Claims for Patent: 6,958,326

Summary for Patent: 6,958,326

Title:	Cyclodextrin-drospirenone inclusion 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 AG (Berlin, DE)
Application Number:	10/022,845
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,958,326
Patent Claims:	1. A composition comprising: i) a granulated preparation comprising a complex between an estrogen and a cyclodextrin; and ii) optionally, one or more excipients, the composition having 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); and the composition being essentially free of polyvinylpyrrolidone. 2. The composition according to claim 1, wherein the estrogen is in an amount from about 0.002% w/w to 2% w/w. 3. The composition according to claim 1, wherein the estrogen is in an amount from about 0.004% w/w to 0.2% w/w. 4. The composition according to claim 1, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, 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. 5. The composition according to claim 1, wherein the estrogen is ethinyl estradiol and the cyclodextrin is .beta.-cyclodextrin, 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. 6. A method for improving the stability of an estrogen in a pharmaceutical composition that comprises an estrogen and one or more excipients in a granulate preparation, which method comprises: i) forming a complex between said estrogen and a cyclodextrin; and ii) granulating the complex to provide the granulate preparation; provided that, the composition is prepared so that it is essentially free of polyvinylpyrrolidone. 7. A process for manufacturing a granulate preparation comprising a complex between an estrogen and a cyclodextrin, which comprises: i) loading the complex, optionally one or more other therapeutically active agent(s), and one or more excipients into a granulator; ii) applying a liquid onto the loaded complex and the one or more excipients, and granulating and drying, so as to obtain granules having a relative humidity not exceeding 60%, as determined at a temperature between 20.degree. C. and 40.degree. C. 8. The process according to claim 7, wherein the complex and the optionally further one or more therapeutically active agent(s) are provided as individual agent(s) without being pre-mixed with excipients. 9. The process according to claim 7, wherein the relative humidity of the granulate preparation does not exceed 55%, as determined at a temperature between 20.degree. C. and 40.degree. C. 10. The process according to claim 7, wherein the relative humidity of the granulate preparation does not exceed 45%, as determined at a temperature between 20.degree. C. and 40.degree. C. 11. The process according to claim 7, wherein the relative humidity of the granulate preparation does not exceed 40%, as determined at a temperature between 20.degree. C. and 40.degree. C. 12. The composition 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. 13. The composition according to claim 1, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof. 14. The composition according to claim 13, wherein the estrogen is ethinyl estradiol. 15. The composition 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. 16. The composition according to claim 1, wherein the cyclodextrin is .beta.-cyclodextrin or an alkylated or acylated derivative thereof. 17. The composition 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. 18. The composition according to claim 1, further comprising one or more other therapeutically active agent(s). 19. The composition according to claim 18, wherein the one or more other therapeutically active agent(s) is a progestogen. 20. The composition according to claim 19, wherein the progestogen is selected from the group consisting of drospirenone, levonorgestrel, norgestrel, gestodene, dienogest, cyproterone acetate, norethisterone, norethisterone acetate, desorgestrel, and 3-keto-desorgestrel. 21. The composition according to claim 20, wherein the progestogen is drospirenone. 22. The composition according to claim 21, wherein drospirenone is in micronized form. 23. The composition according to claim 22, wherein drospirenone is in an amount from about 0.4% to 20% w/w. 24. The composition according to claim 1, wherein the complex is micronized. 25. The composition according to claim 1, further comprising an antioxidant. 26. The composition of claim 1, wherein the granulated preparation has a mean particle size of at least about 100 .mu.m. 27. The method according to claim 6, provided that the one or more excipient(s) is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and maltodextrin. 28. The process according to claim 7, provided that, when the granulated preparation comprises polyvinylpyrrolidone, it is present in an amount of at most 2% w/w. 29. The method according to claim 7, provided that the one or more excipient(s) is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and maltodextrin. 30. The process according to claim 7, wherein the estrogen is selected from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof. 31. The process according to claim 30, wherein the estrogen is ethinyl estradiol. 32. The process of claim 7, wherein the granulating is by fluidized bed granulation.