Cyclodextrin-drospirenone inclusion complexes

• US 6,610,670 B2
• Filed: 12/20/2001
• Issued: 08/26/2003
• Est. Priority Date: 12/20/2000
• Status: Expired due to Fees

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Heil, Wolfgang, Backensfeld, Thomas
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): LEWIS, PATRICK T
• Application Number:
  US10/022,846
• Publication Number:
  US 20020128229A1
• Time in Patent Office: 614 Days
• Field of Search: 514/54, 514/58, 514/843, 514/167, 514/169, 514/171, 514/172, 536/102, 536/103, 536/123.1
• US Class Current: 514/58
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Abstract

Described are inclusion complexes formed between cyclodextrin and drospirenone. In a specific embodiment of the invention, the cyclodextrin is β-cyclodextrin. The invention further relates to methods of providing such an inclusion complex, and to the use of said inclusion complex for improving the solubility of drospirenone, for providing pharmaceutical compositions, for use as a medicament in the treatment of symptoms associated with menopause and in female contraception.

Claims

1. An inclusion complex comprising cyclodextrin and drospirenone.

2. The inclusion complex according to claim 1, wherein the cyclodextrin is selected from the group consisting of α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin and derivatives thereof wherein derivatives are derivatized by being alkylated, acylated, benzylated, or benzoylated at some or all of the primary or secondary hydroxyls of the macrocycle.

3. The inclusion complex according to claim 2, wherein the cyclodextrin is β

-cyclodextrin or γ

-cyclodextrin.

4. The inclusion complex according to claim 3, wherein the cyclodextrin is β

-cyclodextrin.

5. The inclusion complex according to claim 1, wherein the inclusion complex comprising drospirenone and the cyclodextrin is in a molar ratio, respectively, selected from the group consisting of 1:

1, 2;

1, 3;

1, 3;

2, 1;

2, 2;

2, 2;

3 and 1;

3.

6. The inclusion complex according to claim 5, wherein the ratio is 1:

1, 2;

1 or 1;

2.

7. The inclusion complex according to claim 1 further comprising one or more therapeutically active substances, other than drospirenone.

8. A method for producing an inclusion complex of claim 1 comprising combining cyclodextrin and drospirenone at a molar ratio of, respectively, from 0.3:

1 to 20;

1.

9. The method of claim 8, wherein the ratio is 1:

1, 2;

1, 3;

1, 4;

1 or 5;

1.

10. The method of claim 8, wherein the ratio is 2:

1 or 3;

1.

11. The method according to claim 8, comprising the combining of a solution of drospirenone with a solution of cyclodextrin.

12. The method according to claim 8, comprising the combining of solid drospirenone with a solution of cyclodextrin.

13. The method according to claim 8, wherein the cyclodextrin is in a solution comprising a solvent selected from the group consisting of water, ethanol, acetone, acetonitrile, methanol, DMSO, pyridine and combinations thereof.

14. The method of claim 13, wherein the solution comprises water.

15. The method according to 8, wherein the drospirenone is in a solution comprising a solvent selected from the group consisting of water, ethanol, acetone, acetonitrile, methanol, DMSO, pyridine and combinations thereof.

16. The method of claim 15, wherein the solution comprises water, ethanol or both.

17. The method according to claim 8 comprising;

dissolving cyclodextrin in water, optionally with heating, to form a cyclodextrin solution;

dissolving drospirenone in a solvent selected from the group consisting of water, ethanol and mixtures thereof, optionally with heating, to form a drospirenone solution;

combining the cyclodextrin solution and the drospirenone solution to form a combined solution;

stirring the combined solution;

filtering the resultant precipitate;

washing the precipitate with a solvent selected from the group consisting of water, ethanol, ether and acetone;

optionally, suspending the resultant solid in a solvent and washing the suspended material with a solvent selected from the group consisting of water, ethanol, ether and acetone; and

removing substantially all of the solvent from the resultant or suspended material.

18. The method according to claim 17, wherein the removing of solvent is by spray drying.

19. The method according to claim 17, wherein the removing of solvent is by lyophilization.

20. The method according to claim 8, further comprising combining a therapeutically active substance other than drospirenone to the combined solution of drospirenone, to the drospirenone solution, or to the cyclodextrin solution.

22. A pharmaceutical composition comprising an inclusion complex of claim 1 further comprising one or more pharmaceutically acceptable carriers or excipients.

23. The pharmaceutical composition according to claim 22 adapted to be administered by oral, parenteral, mucosal, topical, vaginal, subcutaneous or nasal administration.

24. The pharmaceutical composition according to claim 22, wherein the amount of drospirenone is from approximately 0.1 mg to 10 mg, per administration dose.

25. The pharmaceutical composition according to claim 22, wherein the complex further comprises one or more therapeutically active substances, other than drospirenone.

26. A method for female contraception comprising administering an inclusion complex as defined by claim 1 to a female.

27. A method for treating menopausal symptoms comprising administering an inclusion complex as defined by claim 1 to a female.

28. The method of claim 17, wherein the solvent used to wash the precipitate has been cooled to below 25°

C.

29. The inclusion complex of claim 2, wherein the cyclodextrin is α

-cyclodextrin, β

-cyclodextrin or γ

-cyclodextrin derivatized by being alkylated, acylated, benzylated or benzoylated at some or all of the primary or secondary hydroxyls of the macrocyle.

30. The inclusion complex of claim 1, wherein the complex is in the form of a hydrate containing between about 1% and 25% water.

31. The inclusion complex of claim 7, wherein the therapeutically active substance other than drospirenone is a steroid.

32. The inclusion complex of claim 7, wherein the therapeutically active substance other than drospirenone is an estrogen, progestogen or gestagen.

33. The pharmaceutical composition of claim 25, wherein the therapeutically active substance other than drospirenone is a steroid.

34. The pharmaceutical composition of claim 25, wherein the therapeutically active substance other than drospirenone is an estrogen, progestogen or gestagen.

21. A method for improving the solubility of drospirenone in water comprising complexing drospirenone with cyclodextrin to form an inclusion complex.