Methods and formulations for use in inhibiting conception and in treating benign gynecological disorders

• US 5,340,584 A
• Filed: 02/01/1993
• Issued: 08/23/1994
• Est. Priority Date: 04/12/1991
• Status: Expired due to Fees

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Spicer, Darcy V., Pike, Malcolm C.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US07/952,513
• Time in Patent Office: 568 Days
• Field of Search: 424/422, 424/423, 424/424, 424/426, 424/430, 424/432, 424/433, 424/484, 424/485, 424/486, 424/487, 424/488, 424/489, 424/490, 424/496, 424/497, 424/498, 424/DIG. 14, 514/2, 514/12, 514/21, 514/800, 514/841, 514/842, 514/843, 530/313, 530/850, 530/853, 128/830, 128/832, 128/833
• US Class Current: 424/426
• 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 31/05 Phenols cannabinoids A61K31/658
• 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
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: Y10S 424/14 Topical contraceptives and spermacides
• CPC Class Codes: Y10S 530/85 Reproductive organs or embryos
• CPC Class Codes: Y10S 530/853 Ovary; eggs; embryos

Abstract

Compositions and methods which are effective to inhibit conception and to treat benign gynecological disorders for extended periods of time are described, wherein an effective amount of a gonadotropin hormone releasing hormone composition and an effective amount of an estrogenic composition are provided over a first period of time, in addition to a progestogen and optionally an androgenic composition. According to one protocol, the progestogen is provided for a second, shorter period of time; the progestogen is provided at a higher level for at least 5 to about 20 days, and then at a lower level for the remainder, if any, of the second period of time. In an alternative protocol, the progestogen is provided at a lower level substantially throughout the period of administration of gonadotropin hormone releasing hormone composition and estrogenic composition. An effective amount of the androgenic hormone is optionally provided over the first period of time.

Claims

1. A composition comprising:

a slow-release formulation of a gonadotropin hormone releasing hormone composition which maintains serum level of said gonadotropin hormone releasing hormone composition in a female mammal at a level effective to suppress ovarian estrogen and progesterone production over a first period of time, said GnRH composition being administered so as to provide between about 0.0001 and about 10 mg/kg of body weight per day;

a slow-release formulation of an estrogenic composition which maintains serum level of said estrogenic composition over said first period of time at a level effective to prevent symptoms of estrogen deficiency, said level being equivalent to a serum level of estradiol of between about 25 and about 140 pg/ml; and

a slow-release formulation of a progestogen which maintains serum level of said progestogen at a first level effective to induce a secretory endometrium for at least 5 to about 20 days and at a second lower level effective to decrease endometrial cell proliferation for a remainder, if any, of a second period of time, said second period of time being substantially shorter than and running simultaneously with a portion of said first period of time, said first level being equivalent to a serum level of progesterone of between about 5 and about 20 ng/ml and said second level being equivalent to a serum level of progesterone of between about 0.5 and about 4 ng/ml.

2. A composition according to claim 1, wherein said gonadotropin hormone releasing hormone composition is selected from the group consisting of gonadotropin hormone releasing hormone, gonadotropin hormone releasing hormone analogues, gonadotropin hormone releasing hormone agonists, gonadotropin hormone releasing hormone antagonists and mixtures thereof.

3. A composition according to claim 2, wherein said gonadotropin hormone releasing hormone composition is a gonadotropin hormone releasing hormone agonist selected from the group consisting of leuprolide acetate, goserelin, decapeptyl, buserelin, nafarelin, deslorelin, histrelin, gonadorelin, [(Imbzl)-D-His⁶ -Pro⁹ Net]GnRH and mixtures thereof.

4. A composition according to claim 1, wherein said estrogenic composition is selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol valerate, estrone, diethylstilbestrol, piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol, estrone potassium sulfate, equilelinin, equilelinin sulfate, estetrol and mixtures of two or more thereof.

5. A composition according to claim 1, wherein said progestogen is selected from the group consisting of dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, megestrol acetate and mixture of two or more thereof.

6. A composition according to claim 1, wherein said first period of time is about two months to about six months.

7. A composition according to claim 6, wherein said first period of time is about three months to about four months.

8. A composition according to claim 1, wherein said second period of time is about 5 days to about 90 days.

9. A composition according to claim 8, wherein said second period of time is less than about 1/4 to about 1/2 of said first period of time.

10. A composition according to claim 1, for administration by a subcutaneous, intramuscular, vaginal or transdermal route.

11. A composition according to claim 1, further comprising:

a slow-release formulation of an androgenic hormone which maintains serum level of said androgenic hormone over said first period of time at a level effective to restore androgen levels to normal premenopausal levels for a patient, said level being equivalent to a serum level of testosterone of between about 20 and about 80 ng/dl.

12. A composition according to claim 11, wherein said androgenic hormone is selected from the group consisting of testosterone, androstenedione, dihydrotestosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone, danazol, dromostanolone propionate, ethylestrenol, methandriol, nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymethalone, stanozolol and testolactone.

13. A composition comprising:

a slow-release formulation of a gonadotropin hormone releasing hormone composition which maintains serum level of said gonadotropin hormone releasing hormone composition in a female mammal at a level effective to suppress ovarian estrogen and progesterone production over a period of time, said GnRH composition being administered so as to provide between about 0.0001 and about 10 mg/kg of body weight per day;

a slow-release formulation of an estrogenic composition which maintains serum level of said estrogenic composition over said period of time at a level effective to prevent symptoms of estrogen deficiency, said level being equivalent to a serum level of estradiol of between about 25 and about 140 pg/ml; and

a slow-release formulation of a progestogen which maintains serum level of said progestogen over said period of time at a level effective to decrease endometrial cell proliferation, said level being equivalent to a serum level of progesterone of between about 0.5 and about 4 ng/ml.

14. A composition according to claim 13, wherein said gonadotropin hormone releasing hormone composition is selected from the group consisting of gonadotropin hormone releasing hormone, gonadotropin hormone releasing hormone analogues, gonadotropin hormone releasing hormone agonists, gonadotropin hormone releasing hormone antagonists and mixtures thereof.

15. A composition according to claim 14, wherein said gonadotropin hormone releasing hormone composition is a gonadotropin hormone releasing hormone agonist selected from the group consisting of leuprolide acetate, goserelin, decapeptyl, buserelin, nafarelin, deslorelin, histrelin, gonadorelin, [(Imbzl)-D-His⁶ -Pro⁹ -Net]GnRH and mixtures thereof.

16. A composition according to claim 13, wherein said estrogenic composition is selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol valerate, estrone, diethylstilbestrol, piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol, estrone potassium sulfate, equilelinin, equilelinin sulfate, estetrol and mixtures of two or more thereof.

17. A composition according to claim 13, wherein said progestogen is selected from the group consisting of dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, megestrol acetate and mixtures of two or more thereof.

18. A composition according to claim 13, wherein said period of time is about two months to about six months.

19. A composition according to claim 13, wherein said period of time is about three months to about four months.

20. A composition according to claim 13, for administration by a subcutaneous, intramuscular, vaginal or transdermal route.

21. A composition according to claim 13, further comprising:

a slow-release formulation of an androgenic hormone which maintains serum level of said androgenic hormone over said first period of time at a level effective to restore androgen levels to normal premenopausal levels for a patient, said level being equivalent to a serum level of testosterone of between about 20 and about 80 ng/dl.

22. A composition according to claim 21, wherein said androgenic hormone is selected from the group consisting of testosterone, androstenedione, dihydrotestosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone, danazol, dromostanolone propionate, ethylestrenol, methandriol, nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymethalone, stanozolol and testolactone.

23. A method for preventing conception in a mammal or for treating benign gynecological disorders, comprising:

administering a gonadotropin hormone releasing hormone composition for a first period of time in an amount effective to maintain serum level of said gonadotropin hormone releasing hormone composition at a level effective to suppress ovarian estrogen and progesterone production, said GnRH composition being administered so as to provide between about 0.0001 and about 10 mg/kg of body weight per day;

simultaneously administering an estrogenic composition in an amount effective to maintain serum level of said estrogenic composition over said first period of time at a level effective to prevent symptoms of estrogen deficiency, said level being equivalent to a serum level of estradiol of between about 25 and about 140 pg/ml; and

administering a progestogen for a second, shorter period of time in an amount effective to maintain serum level of said progestogen at a first level effective to induce a secretory endometrium for at least 5 to about 20 days and at a second lower level effective to decrease endometrial cell proliferation for a remainder, if any, of said second period of time, said second period of time being substantially shorter than and running simultaneously with a portion of said first period of time, said first level being equivalent to a serum level of progesterone of between about 5 and about 20 ng/ml and said second level being equivalent to a serum level of progesterone of between about 0.5 and about 4 ng/ml.

24. A method according to claim 23, further comprising administering an androgenic composition over said first period of time in an amount effective to restore effective androgen level to a normal premenopausal level for a patient, said level being equivalent to a serum level of testosterone of between about 20 and about 80 ng/dl.

25. A method according to claim 23, wherein said first period of time is about two months to about six months.

26. A method according to claim 23, wherein said first period of time is about three months to about four months.

27. A method according to claim 23, wherein said second period of time is about 5 days to about 90 days.

28. A method according to claim 23, wherein said second period of time is less than about 1/4 to about 1/2 said first period of time.

29. A method for preventing conception in a mammal or for treating benign gynecological disorders, comprising:

administering a gonadotropin hormone releasing hormone composition for a period of time in an amount effective to maintain serum level of said gonadotropin hormone releasing hormone composition at a level effective to suppress ovarian estrogen and progesterone production, said GnRH composition being administered so as to provide between about 0.0001 and about 10 mg/kg of body weight per day;

simultaneously administering an estrogenic composition in an amount effective to maintain serum level of said estrogenic composition over said period of time at a level effective to prevent symptoms of estrogen deficiency, said level being equivalent to a serum level of estradiol of between about 25 and about 140 pg/ml; and

simultaneously administering a progestogen in an amount effective to maintain serum level of said progestogen over said period of time at a level effective decrease endometrial cell proliferation, said level being equivalent to a serum level of progesterone of between about 0.5 and about 4 ng/ml.

30. A method according to claim 29, further comprising administering an androgenic composition over said first period of time in an amount effective to restore effective androgen level to a normal premenopausal level for a patient, said level being equivalent to a serum level of testosterone of between about 20 and about 80 ng/dl.

31. A method according to claim 29, wherein said period of time is about two months to about six months.

32. A method according to claim 29, wherein said period of time is about three months to about four months.