Details for Patent: 8,298,554
✉ Email this page to a colleague
Title: | Stable pharmaceutical composition and methods of using same |
Abstract: | The present invention relates to, inter alia, pharmaceutical compositions comprising a polyunsaturated fatty acid and to methods of using the same to treat or prevent cardiovascular-related diseases. |
Inventor(s): | Manku; Mehar (Oxford, GB) |
Assignee: | Amarin Pharmaceuticals Ireland Limited (Dublin, IE) |
Filing Date: | Apr 29, 2010 |
Application Number: | 12/769,885 |
Claims: | 1. A pharmaceutical composition comprising at least 95%, by weight of total fatty acids present, eicosapentaenoic acid or ester thereof enclosed in a capsule shell, wherein: (a) the composition has a baseline peroxide value not greater than 5 meq/kg and upon storage of the composition at 25.degree. C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 8 meq/kg (b) the capsule shell is free of succinated gelatin and comprises a film-forming material, a hygroscopic plasticizer selected from glycerin, sorbitol and alkylene glycols, and a non-hygroscopic plasticizer selected from maltitol, lactitol, xylitol, hydrogenated starch hydrolysate and glucose syrup, wherein the hygroscopic plasticizer and non-hygroscopic plasticizer are present in a weight ratio of about 2:1 to about 6:1, and (c) if the capsule shell comprises glycerin and the film-forming material comprises gelatin, the capsule shell has a gelatin:glycerin weight ratio greater than 5:1. 2. The pharmaceutical composition of claim 1 wherein the eicosapentaenoic acid or ester thereof comprises ethyl eicosapentaenoate. 3. The pharmaceutical composition of claim 2 wherein the composition contains less than about 1%, by weight of total fatty acids present, of any individual fatty acid other than ethyl eicosapentaenoate. 4. The pharmaceutical composition of claim 2 wherein the composition contains less than about 0.5%, by weight of total fatty acids present, of any individual fatty acid other than ethyl eicosapentaenoate. 5. The pharmaceutical composition of claim 2 wherein the composition contains less than about 0.3%, by weight of total fatty acids present, docosahexaenoic acid or derivative thereof, if any. 6. The pharmaceutical composition of claim 5 wherein the composition contains substantially no docosahexaenoic acid or derivative thereof. 7. The pharmaceutical composition of claim 1 wherein the composition comprises about 0.1% to about 1%, by weight, of an antioxidant. 8. The pharmaceutical composition of claim 7 wherein the antioxidant is tocopherol. 9. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 25.degree. C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 7 meq/kg. 10. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 25.degree. C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 6 meq/kg. 11. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 30.degree. C. and 65% RH for a period of 6 months, the composition has a second peroxide value not greater than 12 meq/kg. 12. The pharmaceutical composition of claim 11 wherein upon storage of the composition at 30.degree. C. and 65% RH for a period of 6 months, the composition has a second peroxide value not greater than 10 meq/kg. 13. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 30.degree. C. and 65% RH for a period of 6 months, the composition has a second peroxide value not greater than 10 meq/kg. 14. The pharmaceutical composition of claim 13 wherein upon storage of the composition at 30.degree. C. and 65% RH for a period of 6 months, the composition has a second peroxide value not greater than 6 meq/kg. 15. The pharmaceutical composition of claim 1 wherein the film-forming material comprises gelatin and the capsule shell has a weight ratio of gelatin to glycerol of at least about 5.2:1. 16. The pharmaceutical composition of claim 1 wherein the capsule shell has a hygroscopic plasticizer to non-hygroscopic plasticizer weight ratio of about 3:1 to about 5:1. 17. The pharmaceutical composition of claim 1 wherein the composition has a dissolution profile as measured by rotating dialysis cell method wherein: (1) at least about 20% of the eicosapentaenoic acid or ester thereof is dissolved by 10 minutes; (2) at least about 50% of the eicosapentaenoic acid or ester thereof is dissolved by 30 minutes; (3) at least about 80% of the eicosapentaenoic acid or ester thereof is dissolved by 60 minutes; (4) at least about 95% of the eicosapentaenoic acid or ester thereof is dissolved by 100 minutes. 18. The pharmaceutical composition of claim 17 wherein the composition has a dissolution profile as measured by rotating dialysis cell method wherein: (1) at least about 20% of the eicosapentaenoic acid or ester thereof is dissolved by 10 minutes; (2) at least about 45% of the eicosapentaenoic acid or ester thereof is dissolved by 30 minutes; (3) at least about 80% of the eicosapentaenoic acid or ester thereof is dissolved by 60 minutes; and (4) at least about 95% of the eicosapentaenoic acid or ester thereof is dissolved by 100 minutes. 19. The pharmaceutical composition of claim 1 wherein upon administration of said composition to a human subject, the subject achieves an eicosapentaenoic acid T.sub.max within 5.8 hours of said administration. 20. A pharmaceutical composition comprising at least about 95%, by weight of total fatty acids present, ethyl eicosapentaenoate enclosed in a capsule shell, wherein the composition has a baseline peroxide value not greater than 5 meq/kg and upon storage of the composition at 30.degree. C. and 65% RH for a period of 6 months, the composition has a second peroxide value not greater than 5 meq/kg wherein the capsule shell comprises a film-forming material free of chemically modified gelatin, a hygroscopic plasticizer selected from glycerol, sorbitol and alkylene glycols, and a non-hygroscopic plasticizer selected from maltitol, lactitol, xylitol, hydrogenated starch hydrolysate and glucose syrup, the capsule shell having a weight ratio of hygroscopic plasticizer to non-hygroscopic plasticizer of about 2:1 to about 6:1, and wherein if the capsule shell comprises glycerol and the film-forming material comprises gelatin, the capsule shell has a gelatin:glycerol weight ratio greater than 5:1. 21. The pharmaceutical composition of claim 20 wherein the hygroscopic plasticizer comprises glycerol. 22. The pharmaceutical composition of claim 21 wherein the capsule shell has a weight ratio of gelatin to glycerol of at least about 5.2:1. 23. The pharmaceutical composition of claim 22 wherein the non-hygroscopic plasticizer comprises maltitol. 24. The pharmaceutical composition of claim 20 wherein the capsule shell has a hygroscopic plasticizer to non-hygroscopic plasticizer weight ratio of about 3:1 to about 5:1. 25. A pharmaceutical composition comprising at least about 95%, by weight of total fatty acids present, ethyl eicosapentaenoate encapsulated in a capsule shell comprising gelatin, a hygroscopic plasticizer selected from glycerol, sorbitol and alkylene glycols, and a non-hygroscopic plasticizer selected from maltitol, lactitol, xylitol, hydrogenated starch hydrolysate and glucose syrup, wherein the capsule shell has a weight ratio of gelatin to total plasticizer of about 1.75:1 to about 5:1 and a weight ratio of hygroscopic plasticizer to non-hygroscopic plasticizer of about 3:1 to about 5:1 and is free of chemically modified gelatin, the composition has a baseline peroxide value not greater than 5 meg/kg and upon storage of the composition at 25.degree. C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 8 meq/kg and if the film-forming material comprises gelatin, the capsule shell has a gelatin:glycerol weight ratio greater than 5:1. 26. The composition of claim 25 wherein the hygroscopic plasticizer comprises glycerol and sorbitol and the non-hygroscopic plasticizer comprises maltitol. 27. The pharmaceutical composition of claim 25 wherein the composition has a baseline peroxide value not greater than 5 meq/kg and upon storage of the composition at 25.degree. C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 5 meg/kg. 28. The pharmaceutical composition of claim 25 wherein the composition has a dissolution profile as measured by rotating dialysis cell method at a paddle speed 100 rpm and a pH 1.2, wherein: (1) at least about 20% of the ethyl eicosapentaenoate is dissolved by 10 minutes; (2) at least about 50% of the ethyl eicosapentaenoate is dissolved by 30 minutes; (3) at least about 80% of the ethyl eicosapentaenoate is dissolved by 60 minutes; or (4) at least about 95% of the ethyl eicosapentaenoate is dissolved by 100 minutes. 29. The pharmaceutical composition of claim 28 wherein the composition has a dissolution profile as measured by rotating dialysis cell method at a paddle speed 100 rpm and a pH 1.2, wherein: (1) at least about 20% of the ethyl eicosapentaenoate is dissolved by 10 minutes; (2) at least about 45% of the ethyl eicosapentaenoate is dissolved by 30 minutes; (3) at least about 80% of the ethyl eicosapentaenoate is dissolved by 60 minutes; and (4) at least about 95% of the ethyl eicosapentaenoate is dissolved by 100 minutes. 30. The pharmaceutical composition of claim 27 wherein upon administration of said composition to a human subject, the subject achieves an eicosapentaenoic acid T.sub.max within 5.8 hours of said administration. 31. The pharmaceutical composition of claim 30 wherein the capsule shell has a gelatin to glycerol ratio of at least 5.2:1. |