 1997, vol. 18, No. 7, pp.
`635-643.
`Chet Leach, "Enhanced Drug Delivery Through reformulating MD Is
`With HFA Propellants-Drug Deposition and its effect on Preclinical
`and Clinical Programs", Respiratory Drug Delivery V, 1996, pp.
`133-144.
`B. Meakin, "Fine Particle Dose Control of Solution Based pMDis",
`Drug Delivery to the Lungs IX, The Aerosol Society, pp. 1-20. (Dec.
`14 & 15, 1998).
`ABPI Compendium of Data Sheets and Summaries of Product Char(cid:173)
`acteristics, Datapham Publications Limited, London, pp. 81-82,
`(1996-97)
`Paul A. Sanders, Ph.D., "Homogeneous Systems and Their Proper(cid:173)
`ties", Handbook of Aerosol Technology, Second Edition, Van
`Nostrand Reinhold Company, NY, p. 30, 1979.
`G. Brambilla et al., "Modulation of Aerosol Clouds Produced by
`HFA Solution Inhalers", Portable Inhalers, pp. 1559-159, (Nov. 26,
`27, 1998).
`R. 0. Williams, III, et al., European Journal of Pharmaceutics and
`Biopharmaceutics, vol. 44, pp. 195-203 (1997).
`
`2
`
`

`

`US 8,142,763 B2
`
`1
`PRESSURIZED METERED DOSE INHALERS
`(MDI) CONTAINING A SOLUTION
`COMPRISING IPRATROPIUM BROMIDE,
`HFA PROPELLANT, AND CO-SOLVENT AND
`COMPRISING A CONTAINER WITH A
`SPECIFIC INTERNAL SURFACE
`COMPOSITION AND/OR LINING
`
`2
`selected medicaments ipratropium bromide is comprised, for
`which many composition examples are supplied, in which the
`active ingredient is in combination with an organic or inor(cid:173)
`ganic acid.
`W096/32099, W096/32150, W096/32151 and W096/
`32345 disclose metered dose inhalers for the administration
`of different active ingredients in suspension in the propellant,
`wherein the internal surfaces of the inhaler are partially or
`completely coated with one or more fluorocarbon polymers
`1 o optionally in combination with one or more non-fluorocarbon
`polymers.
`Said applications do not however address the technical
`problem of the chemical stability of the active ingredient but
`they rather concern a different problem, namely that of the
`15 adhesion of micronized particles of the suspended active
`ingredient to the internal surfaces of the inhaler, such as the
`can walls, valves and sealings. It is also known from Eur. J.
`Pharm. Biopharm. 1997, 44, 195 that suspensions of drugs in
`HFA propellant are frequently subjected to absorption of the
`20 drug particles on the valves and on the internal walls of the
`inhaler. The properties of an epoxy phenol resin coating of the
`aerosol cans have been studied to circumvent this problem.
`WO 95/17195 describes aerosol compositions comprising
`flunisolide, ethanol and HFA propellants. It is stated in the
`25 document that conventional aerosol canisters can be used to
`contain the composition and that certain containers enhance
`its chemical and physical stability. It is suggested that the
`composition can be preferably contained in vials coated with
`resins such as epoxy resins (e.g. epoxy-phenolic resins and
`epoxy-urea-formaldehyde resins).
`Actually the results reported in Tables 5, 6 and 8 respec(cid:173)
`tively on pages 16 and 19 of the cited application demonstrate
`that flunisolide decomposes only in plastic cans (Table 8), and
`that the percent drug recovery in compositions stored in alu(cid:173)
`minium, glass or epoxy-phenol formaldehyde resin coated
`vials is practically the same (Table 8). In other words there is
`no difference between aluminium, glass type III or epoxy/
`phenol-formaldehyde resin coated aluminium vials coated by
`Cebal. No data are reported for other types of epoxy resins.
`It has now been found that the chemical stability problems
`of active ingredients in solution in HFA propellants can be
`eliminated by storing and delivering said composition
`employing metered-dose inhalers having part or all of their
`internal metallic surfaces consisting of stainless steel, ano-
`45 dised aluminium or lined with an inert organic coating.
`The preferred material for the aerosol cans is anodised
`aluminium.
`In the case of epoxy-phenol resin coating the choice of the
`suitable coating will be opportunely made on the basis of the
`50 characteristics of the active ingredient.
`The most widely used epoxy resins in can coatings are
`produced by the reaction of epichlorohydrin and bisphenol A
`(DGEBPA). Variations in the molecular weight and in the
`polymerisation degree result in resins of different properties.
`Phenoxy resins are other commercially important thermo(cid:173)
`plastic polymers derived from bisphenols and epichlorohy(cid:173)
`drin, characterized in that their molecular weights (MW s) are
`higher, i.e., ca 45000, than those of conventional epoxy res(cid:173)
`ins, i.e., 8000 and lack terminal epoxide functionality.
`Other multifunctional resins are epoxy-phenol-novolac
`and epoxy-cresol-novolac resins obtained by glycidylation of
`the phenol-formaldehyde (novolac) or of the o-cresol-form(cid:173)
`aldehyde ( o-cresol novolac) condensates respectively.
`The inhalers according to the invention effectively prevent
`65 the chemical degradation of the active ingredient.
`Surprisingly and contrary to what reported in the prior art
`with regard to flunisolide, we found a considerable degrada-
`
`The invention relates to the use of pressurised metered dose
`inhalers (MDIS) having part or all of their internal surfaces
`consisting of stainless steel, anodised aluminium or lined
`with an inert organic coating. The invention also relates to
`compositions to be delivered with said MDis.
`Pressurised metered dose inhalers are well known devices
`for administering pharmaceutical products to the respiratory
`tract by inhalation.
`Active materials commonly delivered by inhalation
`include bronchodilators such as B22 agonists and anticholin(cid:173)
`ergics, corticosteroids, anti-leukotrienes, anti-allergies and
`other materials that may be efficiently administered by inha(cid:173)
`lation, thus increasing the therapeutic index and reducing side
`effects of the active material.
`MDI uses a propellant to expel droplets containing the
`pharmaceutical product to the respiratory tract as an aerosol.
`For many years the preferred propellants used in aerosols
`for pharmaceutical use have been a group of chlorofluorocar(cid:173)
`bons which are commonly called Freons or CFCs, such as
`CC13 F (Freon 11 or CFC-11), CC12 F2 (Freon 12 or CFC-12),
`and CClF 2----CClF 2 (Freon 114 or CFC-114 ).
`Recently, the chlorofluorocarbon (CFC) propellants such 30
`as Freon 11 and Freon 12 have been implicated in the destruc(cid:173)
`tion of the ozone layer and their production is being phased
`out.
`Hydrofluoroalkanes [(HFAs) known also as hydro-fluoro(cid:173)
`carbons (HFCs )] contain no chlorine and are considered less 35
`destructive to ozone and these are proposed as substitutes for
`CFCs.
`HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA
`134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have
`been acknowledged to be the best candidates for non-CFC 40
`propellants and a number of medicinal aerosol formulations
`using such HF A propellant systems have been disclosed.
`Many of these applications, in which HFAs are used as
`propellant, propose the addition of one or more of adjuvants
`including compounds acting as co-solvents, surface active
`agents including fluorinated and non-fluorinated surfactants,
`dispersing agents including alkylpolyethoxylates and stabi(cid:173)
`lizers.
`In the international application n°PCT/EP98/03533 filed
`on Oct. 6, 1998 the applicant described solution compositions
`for use in an aerosol inhaler, comprising an active material, a
`propellant containing a hydrofluoroalkane (HFA), a cosol(cid:173)
`vent and further comprising a low volatility component to
`increase the mass median aerodynamic diameter (MMAD) of
`the aerosol particles on actuation of the inhaler.
`Compositions for aerosol administration via MDis can be
`solutions or suspensions. Solution compositions offer several
`advantages: they are convenient to manufacture being com(cid:173)
`pletely dissolved in the propellant vehicle and obviate physi-
`cal stability problems associated with suspension composi- 60
`tions.
`The widespread use of these formulations is limited by
`their chemical instability, causing the formation of degrada(cid:173)
`tion products.
`W094/13262 proposes the use of acids as stabilisers pre(cid:173)
`venting the chemical degradation of the active ingredient in
`aerosol solution formulations comprising HFAs. Among the
`
`55
`
`3
`
`

`

`US 8,142,763 B2
`
`3
`tion of the tested active ingredients when their formulations
`were stored in glass containers type III.
`
`SUMMARY OF THE INVENTION
`
`Pressurised metered dose inhalers for dispensing solution
`of an active ingredient in a hydrofluorocarbon propellant, a
`co-solvent and optionally a low-volatility component charac(cid:173)
`terized in that part or all of the internal surfaces of said
`inhalers consist of stainless steel, anodised aluminium or are
`lined with an inert organic coating.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Pressurised metered dose inhalers are known devices, usu(cid:173)
`ally consisting of a main body or can, acting as a reservoir for
`the aerosol formulation, a cap sealing the main body and a
`metering valve fitted in the cap.
`MD Is are usually made of a conventional material such as
`aluminium, tin plate, glass, plastic and the like.
`According to the invention, part or all of the internal sur(cid:173)
`faces of the inhalers consists of stainless steel, anodised alu(cid:173)
`minium or is lined with an inert organic coating. One of the
`preferred coating consists of epoxy-phenol resin. Any kind of
`stainless steel may be used. Suitable epoxy-phenol resins are
`commercially available.
`Active ingredients which may be used in the aerosol com(cid:173)
`positions to be dispensed with the inhalers of the invention are
`any ingredient which can be administered by inhalation and 30
`which meets problems of chemical stability in solution in
`HFA propellants giving rise to a decomposition when stored
`in conventional materials cans and in particular in aluminium
`cans.
`In the compositions to be delivered with the MDis of the
`invention the hydrofluorocarbon propellant is preferably
`selected from the group of HFA 134a, HFA 227 and mixtures
`thereof.
`The co-solvent is usually an alcohol, preferably ethanol.
`The low volatility component, when present, is selected from 40
`the group of glycols, particularly propylene glycol, polyeth(cid:173)
`ylene glycol and glycerol, alkanols such as decanol (decyl
`alcohol), sugar alcohols including sorbitol, mannitol, lactitol
`and maltitol, glycofural (tetrahydro-furfurylalcohol) and
`dipropylene glycol, vegetable oils, organic acids for example
`saturated carboxylic acids including !auric acid, myristic acid
`and stearic acid; unsaturated carboxylic acids including sor(cid:173)
`bic acid, and especially oleic acid; saccharine, ascorbic acid,
`cyclamic acid, amino acids, or aspartame, esters for example
`ascorbyl palmitate, isopropyl myristate and tocopherol
`esters; alkanes for example dodecane and octadecane; terpe(cid:173)
`nes for example menthol, eucalyptol, limonene; sugars for
`example lactose, glucose, sucrose; polysaccharides for
`example ethyl cellulose, dextran; antioxidants for example
`butylated hydroxytoluene, butylated hydroxyanisole; poly- 55
`meric materials for example polyvinyl alcohol, polyvinyl
`acetate, polyvinyl pyrrolidone; amines for example ethano(cid:173)
`lamine, diethanolamine,
`triethanolamine;
`steroids
`for
`example cholesterol, cholesterol esters. The low-volatility
`component has a vapour pressure at 25° C. lower than 0.1 kPa, 60
`preferably lower than 0.05 kPa.
`The aerosols compositions to be delivered with the pres(cid:173)
`surised MD Is of the invention may contain from 0.2 to 2% by
`weight of said low volatility component.
`Propylene glycol, polyethylene glycol, isopropyl myristate 65
`and glycerol are particularly preferred low-volatility compo-
`nents.
`
`4
`The function of the low volatility component is to modulate
`the MMAD of the aerosol particles. Being used at very low
`concentrations, it does not substantially affect the chemical
`stability of the compositions.
`Examples of active ingredients include: anticholinergics
`such as ipratropium bromide, oxitropium bromide, tiotro(cid:173)
`pium bromide; acetal corticosteroids such as budesonide,
`ciclesonide, rofleponide; chetal corticosteroids such as
`flunisolide, triamcinolone acetonide; other corticosteroids
`10 such as fluticasone propionate, mometasone furoate; short or
`long acting beta-adrenergic agonists such as salbutamol, for(cid:173)
`moterol, salmeterol, TA 2005 and their combinations. The
`active ingredients when possible may be present in racemic
`15 mixtures or in form of a single enantiomer or epimer.
`As said before, WO 94/13262 teaches that problems of
`chemical stability of medicaments and in particular of iprat(cid:173)
`ropium bromide in aerosol solution compositions can be
`solved adding an acid, either an inorganic acid or an organic
`20 acid, to the HFA propellant/cosolvent system.
`Examples of compositions containing ipratropium bro(cid:173)
`mide in HFA 134a/ethanol systems further containing an
`inorganic acid such as hydrochloric, nitric, phosphoric or
`sulfuric acid or an organic acid such as ascorbic or citric acid
`25 are provided.
`We found that in solution compositions comprising iprat(cid:173)
`ropium bromide, a propellant containing a hydrofluoroal(cid:173)
`kane, a cosolvent and further comprising a low volatility
`component:
`a) different decomposition rates occur with different acids:
`for example we found that ipratropium bromide (20 µg/dose)
`in a composition of13% (w/w) ethanol, 1.0% (w/w) glycerol,
`20 µI/can oflN hydrochloric acid and HFA 134a to 12 ml/can
`35 rapidly decomposes and after 3 months storage at 40° C. gives
`85.0% average of drug remaining;
`b) ipratropium bromide with or without acids is stable in
`stainless steel, anodised aluminium or in some types of epoxy
`phenol resin lined cans;
`c) surprisingly certain kinds of materials, such as glass,
`coatings proposed in the prior-art to overcome the physical
`absorption phenomenon of the active ingredient, such as per(cid:173)
`fluoroalkoxyalkanes
`and
`fluorinated-ethylene-propylene
`polyether sulfone resins, or certain kinds of epoxy phenol
`45 coatings turned out to be completely unsatisfactory and inef(cid:173)
`fective in preventing its chemical degradation.
`Another preferred active ingredient for the preparation of
`solution compositions in a HFA/cosolvent system to be dis(cid:173)
`pensed by MD Is according to the present invention is budes-
`50 onide.
`Previously HFA/budesonide compositions have been
`described, in which budesonide is present in suspension in the
`propellant system and the composition further comprises
`additional ingredients such as particular kinds of surfactants
`(EP 504112, WO 93/05765, WO 93/18746, WO 94/21229).
`In WO 98/13031 it is reported that suspension formulations
`ofbudesonide have a propensity to rapidly form coarse floes
`upon dispersion and redispersion which may deleteriously
`affect dosage reproducibility. There is also a tendency for
`budesonide to deposit from suspension onto the walls of the
`container.
`To achieve stable suspensions of particulate budesonide it
`is employed in the prior art a composition containing a mix(cid:173)
`ture of HF A propellants to match the density of the propellant
`mixture to be substantially identical to the density ofbudes(cid:173)
`onide, up to 3% of an adjuvant such as ethanol and small
`amounts of surfactant.
`
`4
`
`

`

`US 8,142,763 B2
`
`6
`HFA 134a to 12 ml/can were distributed in stainless steel,
`anodised aluminium, standard aluminium, glass cans or in
`cans having different internal coatings and were stored at
`various conditions.
`The results are reported in Table 4 and 5.
`The percent drug remaining in the compositions, measured
`by HPLC, shows the favourable effect of stainless steel, ano(cid:173)
`dised aluminium and inert coating on the chemical stability of
`the active ingredient in respect to standard aluminium or glass
`cans. The best results have been obtained with stainless steel,
`anodised aluminium cans and with epoxy-phenol or perfluo(cid:173)
`roalkoxyalkane coatings.
`
`Example 4
`
`A composition containing 48 mg of dexbudesonide (200
`µg/dose), 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA
`134a to 12 ml can was distributed in epoxy-phenol lacquered
`aluminium cans and was stored at 40° C.
`The percent drug remaining in the composition after 8
`months, measured by HPLC, was 95.4% (average value
`referred to two tests).
`The control of the epimeric distribution showed that there
`is no transfer from the 22R to the 22S epimer.
`
`Example 5
`
`10
`
`5
`It is stated in the document that the levels of the adjuvants
`are low to avoid significant solubilization of drug, leading to
`a problem of chemical degradation and particle size increase
`on storage.
`In the solution compositions of the present invention 5
`budesonide is chemically and physically stable.
`The aerosol compositions of the invention distributed in
`inhalers having the internal surfaces consisting of stainless
`steel, anodised aluminium or coated with an inert material
`and preferably with epoxy-phenol resin are stable for long
`periods and do not undergo chemical degradation.
`Also in this case a considerable degradation of the active
`ingredient was noticed when glass containers were used.
`Analogously flunisolide and dexbudesonide (the 22R(cid:173)
`epimer ofbudesonide) solutions in HFA propellant contain(cid:173)
`ing ethanol and a low-volatility component are stable when 15
`stored in inhalers having the internal surfaces consisting of
`anodised aluminium or coated with epoxy-phenol resin. Evi(cid:173)
`dent degradation offlunisolide was noticed when glass con(cid:173)
`tainers were used.
`It has been also found that the low volatility component 20
`may also act as a co-solvent, thus increasing the solubility of
`the drug in the formulation and increasing the physical sta(cid:173)
`bility and/or allowing the possibility to decrease the quantity
`of co-solvent required.
`The following examples further illustrate the invention. In 25
`the examples and tables the different types of epoxy phenol
`resins are indicated with numbers in brackets corresponding
`to:
`(1) Epoxy-phenol lacquered aluminium vials coated by
`Cebal
`(2) Epoxy-phenol lacquered aluminium vials coated by
`Presspart
`(3) Epoxy-phenol lacquered aluminium vials coated by
`Nussbaum & Guhl
`(4) Epoxy-phenol lacquered aluminium vials coated by 35
`Presspart, other than (2)
`
`Example 1
`
`Compositions containing 7.2, 12, 16.8 mg of dexbudes-
`30 onide ( corresponding to 30, 50 and 70 µg/dose respectively),
`ethanol, 0.9 (w/w) PEG 400 or isopropyl myristate (IPM) in
`HFA 227 to 12 ml can was distributed in aluminium anodised
`cans and was stored 70 days at 50° C. The results are reported
`in Table 6.
`The percent drug remaining in the composition measured
`by HPLC shows the favourable effect of anodised aluminium
`cans on the chemical stability of the active ingredient. The
`control of the epimeric distribution showed that there is no
`transfer from the 22R to the 22S epimer.
`
`40
`
`A composition containing 4.8 mg of ipratropium bromide
`(20 µg/dose), 13% (w/w) ethanol, 1.0% (w/w) glycerol and
`HFA 134a to 12 ml/can was distributed in stainless steel,
`anodised aluminium, standard aluminium cans or in cans
`having different internal coatings and were stored at various
`conditions.
`The results are reported in Table 1 and Table 2.
`The percent drug remaining in the composition, measured
`by HPLC, shows that stainless steel and anodised aluminium
`cans as well as epoxy-phenol resins (1 ), (2) and ( 4) coated
`cans are effective in preventing the chemical degradation of 50
`ipratropium bromide, differently from glass cans or other
`tested coatings.
`
`Example 6
`
`The fine particle dose (FPD: weight of particles having an
`45 aerodynamic diameter lower than 4.7 µm) of dexbudesonide
`solution compositions in HFA 134a or HFA 227, prepared
`following the examples 4 and 5, was determined.
`The experiments were performed using the Andersen Cas(cid:173)
`cade Impactor and the data obtained are average values from
`10 shots.
`The results, reported in Table 7 and 8 show that dexbudes(cid:173)
`onide formulations of the invention are characterized by a
`very low dose and a very high fine particle dose.
`The FPD gives a direct measure of the mass of particles
`55 within the specified size range and is closely related to the
`efficacy of the product.
`
`Example 2
`
`The effect of different acids on the chemical stability of the
`composition of Example 1 was studied.
`Citric, ascorbic and hydrochloric acids were added to the
`formulations in the amounts reported in Table 3.
`The stability of the compositions was tested after 1, 2 and 60
`5 months storage at 40° C. in epoxy-phenol resin ( 4) coated
`cans.
`
`Example 3
`
`Compositions containing 12 mg of budesonide (50
`µg/dose), 13% or 15% (w/w) ethanol, 1.3% (w/w) glycerol in
`
`65
`
`Example 7
`
`A compos1t10n containing 60 mg of flunisolide (250
`µg/dose), 15% (w/w) ethanol, 1% (w/w) glycerol in HFA
`134a to 12 ml/can was distributed in anodised aluminium,
`glass cans or in cans having different internal coatings and
`were stored for 41 days at 50° C.
`The results are reported in Table 9.
`The percent drug remaining in the composition, measured
`by HPLC, shows the favourable effect of anodised aluminium
`
`5
`
`

`

`US 8,142,763 B2
`
`7
`and inert coating with epoxy-phenol resins on the chemical
`stability of the active ingredient in respect to glass cans.
`
`Example 8
`
`8
`TABLE 2-continued
`
`Percent ipratropium bromide (IPBr)
`recovered after storing the composition of
`Example 1 for 30 and 60 days at 50° C., or
`for 96 days at 40° C. in cans of different
`types (average values referred to two tests).
`
`% RESIDUAL IPBr
`(% RESIDUAL IPBr RELATIVE TO t ~ 0)
`
`CAN TYPE
`
`Epoxy phenol resin
`(2)
`Epoxy phenol resin
`(3)
`Anodised aluminum
`
`t~o
`
`97.5
`
`98.5
`
`94
`
`Glass type III*
`
`t ~ 30 days
`at50° C.
`
`t ~ 60 days
`at 50° C.
`
`t ~ 96 days
`at 40° C.
`
`90
`(92)
`56.5
`(57.5)
`89
`(95)
`48.5
`(-)
`
`88.5
`(90.5)
`46
`(47)
`87
`(92.5)
`41.5
`(-)
`
`89
`(91)
`52.5
`(53.5)
`90.5
`(96.5)
`47
`(-)
`
`*according to Eur Pharmacopoeia yd Ed Suppl 1999
`
`TABLE3
`
`Percent ipratropium bromide (IPBr)
`recovered after storing the compositions
`of Example 1, witb different acids added,
`in epoxy-phenol (4) coated cans
`(average values referred to two tests)
`
`10
`
`15
`
`The solubility of ipratropium bromide and micronized
`budesonide in ethanol, glycerol and their mixtures has been
`investigated.
`The tests were carried out at room temperature.
`a) Solubility in Ethanol.
`About 8.5 g of absolute ethanol were weighed into a flask.
`The active ingredient (Ipratropium Bromide or Budesonide)
`was added in small amounts, under magnetic stirrer, until no
`further dissolution occurred (i.e.: a saturated solution was
`obtained). The flask was stirred for about 40 minutes, and left
`to settle overnight prior to analysis, to let the system equili(cid:173)
`brate. The flask was kept sealed, to avoid evaporation.
`The solution obtained was then filtered and tested for the
`amount of active ingredient, according to the conventional
`analytical procedure.
`b) Solubility in Ethanol/Glycerol Mixtures.
`The required amounts of ethanol and glycerol were
`weighted into a flask, and mixed by a magnetic stirrer until a
`homogeneous phase was obtained.
`The solubility of ipratropium bromide in ethanol is 42.48 25
`mg/g.
`The solubility data of ipratropium bromide in ethanol/
`glycerol mixtures are listed in Table 10.
`The solubility of micronized budesonide in ethanol is
`31.756 mg/g.
`Solubility data ofmicronized budesonide in ethanol/glyc(cid:173)
`erol mixtures are listed in Table 11.
`The data show that both the tested active ingredients are
`rather soluble in ethanol, and that their solubility increases
`even when small percentages of glycerol are added.
`The increase in solubility is maintained also in presence of
`HFA propellants.
`
`20
`
`30
`
`35
`
`TABLE 1
`
`40
`
`Percent ipratropium bromide (IPBr) recovered
`after storing tbe composition of Example 1
`for 8 montbs at 40° C. in cans of different
`es
`
`CAN TYPE
`
`% RESIDUAL IPBr
`
`45
`
`Epoxy-phenol resin (4)
`Perfluoroalkoxyalkane
`Fluorinated-etbylene-propylene/
`polyetber sulphone (Xylan 8840(R))
`Stainless steel
`Standard aluminium
`
`96
`57
`78
`
`96
`46
`
`TABLE2
`
`Percent ipratropium bromide (IPBr)
`recovered after storing the composition of
`Example 1 for 30 and 60 days at 50° C., or
`for 96 days at 40° C. in cans of different
`types (average values referred to two tests).
`
`Acid
`
`Citric
`
`(0.6%w/w)
`
`(0.3%w/w)
`
`(0.07%w/w)
`
`98
`
`99
`
`99
`
`Ascorbic
`
`119
`
`Hydrochloric
`
`(4µ1-1 N)
`
`(10µ1-1 N)
`
`(20 µ1-1 N)
`
`50
`
`None
`
`101
`
`101
`
`100
`
`97
`
`% RESIDUAL IPBr
`(% RESIDUAL IPBr RELATNE TO t ~ 0)
`
`t ~ 1 montb
`at 40° C.
`
`t ~ 2 montbs
`at40° C.
`
`t ~ 5 montbs
`at40° C.
`
`98
`(100)
`99
`(100)
`98
`(99)
`113
`(95)
`
`100
`(99)
`98
`(97)
`95
`(95)
`97
`(100)
`
`99
`(101)
`100
`(101)
`99
`(100)
`112
`(94)
`
`104
`(102)
`98
`(97)
`98
`(98)
`98