Claims for Patent: 6,787,531

Summary for Patent: 6,787,531

Title:	Pharmaceutical composition for use as a contraceptive
Abstract:	A pharmaceutical composition comprises, as a first active agent, 6.beta.,7.beta.; 15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolacto ne (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, 17.alpha.-ethinylestradiol (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment, the composition consists of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein said daily dosage units comprises the combination of drospirenone and ethinylestradiol. The composition may further comprise 7 or less daily dosage units containing no active agent or containing ethinylestradiol alone.
Inventor(s):	Hilman; Juergen (Berlin, DE), Heil; Wolfgang (Berlin, DE), Lipp; Ralph (Berlin, DE), Heithecker; Renate (Berlin, DE), Huempel; Michael (Berlin, DE), Tack; Johannes W. (Berlin, DE)
Assignee:	Schering AG (Berlin, DE)
Application Number:	09/654,227
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,787,531
Patent Claims:	1. A pharmaceutical composition comprising from about 2 mg to about 4 mg of micronized drospirenone particles, about 0.01 mg to about 0.05 mg of 17.alpha.-ethinylestradiol, and one or more pharmaceutically acceptable carriers, the composition being in an oral dose form exposed to the gastric environment upon dissolution, and the composition being effective for oral contraception in a human female. 2. A composition according to claim 1, wherein the amount of drospirenone is from about 2.5 mg to about 3.5 mg. 3. A composition according to claim 1 wherein the ethinylestradiol is in micronized form or sprayed from a solution onto particles of an inert carrier. 4. A composition according to claim 1, wherein the amount of ethinylestradiol is from about 0.015 mg to about 0.04 mg. 5. A composition according to claim 1, wherein the amount of drospirenone is from about 3.0 to about 3.5 mg and the amount of ethinylestradiol is from about 0.015 to about 0.03 mg. 6. A composition according to claim 1, wherein the pharmaceutically acceptable carrier promotes rapid dissolution of the drospirenone and 17.alpha.-ethinylestradiol, the dissolution being determined by applying the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at a stirring rate of 50 rpm, including 6 covered glass vessels and 6 paddles, the dissolution media being 900 ml of water at 37.degree. C. (.+-.0.5.degree. C.), and wherein rapid dissolution means that at least 70% of the drospirenone, when provided as a tablet containing 3 mg of drospirenone, is dissolved within 30 minutes. 7. A composition according to claim 6, wherein at least 80% of the drospirenone is dissolved within 20 minutes. 8. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of 21 consecutive days, wherein said daily dosage units each comprise a combination of micronized drospirenone particles in an amount of from about 2 mg to about 4 mg and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 9. A kit according to claim 8, which additionally comprises 7 daily dosage units containing no active agent intended for oral administration subsequent to the period of 21 consecutive days, the total number of daily dosage units being at least 28. 10. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of 22, 23 or 24 consecutive days, wherein said daily dosage units each comprise a combination of micronized drospirenone particles in an amount of from about 2 mg to about 4 mg and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and a number of daily dosage units containing no active agent which is 6, 5 or 4, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 11. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of 28, or a multiple of 28, consecutive days, wherein said daily dosage units each comprise a combination of micronized drospirenone particles in an amount of from about 2 mg to about 4 mg and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 12. A kit according to claim 11, which additionally comprises a number of daily dosage units comprising the combination of drospirenone and ethinylestradiol which is a multiple of 21, 22, 23 or 24, and comprises a number of daily dosage units containing no active agent which is a multiple of 7, 6, 5 or 4. 13. A kit according to claim 8, wherein the 21 daily dosage units comprise drospirenone in an amount of from about 2.5 mg to about 3.5 mg and 17.alpha.-ethinylestradiol in an amount of from about 0.015 mg to about 0.04 mg. 14. A kit according to claim 8, wherein the daily dosage units comprise drospirenone in an amount of from about 3.0 to about 3.5 mg and 17.alpha.-ethinylestradiol in an amount of from about 0.015 to about 0.03 mg. 15. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprise a combination of micronized drospirenone particles in an amount of from about 2 mg to about 4 mg and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, wherein at least 1 but no more than 7 of said daily dosage units contain 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg and contain no drospirenone, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 16. A kit according to claim 13, wherein the number of daily dosage units comprising the combination of drospirenone and ethinylestradiol is 21, 22, 23 or 24, and wherein the number of daily dosage units comprising ethinylestradiol without drospirenone is 7, 6, 5 or 4. 17. A kit according to claim 15, wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 2.5 mg to about 3.5 mg and 17.alpha.-ethinylestradiol in an amount of from about 0.015 mg to about 0.04 mg. 18. A kit according to claim 15, wherein the at least 21 daily dosage units comprise drospirenone in an amount of from about 3.0 to about 3.5 mg and 17.alpha.-ethinylestradiol in an amount of from about 0.015 to about 0.03 mg. 19. The composition of claim 1, wherein the drospirenone is in the form of a prodrug of the compound. 20. The composition of claim 1, wherein the 17.alpha.-ethinylestradiol is in the form of an ester or ether of the compound. 21. The composition of claim 1, wherein the drospirenone is provided together with a carrier which is of carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. 22. The kit of claim 8, wherein the drospirenone is provided together with a carrier which is of carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. 23. The kit of claim 15, wherein the drospirenone is provided together with a carrier which is of carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. 24. The kit of claim 8, wherein both the drospirenone and 17.alpha.-ethinylestradiol are micronized. 25. The kit of claim 15, wherein both the drospirenone and 17.alpha.-ethinylestradiol are micronized. 26. The composition of claim 19, wherein the prodrug is an ester of drospirenone. 27. A pharmaceutical composition comprising: from about 2 mg to about 4 mg of drospirenone particles, wherein the drospirenone has a surface area of more than 10 000 cm.sup.2 /g, about 0.01 to about 0.05 mg of 17.alpha.-ethinylestradiol, and one or more pharmaceutically acceptable carriers, the composition being in an oral dose form exposed to the gastric environment upon dissolution, and the composition being effective for oral contraception in a human female. 28. A pharmaceutical composition comprising: from about 2 mg to about 4 mg of drospirenone particles, wherein the drospirenone is in a form, which when provided in a tablet containing 3 mg of drospirenone, has a dissolution such that at least 70% of said drospirenone is dissolved in 900 ml of water at 37.degree. C. (.+-.0.5.degree. C.) within 30 minutes, as determined by USP XXIII Paddle Method using a USP dissolution test apparatus 2 at a stirring rate of 50 rpm, including 6 covered glass vessels and 6 paddles, about 0.01 mg to about 0.05 mg of 17.alpha.-ethinylestradiol, and one or more pharmaceutically acceptable carriers, the composition being in an oral dose form exposed to the gastric environment upon dissolution, and the composition being effective for oral contraception in a human female. 29. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of 21 consecutive days, wherein said daily dosage units each comprise a combination of drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone has a surface area of more than 10 000 cm.sup.2 /g, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 30. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit and intended for oral administration for a period of 21 consecutive days, wherein said daily dosage units each comprise a combination of: drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone is in a form, which when provided in a tablet containing 3 mg of drospirenone, has a dissolution such that at least 70% of said drospirenone is dissolved in 900 ml of water at 37.degree. C. (.+-.0.5.degree. C.) within 30 minutes, as determined by USP XXIII Paddle Method using a USP dissolution test apparatus 2 at a stirring rate of 50 rpm, including 6 covered glass vessels and 6 paddles, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 31. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprise a combination of: drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone has a surface area of more than 10 000 cm.sup.2 /g, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein at least 1 but no more than 7 of said daily dosage units contain 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg and contain no drospirenone, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 32. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit and intended for oral administration for a period of at least 28 consecutive days, wherein at least 21 of said daily dosage units comprise a combination of drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone is in a form, which when provided in a tablet containing 3 mg of drospirenone, has a dissolution such that at least 70% of said drospirenone is dissolved in 900 ml of water at 37.degree. C. (.+-.0.5.degree. C.) within 30 minutes, as determined by USP XXIII Paddle Method using a USP dissolution test apparatus 2 at a stirring rate of 50 rpm, including 6 covered glass vessels and 6 paddles, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, and wherein at least 1 but no more than 7 of said daily dosage units contain 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg and contain no drospirenone, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 33. A composition or kit of claim 28, 30 or 32, wherein at least 80% of said drospirenone is dissolved within 20 minutes by the stated test. 34. A composition or kit according to claim 27, 28, 29, 30, 31, or 32, wherein the 17.alpha.-ethinylestradiol is in micronized form. 35. A composition or kit according to claim 27, 28, 29, 30, 31 or 32, wherein the 17.alpha.-ethinylestradiol is sprayed from a solution onto particles of an inert carrier. 36. A composition or kit according to claim 27, 28, 29, 30, 31 or 32, wherein the amount of drospirenone is from 2.5 to 3.5 mg. 37. A composition or kit according to claim 27, 28, 29, 30, 31 or 32, wherein the amount of 17.alpha.-ethinylestradiol is from 0.015 to 0.04 mg. 38. A composition or kit according to claim 27, 28, 29, 30, 31 or 32 comprising a carrier effective to promote dissolution of drospirenone and ethinylestradiol. 39. A composition or kit according to claim 38 wherein said carrier is polyvinylpyrrolidone. 40. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit, including active daily dosage units which comprise a combination of micronized drospirenone particles in an amount of from about 2 mg to about 4 mg and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, wherein the kit is adapted for administering active daily dosage units for multiple cycles of 28 consecutive days each, followed by administering the active daily dosage units for 21, 22, 23 or 24 consecutive days and subsequently administering daily dosage units containing no active agent, or administering no daily dosage units, for 7, 6, 5 or 4 consecutive days, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 41. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit, including active daily dosage units which comprise a combination of: drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone is in a form, which when provided in a tablet containing 3 mg of drospirenone, has a dissolution such that at least 70% of said drospirenone is dissolved in 900 ml of water at 37.degree. C. (.+-.0.5.degree. C.) within 30 minutes, as determined by USP XXIII Paddle Method using a USP dissolution test apparatus 2 at a stirring rate of 50 rpm, including 6 covered glass vessels and 6 paddles, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, wherein the kit is adapted for administering active daily dosage units for multiple cycles of 28 consecutive days each, followed by administering active daily dosage units for 21, 22, 23 or 24 consecutive days and subsequently administering daily dosage units containing no active agent, or administering no daily dosage units, for 7, 6, 5 or 4 consecutive days, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 42. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, in a packaging unit, including active daily dosage units which comprise a combination of: drospirenone particles in an amount of from about 2 mg to about 4 mg, wherein the drospirenone has a surface area of more than 10 000 cm.sup.2 /g, and 17.alpha.-ethinylestradiol in an amount from about 0.01 to about 0.05 mg, wherein the kit is adapted for administering active daily dosage units for multiple cycles of 28 consecutive days each, followed by administering active daily dosage units for 21, 22, 23 or 24 consecutive days and subsequently administering daily dosage units containing no active agent, or administering no daily dosage units, for 7, 6, 5 or 4 consecutive days, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 43. The kit according to claim 40, 41 or 42, wherein the multiple cycles of 28 consecutive days each is 2 to 4 such cycles. 44. A composition or kit according to claim 27, 28, 29, 30, 31, 32, 40, 41, 42 or 43 wherein the amount of drospirenone is from about 3.0 to about 3.5 mg and the amount of 17.alpha.-ethinylestradiol is from about 0.015 to about 0.03 mg. 45. A composition or kit according to claim 1, 27, 28, 29, 30, 31, 32, 40, 41, 42 or 43, wherein the amount of drospirenone is from 2.5 mg to 3.5 mg, and the amount of 17.alpha.-ethinylestradiol is from 0.015 mg to 0.04 mg. 46. A composition or kit according to claim 1, 8, 15, 27, 28, 29, 30, 31, 32, 40, 41, 42 or 43 wherein the 17.alpha.-ethinylestradiol is provided in an amount of from about 0.01 to about 0.04 mg and the drospirenone is provided in a form whereby the drospirenone is exposed to the gastric environment upon dissolution. 47. A composition according to claim 1, 27 or 28, wherein the composition is provided in a tablet, pill or capsule oral dosage form. 48. A kit according to claim 8, 15, 29, 30, 31, 32, 40, 41, 42 or 43 wherein the daily dosage units are provided in a tablet, pill or capsule oral dosage form. 49. A pharmaceutical composition comprising about 3 mg of micronized drospirenone particles, about 0.03 mg of micronized 17.alpha.-ethinylestradiol, and one or more pharmaceutically acceptable carriers, the composition being in a tablet, capsule or pill oral dose exposed to the gastric environment upon dissolution, and the composition being effective for oral contraception in a human female. 50. A pharmaceutical kit comprising a number of separately packaged, individually removable, daily dosage units, in an oral dose form exposed to the gastric environment upon dissolution, placed in a packaging unit and intended for oral administration for a period of 28 consecutive days, wherein 21 of said daily dosage units comprise a combination of micronized drospirenone particles in an amount of about 3 mg and micronized 17.alpha.-ethinylestradiol in an amount of about 0.03 mg, and wherein 7 of said daily dosage units contain no drospirenone or 17.alpha.-ethinylestradiol, and wherein said daily dosage units comprising drospirenone are effective for oral contraception in a human female. 51. The composition of claim 19, wherein the prodrug is an ester of drospirenone. 52. A kit according to claim 11, which additionally comprises daily dosage units comprising the combination of drospirenone and ethinylestradiol for 21, 22, 23 or 24 consecutive days and subsequent daily dosage units containing no active agent for 7, 6, 5 or 4 consecutive days.