Claims for Patent: 7,163,931

Summary for Patent: 7,163,931

Title:	Compositions of estrogen-cyclodextrin complexes
Abstract:	Pharmaceutical compositions comprising low doses of sensitive complexes between an estrogen and a cyclodextrin are provided with improved stability. In specific embodiments the composition comprises a complex between ethinyl estradiol and .beta.-cyclodextrin in a granulate preparation and in yet another embodiment the composition comprises a limited amount of polyvinylpyrrolidone since this excipient was found to degrade ethinyl estradiol. Furthermore, a method for improving the stability of an estrogen in a composition and for manufacturing such a stable composition is provided. Essentially, the granulate preparation are manufactured under careful control of the relative humidity.
Inventor(s):	Backensfeld; Thomas (Berlin, DE), Heil; Wolfgang (Berlin, DE), Lipp; Ralph (Berlin, DE)
Assignee:	Schering Aktiengesellchaft (Berlin, DE)
Application Number:	11/102,681
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,163,931
Patent Claims:	1. A method for inhibiting ovulation in a female comprising administering to the female a composition comprising: i) a complex between an estrogen and a cyclodextrin; ii) drospirenone; and iii) one or more excipients, the composition having a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of said estrogen after storage for 12 months at 40.degree. C. and 75% relative humidity (RH). 2. The method of claim 1, wherein the complex between an estrogen and a cyclodextrin is a granulate preparation having a relative humidity of at most 60%, as determined at a temperature between 20.degree. C. and 40.degree. C. 3. The method of claim 1, wherein the estrogen is in an amount corresponding to a therapeutically equivalent amount of ethinyl estradiol of from about 0.002% w/w to 2% w/w, based on the total composition. 4. The method of claim 1, wherein the estrogen is in an amount from about 0.002% w/w to 2% w/w, based on the total composition. 5. The method of claim 1, wherein the estrogen is in an amount from about 0.004% w/w to 0.2% w/w, based on the total composition. 6. The method of claim 1, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, and the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-.beta.-cyclodextrin complex of from about 5% w/w to 20% w/w. 7. The method of claim 1, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, and the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-.beta.-cyclodextrin complex of from about 8% w/w to 15% w/w. 8. The method of claim 1, wherein the amount of drospirenone is from about 0.4% to 20% w/w. 9. The method of claim 1, wherein the amount of drospirenone is from about 0.8% w/w to 10% w/w, based on the total composition. 10. The method of claim 1, wherein the amount of drospirenone is from about 1.5% w/w to 5% w/w, based on the total composition. 11. The method of claim 1, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 2% w/w. 12. The method according to claim 1, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 1% w/w. 13. The method according to claim 1, wherein the one or more excipients comprises polyvinylpyrrolidone in ah amount of at most 0.5% w/w. 14. The method according to claim 1, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 0.2% w/w. 15. The method according to claim 1, wherein the composition is essentially free of polyvinylpyrrolidone. 16. The method according to claim 1, wherein the composition comprises one or more excipient(s) which is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and maltodextrin. 17. The method according to claim 1, wherein the estrogen in the composition is selected from the group consisting of ethinyl estradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof. 18. The method according to claim 1, wherein the estrogen is ethinyl estradiol. 19. The method according to claim 1, wherein the cyclodextrin is selected from the group consisting of .alpha.-cyclodextrin, .beta.-cyclodextrin, .gamma.-cyclodextrin and alkylated or acylated derivatives thereof. 20. The method according to claim 1, wherein the cyclodextrin is .beta.-cyclodextrin or an alkylated or acylated derivative thereof. 21. The method according to claim 1, wherein the estrogen is in an amount relative to the cyclodextrin such that a molar ratio between the estrogen and the cyclodextrin is from about 2:1 to 1:10. 22. The method according to claim 1, wherein the drospirenone is in micronized form. 23. The method according to claim 1, wherein the complex between an estrogen and a cyclodextrin is micronized. 24. The method according to claim 1, wherein the composition further comprises an antioxidant. 25. The method according to claim 1, wherein the granulated preparation has a mean particle size of at least about 100 .mu.m. 26. The method of claim 1, wherein the composition has a stability such that said estrogen is in an amount of at least 90% w/w in relation to the initial content of said estrogen after storage for 12 months at 40.degree. C. and 75% relative humidity (RH). 27. A method for hormone replacement therapy in a female comprising administering to the female a composition comprising: i) a complex between an estrogen and a cyclodextrin; ii) drospirenone; and iii) one or more excipients, the composition having a stability such that said estrogen is in amount of at least 85% w/w in relation to the initial content of said estrogen after storage for 12 months at 40.degree. C. and 75% relative humidity (RH). 28. The method of claim 27, wherein the complex between an estrogen and a cyclodextrin is a granulate preparation having a relative humidity of at most 60%, as determined at a temperature between 20.degree. C. and 40.degree. C. 29. The method of claim 27, wherein the estrogen is in an amount corresponding to a therapeutically equivalent amount of ethinyl estradiol of from about 0.002% w/w to 2% w/w, based on the total composition. 30. The method of claim 27, wherein the estrogen is in an amount from about 0.002% w/w to 2% w/w, based on the total composition. 31. The method of claim 27, wherein the estrogen is in an amount from about 0.004% w/w to 0.2% w/w, based on the total composition. 32. The method of claim 27, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, and the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-.beta.-cyclodextrin complex of from about 5% w/w to 20% w/w. 33. The method of claim 27, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, and the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-.beta.-cyclodextrin complex of from about 8% w/w to 15% w/w. 34. The method of claim 27, wherein the amount of drospirenone is from about 0.4% to 20% w/w. 35. The method of claim 27, wherein the amount of drospirenone is from about 0.8% w/w to 10% w/w, based on the total composition. 36. The method of claim 27, wherein the amount of drospirenone is from about 1.5% w/w to 5% w/w, based on the total composition. 37. The method of claim 27, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 2% w/w. 38. The method according to claim 27, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 1% w/w. 39. The method according to claim 27, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 0.5% w/w. 40. The method according to claim 27, wherein the one or more excipients comprises polyvinylpyrrolidone in an amount of at most 0.2% w/w. 41. The method according to claim 27, wherein the composition is essentially free of polyvinylpyrrolidone. 42. The method according to claim 27, wherein the composition comprises one or more excipient(s) which is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and maltodextrin. 43. The method according to claim 27, wherein the estrogen in the composition is selected from the group consisting of ethinyl estradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof. 44. The method according to claim 27, wherein the estrogen is ethinyl estradiol. 45. The method according to claim 27, wherein the cyclodextrin is selected from the group consisting of .alpha.-cyclodextrin, .beta.-cyclodextrin, .gamma.-cyclodextrin and alkylated or acylated derivatives thereof. 46. The method according to claim 27, wherein the cyclodextrin is .beta.-cyclodextrin or an alkylated or acylated derivative thereof. 47. The method according to claim 27, wherein the estrogen is in an amount relative to the cyclodextrin such that a molar ratio between the estrogen and the cyclodextrin is from about 2:1 to 1:10. 48. The method according to claim 27, wherein the drospirenone is in micronized form. 49. The method according to claim 27, wherein the complex between an estrogen and a cyclodextrin is micronized. 50. The method according to claim 27, wherein the composition further comprises an antioxidant. 51. The method according to claim 27, wherein the granulated preparation has a mean particle size of at least about 100 .mu.m. 52. The method of claim 27, wherein the composition has a stability such that said estrogen is in an amount of at least 90% w/w in relation to the initial content of said estrogen after storage for 12 months at 40.degree. C. and 75% relative humidity (RH).