Hormone preparation and method

• US 5,382,573 A
• Filed: 10/29/1993
• Issued: 01/17/1995
• Est. Priority Date: 09/24/1987
• Status: Expired due to Term

• Current Assignee: Jencap Research Ltd.
• Original Assignee: Jencap Research Ltd.
• Inventors: Casper, Robert F.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US08/143,055
• Time in Patent Office: 445 Days
• Field of Search: 514/170, 514/171
• 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 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Abstract

This invention is concerned with a contraceptive formulation and a method of contraception which employs a combination of estrogen and progestin and wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity. The invention also concerns a hormonal replacement formulation and method for use in menopausal or castrate women which employs a similar combination of estrogen and progestin.

Claims

1. A pharmaceutical preparation for administration to a female in need of hormone replacement therapy comprising repeating cycles of a pharmaceutical regimen, each cycle comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain

i) an amount of a substance exhibiting estrogen activity or

ii) an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity, and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulfate, and the amount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone.

2. A pharmaceutical preparation according to claim 1 wherein the daily unit doses of said estrogen dominant phases contain an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases contain an amount of substance exhibiting progestin activity which exhibits a progestin activity equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases.

3. A pharmaceutical preparation according to claim 1, wherein all of said daily unit doses contain a uniform amount of said substance exhibiting estrogen activity.

4. A pharmaceutical preparation according to claim 1, wherein the daily unit doses of said estrogen dominant phases are free of substance exhibiting progestin activity.

5. A pharmaceutical preparation according to claim 1, wherein said substance exhibiting estrogen activity is selected from the group consisting of 17α

-ethinyl estradiol, 17β

-estradiol, 17β

-estradiol valerate, conjugated equine estrogens, piperazine estrone sulfate, and estropipate, and said substance exhibiting progestin activity is selected from the group consisting of norethindrone, desogestrel, levo-norgestrel, norgestimate, progesterone, medroxy-progesterone acetate, gestodene, and cyproterone acetate.

6. A pharmaceutical preparation according to claim 1, wherein said daily unit doses are in a form selected from the group consisting of orally administrable form, transdermally administrable form, and buccally administrable form.

7. A pharmaceutical preparation according to claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of two daily unit doses each alternating with progestin dominant phases of two daily unit doses each.

8. A pharmaceutical preparation according to claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of three daily unit doses each.

9. A pharmaceutical preparation according to claim 1, wherein said preparation is a hormone replacement therapy preparation, and each of said daily unit doses contains an amount of substance exhibiting estrogen activity which exhibits an estrogen activity equivalent to from 0.3 to 2.5 mg of piperazine estrone sulfate, and an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 5 mg norethindrone.

10. A pharmaceutical preparation according to claim 9, wherein each estrogen dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate, and each progestin dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.

11. A pharmaceutical preparation according to claim 9, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.35 mg norethindrone.

12. A pharmaceutical preparation according to claim 9, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.15 mg norethindrone, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.35 mg norethindrone.

13. A pharmaceutical preparation according to claim 9, wherein three unit doses of 1.0 mg of 17-estradiol are alternated with three unit doses of 1.0 mg of 17-estradiol and 0.35 mg norethindrone.

14. A pharmaceutical package containing a least one cycle of a pharmaceutical regimen for administration to a female in need of hormone replacement therapy, each said cycle comprising repeating cycles of a pharmaceutical regimen, each cycle comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain i) an amount of a substance exhibiting estrogen activity or ii) an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity, and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulfate, and the amount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone.

15. A pharmaceutical package according to claim 14, wherein the daily unit doses of said estrogen dominant phases contain an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases contain an amount of substance exhibiting progestin activity which exhibits a progestin activity equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases.

16. A pharmaceutical package according to claim 14, wherein all of said daily unit doses contain a uniform amount of said substance exhibiting estrogen activity.

17. A pharmaceutical package according to claim 14, wherein the daily unit doses of said estrogen dominant phases are free of substance exhibiting progestin activity.

18. A pharmaceutical package according to claim 14, wherein said substance exhibiting estrogen activity is selected from the group consisting of 17α

-ethinyl estradiol, 17β

estradiol, 17β

-estradiol valerate, conjugated equine estrogens, piperazine estrone sulfate, and estropipate, and said substance exhibiting progestin activity is selected from the group consisting of norethindrone, desogestrel, levo-norgestrel, norgestimate, progesterone, gestodene, cyproterone acetate and medroxy-progesterone acetate.

19. A pharmaceutical package according to claim 14, wherein said daily unit doses are in a form selected from the group consisting of orally administrable form, transdermally administrable form, and buccally administrable form.

20. A pharmaceutical package according to claim 14, containing a series of consecutive daily unit doses arranged in estrogen dominant phases of two daily unit doses each alternating with progestin dominant phases of two daily unit doses each.

21. A pharmaceutical package according to claim 14, containing a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of three daily unit doses each.

22. A pharmaceutical package according to claim 14, containing a hormone replacement therapy preparation, wherein each of said daily unit doses contains an amount of substance exhibiting estrogen activity equivalent to from 0.3 to 2.5 mg of piperazine estrone sulfate, and an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 5 mg norethindrone.

23. A pharmaceutical package according to claim 22, wherein each estrogen dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate, and each progestin dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.

24. A pharmaceutical package according to claim 22, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.35 mg norethindrone.

25. A pharmaceutical package according to claim 22, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.15 mg norethindrone, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17β

-estradiol and 0.35 mg norethindrone.

26. A pharmaceutical package according to claim 22, wherein three unit doses of 1.0 mg of 17β

-estradiol are alternated with three unit doses of 1.0 mg of 17β

-estradiol and 0.35 mg of norethindrone.