United States Patent [19J
`Mistry et al.
`
`[54] PRESSURIZED AEROSOL INHALATION
`COMPOSITIONS
`
`[75]
`
`Inventors: Suresh N Mistry, Birstall; Mark
`Gibson, Shepshed, both of United
`Kingdom
`
`[73] Assignee: Fisons pie, Suffolk, United Kingdom
`
`[21] Appl. No.: 08/478,338
`
`[22] Filed:
`
`Jun. 7, 1995
`
`Related U.S. Application Data
`
`[63] Continuation of application No. 08/211,229, Aug. 3, 1994,
`abandoned, which is a continuation of application No.
`PCT/GB92/01749, Sep. 23, 1992.
`Foreign Application Priority Data
`
`[30]
`
`Sep. 25, 1991
`Sep. 28, 1991
`Nov. 19, 1991
`Feb. 14, 1992
`
`[GB]
`[GB]
`[GB]
`[GB]
`
`United Kingdom ................... 9120396
`United Kingdom ................... 9120675
`United Kingdom ................... 9124661
`United Kingdom ................... 9203212
`
`Int. Cl.7 ....................................................... A61K 9/12
`[51]
`[52] U.S. Cl. ................................. 424/45; 424/43; 424/46;
`514/937
`[58] Field of Search .................................. 424/45, 46, 43;
`252/305; 514/937
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,025,635
`
`5/1977 Hodson et al. .
`
`I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US006123924A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,123,924
`Sep.26,2000
`
`4,752,466
`4,869,899
`5,225,183
`5,605,674
`5,658,549
`
`6/1988 Saferstein et al. .
`9 /1989 Burghart et al. .
`7/1993 Pusewal et al.
`.......................... 424/45
`2/1997 Pusewal et al.
`.......................... 424/45
`8/1997 Akehurst et al. ......................... 424/45
`
`FOREIGN PATENT DOCUMENTS
`
`8705211
`0372777
`423695
`528270
`86/01405
`87/05210
`87/05211
`8705210
`04011
`91/11173
`
`9/1987 European Pat. Off ..
`6/1990 European Pat. Off ..
`4/1991 European Pat. Off ..
`5 /1972 Switzerland .
`3/1986 WIPO .
`9/1987 WIPO .
`9/1987 WIPO .
`9/1987 WIPO .
`4/1991 WIPO .
`8/1991 WIPO .
`
`OTHER PUBLICATIONS
`
`WO,A,8 705 211 ; Sep. 11, 1987; see the whole document.
`
`Primary Examiner-James M. Spear
`Attorney, Agent, or Firm-Nixon & Vanderhye
`
`[57]
`
`ABSTRACT
`
`Pressurized aerosol inhalation composition consisting essen(cid:173)
`tially of a liquefied hydrofluoroalkane, a powdered medica(cid:173)
`ment dispersible to form a suspension in the liquefied
`hydrofluoroalkane, and polyvinylpyrrolidone present in a
`concentration of 0.00001 to 10% w/w.
`
`16 Claims, No Drawings
`
`Complex Ex. 1003
`
`1
`
`

`

`6,123,924
`
`1
`PRESSURIZED AEROSOL INHALATION
`COMPOSITIONS
`
`This is a Rule 62 continuation of application Ser. No.
`08/211,229, filed Aug. 3, 1994, now abandoned, and a
`continuation of PCT/GB92/01749 filed Sep. 23, 1992.
`This invention relates to pressurised aerosol
`compositions, in particular compositions of inhalation medi(cid:173)
`caments.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`Pressurised aerosols for the administration of
`medicaments, and indeed for other applications, convention(cid:173)
`ally contain one or more liquefied chlorofluorocarbons
`(CFC's) as propellant. Such materials are suitable for use in
`such applications since they have the right vapour pressures
`( or can be mixed in the right proportions to achieve a vapour
`pressure in the right range) and are essentially taste- and
`odour-free.
`In recent years there has been increasing concern about
`the depletion of the ozone layer in the upper atmosphere.
`This is believed to be due to the release into the atmosphere
`of CFC' s and has led to a search for alternative agents for
`use in all applications of CFC's. To this end, aerosols for 25
`many applications are now pressurised using pressurised
`gases such as nitrogen or hydrocarbons. However, such
`propellants are generally not suitable for use in the admin(cid:173)
`istration of inhalation medicaments since they are toxic
`and/or the pressure within the canister falls each time the
`device is used which leads to unreproducible dosing.
`The use of hydrofluorocarbons as aerosol propellants has
`also been suggested. However, considerable difficulties have
`been encountered in finding suspending agents which are
`soluble in hydrofluoroalkanes and capable of stabilising
`medicament suspensions.
`
`30
`
`DESCRIPTION OF THE INVENTION
`
`2
`terised by their weight average molecular weights, viscosity
`average molecular weights or number average molecular
`weights, it is more usual to characterise polymers, in par(cid:173)
`ticular polymers such as polyvinylpyrrolidone, by K values,
`in which K is determined from viscosity measurements
`using the Fikentscher equation (H. Fikentscher,
`Cellusochemie, 1932, 13, 58-64 and 71-74). In particular
`we prefer the polymer to have a K value of from 10 to 150,
`more preferably 15 to 120; Particular K values and ranges
`10 that may be mentioned include 10-14, 15-18, 29-32,
`88-100 and 115-125.
`Suitable polymers containing carboxylic acid ester con(cid:173)
`taining recurring structural units include polyvinylacetate
`and copolymers of vinyl acetate and vinyl pyrrolidone, that
`15 is polyvinylpyrrolidone/vinyl acetate copolymer. We have
`found that polyvinylacetate with a weight average molecular
`weight of 250,000 gives particularly stable suspensions.
`Other polymers that may be mentioned include acrylic
`acid/methacrylic acid ester copolymers, especially those in
`20 which the methyl and ethyl ester groups have been replaced
`with a low content of trimethylammomiumethyl groups,
`preferably at a ratio of 1:20, especially at a ratio of 1:40. We
`have found that such copolymers having a weight average
`molecular weight of 150,000 give stable suspensions.
`The amount of polymer in the composition will depend on
`the active ingredient to be dispersed, its concentration and
`the particular polymer selected. However, in general the
`amount of polymer is from 0.00001 to 10% w/w, more
`preferably 0.001 to 5% w/w and especially 0.001 to 1 % w/w.
`The compositions may, in addition to the polymer, contain
`other excipients, in particular excipients intended to improve
`valve lubrication and excipients to modify flavour. Particular
`lubricants that may be mentioned include polyethoxylated
`35 compounds, especially polyethylene glycol. We prefer poly(cid:173)
`ethylene glycol having a mean molecular weight of from
`200 to 3000, preferably 400 to 2000, eg 1500. Other
`polyethoxylated compounds that may be used as lubricants
`include polysorbates, eg polysorbate 80, and alkyl aryl
`40 polyether alcohols, eg tyloxapol. Other lubricating excipi(cid:173)
`ents that may be mentioned include high molecular weight
`fully halogenated chlorofluorocarbons and esters of medium
`chain fatty acids. The amount of lubricant in the composition
`will depend on the other components of the composition, the
`45 active ingredient, the nature of the valve, etc. In general, we
`prefer a concentration of 0.01 to 4% w/w and more prefer(cid:173)
`ably 0.1 to 2% w/w.
`Flavour modifying excipients that may be added to the
`composition include peppermint oil, menthol, Dentomint
`50 (Dentomint is a tradename), saccharin and saccharin
`sodium. When the flavour modifying excipient is a solid,
`preferably it is micronised. The concentration will depend
`on the individual composition and the flavour modifying
`excipient. In general, we prefer a concentration of 0.005 to
`55 4% w/w; more preferably 0.01 to 1 % w/w.
`By the term 'hydrofluoroalkane' we mean a compound of
`general formula
`
`Surprisingly, we have found that certain polymers are
`both soluble in the aerosol propellants and capable of
`stabilising medicament compositions.
`Thus, according to the invention, we provide a pressurised
`aerosol composition comprising a liquefied
`hydrofluoroalkane, a powdered medicament dispersable
`therein and a polymer soluble in the liquefied
`hydrofluoroalkane, characterised in that the polymer
`includes recurring structural units, the units being selected
`from amide containing units and carboxylic acid ester con(cid:173)
`taining units.
`The polymer may be a homopolymer, that is the polymer
`consists of the same recurring structural units, or it may be
`a copolymer, that is the polymer contains recurring units in
`addition to either amide containing units or carboxylic acid
`ester units. The polymer may also be a copolymer of amide
`contammg units and carboxylic acid ester units. Such
`copolymers may be either block copolymers or random
`copolymers.
`We prefer polymers which include recurring structural
`units containing an amide group. We particularly prefer the
`amide containing unit to be l-ethylene-pyrrolidin-2-one. We
`especially prefer the polymer to be a homopolymer contain(cid:173)
`ing recurring l-ethylene-pyrrolidin-2-one, that is polyvi(cid:173)
`nylpyrrolidone.
`In general, we have found that polyvinylpyrrolidones 65
`having a wide range of average molecular weights give
`acceptable suspensions. Although polymers can be charac-
`
`60 in which x is an integer from 1 to 3, y+z=2x+2 and y and z
`are both at least 1.
`Particular hydrofluoroalkanes of interest are CF3 CFH2
`(Propelant 134a), CH3 CHF2 (Propellant 152a) and
`CF3 CHFCF3 (Propellant 227). We particularly prefer com(cid:173)
`positions including propellant 227.
`In general the vapour pressure of the propellant mixture
`should be in the range suitable and permitted for aerosol
`
`2
`
`

`

`6,123,924
`
`3
`propellants. The vapour pressure may be varied by mixing
`one or more hydrofluoroalkanes and/or some other suitable
`vapour pressure modifying agent in appropriate proportions.
`We prefer the vapour pressure of the mixture to be in the
`range 20 to 100 psig, more preferably 40 to 80 psig, eg about 5
`60 psig.
`In certain case we have found it advantageous to add to
`the compositions excipients capable of increasing the solu(cid:173)
`bility of the polymer or of other excipients, in the propellant.
`In general we have found that the polymers selected have a 10
`solubility in the propellant of at least 0.0001 % w/w, pref(cid:173)
`erably at least 0.001 % w/w, particularly 0.01 % w/w and
`especially 0.1 % w/w. Excipients capable of increasing the
`solubility of the polymer include liquid excipients which are
`more polar than the liquefied propellant, where polarity is 15
`defined in terms of relative Kauri butanol values, as
`described in European patent application O 372 777. Par(cid:173)
`ticular excipients that may be mentioned include alcohols eg
`ethanol and isopropanol. However, in contrast to the teach(cid:173)
`ing of EP O 373 777, we have found that only very small 20
`quantities of such excipients are required. In particular we
`have found that good compositions can be prepared in
`propellant 134a with a polyvinylpyrolidone as polymer with
`a variety of active ingredients and less than 10% w/w,
`preferably less than 5% w/w, more preferably less than 2% 25
`w/w, eg 0.2% w/w ethanol.
`Medicaments which may be dispersed in the propellant
`mixture according to the invention include any medicaments
`which are conventionally administered to the lung and/or
`nose by inhalation of a pressurised aerosol formulation. 30
`Such medicaments include drugs for use in the prophylactic
`or remedial treatment of reversible obstructive airways
`disease, eg drugs such as sodium cromoglycate, nedocromil
`sodium, inhaled steroids, eg beclomethasone dipropionate,
`fluticasone propionate, budesonide and tipredane, and 35
`bronchodilators, eg salbutamol, reproterol, terbutaline,
`formoterol, pirbuterol, isoprenaline, salmeterol, fenoterol
`and salts thereof, ad anticholinergic agents such as ipratro(cid:173)
`pium bromide, oxitropium bromide and atropine and com(cid:173)
`binations of two or more of these agents, eg a combination 40
`of a prophylactic agent with a bronchodilator, eg sodium
`cromoglycate with salbutamol.
`Other medicaments that may be mentioned include
`antihistamines, eg clemastine, pentamidine and salts thereof,
`acetyl-~-methylcholine bromide, peptide hormones such as 45
`insulin and amylin, bradykinin antagonists, PLA2 inhibitors,
`PAF antagonists, lipoxygenase inhibitors, leukotriene
`antagonists, CNS active drugs, such as NMDA antagonists,
`glutamate antagonists, CCK agonists and antagonists; mac(cid:173)
`rolide compounds including FK 506, rapamycin, 50
`cyclosporin and structurally related compounds, vitamins,
`vaccines, eg MMR vaccine and polio vaccine and vectors for
`gene therapy, eg plasmids containing genes intended to
`correct genetic disorders such as cystic fibrosis.
`Where the medicament is intended for delivery to the 55
`lung, it preferably has a particle size distribution such that a
`high proportion of the particles are of a size capable of
`penetrating deep into the lung. In particular, the medicament
`is preferably in a form having a mass median diameter of
`from 0.01 to 10 µm, more preferably from 0.1 to 4 µm, eg 60
`about 2 or 3 µm.
`The amount of medicament in the composition will
`depend on the nature of the active ingredient and the
`condition to be treated. However, the composition prefer(cid:173)
`ably comprises from 0.01 to 15% w/w, preferably from 0.1 65
`to 10% w/w, and most preferably from 0.5 to 5% w/w
`medicament.
`
`4
`According to a further aspect of the invention there is
`provided a method of producing a pressurised aerosol com(cid:173)
`position as herein described, which comprises dispersing the
`powdered medicament and the polymer in the liquefied
`hydrofluoroalkane.
`In particular, the compositions may be produced by cold
`fill or pressure fill techniques. In cold filling, the ingredients
`are placed in a cooled mixing vessel, cooled liquefied
`propellant added and a dispersion produced by vigorous
`stirring. Alternatively, a slurry may be prepared of the
`ingredients in a portion of cooled liquid propellant and the
`remainder of the liquefied propellant added under vigorous
`stirring. Aliquots of the dispersed composition are then filed
`into cooled aerosol cans and sealed with a suitable valve, eg
`a metering valve.
`In pressure filling, the ingredients are placed in a pressure
`vessel, liquefied propellant added under pressure through a
`valve and a dispersion of the ingredients in the liquefied
`dispersed composition are then filled, under pressure,
`through the valve into suitable cans provided with appro(cid:173)
`priate valves, eg metering valves.
`The compositions according to the invention are advan(cid:173)
`tageous in that the solubility of the polymer is such as to
`ensure good dispersion of the medicament and smooth
`operation of the aerosol valve.
`The compositions of the present invention may also be
`advantageous in that they are substantially taste- and odour(cid:173)
`free and have suitable vapour pressures for the administra(cid:173)
`tion of medicaments by inhalation, yet are environmentally
`safe and acceptable, especially when compare with compo(cid:173)
`sitions including chlorofluorocarbons. In addition, they may
`be less irritant than corresponding compositions including
`conventional surfactants such as oleic acid and sorbitan
`trioleate.
`The performance of the compositions according to the
`present invention can be assessed using the following test
`procedures:
`1. Settling times
`A glass bottle containing the composition is gently shaken
`five times and then stood upright. The time interval between
`standing the bottle upright and the first appearance of
`flocculation or separation of powder in the propellant deter(cid:173)
`mined (S 1 ). Timing is continued until complete separation,
`defined as when three lines of standard newspaper print can
`be read through the propellant from the top or bottom,
`depending on whether the active ingredient floats or sinks
`(S 2 ). In some compositions, complete separation does not
`occur. For these compositions, a turbidity factor ranging
`from 1 to 5 is determined, 1 denoting that a small proportion
`of the active ingredient is suspended and 5 denoting that the
`majority of the active ingredient is suspended.
`2. Dispersion Tests
`Dispersion testing on compositions formulated m cans
`having a metering valve can be assessed using a glass
`multistage liquid impinger, eg of the type described by J. H.
`Bell et al, J. Pharm. Sci., 1971, 60(10), 1559.
`3. Lubrication
`The lubricating effects of the composition can be assessed
`by filling the formulation into a can and closing the can with
`a modified metering valve from which the return spring has
`been removed. The stem of the valve is subjected to a
`compression force and the reading recorded in Newtons.
`This gives a measure of the lubricating efficacy of the
`composition.
`4. Dose uniformity
`Dose uniformity is assessed by discharging a metered
`dose aerosol can containing the composition into a filter tube
`
`3
`
`

`

`6,123,924
`
`5
`
`5
`which has sufficient air flowing through it to entrain all the
`dose. The tube is washed out with a suitable solvent and the
`amount of medicament assayed. The medicament entrained
`on the mouthpiece is also washed off and assayed. The
`variation of dose evaluated throughout the life of the can is
`a measure of dose uniformity. In a variation of this test, dose
`uniformity after standing can be assessed by shaking the
`aerosol can, allowing to stand for a predetermined time and
`assessing dose in the manner described above.
`5. Caking potential
`Compositions to be assessed are filled into plastic coated
`glass bottles. The assessment is carried out by allowing the
`samples to be stored for a period of time in order that
`complete sedimentation and compaction of the powder mass
`can take place, eg 3 months. After that period, the glass
`bottles are shaken by gentle twisting of the hand to totally
`invert the bottles. The number of bottle inversions required
`to completely resuspend the drug is noted. The number gives
`a measure of the degree of compaction of the composition.
`Since ease of drug particle redispersion is essential for dose 20
`uniformity, any composition requiring more tan 5 shakes
`suggests possible problems in long-term storage.
`The invention will now be illustrated, but in no way
`limited, by the following Examples.
`
`6
`caprylic/capric/diglyceryl succinate. It has a turbidity point
`below -20° C., is soluble in alcohol, has a viscosity of
`approximately 250 mPa.s and a density of approximately 1.
`Miglyol® 840
`A propylene glycol diester of saturated vegetable fatty
`acids with Cg/Cm chain lengths, classified by the CFTA as
`propyleneglycol dicaprylate/dicaprate. It meets the require(cid:173)
`ments of the German Pharmacopoeia, DAR9, 1st
`supplement, for the monograph "Propyleneglycoloctanoato(cid:173)
`decanoate". It has a turbidity point below -30° C. and is
`10 soluble in 90% ethanol.
`Polyvinylpyrrolidones
`All polyvinylpyrrolidones used were essentially linear
`homopolymers formed by the free radical polymerisation of
`N-vinylpyrrolidone. PVP(K29/31), PVP(K90), PVP(K120),
`15 PVP(C15) and PVP(C30) refer to the polyvinylpyrrolidones
`obtainable from GAF Chemical Corporation and sold under
`the Trade Mark PLASDONE®. PVP/17PF refers to KOL(cid:173)
`LIDON 17PF, a polyvinylpyrrolidone available from BASF
`(KOLLIDON is a registered Trade Mark).
`The manufacturing processes for polyvinylpyrrolidone
`and the other polymers used herein produce polymer mix(cid:173)
`tures containing molecules of unequal chain length and thus
`different molecular weights. Such polymers are usually
`characterised by their K values, in which K is determined
`from viscosity measurements using the Fikentscher equation
`(H. Fikentscher, Cellusochemie, 1932, 13, 58-64 and
`71-74). The polymers can also be characterised by their
`average molecular weights (Mw), viscosity average molecu(cid:173)
`lar weights (Mv) and number average molecular weights (
`Mn).
`3° Characterising data for the polyvinylpyrrolidones used
`were as follows:
`
`25
`
`EXAMPLES
`
`Method
`The required amounts of micronised active ingredient,
`suspending agent and other excipients, were weighed into
`plastic coated glass bottles and crimped with an appropriate
`valve. The desired amount of liquefied propellant was then
`transferred using a transfer button and the contents of the
`bottle sonicated to ensure thorough mixing. Unless other(cid:173)
`wise stated, the fill volume for the bottles was 20 ml.
`
`Materials
`
`Active ingredients
`All active ingredients were micronised. In general, the
`active ingredients were anhydrous, although nedocromil
`sodium and sodium cromoglycate were used in their equi(cid:173)
`librium hydrated form which each contain about 10% w/w
`water at room temperature.
`Polyethyleneglycols (PEG)
`The average molecular weight of the polyethyleneglycol
`used is indicated by the number 200, 400, etc following 45
`PEG.
`Halocarbon oil
`Halocarbon oil is the proprietary name given to a series of
`high molecular weight fully halogenated chlorofluorocar(cid:173)
`bons of chlorotrifluoroethylene telomers obtainable from 50
`Halocarbon Products Corporation, New Jersey, USA.
`Miglyols
`Miglyol® neutral oils
`Miglyol® neutral oils are esters of medium chain fatty
`acids and are sometimes referred to as fractionated coconut
`oils. Miglyol is a trademark of Huls AG. The following oils
`were used.
`Miglyol®810
`A triglyceride of fractionated Cg/Cm coconut oil fatty
`acids classified by the CTFA as caprylic/capric triglyceride. 60
`It meets the requirements of the British Pharmacopoeia 1988
`for the monograph "Fractionated Coconut Oil". It is a low
`viscosity of oil of neutral taste and smell, with a turbidity
`point below 0° C.
`Miglyol® 829
`Aglyceryl ester of fractionated Cg/Cm coconut fatty acids
`linked to succinic acid and is classified by the CTFA as
`
`35
`
`40
`
`55
`
`PVP 17 PF
`K29/32
`K90
`K120
`C15
`C30
`
`K
`
`15 - 18
`29 - 32
`94 ± 6
`120 ± 5
`17 ± 1
`30.5 ± 1
`
`Mw
`
`9000
`
`1,280,000
`2,800,000
`10500
`62500
`
`Mv
`
`63000
`1,450,000
`7000
`3800
`
`Mn
`
`2500
`
`3000
`16500
`
`Polyvinylpyrrolidone/vinylacetate copolymers
`Polyvinylpyrrolidone/vinylacetate copolymers are obtain(cid:173)
`able from GAF Chemical Corporation. The E- and I- series
`of PVPNA copolymers were supplied as 50% solutions in
`ethanol and isopropanol respectively. S-630 refers to the
`white, spray dried polymer of PVP/VA having the charac(cid:173)
`teristics set out below. Characterising data for PVPNA used:
`
`PVP/VA
`
`K value
`
`VP/VA ratio
`
`S-630
`E-535
`1-535
`E-335
`
`30-50
`30-50
`25-35
`25-35
`
`60/40
`50/50
`50/50
`30/70
`
`Acrylic acid/methacrylic acid ester copolymers
`The acrylic acid/methacrylic acid ester copolymers used
`were copolymers synthesized from acrylic and methacrylic
`acid ethyl and methyl esters with a low content of quaternary
`ammonium groups. The molar ratio of these ammonium
`groups to the neutral (meth)acrylic acid esters if 1:40. The
`weight average molecular weight is approximately 150000.
`65 the polymer used was EUDRAGIT RS PM, obtainable from
`Rohn Pharma GmbH. (EUDRAGIT is a registered Trade
`Mark).
`
`4
`
`

`

`6,123,924
`
`8
`
`-continued
`
`b)
`
`1.
`2.
`3.
`4.
`c)
`
`1.
`2.
`
`with 0.5% w/v PVP/VA S-630
`
`Salbutamol sulphate
`Sodium cromoglycate
`Reproterol hydrochloride
`Budesonide
`with 0.1 % w/v PVP(17PF)
`
`Terbutaline sulphate
`Fenoterol hydrobromide
`
`4 mg/ml
`50 mg/ml
`10 mg/ml
`4 mg/ml
`
`5 mg/ml
`4 mg/ml
`
`D. Compositions contammg acrylic acid/methacrylic acid
`ester copolymers and propellant 227
`The following active ingredients were formulated at the
`concentration shown with 0.1 % w/v EUDRAGIT RS
`(EUDRAGIT is a Trade Mark of Rohn Pharma GmbH) in
`propellant 227.
`
`a)
`
`1. Terbutaline
`2. Beclomethasone dipropionate
`3. Salbutamol sulphate
`4. Fluticasone
`5. Reproterol hydrochloride
`6. Fenoterol
`7. Sodium cromoglycate
`8.
`Ipratropium bromide
`9. Clemastine
`10. Acetyl-13-methylcholine bromide
`compositions including 0.5% w/w PEG 600
`
`11. Beclomethasone dipropionate
`12. Sodium cromoglycate
`13. Reproterol hydrochloride
`14. Fenoterol hydrobromide
`
`5 mg/ml
`5 mg/ml
`4mg/ml
`4mg/ml
`10 mg/ml
`4mg/ml
`10 mg/ml
`0.8 mg/ml
`4mg/ml
`10 mg/ml
`
`5 mg/ml
`50 mg/ml
`10 mg/ml
`4mg/ml
`
`30
`
`b)
`
`7
`
`Polyvinylacetate
`The polyvinylacetate used had a weight average molecu(cid:173)
`lar weight of about 26,000.
`A Compositions containing polyvinylpyrrolidone and pro-
`pellant 227
`The following active ingredients were formulated at the
`concentration shown with PVP in propellant 227 PLAS(cid:173)
`DONE C30 (PLASDONE is a registered Trade Mark of
`GAF Chemicals Corporation).
`
`a)
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`10.
`11.
`12.
`13.
`b)
`
`1.
`2.
`3.
`c)
`
`1.
`
`with 0.05% w/w PVP(C-30)
`
`Terbutaline sulphate
`Beclomethasone dipropionate
`Salbutamol sulphate
`Fluticasone propionate
`Reproterol hydrochloride
`Fenoterol hydrobromide
`Sodium cromoglycate
`Sodium cromoglycate
`Ipratropium bromide
`Pentamidine isoethionate
`Clemastine
`Acetyl-13-methylcholine bromide
`Budesonide
`with 0.1 % w/v PVP(17PF)
`
`Fenoterol hydrobromide
`Terbutaline sulphate
`Salbutamol sulphate
`with 0.025% w/v PVP(C30)
`
`Tipredane
`
`5 mg/ml
`5 mg/ml
`4mg/ml
`4mg/ml
`10 mg/ml
`4mg/ml
`10 mg/ml
`50 mg/ml
`0.8 mg/ml
`4mg/ml
`4mg/ml
`10 mg/ml
`4mg/ml
`
`4mg/ml
`5 mg/ml
`4mg/ml
`
`10 mg/ml
`
`B. Compositions contammg polyvinylpryyolidone/vinyl
`acetate copolymer in propellant 227
`The following active ingredients were formulated in pro(cid:173)
`pellant 227 at the concentrations shown.
`
`a)
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`10.
`11.
`b)
`
`1.
`
`with 0.05% w/v PVP/VA S-630
`
`Terbutaline sulphate
`Beclomethasone dipropionate
`Salbutamol sulphate
`Fluticasone propionate
`Reproterol hydrochloride
`Fenoterol hydrobromide
`Sodium cromoglycate
`Sodium cromoglycate
`Ipratropium bromide
`Acetyl-13-methylcholine bromide
`Budesonide
`with 0.025% w/v PVP/VA S-630
`
`Tipredane
`
`5 mg/ml
`5 mg/ml
`4mg/ml
`4mg/ml
`10 mg/ml
`4mg/ml
`10 mg/ml
`50 mg/ml
`0.8 mg/ml
`10 mg/ml
`4mg/ml
`
`10 mg/ml
`
`5
`
`10
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`C. Compositions containing PVP or PVP NA, propellant 227 55
`and polyethylene glycol
`The following active ingredients were formulated in pro(cid:173)
`pellant 227 at the concentration shown with 0.5% w/v
`PEG600.
`
`a)
`
`1.
`2.
`3.
`
`with 0.05% w/v PVP(C30)
`
`Salbutamol sulphate
`Sodium cromoglycate
`Reproterol hydrochloride
`
`4mg/ml
`50 mg/ml
`10 mg/ml
`
`60
`
`65
`
`E. Compositions in propellant 134a
`The following active ingredients were formulated at the
`concentration shown in propellant 134a.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`Tipredane
`PVP(C30)
`ethanol
`Tipredane
`PVP(C30)
`ethanol
`Nedocromil sodium
`PVP(C30)
`ethanol
`Nedocromil sodium
`PVP(C30)
`ethanol
`Tipredane
`PVP/VA S-630
`ethanol
`Tipredane
`PVP(C30)
`ethanol
`Tipredane
`PVP(C30)
`ethanol
`Nedocromil sodium
`PVP/VA S-630
`ethanol
`Nedocromil sodium
`PVP/C30
`ethanol
`Nedocromil sodium
`PVP(C30)
`ethanol
`Tipredane
`
`10 mg/ml
`0.1% w/w
`5.0% w/w
`10 mg/ml
`0.1% w/w
`10.0% w/w
`20 mg/ml
`0.1% w/w
`5.0% w/w
`20 mg/ml
`0.1% w/w
`10.0% w/w
`10 mg/ml
`0.1% w/w
`5.0% w/w
`10 mg/ml
`0.25% w/w
`5.0% w/w
`10 mg/ml
`0.5% w/w
`5.0% w/w
`20 mg/ml
`0.1% w/w
`5.0% w/w
`20 mg/ml
`0.25% w/w
`5.0% w/w
`20 mg/ml
`0.5% w/w
`5.0% w/w
`10 mg/ml
`
`5
`
`

`

`6,123,924
`
`9
`
`-continued
`
`PVP(C30)
`PEG 600
`ethanol
`Tipredane
`PVP(C30)
`PEG 600
`ethanol
`Nedocromil sodium
`PVP(C30)
`PEG 600
`ethanol
`Nedocromil sodium
`PVP(C30)
`PEG 600
`ethanol
`Nedocromil sodium
`PVP(C30)
`PEG 600
`ethanol
`Beclomethasone
`dipropionate
`PVP/VA S-630
`ethanol
`Beclomethasone
`dipropionate
`PVP/VA S-630
`ethanol
`Beclomethasone
`dipropionate
`PVP(C30)
`ethanol
`
`0.1% w/w
`0.5% w/w
`5.0% w/w
`10 mg/ml
`0.1% w/w
`0.5% w/w
`10.0% w/w
`20 mg/ml
`0.1% w/w
`0.5% w/w
`5.0% w/w
`20 mg/ml
`0.1% w/w
`0.5% w/w
`10.0% w/w
`20 mg/ml
`0.05% w/w
`0.5% w/w
`0.2% w/w
`5 mg/ml
`
`0.1% w/w
`2.0% w/w
`5 mg/ml
`
`0.1% w/w
`5.0% w/w
`5 mg/ml
`
`0.1% w/w
`5.0% w/w
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`F. Compositions containing polyvinylacetate
`
`a)
`
`1.
`
`2.
`
`b)
`
`1.
`
`2.
`
`in propellant 134a
`
`Tipredane
`Polyvinylacetate
`Nedocromil sodium
`Polyvinylacetate
`in propellant 227
`
`Tipredane
`Polyvinylacetate
`Nedocromil sodium
`Polyvinylacetate
`
`10 mg/ml
`0.042% w/w
`20 mg/ml
`0.042% w/w
`
`10 mg/ml
`0.035% w/w
`20 mg/ml
`0.035% w/w
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`G. Compositions using polyvinylpyrrolidone of different K
`values
`
`The following active ingredients were formulated in pro(cid:173)
`pellant 227 at the concentrations shown, with 0.1 % w/w 50
`polyvinylpyrrolidone having the K value shown:
`
`a)
`
`1.
`2.
`3.
`4.
`5.
`b)
`
`1.
`2.
`e)
`
`1.
`2.
`
`PVP(K29/32)
`
`Tipredane
`Nedocromil sodium
`Sodium cromoglycate
`Reproterol hydrochloride
`Salbutamol sulphate
`PVP(K90)
`
`Tipredane
`Nedocromil sodium
`PVP(K120)
`
`Tipredane
`Nedocromil sodium
`
`10 mg/ml
`20 mg/ml
`20 mg/ml
`4 mg/ml
`4 mg/ml
`
`10 mg/ml
`20 mg/ml
`
`10 mg/ml
`20 mg/ml
`
`55
`
`60
`
`65
`
`10
`
`-continued
`
`PVP(C15)
`
`Tipredane
`Nedocromil sodium
`
`10 mg/ml
`20 mg/ml
`
`d)
`
`1.
`2.
`
`H. Compositions using polyvinylpyrrolidone/vinylacetate
`copolymers of different vinylpyrrolidone/vinylacetate ratios
`Tipredane and nedocromil sodium were formulated in
`propellant 227 at the concentrations shown, with 0.1 % w/w
`PVP/VA having the vinylpyrrolidone/vinylacetate ratio
`shown.
`
`a) Nedocromil sodium 20 mg/ml
`
`1.
`2.
`3.
`b) Tipredane 10 mg/ml
`
`PVP/VA E-535
`PVP/VA I-535
`PVP/VA E-335
`
`1.
`2.
`3.
`
`PVP/VA E-535
`PVP/VA I-535
`PVP/VA E-335
`
`(50/50)
`(50/50)
`(30/70)
`
`(50/50)
`(50/50)
`(30/70)
`
`I. Further tipredane formulations
`
`Tipredane
`(mg/ml)
`
`PVP/VA S-630
`%w/w
`
`PVP/C30
`%w/w
`
`Ex
`
`Propellant
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`
`4
`4
`4
`4
`10
`10
`10
`10
`30
`30
`30
`30
`4
`4
`4
`4
`10
`10
`10
`10
`30
`30
`30
`30
`4
`4
`4
`4
`10
`10
`10
`10
`30
`30
`30
`30
`4
`4
`4
`4
`10
`10
`
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`227
`227
`227
`227
`227
`227
`227
`227
`227
`227
`227
`227
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`134a
`227
`227
`227
`227
`227
`227
`
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`0.0025
`0.01
`
`6
`
`

`

`6,123,924
`
`12
`
`What is claimed is:
`1. A pressurized aerosol inhalation composition consisting
`essentially of:
`
`11
`
`-continued
`
`Tipredane
`(mg/ml)
`
`PVP/VA S-630
`%w/w
`
`PVP/C30
`%w/w
`
`Propellant
`
`10
`10
`30
`30
`30
`30
`
`0.025
`0.05
`0.0025
`0.01
`0.025
`0.05
`
`227
`227
`227
`227
`227
`227
`
`Ex
`
`43
`44
`45
`46
`47
`48
`
`J. Compositions containing flavouring agents
`The following compositions were made up in propellant
`227, with 0.1 % w/w PVPNA S-630.
`
`1.
`
`2.
`
`3.
`
`Nedocromil sodium
`peppermint oil
`Nedocromil sodium
`menthol
`saccharin
`Tipredane
`menthol
`saccharin
`
`20 mg/ml
`0.1% w/w
`20 mg/ml
`0.05% w/w
`0.03% w/w
`10 mg/ml
`0.05% w/w
`0.03% w/w
`
`K. Compositions containing additional excipients
`The following composition was made up in propellant
`227, to examine the effects of different excipients as valve
`lubricants.
`
`a)
`
`b)
`
`c)
`
`d)
`
`Nedocromil sodium
`PVP/C30
`Lubricant
`Menthol
`Saccharin, micronised
`Lubricants:
`PEG 200
`PEG 400
`PEG 600
`PEG 1000
`Miglyol 810
`Miglyol 829
`Miglyol 840
`Ethyl oleate
`Halocarbon oil 27
`Tyloxapol
`Polysorbate 80
`Nedocromil sodium
`PVP (C30)
`PEG 1500
`Menthol
`Saccharin, micronised
`Tipredane
`PVP (C30)
`Lubricant
`Lubricants: PEG 600
`PEG 1000
`Tipredane
`PVP (C30)
`Lubricant
`Lubricants: PEG 600
`PEG 1000
`PEG 1500
`
`20 mg/ml
`0.1% w/w
`0.5% w/w
`0.05% w/w
`0.03% w/w
`
`20 mg/ml
`0.10% w/w
`0.20% w/w
`0.05% w/w
`0.03% w/w
`10.0 mg/ml
`0.10% w/w
`0.50% w/w
`
`10.0 mg/ml
`0.10% w/w
`0.20% w/w
`
`5
`
`10
`
`15
`
`a liquefied hydrofluoroalkane;
`a powdered medicament dispersible to form a suspension
`in the liquefied hydrofluoroalkane; and
`polyvinylpyrrolidone present in a concentration of
`0.00001 to 10% w/w.
`2. A composition according to claim 1, wherein the
`medicament is selected from the group consisting of one or
`more of terbutaline sulphate, beclomethasone dipropionate,
`salbutamol sulphate, fluticasone pripionate, reproterol
`hydrochloride, fenoterol hydrobromide, sodium
`cromoglycate, nedocromil sodium, tipredane, pentamidine
`isoethionate, clemastine, acetyl-~-methylcholine bromide
`and budesonide.
`3. A process for the preparation of a composition accord(cid:173)
`ing to claim 1, which comprises dispersing the powdered
`medicament and the polyvinylpyrrolidone in the liquefied
`hydrofluoroalkane.
`4. A composition according to claim 1, wherein the
`powdered medicament has a mass median diameter of 0.01
`25 to 10 µm.
`5.