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Claims for Patent: 6,011,062

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Claims for Patent: 6,011,062

Title: Storage-stable prostaglandin compositions
Abstract:The use of polyethoxylated castor oils in prostaglandin compositions enhances the prostaglandin's chemical stability.
Inventor(s): Schneider; L. Wayne (Crowley, TX), Bawa; Rajan (Fort Collins, CO), Weiner; Alan L. (Arlington, TX)
Assignee: Alcon Laboratories, Inc. (Fort Worth, TX)
Application Number:09/246,072
Patent Claims: 1. An aqueous pharmaceutical composition comprising a therapeutically effective amount of a prostaglandin, a polyethoxylated castor oil in an amount effective to enhance the chemical stability of the prostaglandin, an antimicrobial preservative and a pharmaceutically acceptable vehicle, wherein the polyethoxylated castor oil is selected from the group consisting of PEG-5 to PEG-200 hydrogenated castor oils.

2. The composition of claim 1 wherein the polyethoxylated castor oil is selected from the group consisting of PEG-25 to PEG-55 hydrogenated castor oils.

3. The composition of claim 2 wherein the polyethoxylated castor oil is PEG-40 hydrogenated castor oil.

4. The composition of claim 1 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pen tanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid amide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid N,N-dimethylamide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid cyclopentyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid adamantyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester; (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,2 0-tetranor-5,13-prostadienoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17 ,18,19,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pe ntanor-5-prostenoic acid isopropyl ester; (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,2 0-pentanor-5-prostenoic acid tertbutyl ester; (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-pro stenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18, 19,20-pentanor-5-prostene-11,15-diol; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenol; 9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentan or-13-prostynoic acid; latanoprost; 15-keto latanoprost; cloprostenol isopropyl ester; (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16- [(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid; (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16- [(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pe ntanor-5-prostenoic acid isopropyl ester; (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor -5-prostenoic acid isopropyl ester; (5Z, 13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetr anor-5,13-prostadienoic acid amide; PGF.sub.2.alpha. isopropyl ester; fluprostenol isopropyl ester; and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-but enyl]-4-hydroxy-3-furanyl]-4-heptenoate.

5. The composition of claim 4 wherein the prostaglandin is selected from the group consisting of fluprostenol isopropyl ester; isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1 -butenyl]-4-hydroxy-3-furanyl]-4-heptenoate; latanoprost; and 15-keto latanoprost.

6. The composition of claim 1 wherein the composition is a topically administrable ophthalmic composition and the prostaglandin is selected from the group consisting of fluprostenol isopropyl ester and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-but enyl]-4-hydroxy-3-furanyl]-4-heptenoate.

7. The composition of claim 6 wherein the fluprostenol isopropyl ester is 1R-[1.alpha.(Z),2.beta.(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3-h ydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester.

8. The composition of claim 7 wherein the composition has a pH of 5.8-6.2 and comprises 0.0001-0.005%(w/v) 1R-[1.alpha.(Z),2.beta.(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3-h ydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester; 0.5%(w/v) PEG-40 hydrogenated castor oil; 0.12%(w/v) tromethamine; 0.3%(w/v) boric acid; 4.6%(w/v) mannitol; 0.01%(w/v) disodium edetate; and 0.015%(w/v) benzalkonium chloride.

9. The composition of claim 8 wherein the concentration of 1R-[1.alpha.(Z),2.beta.(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3-h ydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester is selected from the group consisting of 0.0015%(w/v) and 0.004%(w/v).

10. The composition of claim 1 wherein the composition has a pH of 5.8-6.2 and comprises 0.01%(w/v) isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-but enyl]-4-hydroxy-3-furanyl]-4-heptenoate; 0.5%(w/v) PEG-40 hydrogenated castor oil; 0.12%(w/v) tromethamine; 0.3%(w/v) boric acid; 4.6%(w/v) mannitol; 0.01%(w/v) disodium edetate; and 0.015%(w/v) benzalkonium chloride.

11. The composition of claim 1 wherein the composition has a pH of 5.8-6.2 and comprises 0.002%(w/v) 1R-[1.alpha.(Z),2.beta.,(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3- hydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester; 0.02%(w/v) brimonidine; 0.5%(w/v) PEG-40 hydrogenated castor oil; 0.785%(w/v) tromethamine; 0.6%(w/v) boric acid; 4.25%(w/v) mannitol; 0.01%(w/v) disodium edetate; and 0.015%(w/v) benzalkonium chloride.

12. A method of enhancing the chemical stability of an aqueous composition comprising a therapeutically-effective amount of a prostaglandin, wherein the method comprises adding a chemically-stabilizing amount of a polyethoxylated castor oil selected from the group of PEG-5 to PEG-200 hydrogenated castor oils to the composition.

13. The method of claim 12 wherein the polyethoxylated castor oil is selected from the group of PEG-25 to PEG-55 hydrogenated castor oils.

14. The method of claim 13 wherein the polyethoxylated castor oil is PEG-40 hydrogenated castor oil.

15. The method of claim 12 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid; (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentano r-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pe ntanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid amide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid N,N-dimethylamide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid cyclopentyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid adamantyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester; (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,2 0-tetranor-5,13-prostadienoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17 ,18,19,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pe ntanor-5-prostenoic acid isopropyl ester; (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,2 0-pentanor-5-prostenoic acid tertbutyl ester; (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-pro stenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18, 19,20-pentanor-5-prostene-11,15-diol; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19 ,20-pentanor-5-prostenol; 9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentan or-13-prostynoic acid; latanoprost; 15-keto latanoprost; cloprostenol isopropyl ester; (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16- [(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid; (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16- [(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pe ntanor-5-prostenoic acid isopropyl ester; (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor -5-prostenoic acid isopropyl ester; (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20- tetranor-5,13-prostadienoic acid amide; PGF.sub.2.alpha. isopropyl ester; fluprostenol isopropyl ester; and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-but enyl]-4-hydroxy-3-furanyl]-4-heptenoate.

16. The method of claim 15 wherein the composition comprises 0.001-0.005% (w/v) prostaglandin; 0.5%(w/v) PEG-40 hydrogenated castor oil; 0.12%(w/v) tromethamine; 0.3%(w/v) boric acid; 4.6%(w/v) mannitol; 0.01%(w/v) disodium edetate; and 0.015%(w/v) benzalkonium chloride; and the prostaglandin is selected from the group consisting of fluprostenol isopropyl ester and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-but enyl]-4-hydroxy-3-furanyl]-4-heptenoate.

17. The method of claim 16 wherein the fluprostenol isopropyl ester is 1R-[1.alpha.(Z),2.beta.(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3-h ydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester.

18. The method of claim 15 wherein the composition comprises 0.002%(w/v) 1R-[1.alpha.(Z),2.beta.(1E,3R*),3.alpha.,5.alpha.]-7-[3,5-dihydroxy-2-[3-h ydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester; 0.02%(w/v) brimonidine; 0.5%(w/v) PEG-40 hydrogenated castor oil; 0.785%(w/v) tromethamine; 0.6%(w/v) boric acid; 4.25%(w/v) mannitol; 0.01%(w/v) disodium edetate; and 0.015%(w/v) benzalkonium chloride.

19. The method of claim 12 wherein the composition is a topically administrable ophthalmic composition.

20. The method of claim 12 wherein the amount of hydrogenated polyethoxylated castor oil is between about 0.02 and 20 wt. %.
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