Title of Invention

A COMPOSITION IN FORM OF AN EMULSION PRE-CONCENTRATE OR A MICROEMULSION PRE-CONCENTRATE FOR ORAL ADMINISTRATION

Abstract

A composition in form of an emulsion pre-concentrate or a microemulsion pre- concentrate for oral administration A composition in form of an emulsion pre-concentrate or a microemulsion pre-concentrate suitable for oral administration comprising: 1) a cyclosporine or macrolide, and a carrier medium comprising 2) a second component selected from the group consisting of (i) glyceryl di C6-C16 fatty acid ester, (ii) glyceryl mono C6-C14 fatty acid ester, (iii) a mixture of mono-, diglycerides of C6-C16 fatty acids, (iv) propylene glycol mono C6-C12 fatty acid ester, (v) fatty alcohols, and 3) a lipophilic component, and 4) a surfactant, with the proviso that when component 2) consists of a mixture of mono-, diglycerides of C8-C10 fatty acids, said composition is free of a C6-C12 fatty acid triglyceride.

Full Text

4-30410/A EMULSION PRECONCENTRATES CONTAINING CYCLOSPORIN OR A BACROLIOE The invert invention relates to novel galena Positions, in particular novel galena in which the active ingredient is a difficultly sociable active agent e.g. a Macrolide, or in particular a cyclic poly-N-meshed undecapeptide, or a cyclosporin. Cyclosporins also in chide pentoxide variants. See e.g. GB patent publications nps. 2 222 770 and 2 257 359 A and equivalents world-wide. As discussed in the said GB patent publications, the cyclosporins present highly specific difficulties in relation to administration generally and galena in particular, including in particular problems of stability, drug bioavailability, and variability in inter- and intra-patient dose response. In order to meet these and related difficulties, in GB patent publication no. 2 222 770 and 2 257 359 A, galena conditions are disclosed comprising a cyclosporin as active ingredient and which take the fumy of, inter alia, an emulsion, e.g. micro emulsion, or emulsion, e.g. micro emulsion, pre-concentrate. Such conditions typically 1) a hydrophilic , 2) a lipophilicity , and 3) a surfactant. In accordance with the present invention it has now surprisingly been found that particularly stable emulsion, e.g. microemulsion, or emulsion, e.g. micro emulsion, pre-concentrate galena conditions with difficultly soluble active agents having particularly interesting bioavailability characteristics and reduced variability in inter- and intra-subject bioavailability parameters, are obtainable using at least one selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ii) polyethylene glycol glyceryl fatty acid ester, (iii) glyceryl di fatty acid ester, (iv) glyceryl mono fatty acid ester, (v) a mature of mono-, diglycerides of fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylene polyol ether or ester, e.g. polyglycolised glycerides, hereinafter referred to as "secondary connect". These compositions may be encapsulated in hard and soft gelatine capsules. Other examples may be made excluding Synperonic® PE L44, GMOrphic® 80, Tegin® O, Labrafil® M 2125 CS, Alpha-tocopherol, ethanol, propylene glycol. Further examples may be made replacing triethyl citrate, N-Methylpyrrolidone, Sunfat® GDC-N, Lauroglycol® 90, oleyl alcohol, Cetiol® HE, acetyl triethyl citrate, benzyl alcohol, or oleic acid by any of the second specified above. The examples illustrate useful for example in the prevention of transplant rejection or for the treatment of autoimmune disease, on administration of from 1 to 5 unit dosages/day at a dose of 2 to 5 mg/kg per day. The examples are described with particular reference to Ciclosporin but equivalent conditions may be obtained any Macrolide or other active agent. On visual inspection after dilution, each of the compositions forms a clear and stable microemulsion. 1. A in form of an emulsion pre-concentrate for oral administration comprising 1) a cyclosporine or Macrolide, and a carrier medium comprising 2) a second component selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ii) polyethylene glycol glyceryl fatty acid ester, (iii) glyceryl di fatty acid ester, (iv) glyceryl mono fatty acid ester, (v) a mixture of mono-, diglycerides of fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylene polyol ether or ester, 3) a lipophilicity component, and 4) a surfactant, with the proviso that when component 2) (a) consists of triethyl citrate, said composition is free or substantially free of ethanol, and/or (b) consists of a mixture of mono-, diglycerides of fatty acids, said onyx is free or substantiate free of a fatty acid triglyceride, 2. A conqxsition in form of an emulsion or micro emulsion pre-concentrate for oral administration comprising 1) a cyclosporine or Macrolide, and a carrier medium composing 2) a second consonant selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ii) polyethylene glycol glyceryl fatty acid ester, (iii) glyceryl di fatty acid ester, (iv) glyceryl mono fatty acid ester, (v) a mixture of mono-, diglycerides of fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylene polyol ester or alkylene triols ether, 3) a lipophilicity connect, and 4) a surfactant, with the proviso that when component 2) (a) consists of triethyl citrate, said composition is free or substantially free of ethanol, and/or (b) consists of triethyl citrate, acetyl triethyl citrate or glycerol triacetate, cyclosporin is not present, and/or (c) consists of a mixture of mono-, diglycerides of fatty acids, said composition is free or substantially free of a fatty acid triglyceride. 3. A composition in form of an emulsion or micro emulsion pre-concentrate for oral administration comprising 1) a cyclosporine or Macrolide, and a carrier medium comprising 2) a second connect selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ix) glycerol triacetate, 3) selected from the group consisting of (i) transesteiified ethoxylated vegetable oil, (ii) mixed mono-, di- tri-glycerides, (iii) propylene glycol mono- and di-fatty acid esters, and (iv) esterified compounds of fatty acid and primary alcohol, 4) a surfactant, with the proviso that when component 2) consists of triethyl citrate, said composition is free or substantially free of ethanol. 4. A composition in form of an emulsion or micro emulsion pre-concentrate for oral administration comprising 1) a cyclosporine or Macrolide, and a carrier medium chorusing 2) a second component selected from the group consisting of a) (i) triethyl citrate or acetyl triethyl citrate, (ix) glycerol triacetate, and a second component selected from the group consisting of b) (ii) polyethylene glycol glyceryl C6-C10 fatty acid ester, (iii) glyceryl di C6-C16 fatty acid ester, (iv) glyceryl mono fatty acid ester, (v) a mixture of mono-, diglycerides fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyrrolidone, (x) benzyl alcohol, and (xi) alkylene polyol ether or ester, 3) a lipophilicity connect, and 4) a surfactant. 5. A composition in form of an emulsion or micro emulsion pre-concentrate for oral administration coursing 1) a cyclosporine or Macrolide, and a carrier medium comprising 2) a second consonant selected from the group consisting of (i) triethylcitrate or acetyl triethyl citrate, (ii) polyethylenes glycol geyser add ester. (iii) glyceryl di fatty acid ester, " (iv) glyceryl mono fatty acid ester, (v) a mixture of mono-, diglycerides of fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyrrolidone, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylene polyol ether or ester, 3) a surfactant, 4) one or more antioxidants selected from the group consisting of ascorbic palpitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherol in about 0.05 to 1 % by weight of the total weight of the composition with the proviso that when consists of triethyl citrate, said composition is free or substantially free of ethanol, and/or (a) consists of a mixture of mono-, diglycerides of fatty acids, said composition is free or substantially free of a C6-C12 fatty acid triglyceride. 6. A composition according to claim 5 wherein the antioxidant present is a-tocopherol. 7. Use of a composition in form of an emulsion or micro emulsion pre-concentrate for oral administration in kidney or heart transplant comprising 1) a cyclosporine or Macrolide, and a carrier medium consign 2) a second consonant selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ii) polyethylene glycol glyceryl fetty acid ester, (m) glyceryl di - fetty add ester, (iv) glyceryl mono fetty acid ester. (v) a mixture of mono-, diglycerides of fatty acids, (vi) propylene glycol mono fatty acid ester, (vii) fatty acids and alcohols, (viii) N-methyl pyridine, (ix) glycerol triacetate, (x) benzyl alcohol, and (xi) alkylene polyol ether or ester, 3) a lipophilicity component, and 4) a surfactant, with the proviso that when component 2) (a) consists of triethyl citrate, said composition is free or substantially free of ethanol, and/or (b) consists of a mixture of mono-, diglycerides of fatty acids, said composition is free or substantially free of a C6-C12 fatty acid triglyceride. 8. A use or composition according to any one of the preceding claims comprising the cyclosporine or Macrolide in an amount of 1 to 15% by weight of the composition. 9. A use or composition according to any one of the preceding claims comprising the second component in an amount of 5 to 50 %, the lipophilic component in an amount of 5 to 85 %, and the surfactant in an amount of 5 to 80 % by weight of the carrier medium. 10. A use or condition according to any preceding claim, the relative proportion of the cyclosporine or Macrolide, the second consonant, the lipophilic consonant and the surfactant in said conviction being such that upon division with water to a ratio of 1 part by weight of said composition to 1 to 10 parts by weight of water, an oil-in-water micro emulsion having particles of a mean size of less than 200 nm, is spontaneous funned. 11. A use or composition according to any preceding claim wherein the cyclosporine is Cyclosporin A. 12. A use or composition according to any preceding claim wherein the second component is N-methylpyrrolidone. 13. A use or composition according to any preceding claim wherein the surfactant is selected from the group consisting of (i) reaction products of natural or hydrogenated vegetable oil and ethylene oxide, and (ii) polyoxyethylene sorbitan fatty acid esters. 14. A use or composition according to any preceding claim wherein the ratio of the cyclosporine or macrolide: second component: lipophilic component: surfactant is 1 : 0.1 to 10 : 1 to 10 : 1 to 10 on the basis of weight. 15. A use or composition according to any preceding claim wherein a hydrophilic cosurfactant is additionally present. 16. A use or composition according to claim 15 wherein the hydrophilic cosurfactant is polyoxyethylene polyoxypropylene block copolymer. 17. A use or composition according to claim 15 or 16 wherein the second connects and the hydrophilic cosurfactant are combined in the ratio of 1 : 0.1 to 5 on the basis of weight. 18. A use or according to any preceding claim wherein a nurtures of polyethylene glycol and the second is used. 19. A use or condition of any preceding claim in unit dosage form. 20. A method of reducing the variability of bioavailability levels of a cyclosporin or macrolide for patients during cyclosporin or macrolide therapy, said method comprising orally administering an oral pharmaceutical composition according to any one of claims 2 to 19. 21. A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin or macrolide therapy a composition according to any preceding claim. 22. Use of a according to any one of claims 2 to 20 in the manufecture of a medicament for orally administering to a patient in need of cyclosporin or macrolide therapy. 23. The use of a according to any one of claims 2 to 20 in the manufacture of a medicament for the treatment and prevention of an autoimmune or inflammatory condition or for the treatment and prevention of transplant rejection or for the treatment of nematic-drug resistance. 24. A composition in form of an emulsion or micro emulsion pre-concentrate for oral administration comprising 1) a cyclosporine or macrolide, and a carrier medium comprising 2) a second selected from the group consisting of (i) triethyl citrate or acetyl triethyl citrate, (ii) polyethylene glycol glyceryl fatty acid ester, (iii) glyceryl di fatty acid ester, (iv) glyceryl mono fatty acid ester, (v) a mixture of mono-, diglycerides of fatty acids, (vi) propylene glycol mono C6-C12 fatty acid ester, (vii) acids and alcohols, (viii) N-methyl pyrrolidone, (ix) glycerol triacetate. (x) benzyl alcohol, and , (xi) alkylene polyol ether or ester, 3) a lipophilic component, and 4) a surfactant, with the proviso that when component 2) (a) consists of triethyl citrate, said composition is free or substantially free of ethanol, and/or (b) consists of a mixture of mono-, diglycerides of fatty acids, said composition is free or substantially free of a fatty acid triglyceride. 25. A composition in form of an emulsion pre-concentrate for oral administration, substantially as hereinabove described and exemplified.

Documents:

in-pct-2000-344-che-abstract.pdf

in-pct-2000-344-che-claims filed.pdf

in-pct-2000-344-che-claims grant.pdf

in-pct-2000-344-che-correspondnece-others.pdf

in-pct-2000-344-che-correspondnece-po.pdf

in-pct-2000-344-che-description(complete)filed.pdf

in-pct-2000-344-che-description(complete)grant.pdf

in-pct-2000-344-che-drawings.pdf

in-pct-2000-344-che-form 1.pdf

in-pct-2000-344-che-form 26.pdf

in-pct-2000-344-che-form 3.pdf

in-pct-2000-344-che-form 5.pdf

in-pct-2000-344-che-other document.pdf

in-pct-2000-344-che-pct.pdf