(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I IIIII IIIIIIII II IIIIII IIIII IIII I II Ill lllll lllll lllll lllll llll 1111111111111111111
`
`(43) International Publication Date
`17 January 2002 (17.01.2002)
`
`PCT
`
`(10) International Publication Number
`WO 02/03958 Al
`
`(51) International Patent Classification 7:
`9/72, 47/24
`
`A61K 9/12,
`
`(21) International Application Number:
`
`PCT/SEOl/01606
`
`(22) International Filing Date:
`
`10 July 2001 (10.07.2001)
`
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, L:I', LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA,
`zw.
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`0016876.5
`
`English
`
`English
`
`11 July 2000 (11.07.2000) GB
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, Cl, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for all designated States except US): AS(cid:173)
`TRAZENECA AB [SE/SE]; S-151 85 Sodertlilje (SE).
`
`Declaration under Rule 4.17:
`ofinventorship (Rule 4.17(iv)).for US only
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): ROGUEDA, Philippe
`[FR/GB]; AstraZeneca R & D Cham wood, Bakewell Road,
`Loughborough LEl 1 5RH (GB).
`
`(74) Agent: ASTRAZENECA AB; Global Intellectual Prop(cid:173)
`erty, S-151 85 Sodertalje (SE).
`
`Published:
`with international search report
`be.fore the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`
`For two-letter codes and other abbreviations, re.fer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`---iiiiiiiiiii
`iiiiiiiiiii == -iiiiiiiiiii ---== -
`
`iiiiiiiiiii
`
`iiiiiiiiiii -
`
`"' 0-,,
`~
`=-----------------------------------------
`--...
`N (54) Title: NOVEL AEROSOL FORMULATION CONTAINI'NG A POLAR FLUORINATED MOLECULE
`= 0 (57) Abstract: The present invention relates to a stable pharmaceutical aerosol formulation intended for inhalation. The formulation
`> contains an active substance, an aerosol propellant, a polar flurorinated molecule and an excipient. The preferred propellant is 1IFA
`
`;;-,- 134a or HFA 227 or a mixture thereof.
`
`Complex Ex. 1004
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`WO 02/03958
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`PCT/SEOl/01606
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`NOVEL AEROSOL FORMULATION CONTAINING A POLAR FLUORINATED MOLECULE
`
`The present invention relates to a pharmaceutical aerosol formulation for the
`administration of a pharmaceutically active substance by inhalation.
`
`5
`
`Pressurised metered dose inhalers (pMDI's) are known in the art. Long standing problems
`with pMDI's containing suspension formulations include creaming of the suspension,
`coarse drug suspension, drug :flocculation and adhesion to dispensing device.
`
`10
`
`It has now surprisingly been found that these problems can be overcome with a novel
`pharmaceutical formulation containing a polar fluorinated molecule in conjunction with a
`suitable excipient. The formulations of the invention give rise to improved aerosol drug
`suspension characteristics, i.e. increase of phase separation times ( creaming or
`sedimentation), production of a finer suspension, reduction of particles adhesion to the can
`15 walls and inhibition of particle :flocculation.
`
`In a first aspect the invention therefore provides a pharmaceutical formulation comprising a
`drug, an aerosol propellant, a polar :fluorinated molecule and an excipient soluble in the
`polar fluorinated molecule.
`
`Suitable drugs which can be used in the formulation of the invention include all drugs that
`can be administered via the inhalation route, for example steroids, peptides,
`oligonucleotides, small organic moecules etc., in particular those administered via a pMDI.
`Such drugs, which are not limited to those for treating respiratory diseases, include those
`suitable for administration by nasal delivery and nebulised delivery.
`
`In preferred embodiements, the invention provides stable dispersion for the pulmonary or
`nasal delivery of one or more bioactive molecules, for local or systemic administration,
`comprising a fluorinated molecule and an excipient in a propellant or propellant mixture.
`
`The biocative agent may be selected from any therapeutic or diagnostic agent. For
`example it may be from the group of antiallergics, bronchodilators, bronchoconsitrictors,
`pulmonary lung surfactants, analgesics, antibiotics, leukotrine inhibitors or antagonists,
`anticholinergics, mast cell inhibitors, antihistamines, antiin:flammatories, antineoplastics,
`anaesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids,
`genetic material, viral vectors, antisense agents, proteins, peptides and combinations
`thereof.
`
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`Examples of specific drugs which can be formulated according to the invention include
`mometasone, ipratropium bromide, tiotropium and salts thereof, salemeterol, fluticasone
`propionate, beclomethasone dipropienate, reproterol, clenbuterol, rofleponide and salts,
`nedocromil, sodium cromoglycate, flunisolide, budesonide, formoterol fumarate dihydrate,
`Symbicort™ (budesonide and formoterol), Viozan™, 3-[2-(4-hydroxy-2-oxo-3H-l,3-
`benzothiazol-7-yl)ethylamino ]-N-[2-[2-( 4-
`. methylphenyl)ethoxy)ethyl]propansulphonamide, terbutaline, terbutaline sulphate,
`salbutamol base and sulphate, fenoterol, 3-[2-(4-Hydroxy-2-oxo-3H-l,3-benzothiazol-7-
`yl)ethylamino ]-N-[2-[2-( 4-methylphenyl)ethoxy] ethyl]propanesulphonamide,
`hydrochloride. All of the above compounds can be in free base form or as
`pharmaceutically acceptable salts as known in the art.
`
`Suitable aerosol propellants include those known in the art such as hydrofluoroalkane
`propellants including 1,1,1,2-tetrafluorethane (P134a) or l,l,l,2,3,3,3-heptafluoropropane
`(P227). Preferred propellants include PI34a or P227 or a mixture of Pl34a and P227, in
`particular a density-matched mixture of the two.
`
`Suitable polar fluorinated molecules include those commercially available from companies
`such as Apollo chemicals and Fluorochem. Preferably the polar fluorinated molecules are
`pharmaceutically acceptable and are non-toxic and non-irritant. Suitable polar fluorinated
`molecules must be miscible in sufficient quantity in the propellant and to be able to
`solubilise the excipient. The fluorinated molecules are preferably liquid at room
`temperature, although solids are also possible. Preferably the polar fluorinated molecules
`are linear, more preferably with a short carbon chain. Most preferably the polar
`fluorinated molecules have oxygen functionality, i.e. contain an oxygen containing group
`including fluorinated alcohols, ethers, carboxylic acid, esters, aldehydes and ketones,
`amines and their mixtures, and any other fluorinated compounds with oxygen based
`functional groups.
`
`Suitable examples of polar fluorinated _molecules include:
`n Butyl Pentafluoropropionate, Ethyl Perfluoro n-Dodecanoate, Fluorinert (FC-75),
`2,2,3,3,3 Pentafluoropropyl Methyl Ether, Methyl Perfluorodecanoate, 2H Perfluoro-
`5,8, 11.:Trimethyl-3,6,9, 12-Tetrafluoropropylether, Fluorad (FC-430), 1, 1,2,2,
`Tetrafluoroethyl 2,2,3,3 Tetrafluoropropylether, 1H,1H,2H,2H Perfluorooctan-1-ol, 4,4,4
`Trifluorobutan-1-ol, Fomblin (MF 402), Fomblin (ZDOL), Perfluoroheptanoic Anhydride,
`Methyl Perfluoro 2,5,8,11-Tetramethyl 3,6,9,12, Tetraoxapentadecanoate, N,N-Diethyl-
`2,3,3,3 Tetrafluoropropionamide, Ethyl 1 lH-Perfluoroundecanoate, 1H,1H,2H,3H,3H
`Perfluoro-1,2-N onandiol, lH, 1 H, Perfluorononan-1-ol,
`
`5
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`
`s
`
`Aflunox (606, 1406, 2507, 6008, 14013), Allyl Heptafluorobutyrate, Allyl
`Heptafluoroisopropyl Ether, Ally! 1,1,2,3,3,3-Hexafluoropropyl Ether, Allyl
`Perfluoroheptanoate, Allyl Perfluorooctanoate, Allyl lH,lH Perfluorooctyl Ether, Allyl
`Perfluoropentanoate, 4-Amino-2,2-Difluorobutyric Acid, 2-Amino-3-Fluorobutyric Acid,
`4-Amino-2-Fluorobutyric Acid, 2-Amino-4-Iminoheptafluoropent-2-ene, 2-Amino-4,4,4-
`Trifluorobutyric Acid, 3-Amino-4,4,4-Trifluorobutyric Acid, 1,1-
`Bis( diethylamino )tetrafluoro-1-Propene, Bis(heptafluoroisopropyl)ketone,
`Bis(hexafluoroisopropyl)maleate, Bis(hexafluoroisopropyl)itaconate, Bis[2-iodo-3-
`(perfluorooctyl)propyladipate, Bis(pefluorooctyl)itaconate, Bis(perfluorooctyl)maleate,
`10 Bis(2,2,2-trifluoroethyl)itaconate, Bis(2,2,2-trifluoroethyl)maleate, lH,IH-2,5-
`Bis( trifluoromethyl)-3, 6-Dioxaundecafluorononanol, 3 ,3-Bis( trifluoromethyl)-3-
`Hydroxypropionic Acid, 2,2 Bis (trifluoromethyl) Propionic Acid, n-Butyl-1,1,2,2-
`Tetrafluoroethyl Ether, n-Butyl Trifluoroacetate, tert-Butyl Trifluoroacetate,
`l,l,l,5,5,6,6,7,7,7-,Decafluoro-2,4-Heptanedione, 1H,1H,6H-Decfluorohexan-1-ol, 2H,3H-
`·1s Decafluoropemtane, Diethyl Difluoromalonate, 2,2-Difluoroethanol, 2,2-Difluoroethyl
`acetate, 2,2-Difluoroethyalamine, DL-4,4-Difluoroglutamic acid, 2,2-Difluoromalonamide,
`Difluoromethyl, 2,2,3,3,3-Pentafluoropropyl Ether, Dif~.uoromethyl 2,2,2-Trifluoroethyl
`Ether, Difluoromethy 2,2,2-Trifluoroethyl Ether, 1,3-Difluoro-2-propanol, Dimethyl,
`Hexafluoroglutarate, Dimethyl Octafluoroadipate, Dimethyl Perfluoroazelate, Dimethyl
`Perfluoro-1, 10-decanedicarboxylate, Dimethyl Perfluorosebacate, Dimethyl
`Perfluorosuberate, Dimethyl Tetrafluorosuccinate, Dimethyl 2,2,2-Trifluoropropionyl
`Carbinol, 4-Ethoxy-1, 1,2-Trifluorobut-1-ene, Ethyl 3-Amino-4,4,4-trifluorocrotonate,
`Ethyl Ethoxymethylene-3-oxo-4,4,4-trifluorobutyrate, Ethyl 4-Fluoro-3-methyl-2-
`pentenoate, Ethyl 2-Fluoropropionate, Ethyl Heptafluorobutyrate, Ethyl
`2s Heptafluorobutyrylacetate, Ethyl 3-Hydroxy-4,4,4-trifluorobutyrate, Ethyl 2-Methyl-3-
`hydroxy-4,4,4-trifluorobutyrate, Ethyl Pentafluoropropionate, Ethyl Perfluoroheptanoate,
`Ethyl Perfluoro-n-dodecanoate including all compounds like CnF2n+lC02CH2CH3, n= 4
`to 16 ( some H substitution possible in the CF .chain, and double bonds), Ethyl Perfluoro-n(cid:173)
`dodecanoate, Ethyl 7H-Perfluoroheptanoate, Ethyl Perfluorononanoate, Ethyl 9H-
`Perfluorononanoate, Ethyl Perfluorooctanoate, Ethyl Perfluoropentanoate, Ethyl 5H(cid:173)
`Perfluoropentanoate, Ethyl 1 lH-Perfluoroundecanoate, Ethyl 1,1,2,2-Terafluoroethyl
`Ether, Ethyl 4,4,4-Trifluorobutyrate, Ethyl 3-(Trifluoromethyl)crotonate, Ethyl 4,4,4-
`Trifluoro-3-(trifluoromethyl)crotonate, Fluorinert (FC40, FC430, FC70, FC71, FC72,
`FC77, FC84, FC87, FCI04, FC6001, FC6003), DL-2-Fluoro-3-alanine, 2-Fluoroethanol,
`35 D-Erytbro-4-Fluoroglutamic Acid, 2-Fluoroethyl Methacrylate, DL-4-Fluoroglutamic
`Acid, L-Erytbro-4-Fluoroglutamic Acid, D-Tbreo-4-Fluoroglutamic Acid, DL-Tbreo-4,
`Fluoroglutamic Acid, L-Threo-4-Fluoroglutamic Acid, DL-Erythro-4-Fluoroflutamine, L-.
`Erythro-4-Fluoroglutamine, DL-Tbreo-4-Fluoroglutamine, DL-Erytbro-4-
`
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`Fluoroisoglutamine, L-Erythro-4-Fluoroisoglutamine, DL-Threo-4-F~uoroisoglutamine, 3-
`Fluoro-DL-N orleucine, Flutec (PPl, PP2, PP3, PP9, PPIO, PPl l, PP25, PP50), Fomblin
`(M, Y (L-Vac), Y (H-Vac), Z15, MF402, ZDOL), Galden (HT70, HT85, HT90, HTIOO,
`HTl 10, HT135, HT200, HT230, HT250, HT270), lH,lH Heptafluorobutan-1-ol, lH,lH-
`s Heptafluorobutyl Acetate, Heptafluorobutyramide, Heptafluorobutyric Acid,
`Heptafluorobutyric Anhydride, 4,4,5,5,6,6,6-Heptafluorohexanoic Acid, 4,4,5,5,6,6,6-
`Heptafluorohexan-l-ol, 4,4,5,5,6,6,6-Heptafluorohex-2-en-1-ol, Heptafluorosiopropyl
`Methyl Ether, l,1,l,3,5,5,5-Heptafluoropentane-2,4-dione, Heptafluoropenta-2-ol, 2-
`Heptafluoropropoxy-2,3 ,3,3-tetrafluoropropan-l-ol, Heptafluoropropyl Methyl Ether,
`10 Heptafluoropropyl 1,2,2,2-tetrafluoroethyl Ether, Heptafluoropropyl Trifluorovinyl Ether,
`2,2,3,4,4,4-Hexafluorobutan-1-ol, 2,2,3,3,4,4-Hexafluorobutan-l-ol, 2,2,3,4,4,4,
`Hexafluorobutyl Difluoromethyl Ether, 2,2,3,4,4,4-Hexafluorobutyl Methacrylate,
`Hexafluoroglutaramide, Hexafluoroglutaric Acid, Hexafluoroisopropanol, l,l,1,3,3,3-
`Hexafluoroisopropyl Acrylate, mono-Hexafluoroisopropyl Itaconate, mo.no-
`1s Hexafluo!oisopropyl Maleate, 1, 1, 1,3,3,3-Hexafluoroisopropyl methacrylate,
`Hexafluoroisopropyl Methyl Ether, Hexafluoroisopropylurethane-N-ethyl Methacrylate,
`Hexafluoroleucine, Hexafluoro-2-methylisopropanol; Hexafluoro-1,5-pentanediol,
`3,3,4,5,5,5-Hexafluoropentan-2-ol, l,l,2,3,3,3-Hexafluoropropyl Ethyl Ether, l,1,2,3,3,3-
`Hexafluoropropyl Methyl Ether, 4,4,4,6,6, 6-Hexafluoro-4-( trifluoromethyl)hexan-1-ol,
`4,5,5,6,6,6-Hexafluoro4-(trifluoromethyl) hex-2-enoic Acid, 4,5,5,6,6,6-Hexafluoro-4-
`(tri:fluoromethyl) hex-2-en-1-ol, Hexa:fluoro-DL-valine, Isopropyl Trifluoroacetate, N,
`Methylbis(hepta:fluorobutyramide ), Methyl Heptafluorobutyrate, Methyl
`Hepta:fluoropropyl Ketone, Methyl 2,2,3,3,4,4-hexa:fluorobutyrate, Methyl 2-hydroxy-2-
`( tri:fluoromethyl)pen-4-enoate, N-Methyl-N, methoxytrifluoroacetamide, Methyl
`2s Nonafluorobutyl Ether, Methyl Nonafluorobutyl Ketone, Methyl 2,2,3,3,4,4,5,5-
`octafluoropentanoate, Methyl Pentafluorobut-3-enoate, Methyl Pentafluoropropionate,
`Methyl Pentafluoropropionylacetate, Methyl Perfluorodecanoate, Methyl
`Perfluorododecanoate, Methyl Perfluoroheptanoate, Methyl 7H-Perfluoroheptanoate,
`Methy Per:fluorohexadecanoate, Methyl Perfluoro(2-methyl-3-oxahexanoate), Methyl
`Perfluorononanoate, Methyl Perfluorooctadecanoate, Methyl Perfluoropentadecanoate,
`Methyl Perfluorotetradecanoate, Methyl Perfluoro-2,5,8, 1 l-tetramethyl-3,6,9, 12-
`tetraoxapentadecanoate, Methyl Perfluorotridecanoate, Methyl Perfluoroundecanoate,
`Methyl 2,3,3,3-Tetrafluoropropionate, Methyl Trifluoroacetate, Methyl 4,4,4-
`trifluoroacetoacetate, 2-Methyl-4,4,4-trifluorobutanol, Methyl 4,4,4,-trifluorocrotonate,
`.Methyl 2-(trifluoromethyl), 3,3,3-trifluoropropionate, Methyl Trifluoropropenoate, Methyl
`Trifluoropyruvate, (Nonafluoro-n-butyl)epoxide, 2-(Nonafluorobutyl)ethyl acrylate, 2-
`(Nonafluorobutyl)ethyl methacrylate, 6-(nonafluorobutyl)hexanol, 3-(Nonafluorobutyl)-2~
`hydroxypropyl Acrylate, 3-(Nonafluoro-n-butyl)prop-2-enol, 3-(N onafluoro-n-butyl) 1,2,-
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`propenoxide, 1H,1H,2H,2H-Nonafluorohexan-1-ol, lH,lH-Nonafluoropentan-1-ol,
`2,2,3,3,4,4,5 ,5-0ctafluoro-1,6-hexanediol, 2,2,3,3,4,4,5,5-0ctafluorohexane-1,6-diacrylate,
`2,2,3,3,4,4,5,5, Octafluorohexane-1,6-diamethacrylate, 3,3,4,4,5,5,6,6-0ctafluoro-l,8-
`octanediol, lH, 1 H, lH-Octafluoropenta-1-ol, 2,2,3 ,3 ,4,4,5 ,5 Octofluoro-1,6-hexanediol,
`1, 1, 1,2,2-Pentafluorobutan-2-ol, 1, 1, 1,2,2-Pentafluoro-6,6-dimethyl-3 ,5-heptadione, 6-
`(Pentafluoroethyl)hexan-1-ol, 4,4,5,5,5-Pentafluoropentan-1-ol~ 2,2,3,3,3-
`Pentafluoropropan-1-ol, Pentafluoropropionaldehyde Hydrate, Pentafluoropropionaldehyde
`Methyl Hemiacetal, Pentafluoropropionamide, 2,2,3,3,3-Pentafluoropropyl Acrylate,
`2,2,3,3,3-Pentafluoropropyl Methacrylate, 2,2,3,3,3-Pentafluoropropyl Methyl Ether,
`2,2,3,3,3-Pentafluoropropyl 1, 1,2,2-Tetrafluoroethyl Ether, lH, lH, 1 OH, 1 OH-Perfluoro-
`1, 10-decanediol, lH, 1 H-Perfluorodecan-1-ol, 1 H, 1 H,2H,2H-Perfluorodecan- l -ol,
`l_H, 1 H,2H,2H-Perfluorodecanethiol, 1 H, 1 H,2H,2H-Perfluorodecyl Acrylate,
`lH, 1H,2H,2H-Perfluorodecyl Methacrylate, 3-(Perfluoro-n-decyl)prop-2-enol, 3-
`(Perfluoro-n-decyl)-1,2-propenoxide, lH, lH-Perfluoro-(3, 7-dimethyloctan-1-ol), 2H-
`Perfluoro-( 5,8-dimethyl-3 ,6,9-trioxadodecane ), IH, lH, 12H, 12H-perfluoro-1, 12-
`dodecanediol, 1 H, 1 H-Perfluorododecan-1-ol, lH, 1H,2H,2H-Perfluorododecan-l-ol,
`1 H, 1H,2H,2H-Perfluorododecyl Acrylate, 1 H, 1 H,2H,2H-Perfluorododecyl Methacry late,
`7H-Perfluoroheptanal, 7H-Perfluoro-1, 1-heptanediol, Perfluoroheptanoic Anhydride,
`lH,lH-Perfluoroheptan-1-ol, 1H,1H,7H~Perfluoroheptan-1-ol,
`Perfluoroheptoxypoly(propyloxy) Acrylate, Perfluoroheptoxypoly(propyloxy)
`Methacrylate, 1 H, 1 H, 7H-Perfluoroheptyl Methacrylate, 1 H, 1 H-Perfluorohexadecan-1-ol, 3
`Perfluorohexy-2-Hydroxypropyl Methacrylate, 2-(Perfluoro-n-hexyl)acetaldehyde
`Dimethyl Acetal, 3-Perfluorohexyl-2-hydroxypropyl Acrylate, 3-Perfluorohexyl-2-
`hydroxypropyl Methacrylate, 3-(Perfluorohexyl)propan-1-ol, J-(Perfluoro-n-hexyl)prop-2-
`enol, 3-(Perfluoro-n-hexyl)-1,2-propenoxide, 11-(Perfluoro-n-hexyl)undecanol, 11-
`(Perfluoro-n-hexyl)undec-l 0-enol, 6, (Perfluorosiopropyl)hexan-1-ol, 3-(Perfluoro-3-
`methylbutyl)-2-hydroxy Propyl Acrylate, 3-(Perfluoro-3-methylbutyl)-2-hydroxy Propyl
`Methacrylate, lH, 1H,2H,2H-Perfluoro-9-methyldecan-l-ol, 2-(Perfluoro-9-
`methyldecyl)ethyl Acrylate, 2H-perfluoro-5-methyl-3 ,6-dioxanonane, lH, 1 H,2H,2H-
`Perfluoro-11-methyldodecan-l-ol, Perfluoro-(2-methylhept-3-ene-5-one ), IH, IH,2H,2H,
`Perfluoro-5-methylhexan-l-ol, 2-(Perfluoro-5-methylhexyl)ethyl Acrylate, 2 (perfluoro-5-
`methylhexyl)ethyl Methacrylate3-(Perfluoro-5-methylhexyl)-2-hydroxypropyl Acrylate, 3-
`(Perfluor-5-methylhexyl)-2-hydroxypropyl_ Methacrylate, lH, 1H,2H,2H,-Perfluoro-7-
`methylocatn-1-ol, 2-(Perfluoro-7-methyloctyl)ethyl Acrylate, 2-(Perfluoro-7-
`35 methyloctyl)ethyl Methacrylate, 6~(Perfluoro-7-methyloctyl)hexanol, 3-(Perfluoro:-7-
`methyloctyl)-2-hydroxypropyl Acrylate, 3-(Perfluoro-7-methyloctyl)-2-hydroxypropyl
`Methacrylate, lH, 1H,2H,3H,3H-Perfluoro-l ,2-nonanediol, lH, 1H,9H,9H-Perfluoro-l ,9-
`nonanediol, lH,IH-Perfluorononan-1-ol, IH,1H,9H-perfluorononan-1-ol, 1H,1H,9H-
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`Per:fluoronon-1-ene, 1 H, 1 H,9H-Per:fluorononyl Acrylate, 1H,2H,9H-Per:fluorononyl
`Methacrylate, lH,lH-Per:fluorooctadecan-1-ol, 1H,1H,8H,8H-Per:fluoro-l,8-octanediol, n~
`Per:fluoroctanoic acid Ammonium Salt, lH, lH-Per:fluorooctan-1-ol, lH, 1H,2H,2H(cid:173)
`Per:fluorooctan-l-ol, lH, 1H,8H-Per:fluorooctan-1-ol, Per:fluorooctoxy-poly(isobutoxy)-2-
`chloropropoxy-1,2-propyl Diacrylate, 2-(Per:fluoro-n-octyl)acetaldehyde, 2-(Per:fluoro-n,
`octyl)acetaldehyde Diethyl Acetate, Per:fluorooctyl Acrylate, lH,lH-Per:fluorooctyl
`Acrylate, IH,IH,2H,2H-Per:fluorooctyl Acrylate, 6-(Per:fluorooctyl)hexanol, 3-
`(Per:fluorooctyl)-2-hydroxypropyl Acrylate, 3-(Per:fluorooctyl)-2-hydroxypropyl
`Methacrylate, mono-Per:fluorooctyl Itaconate, mono-Per:fluorooctyl Maleate,
`Per:fluorooctyl Methacrylate, lH,lH-Per:fluorooctyl Methacrylate, 3-
`(Per:fluorooctyl)propanol, 3-(Per:fluorooctyl)prop-2-enol, 11-(Pe:fluoro-n-octyl)undec-1 O(cid:173)
`en-1-ol, 1H,1H,5H,5H-Per:fluoropentyl-1,5-dimethacrylate, Pe:fluoropolyether linear &
`PFO-XR75, Per:fluorosebacic Acid, lH,lH-Per:fluorotetradecan-1-ol, 1H,1H,13H(cid:173)
`Per:fluorotridecan-l-ol, Perfluoro-2-tri:fluoromethyl-4-oxanonane, Per:fluoro-(3,5,5-
`trimethylhexanoic)acid, IH,1H-Per:fluoro(3,5,5-trimethylhexan-1-ol), 2H-Per:fluoro(cid:173)
`(5,8,11-trimethyl-3,6,9,12-tetraoxatetradecane), 1H,1H,2H,3H,3H-Perfluoro-1,2,(cid:173)
`undecanediol, Perfluoroundecanoic Acid, lH,lH-Per:fluoroundecan-1-ol, lH,lH,l lH(cid:173)
`Perfluoroundecan-1-ol, lH,lH,l IH-Per:fluoroundecyl Acrylate, lH,lH,l lH(cid:173)
`Perfluoroundecyl Methacrylate, Polyperfluoroethylene glycol Diacrylate,
`Polyper:fluoroethylene glycol Dimethacrylate, Sodium Heptafluorobutyrate, Sodium
`Pent~fluoropropionate, 2,2,3,3-Tetrafluoro-1,4-butanediacrylate, 2,2,3 ,3-
`Tetrafluoro 1,4,butanedimethacrylate, 1, 1,3 ,3-Tetrafluorodimethyl Ether, 1, 1,2,2-
`Tetrafluoroethyl 2,2,3 ,3-tetrafluoropropyl Ether, 1, 1,2,2, Tetrafluoroethyl 2,2,2-
`trifluoroethyl Ether, 1122 Tetra:fluoroethyl 222 Trifluoroethyl Ether, 1,2,2,2-
`Tetrafluoroethyl Tri:fluoromethyl Ether, 4,5,5,5-Tetrafluoro-4-
`(heptafluoropropoxy)pentanoic Acid, 4,5,5,5-Tetrafluoro-4-(heptafluoropropoxy)pentan-1-
`ol, Tetra:fluorosuccinic acid, 4,5,5,5-Tetra:Ouoro-4-(tri:fluoromethoxy)pentan-1-ol, 4,5,5,~(cid:173)
`Tetrafluoro-4-( trifluoromethy)pentan-1-ol, 4,5 ,5 ,5-Tetrafluoro-4-(trifluoromethyl)pent-2-
`en-1-ol, N-(N-Trifluoroacetyl-L-cysteinyl)glycine Methyl Ester, DL-3,3,3-Trifluoro-2-
`alanine, 4,4,4-Trifluorobutan-1-ol, 1, 1, l-Trifluorobutan-2-one, 4,4,4-Tri:fluorobutan-2-one,
`4, 4,4-Trifluorobut-2-en- l -ol, 1, 1,2-Trifluoro-2-chloroethyl 2,2,2-trifluoroethyl ether, 4 ,4,4-
`Trifluorocrotonamide, 4,4,4-Trifluoro-3;3-dimethoxybutanol, 2,2,2-Trifluoroethanol, 2,2,2-
`. Trifluoroethyl Butyrate, 1,2,2-Trifluoroethyl Trifluoromethyl Ether, 1,1,l-Trifluoro-2,4-
`hexanedione, Beta-Trifluoromethylcrotonic Acid, DL-2-(Trifluoromethyl)leucine, DL-2-
`(Trifluoromethyl)norleucine, DL-2-(Trifluoromethyl)norvaline, 2-
`(Trifluoromethyl)propan-2-ol, 6,6,6-Trifluoronorleucine, 5,5,5-Trifluoronorvaline, 1, 1, 1-
`Trifluoropropan-2-ol, 3,3 ,3-Trifluoropropan-1-ol, 1, I, 1-Trifluoro-2-propyl Acetate, 4,4,4-
`Trifluoro-3-(tri:fluoromethyl)butan-l-ol, 2-Allyl Hexafluorosiopropanol, Butyl
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`Difluoroacetate, n-Butyl Pentafluoropropionate, tert-Butyl Pentafluoropropionate, N,N(cid:173)
`Diethyl-2,3,3,3-tetrafluoropropionamide, 22 Difluoroethyl Trifluoromethyl Ether, 1-
`(Ethoxy)nonafluorobutane, 3-Fluoropropan-1-ol, 3H-Heptafluoro-2,2,4,4-tetrahydroxy
`Pentane, 2,2,3,3,4,4-Hexafluoro-1,5-pentyl Diacrylate, 1, 1,2,3,3,3-Hexafluoropropyl 2,2,2-
`trifluoro Ethyl Ether, Methyl 2,2-Difluoro-3-oxopentanoate, Methyl 2,
`Methoxytetrafluoropropionate, Methyl Perfluoro-2,5,8, 1 l-tetramethyl-3,6,9, 12-
`tetraoxapentadecanoate, Methyl 3,3,3-Trifluoro-DL-lactate, 3,3,4,4,4-Pentafluorobutan-2-
`one, Pentafluorodiemethyl Ether, Pentafluoroethyl Methyl Ether, 2,2,3,3,3-
`Pentafluoropropyl Trifluoromethyl Ether, 2-(Perfluoroalkyl)ethanol,
`Perfluoroallylfluorosulphate, Perfluoro-2,5,8,l l,14,17,20-heptamethyl-3,6,9,l2,15,18-
`hexaoxahenelcosanoyl Fluoride, Mono-Perfluorooctyl Itaconate, 2H-Perfluoro-
`5,8, 11, 14, 17-pentamethyl-3 ,6,9, 12, 15, 18-hexaoxahenicosane, Perfluoropolyether Dinitrile,
`Polyfluoropolyethyleneacrylate, Polyfluoropolyethylenemethacrylate, 2,2,2-Trifluoroethyl
`Trifluoromethyl Ether, Perflurodecaline, Perfluorooctyl Bromide, di-Chloro-octyl Bromide
`and 1H,1H,5H Ocrafluoro-1-pentanol.
`
`Preferably the fluorinated polar molecule is n-Butyl Pentafluoropropionate, Ethyl Perfluoro
`n-Dodecanoate, Fluorinert (FC-75), 2,2,3,3,3 Pentafluoropropyl Methyl Ether, Methyl
`Perfluorodecanoate, 2H Perfluoro-5,8,11-Trimethyl-3,6,9, 12-Tetrafluoropropylether,
`Fluorad (FC-430), 1,1,2,2, Tetrafluoroethyl 2;2,3,3 Tetrafluoropropylether, 1H,1H,2H,2H
`Perfluorooctan-1-ol, 4,4,4 Trifluorobutan-1-ol, Fomblin (MF 402), Fomblin (ZDOL),
`Perfluoroheptanoic Anhydride, Methyl Perfluoro 2,5,8,11-Tetramethyl 3,6,9,12,
`· Tetraoxapentadecanoate, N,N-Diethyl-2,3,3,3 Tetrafluoropropionamide, Ethyl 1 lH(cid:173)
`Perfluoroundecanoate, lH, 1H,2H,3H,3H Perfluoro-1,2-N onandiol, lH, lH,
`Pertluorononan-1-ol or 1,1,2,2 Tetrafluoroethyl 2,2,2 Trifluoroethyl ether.
`
`Even more preferred fluorinated molecules are 1H,1H,2H,2H Perfluorooctan-1-ol and
`1,1,2,2 Tetrafluoroethyl 2,2,2 Trifluoroethyl ether.
`
`· The excipient for use in the forinulati.on can be a surfactant or a polymer and combinations
`thereof, copolymers are particularly favoured. The excipient can either be soluble or
`miscible in the polar fluorinated molecule. Suitable excipients include:
`
`. Acrylidone 1005, Crodesta Fl 60, Methoxy PEG Amine, Methoxy PEG carboxymethyl, 4
`arms PEG, Cholic acid, MYRJ 52 P, APG-810-XL, APG-1014-XL, Glucopon 215,
`Glucopon 600, Brij 52, Gum Xanthan, Salicylic Acid, D-Lacotose monohydrate, a Lactose
`monohydrate, Lecithin egg, Carrageean, Sokalan C05, Eudragit RLPO, Eudragit RSPO,
`Eudragit ElOO, Eudragit Sl00, Eudragit LlOO, Poly (DL-lacide coGlycolide), Gantrez S-97
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`BF, Gantrez AN-119, Gantrez AN-169, Myristic acid, Poly (lactide EO Lactid), Poly
`(methyl methacrylate-13 -ethylene oxide), Lactose, Carboxymethyl cellulose Sodium Salt;
`1-0-n-Octyl PD glucopyranoside, AOT DI-CF4H, Dioctyl-sulfosuccinate sodium salt
`(AOT), Phospholipon 100, Crodesta FlO, Cfl:1,4esta SL 40, APG 3399, Methoxy-PEG-
`s DSPE MW 2000, Methoxy,-PEG-DSPE MW. 5000, N Dodecyl j3 D Maltoside, N Octyl j3 D
`Glucopyranoside, a cyclodextcin, 13 cyclodextrin hydrate, j3 cyclodextrin, Y cyclodextrin
`hydrate, Y cyclodextrin, Y cyclodextrin hydrate, Deoxycholic acid, Taurocholic acid, D(cid:173)
`Mannitol, Poly (Methyl Methacrylate ), Montanov 202, Montanov 68 EC, n Dodecyl j3 D
`Glucopyranoside, N Decyl 13 D Glucopyranoside, n Decyl 13 D Maltopyranoside,
`10 Glucamate DOE-120, Glucate SS, Glucamate SSE-20, Glucam DOE-120, Glucam PIO,
`Glucam E20, Glucam P20 disteared, Glucam P20, Glucquat 125, Brij 30, Brij 96,
`Crodasinic LS 30, Crossential L99, Copolymer VC 713, Copolymer 958, Glucopon 650
`EC, a Tocopherol, PVP K30, K25 and Plasdone K-29/32, PEG 600 and 1000, Three-Arm
`Poly ( ethylene glycol),
`lactose based compounds ( eg Poly (lactide -co glycolide ), Lactitol, Lactose, Cellulose
`based compounds (e.g. Carboxymethylcellulose, Cellulose, Hydroxypropyl cellulose), Faty
`acids ( e.g. Castor oil), PEG and derivatives ( e.g. Star PEG), Sugar compounds ( e.g. Alkyl
`polyglµcosides, Methyl glucosides, Sucrose esters, such as Berol AG6202, Glucopon
`chemical range, Montanov 68, Montanov 202, Grilloten LSE87, Crodesta chemical range),
`Poly(ethylene Oxide) compounds (e.g. Hydroxy terminated Three-Arm Polyethylene
`oxide, Hydroxy terminated Eight-Arm Polyethylene oxide, Carboxy terminated Eight-Arm
`Polyethylene Oxide, 4 Arms Star Polyethylene Oxide, Poly(methyl methacrylate b(cid:173)
`ethylene oxide), Poly(t-butyl methacrylate -b-ethylene oxide), Poly(lactide-ethylene oxide(cid:173)
`lactide triblock copolymer), n -Diacrylonyl terminated poly(lactide-ethylene oxide-lactide)
`triblock copolymer, Poly(lactone-l3-ethylene oxide-j3-lactone) triblock copolymer,
`Poly( ethylene oxide-l3-caprolactone ), Poly( ethylene oxide-)3-propylene oxide) also known
`as PEO-PPO copolymers, Poly(methy methacrylate-l3-ethylene oxide) also known as
`PMMA-PEO copolymers)). Further examples include Citric acid, Dibutyl Sebacate, Edetic
`acid, Glyceryl monooleate & monostearate, Glycofinol, Crodamol chemical _range,
`30 Maltitol, Maltodextrin, Triglyceride, Polymethacrylate, Pqlyosyethylene alkyl ether,
`Sodium citrate dihydrate, Sorbitol, Mirj and Brij chemical range, Pluronic chemical range,
`Acrylidone 1005, Fluorinated AOT with different degrees of fluorination, Cholic acid,
`Copolymer 958, Copolymer VC713, Crossential L99, Crodasinic LS30, AOT Sodium salt,
`Phospholipon 100H, Salycilic acid, Sokalan COS, Poly (lactide co glycolide),
`Poly( ethylene -13- methyl methacrylate ), Poly( ethylene -)3-2- vinyl pyridine),
`Poly(ethylene-)3-4-vinyl pyridine), Poly(methyl methacrylate -P- sodium acrylate),
`Poly(methyl methacrylate-P-sodium methacrylate), PEG derivative compounds (Amino
`acid - PEG, Carboxyl - PEG copolymers, Methoxy PEG amine, Methoxy PEG
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`carboxymethyl, Branched PEG 4 arms, star PEG, PEG-PLA-PEG triblock copolymer
`etc ... ), sugar branched cyclodextrins derivatives, PEO cyclodextrins derivatives, and
`Dendrimer-PEO-Dendrimer triblock-copolymers.
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`Preferably the excipient is PEG based. Preferred excipients include Methoxy-PEG-DSPE
`MW 5000, Eudragit EIOO, Glucamate DOE 120, Methoxy-PEG-DSPE MW 2000,
`Acrylidone 1005, Crodesta FI60, Methoxy PEG Amine, Methoxy PEG carboxymethyl, 4
`arms PEG, Cholic acid, MYRJ 52 P, APG-810-XL, APG-1014-XL, Glucopon 215,
`Glucopon 600, Brij 52, Gum Xanthan, Salicylic Acid, D-Lacotose monohydrate, a Lactose
`10 monohydrate, Lecithin egg, Carrageean, Sokalan C05, Eudragit RLPO, Eudragit RSPO,
`Eudragit ElOO, Eudragit SlOO, Eudragit 1100, Poly (DL-lacide coGlycolide), Gantrez S-97
`BF, Gantrez AN-119, Gantrez AN-169, Myristic acid, Poly (lactide EO Lactid), Poly
`· (methyl methacrylate-B-ethylene oxide), Lactose, Carboxymethyl cellulose Sodium Salt, 1-
`0-n-Octyl B D glucopyranoside, AOT DI-CF4H, Dioctyl-sulfosuccinate sodium salt
`(AOT), Phospholipon 100, Crodesta F10, Crodesta SL 40, APG 3399, Methoxy-PEG(cid:173)
`DSPE MW 2000, Methoxy-PEG-DSPE MW 5000, N Dodecyl p D Maltoside, N Octyl p D
`Glucopyranoside, a cyclodextrin, P cyclodextrin hydrate, B cyclodextrin, gamma
`cyclodextrin hydrate, gamma cyclodextrin, gamma cyclodextrin hydrate, Deoxycholic acid,
`Taurocholic acid, D-Mannitol, Poly (Methyl Methacrylate ), Montanov 202, Montanov 68
`20 Ee; n Dodecyl p D Glucopyranoside, N Decyl B D Glucopyranoside, n Decyl B D
`. Maltopyranoside, Glucamate DOE-120, Glucate SS, Glucamate SSE-20, Glucam DOE-
`120, Glucam PIO, Glucam E20, Glucam P20 disteared, Glucam P20, Glucquat 125, Brij
`30, Brij 96, Crodasinic LS 30, Crossential 199, Copolymer VC 713, Copolymer 958,
`Glucopon 650 EC, a Tocopherol, PVP K30, K25 and Plasdone K-29/32, PEG 600 and
`1000, Three-Arm Poly (ethylene glycol).
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`Most preferably the excipient is Methoxy-PEG-DSPE MW 5000;
`Eudragit ElOO, Glucamate DOE 120 or Methoxy-PEG-DSPE MW 2000.
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`The grades of fluorinated molecules and excipients mentioned herein are purely indicative
`and do not limit the scope of this invention. Preferably the fluorinated molecules and
`excipients are pharmaceutically acceptable.
`
`Other ingredients, for example other co-solvents, stabilisers, surfactants, lubricants,
`excipients, preservatives, buffers, antioxidants, sweeteners, water trapping agents, bulking
`agents, and taste masking agents may be included in the formulation of the present
`invention as desired.
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`The formulation of the present invention may be prepared, for example, by mixing the
`fluorinated polar molecule with the excipient, then adding the drug powder to the mixture·.
`Propellant is then added to the drug slury, the formulation obtained is then dispensed in
`aliquots into specified pMDI which is suitable for.nasal or pulmonary drug delivery by any
`known method, for example under pressure (addition of propellant under pressure) or by
`cold filling (addition of propellant at a temperature below its boiling point). The
`pharmaceutically active component may be processed in order to obtain a desired particle
`size distribution or specific surface properties. For example the pharmaceutically active
`component may be micronised by conventional methods prior to mixing, or the mixture of
`pharmaceutically active component may be micronised by conventional methods, after
`mixing.
`
`Suitably the concentration of the fluorinated polar molecule is from 0.0001 to 55 %
`weight/weight, more preferably from 0.1 to 25%, and most preferably from 0.3 to 15%.
`The concentaration of excipient is suitably fro.m 0.001 % to 1 %, preferably 0.01 to 1 %.
`
`The pMDI device for use with the formulation of the present invention preferably
`comprises a metal can, for example an aluminium can, closed with a suitable metering
`valve. Plastic and glass cans can also be used. Suitable cans, coated cans such as cans
`coated with a fluoropolymer, and metering valves are known in the art.
`
`The pharmaceutical formulations of the present invention are useful for the local or
`systemic treatment of diseases and may be administered for example via the upper and
`lower respiratory tract, including by the nasal route. As such the present invention also
`prpvides the pharmaceutical aerosol formulation as defined herein for use in therapy; the
`use of the pharmaceutical aerosol formulation for the manufacture of a medicament for the
`treatment of diseases vfa the respiratory tract; and a method for the treatment of a patient in
`need of therapy, comprising administering to said patient a therapeutically effective
`amount of the pharmaceutical aerosol formulation of the present invention. It is expected
`that inflammatory diseases in the respiratory tract, for example asthma, rhinitis, COPD,
`alveolitis, bronchiolitis and bronchitis can be treated using the present pharmaceutical
`aerosol formulation.
`
`The pharmaceutical formulation of the present invention is also useful for systemic
`delivery for many other non-respiratory diseases e.g. cancer, pain control, anaesthesia,
`infection, vaccinations etc.
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`In a further aspect the invention provides the use of a polar fluorinated