SK123997A3 - Once-a-month-injectable useful as depot contraceptive and in hormone replacement therapy for perimenopausal and premenopausal women - Google Patents

Abstract

A once-a-month-injectable that contains an oestrogen and a gestagen component as active substances is used to prepare a contraceptive medicament useful at the same time in the hormone replacement therapy for perimenopausal and premenopausal women. A reliable contraceptive effect with a "natural" oestrogen (without ethinyl oestradiol) is achieved with this medicament, as well as an effective therapy of the first oestrogen deficiency symptoms and the prevention of osteoporosis.

Description

INJECTION RAISED BY MONTHLY AS DEPOTENTIAL ANTI-CONCEPTION AND HORMONAL SUBSTITUTION THERAPY FOR WOMEN IN Feather- and Pre-menopause

Technical field

The present invention relates to the use of a once-a-month-injectable-composition comprising estrogenic and gestagenic components as an active ingredient in the manufacture of a contraceptive formulation and concomitant hormone replacement therapy for women in peri- and conversion).

BACKGROUND OF THE INVENTION

Injection once a month within the meaning of the present invention means a hormone preparation which is injected once a month to prevent pregnancy in women of childbearing age. In this hormonal preparation, both the active ingredients are comprised of both gestagenic and estrogenic ingredients, each having a sufficiently long efficacy to achieve a contraceptive effect for a period of one month.

They are also applicable. progestogen-only-injectables that maintain longer contraceptive protection but with poor cycle control.

The best-known representatives of such monthly injections are Cyclofem (HRP 112, Cycloprovera) and Mesigyna (HRP 102). The first contains 25 mg of medroxyprogesterone acetate as a gestagen and 5 mg of estradiolcypionate as an estrogenic component in a microcrystalline suspension, the second containing 50 mg of norethisterone enentate as a gestagen and 5 mg of estradiol valerate as an estrogenic component in an oily solution. Although women who choose this method of protection have to visit the parent planning center or the doctor every month for an injection, these injections are well tolerated once a month. Vaginal bleeding occurs as menstruation quite regularly and presumably, which is essential for the widespread acceptability of this same method in many cultural areas (Biennial Report 1988-1989, Research in Human Reproduction, WHO).

A method for the hormonal treatment of menopausal, including perimenopausal and postmenopausal disorders, is particularly known from US patent 4826831, which mainly relates to the treatment of continuous use of gestagen in conjunction with estragon. Tarragon can be administered continuously or also cyclically, i. with breaks in serving.

Numerous estragones and gestagens which are suitable for the purposes of the present invention are mentioned, among others norethisterone acetate and medroxyprogesterone acetate as gestagens as well as estradiol valerate. In principle, all estrogens and gestagens that are also contemplated for oral contraceptives are useful. Adequate contraceptive protection is not clearly indicated by the treatments described.

Norethisterone acetate / estradiol valerate is listed, inter alia, as one possible combination. The amounts of gestagen and estrogen to be used are low: gestagen in a daily amount corresponding to 0.025 mg to 0.075 mg levonorgestrel and estragon in a daily amount corresponding to 0.5 to 2.0 mg estradiol. In the case of oral administration of the active ingredient, an amount of estradiol valerate in the range of 0.5 g to 2.0 mg per day for estradiol valerate is administered daily; for norethisterone acetate the daily amount is from 0.1 mg to 1.0 mg and for medroxyprogesterone acetate 1.0 mg to 15.0 mg. US-PS 4826831 also encompasses the non-oral use of said active ingredients by means of implants or intramuscular injection. The required daily dosage is then slightly lower than in the case of oral administration due to the direct passage of the active ingredient into the bloodstream. For estrogen implant, doses of 20 mg to 100 mg estradiol valerate are reported. The gestagen depot formulation for 3 months should contain 50-500 mg medroxypragesterone acetate or 20-400 mg norethisterone enentate. This patent also relates to pharmaceutical formulations for carrying out this method. This method effectively prevents the problems caused by the natural loss of estragon, which starts already in premenopause, such as hot flushes, vaginal dryness, the risk of osteoporosis, the increasing risk of myocardial infarction in women over 60 (cardiovascular complications), but is based on gestagen The components suppressed the induction of bleeding, but the risk for the formation of endometrial carcinomas does not increase.

US-A-48826831 strongly emphasizes that oral administration is not a method of preventing pregnancy.

For the purposes of the present invention, feathers and premenopause are interpreted in their conventional meaning as described in The Controversial Climacteric, P.A. van Keep et al., Ed., MTP Press (1981) at p. 9th

It is an object of the present invention to provide a depot preparation which is suitable for both women in feathers and premenopause, both for the contraceptive still required and already suitable for this period of life (Hormone Replacement Therapy = HRT).

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that such a preparation for pre- and perimenopausal women can surprisingly be manufactured on the basis of a monthly injection. While the method described in US-PS 4826831 was intended to directly prevent bleeding of treated women, monthly bleeding occurs in women in feathers or premenopause after the monthly injection of the invention at the end of the treatment period; no amenorrhea is also induced.

Injections administered once a month within the meaning of the present invention are meant to include both the aforementioned products and all other conceivable combinations of natural estrogen with gestagen. Both active ingredients must be formulated in a depot preparation, whereby the depot effect is achieved either by a particular type of galenic formulation (e.g. a microcrystalline suspension) or else by a chemical structure of the gestagen and / or estrogen (e.g. by esterification of the free hydroxy group).

In principle, all natural estrogens and all gestagens which are suitable for use in oral contraceptives and which can be converted into galenic formulations or derivatized in a chemical form, which exhibit a depot effect and which are obtainable as an intramuscularly administered dosage form, are suitable. . Suitable estrogens are, in particular, 17B-estradiol, estradiol-3-benzoate, estradiol-17-valerate, -cypionate, -undecylate, -enentate and / or other estradiol esters (US-PS 2611773, US-PS 2990414, US- PS 2054271, USPS 2225415 and US-PS 2156599). The gestagenic component is preferably selected from the group consisting of norethisterone acetate, norethisterone enentate, medroxyprogesterone acetate and cyproterone acetate.

In the following Tables 1A and 2A, a list of selected estrogens or gestagens, which are useful according to the invention, is given with data on the range of preferred amounts. Tables 1B and 2B show particularly advantageous amounts of the respective estrogen or gestagen, which should be included in the monthly injection according to the present invention.

Table 1A

batching minimum (Mg) maximum 17B-estradiol 4 10 estradiol valerate 4 10 of estradiol 4 10

estradiol 17S 5 estradiol valerate 5 estradiol cypionate 5

Table 1B dosage (mg)

Table 2A Table 2B

dosage (mg) minimum maximum norethisterone acetate 20 60 norethisterone enentate 20 60 medroxyprogesterone acetate 12.5 30 cyproterone acetate 40 100

batching (Mg) norethisterone 50 norethisterone enanthate 50 medroxyprogesterone acetate 25 cyproterone acetate 50

The medroxyprogesterone acetate / estradiol cypionate combination is preferred for the manufacture of a monthly injection for peri- and premenopausal contraception; the combination of norethisterone enentate / estradiol solvate is particularly preferred.

Particular advantages of the monthly injection which, in the case of premenopausal women, can surprisingly serve both as contraceptives and as hormone replacement therapy are to be noted first of all:

* safer contraceptive effect without ethinylestradiol with natural estrogen, * this accompanying effective therapy for beginning estrogen - extinction phenomena (suppression of menopausal symptoms), * simultaneous optimal prevention of osteoporosis, * excellent tolerance and cycle control, * virtually no changes in blood pressure, * very low, almost absent side effects and effects on metabolic and haemostatic parameters, * avoidance of liver burden as well as gastrointestinal disorders due to parenteral administration, * maintenance of beneficial side effects of oral contraceptives (protection against ovarian and endometrial cancer and Pelvic Inflammatory Disease).

All of these properties have been documented in a 3-year clinical trial with Mesigyna in a team of 17 patients over 35 years of age.

A particularly preferred form of the gestagen / estrogen-based combination of norethisterone enentate / estradiol valerate provides not only a prophylactic effect with respect to osteoporosis, but with this combination, estragone has been shown to suppress bone loss as well as a norethisterone enentate-induced effect on k construction.

DETAILED DESCRIPTION OF THE INVENTION

Formulation examples

Mesygina

Each ampoule contains mg norethisterone enentate + mg estradiol valerate in 1 ml castor oil / benzyl benzoate 6/4 (v / v)

Formulation with cyproterone acetate

Each ampoule contains mg cyproterone acetate + mg estradiol valerate in 1 ml castor oil / benzyl benzoate 6/4 (v / v)

Claims (4)

Use of a once-a-month-injectable injection containing an estrogen and gestagenic component as an active ingredient in the manufacture of a preparation for contraception and concomitant hormone replacement therapy for women in feathers and premenopause. Use according to claim 1, characterized in that the estrogenic component is selected from the group consisting of 17β-estradiol, estradiol-3-benzoate, estradiol-17-valerate, - cypionate, -undecylate, - enentate, and other estradiol esters. . Use according to claim 1, characterized in that the gestagenic component is selected from the group consisting of norethisterone acetate, norethisterone enentate, medroxyprogesterone acetate and cyproterone acetate. Use of the combinations norethisterone enentate / estradiol valerate, medroxyprogesterone acetate / estradiol cypionate according to claims 2 and 3.