Antiprogestin method for reducing side effects associated with low dosage HRT and oral contraception

• US 7,704,983 B1
• Filed: 09/01/1993
• Issued: 04/27/2010
• Est. Priority Date: 03/02/1992
• Status: Expired due to Fees

• Current Assignee: Eastern Virginia Medical School
• Original Assignee: Eastern Virginia Medical School
• Inventors: Chwalisz, Krzysztof, Hodgen, Gary D.
• Primary Examiner(s): Richter; Johann R
• Assistant Examiner(s): Soroush; Ali
• Application Number:
  US08/115,008
• Time in Patent Office: 6,082 Days
• Field of Search: 514178-179, 514/182, 514/843, 514/170
• US Class Current: 514/170
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Abstract

Menses regulation and, when desired, contraception is achieved at low doses of estrogen and progestin, which otherwise would create episodes of breakthrough bleeding and/or withdrawal amenorrhea, by periodically inducing menses with an antiprogestin.

Claims

1. A method of avoiding the bleeding problems associated with administering to a female mammal for contraception dosage amounts of an estrogen low enough to create incidents of breakthrough bleeding and withdrawal amenorrhea, which comprises (a) administering the estrogen daily without interruption and (b) periodically, at intervals of at least about a month, administering to the female an amount of an antiprogestin effective to reduce or eliminate breakthrough bleeding and, optionally, to induce sloughing of accumulated endometrial tissue and thereby induce menses.

2. A method of claim 1, wherein the estrogen and the daily dose thereof is ethinyl estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.

3. A method of claim 1, wherein the estrogen is administered in combination with progestin.

4. A method of claim 3, wherein the amounts of the estrogen and the progestin which are administered are effective to suppress endometrial proliferation.

5. A method of claim 3, wherein the administration of the progestin is continued uninterrupted throughout the cycle.

6. A method of claim 3, wherein the administration of progestin is interrupted proximate the day of antiprogestin administration.

7. A method of claim 1, wherein the antiprogestin is administered about monthly.

8. A method of claim 1, wherein the antiprogestin is administered orally.

9. A method of claim 1, wherein the antiprogestin is onapristone or mifepristone.

10. The method of claim 3, wherein the progestin is gestodene or norethindrone acetate.

11. The method of claim 3, wherein the estrogen, the progestin and the antiprogestin are administered orally;

wherein the administration of the progestin and the estrogen is continued uninterrupted throughout the cycle and wherein the estrogen and the daily dose thereof is ethinyl estradiol or estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.

12. A kit containing at least about 20 estrogen and progestin-containing tablets, which collectively are effective when taken on successive days to achieve continuous oral contraception in a gonadal female human being but which contain amounts thereof which are too low to avoid breakthrough bleeding incidents where administration of the tablets is interrupted for a week during each monthly cycle to induce menses;

and containing a tablet, arranged in the kit so as to be taken after at least 20 of the estrogen and progestin-containing tablets have been taken, which contains an amount of antiprogestin effective to induce menses.

13. A kit according to claim 12, containing 28 of the estrogen and progestin-containing tablets, arranged to be taken sequentially with the antiprogestin-containing tablet positioned as the 20^th or later tablet in the sequence.

14. A kit according to claim 12, wherein the antiprogestin is onapristone or mifepristone;

and wherein the progestin is gestodene or norethindrone acetate.

15. A kit according to claim 12, wherein the estrogen and the daily dose thereof is ethinyl estradiol or estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.

16. A pharmaceutical composition in solid oral unit dosage form comprising amounts of an estrogen and of a progestin contraceptively equivalent to 5 mcg to 35 mcg of ethinyl estradiol and 0.5 mg to 1.5 mg of norethindrone acetate, respectively, and an amount of an antiprogestin effective to induce menses in a female human being who has ingested daily for at least 20 days corresponding amounts of the estrogen and the progestin.

17. A pharmaceutical composition according to claim 16, containing (a) 5-15 mcg of estradiol or ethinyl estradiol or an ester thereof;

(b) 0.5 to 0.75 mg norethindrone acetate or 10 to 15 mcg of gestodene and (c) 50 to 500 mg of onapristone or mifepristone.

18. A method of contraception, comprising administering to a woman in need thereof an effective amount of estrogen, alone or in combination with an effective amount of a progestin, and an amount of antiprogestin effective to ameliorate uterine bleeding problems associated with hormone replacement therapy or contraception.

19. A method of claim 18, wherein the antiprogestin is administered periodically.

20. A method of claim 18, wherein the antiprogestin is administered continuously.

21. A method of avoiding the bleeding problems associated with administering to a female mammal dosage amounts of an estrogen low enough to create incidents of breakthrough bleeding and withdrawal amenorrhea during contraception, which comprises (a) administering the estrogen daily without interruption and optionally a progestin and (b) periodically, at intervals of at least about a month, administering to the female an amount of an antiprogestin effective to reduce or eliminate breakthrough bleeding and, optionally, to induce sloughing of accumulated endometrial tissue whereby menses is induced.

22. The method of claim 21, wherein the estrogen is administered in combination with a progestin in amounts effective to block folliculogenesis and thereby creating a contraceptive state therein and inducing menses upon the administration of antiprogestin.

23. The method of claim 22, wherein the estrogen is administered in combination with a progestin in an amount effect to suppress endometrial proliferation.

24. The method of claim 22, wherein the administration of the progestin and estrogen is continued uninterrupted throughout the cycle, including during menses.

25. The method of claim 22, wherein the administration of the progestin and estrogen is interrupted proximate the day of antiprogestin administration.

26. The method of claim 21, wherein the antiprogestin is administered about monthly.

27. The method of claim 22, wherein the antiprogestin is administered orally.

28. The method of claim 22, wherein the antiprogestin is mifepristone.

29. The method of claim 22, wherein the estrogen is ethinyl estradiol.

30. The method of claim 22, wherein the progestin is norethindrone acetate.

31. The method of claim 21, wherein the amounts of an estrogen and a progestin administered are effective to block folliculogenesis and thereby create a contraceptive state therein;

wherein the antiprogestin is administered orally about monthly; and

wherein the administration of the progestin and the estrogen is continued uninterrupted throughout the cycle, including the menses.

32. The method of claim 31, wherein the antiprogestin is administered at longer than monthly intervals.

33. The method of claim 31, wherein the administration of the progestin is interrupted proximate the day of the antiprogestin administration.

34. The method of claim 31, wherein the antiprogestin is administered orally.

35. The method of claim 31, wherein the antiprogestin is mifepristone.

36. The method of claim 31, wherein the estrogen is ethinyl estradiol or estradiol.

37. The method of claim 31, wherein the progestin is norethindrone acetate.

38. A kit containing at least about 20 estrogen and progestin-containing tablets, which are taken on successive days to achieve continuous oral contraception in a gonadal female human being but which contain amounts thereof which are too low to avoid breakthrough bleeding incidents where administration of the tablets is interrupted for a week during each monthly cycle to induce menses;

and containing a tablet, arranged in a kit so as to be taken after at least 20 of the estrogen and progestin-containing tablets have been taken, which contains an amount of an antiprogestin effective to induce menses.

39. A kit according to claim 38, containing 28 of the estrogen and progestin containing tablets, arranged to be taken sequentially with the anti-progestin containing tablet positioned as the 20^th or later tablet in the sequence.

40. A kit according to claim 38, wherein the estrogen is ethinyl estradiol, the progestin is norethindrone acetate and the antiprogestin is mifepristone.

41. A kit according to claim 38, wherein the estrogen is ethinyl estradiol, the progestin is gestodene and the antiprogestin is onapristone.