Method and formulations for use in treating benign gynecological disorders

• US 5,340,585 A
• Filed: 05/17/1993
• 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:
  US08/062,883
• Time in Patent Office: 463 Days
• Field of Search: 424/426, 424/422, 424/423, 424/424, 424/432, 424/433, 424/443, 424/484, 424/485, 424/486, 424/487, 424/488, 424/489, 424/490, 424/496, 424/497, 424/DIG. 14, 514/843, 514/2, 514/12, 514/21, 514/800, 514/841, 514/842, 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 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• 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: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: Y10S 424/14 Topical contraceptives and spermacides

Abstract

Compositions and methods which are effective to treat benign gynecological disorders for extended periods of time in women in who the risk of endometrial stimulation is minimized or absent 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 period of time, optionally with addition of an androgenic composition.

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 period of time, wherein said gonadotropin hormone release hormone composition is administered at a rate between about 0.0001 and 10 mg/kg of body weight per day; and

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 and signs of estrogen deficiency, wherein said serum level of said estrogenic composition is equivalent to serum estrodiol levels in the range of about 25 to about 140 pg/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 period of time is about one month to about five years.

6. A composition according to claim 5, wherein said period of time is about three months to about four months.

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

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

a slow-release formulation of an androgenic hormone which increases serum level of said androgenic hormone over said period of time to a level not exceeding normal premenopausal levels for a patient, wherein said serum level of said androgenic composition is equivalent to serum testosterone levels in the range of about 20 to about 80 ng/dl.

9. A composition according to claim 8, 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.

18. A composition according to claim 1, wherein said serum level of said estrogenic composition is equivalent to serum estradiol levels in the range of about 30 to about 50 pg/ml.

19. A composition according to claim 1, wherein said serum level of said androgenic composition is equivalent to serum testosterone levels in the range of about 40 to about 60 ng/dl.

10. A method for treating benign gynecological disorders in a patient in whom risk of endometrial stimulation by estrogenic compositions is minimized or absent, 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, wherein said gonadotropin hormone releasing hormone composition is administered at a rate between about 0.0001 and 10 mg/kg of body weight per day; and

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 signs and symptoms of estrogen deficiency, wherein said serum level of said estrogenic composition is equivalent to serum estradiol levels in the range of about 25 to about 140 pg/ml.

11. A method according to claim 10, 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.

12. A method according to claim 11, 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.

13. A method according to claim 10, 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.

14. A method according to claim 10, further comprising administering an androgenic composition over said period of time in an amount effective to increase effective androgen level to a level not exceeding normal premenopausal levels for a patient, wherein said serum level of said androgenic composition is equivalent to serum testosterone levels in the range of about 20 to about 80 ng/dl.

15. A method according to claim 14, 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.

16. A method according to claim 10, wherein said period of time is about one month to about five years.

17. A method according to claim 16, wherein said period of time is about three months to about four months.

20. A method according to claim 10, wherein said serum level of said estrogenic composition is equivalent to serum estradiol levels in the range of about 30 to about 50 pg/ml.

21. A method according to claim 10, wherein said serum level of said androgenic composition is equivalent to serum testosterone levels in the range of about 40 to about 60 ng/dl.