Combined contraceptive preparation on natural oestrogen basis

The subject of the invention is a multi-component hormonal contraceptive based on natural estrogen, consisting of several sets of units dosed daily during the menstrual cycle. The units of the first set of the preparation contain as active substance the natural estrogenic component; the second set units contain as an active ingredient the natural estrogen component and the gestagen component; and the third set units contain as an active ingredient the natural estrogen component.

Hormonal oral contraceptives appeared on the market in the early sixties, and further research on them led to a reduction in the necessary dosage of hormones. Currently, oral contraceptive preparations mainly consist of an estrogen component and a gestagen component, which are taken in low doses. Hormonal contraceptive preparations are administered in various compositions and doses, in the form of single, two- or multi-component oral preparations, for 21 or 28 days of the menstrual cycle.

One-component preparations, also called combined preparations, contain a constant amount of estrogen and gestagen in each daily dose. Even dosing of both hormones from the first day of use provides a relatively high level of contraceptive protection.

Combined preparations in all forms cause effective inhibition of the LH peak of ovulation (i.e. secretion of lutenizing hormone, which stimulates the release of an egg from the ovary, and thus inhibits ovulation), and the production of hormones

186 339 corpus-luteum (M. Elstein and co-authors: "Studies on Iow dose oral contraceptives: cervical mucus and plasma hormone changes in relation to circulating d-norgestral over 17-ethinyl estradiol concentrations", Fertil Steril 27 (1976) p. 892; HD Taubert und H. Kuhl, "Kontrazeption mit Hormonen Hrsg.", Georg Thieme Verlag, Stuttgart / New York (1995)).

As a result of the action of gestagen, early changes and secretion of underdeveloped endometrium occur, leading to early bleeding, especially in the first dosing cycle.

Currently used, significantly modified combined or multi-component contraceptive preparations can be dosed in two or three phases. Two-phase preparations are those that in the first phase of taking contain lower doses of gestagen (compared to conventional combined preparations), and in the second - higher, at constant doses of estrogen. For a 21 or 22 day pill cycle, reduced doses of gestagen are given for 11 days.

Three-phase preparation pills, taken in the first days of the cycle, contain small doses of estrogen and small doses of gestagen, with gestagen doses increasing in the next stages of the cycle, reaching their maximum in the last 7-10 days of the cycle, while estrogen doses remain at the same level, or increase in the middle of the cycle within 5-6 days, analogous to the normal physiological menstrual cycle. Three-phase preparations, compared to biphasic preparations, allow to reduce the total amount of dosed gestagen (L. Carlborg L., "Comparison of contraceptive acceptability of levonorgestrel and ethinyl oestradiol administered in one threephasic (Trionetta) and one monophasic (Neoletta) version", Contraception 27 (1983) p. 5).

Biphasic (sequential) preparations contain only the estrogenic component in the pills taken in the first 7 to 11 days, while in the next 10 to 14 days they also have the gestagen component. Thanks to this, the endometrium undergoes changes analogous to those in the normal menstrual cycle.

Sequential preparations, however, lower the basic level of gonadotropin, as in the case of combined preparations (K. Aktories and co-authors, "Die Beeinflussung des Ovarialzyklus durch verschiedene Typen hormonaler Kontrazeptiva", Geburtshilfe 36 (1976) p. 318).

Most of the combined oral contraceptive preparations known to date contain ethinyl estradiol as the estrogenic component, or mestranol, or its 3-methyl ester, wherein mestranol is metabolized to ethinyl estradiol. However, ethinyl estradiol, a synthetic estrogen, has a number of side effects. Although it is absorbed fairly quickly in the stomach and intestines, it is metabolized already in the small intestinal mucosa, or in the liver, with the metabolism process being very diverse in different people, which causes a differentiation in the bioavailability of ethinylestradiol. In addition, ethinyl estradiol acts as a P-450 inhibitor, thereby inhibiting its own metabolism (FP Guengerich, "Oxidation of alpha-ethinylestradiol by human liver cytochrome P-450", Molec, Pharmacol. 33 (1988) p. 500; R. Bocker and co-authors,, Jn vitro interaction of contraceptive steroids with human liver cytochrome P-450 enzymes ”, Advances Contraception 7 (1991) p. 140). When taking contraceptives containing ethinylestradiol and gestagen, the latter, as well as a number of other substances and drugs that are subject to the same metabolism, can lead to the accumulation of foreign organic substances in the body. Ethinylestradiol is also a potential carcinogen (BT Zhu and co-authors, "The carcinogenic activity of ethinyl estrogens is determined by both their hormonal charasteristics and their conversion to catechol metabolites", Endocrinol. 132 (1993) p. 577).

The administration of natural estrogen instead of ethinyl estradiol was proposed in German Patent Nos. DE 41 04 385 and De 42 24 534.

U.S. Patent No. 4,921,843 describes a contraceptive preparation in which a placebo is administered between the last daily doses of the second component and the initial daily doses of the first component.

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The disadvantage of this contraceptive is that the maturation of the ovum in the follicle begins with placebo.

Administration of only natural estrogen as an estrogenic component has not yet found practical application and, according to the opinion of Taubert and Kuhl (Georg Thieme Verlag, Stuttgart / New York (1995)), such use would be erroneous. The gestagen component alone has a contraceptive function. However, under the influence of natural estrogen, the proliferation (i.e. hyperplasia) of the endometrium is insufficient, which causes menstrual anomalies, such as indirect bleeding and non-bleeding cycles.

A number of attempts have also been made to develop a so-called natural birth control pill based on natural estrogen, such as: 17P-estradiol, ester of natural ββ-estradiol, conjugated estrogen, phytoestrogen and estrone, and estriol and their derivatives). An example would be a preparation containing estradiol (estradiol valerate, administered in an amount of 1 mg to 2 mg for 10 or 11 days) and cyproterone acetate (administered in an amount of 1 mg to 2 mg for 10 or 11 days), which causes 33% of bleeding indirect (E. Hirvonen et al., "Oral contraceptive containing natural estradiol for premenopausal", Maturitas 21 (1995) p. 27). Another example is a 21-day preparation containing estradiol (3 mg) and desogestrel (0.15 mg), which causes 30% of indirect bleeding (BH Coelingh, 'reserach in contracepton', 10^th Congress of Europan Association of Gynaecologists and Obstetricians (1995)).

Studies have also been carried out to achieve acceptable control of the menstrual cycle using both fixed doses of gestagen for 24 days and different doses of estradiol (2 mg, 4 mg and 2 mg for 7, 14 and 7 days) and fixed doses. gestagen, administered for 21 days. Only slight improvement was obtained, as indirect bleeding was as much as 25% (E. Schleussner, Mitteilungen an die Jenapharm GmbH (1995)), which did not differ significantly from the contraceptive preparations described above.

The review of the state of the art described above shows that the contraceptive preparations used so far, as well as the dosage methods, did not provide a satisfactory effect.

From US Patent No. US 4,292,315 a hormonal contraceptive preparation is known, comprising 21 or 28 daily doses divided into 3, 4 or 5 sets. In one embodiment of the invention, 21 daily doses consist of 4 sets of pills containing low doses of estrogen and progestin (i.e., a compound with progesterone activity). The first set includes 7 pills containing 0.02 mg ethinylestradiol (estrogen component) and 0.37 mg norethindron (gestagen component), the second set includes 4 pills containing 0.35 mg norethindron and 0.02 mg ethinylestradiol, the third set contains 7 pills containing 1 mg of norethindron acetate and 0.05 mg of ethinylestradiol, and the fourth set includes 3 pills containing 0.35 mg of norethindron and 0.02 mg of ethinylestradiol. In another embodiment of the invention, 21 daily doses consist of 4 sets of pills containing low doses of estrogen and progestin. The first set includes 7 pills containing 0.02 mg ethinylestradiol and 0.35 mg norethindron, the second set includes 2 pills containing 0.35 mg norethindron and 0.02 mg ethinylestradiol, the third set includes 10 pills containing 1-2.5 mg norethindron acetate and 0.05 mg ethinylestradiol, and the fourth set includes 2 pills containing 0.35 mg norethindron and 0.02 mg ethinylestradiol. In yet another embodiment of the invention, 21 daily doses consist of 3 sets of pills containing low doses of estrogen and progestin. The first set includes 7 pills containing 0.02 mg ethinylestradiol and 0.35 mg norethindron, the second set includes 7 pills containing 0.35 mg norethindron and 0.02 mg ethinylestradiol, the third set includes 7 pills containing 1 mg norethindron acetate and 0.05 mg ethinylestradiol. Each of these preparations may contain an additional set of 7 pills, containing iron and pharmacologically inactive placebo.

From German Patent DE 44 29 374, which is owned by the applicant, a hormonal contraceptive is known, comprising 28 daily doses divided into three sets. The first set, containing 3 or 4 pills, contains at least one estrogen component, the second set, containing 20 to 22 pills, contains at least one

186 339 the estrogen component and at least one gestagen component, while the third kit, comprising 3 or 4 pills, contains at least one estrogen component. The estrogenic component based on natural estrogen contains in the first set estradiol valerate in an amount of 1.5 to 2.0 mg / day, in the second set - estradiol in an amount of 1.5 to 4 mg / day, and in the third set - estradiol valerate in an amount of 1.5 to 2 mg / day. Whereas the gestagen component of the second set contains dienogest in a constant amount of 2 mg / day.

The purpose of the invention is to develop such a multi-component hormonal contraceptive based on natural estrogen, which will improve the course of cyclical menstrual bleeding, provide a high degree of contraception and minimize or eliminate side effects, including carcinogenicity and accumulation of foreign organic substances, and thus eliminate the disadvantages of previously known hormonal contraceptive preparations.

The essence of the invention is a multi-component hormonal contraceptive based on natural estrogen, which is characterized by the fact that it consists of four sets of units dosed daily during the menstrual cycle, the first set of which consists of 2 to 4 units containing as the active substance only natural estrogen; the second set consists of 16 to 22 units divided into 2 groups, composed of 3 to 5, respectively, and 13 to 17 units, each containing at least one natural estrogen and at least one synthetic or natural gestagen; the third set consists of 2 to 4 units containing as active substance only natural estrogen; while the fourth set consists of 2 to 4 units containing pharmacologically inactive placebo. The content of natural estrogen remains the same in every set, and decreases from the first to the third set, while the content of gestagen in the second group of the second set is greater than in the first group of this set.

The estrogenic active substance is preferably in the form of estradiol, an estradiol compound from which estradiol, conjugated equine estrogen or phytoestrogen is formed in the body.

In contrast, the gestagen active substance is preferably in the form of natural progesterone, medroxyprogesterone acetate, or a synthetic gestagen.

The advantage of the multi-component hormonal contraceptive based on the natural estrogen according to the invention is a high degree of contraceptive protection, no accumulation of foreign organic substances and carcinogenic properties in the body, and a significant improvement in cyclic bleeding and a high degree of body acceptance.

The invention is illustrated by the following preferred solutions.

Example I.

A hormonal contraceptive was used, consisting of sets of pills with composition and time of dosing in the menstrual cycle as follows:

cycle days composition up to 3 3 mg estradiol valerate / day to 7 2 mg estradiol valerate / day + + 0.075 mg desogestrel / day 8 to 23 2 mg estradiol valerate / day + + 0.15 mg desogestrel / day

24, 25 1 mg estradiol valerate / day to 28 placebo

The study was conducted on 101 patients aged 18 to 25 years. The duration of pill administration was 6 menstrual cycles in each case. The average incidence of menstrual bleeding and spotting decreased from 20.2% in the first cycle to 10.7% in the sixth pill-taking cycle. No pregnancy was reported when using the pills. Radioimmunological serum progesterone levels were measured on 57, 22 and 24 days of each of 57 patients out of 101. Only one patient in the fourth cycle had a limit progesterone value of 4 ng / ml. In all others

186 In 339 cases, serum progesterone levels were significantly less than 2 ng / ml. This means that the formulation according to the invention effectively inhibits ovulation.

Example II

A hormonal contraceptive was used, consisting of sets of pills with composition and time of dosing in the menstrual cycle as follows:

cycle days composition up to 3 3 mg 17β-estradiol / day to 7 2 mg 17β - estradiol / day + + 0.075 mg desogestrel / day 8 to 23 2 mg 170 - estradiol / day + + 0.15 mg desogestrel / day

24, 25 1 mg 17β - estradiol / <Zi: day to 28 placebo

Studies conducted on a smaller number of patients showed similar results as when using the preparation according to example I.

Example III

A hormonal contraceptive was used, consisting of sets of pills with composition and time of dosing in the menstrual cycle as follows:

cycle days composition up to 3 2.5 mg conjugated horse estrogen / day (CEE) up to 7 1.25 mg CEE / day + 1 mg desogestrel / day up to 23 1.25 mg CEE / day + 2 mg desogestrel / day

24, 25 0.6 mg CEE / day to 28 placebo

87 patients aged 35 to 47 years were subjected to clinical trials. The duration of pill intake was six menstrual cycles. The incidence of menstrual bleeding and spotting has decreased from 15.7% in the first cycle to 7% in the last pill cycle.

17 women were tested for oral glucose tolerance before taking the pills and on the last day of cycle 6. In no case were there deviations from the normal range of insulin concentration (2 - 25 mU / L). Therefore, the results of insulin / glucose measurements in all women were also within the normal range. However, a significant increase in C peptide concentration was observed. However, HbA1c levels showed no significant change between the control cycle and the 6th pill cycle. Fasting glucose was significantly elevated at the end of pill intake in four patients compared to the control cycle. Oral glucose tolerance tests showed only three women with limited glucose tolerance, two of whom were overweight.

Test results confirm very good tolerance of the contraceptive preparation according to the invention for metabolism.

Example IV

A hormonal contraceptive was used, consisting of sets of pills with composition and time of dosing in the menstrual cycle as follows:

cycle days composition up to 2.5 mg conjugated equine estrogen / day (CEE) up to 7 1.25 mg CEE / day + 150 mg progesterone / day up to 23 1.25 mg CEE / day + 300 mg progesterone / day

24, 25 0.6 mg CEE / day to 28 placebo

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In Example 4, progesterone was used instead of dienogest as a gestagen component.

Example V

A hormonal contraceptive was used, consisting of sets of pills with composition and time of dosing in the menstrual cycle as follows:

cycle days composition up to 3.3 mg estradiol valerate / day up to 7 1 mg estradiol valerate / day + 0.01 mg ethinyl estradiol / day + 1 mg dienogest / day 8 to 23 1 mg estradiol valsrionate / day + 0.01 mg ethinyl estradiol / day + 2 mg dienogest / day

24, 25 1 mg estrodiolι valerate. Thirty to 28 placebo

In Phases 2 and 3 (Example V), 20 daily doses of 1 mg / day natural estrogen supplemented with trace amounts (0.01 mg) of synthetic estrogen were taken.

60 women, aged 18 to 40 years, who received the preparation according to example V for six menstrual cycles were subjected to clinical examination. The obtained test results showed complete inhibition of follicular maturation in the follicle (progesterone determination and sonography) and very good cycle control (menstrual bleeding decreased from 12.1% in the first cycle to 6% in the last cycle of taking the preparation). This means that taking the preparation of the invention provides a high degree of contraceptive protection (low Pearl Index), does not cause side effects and stabilizes the course of the menstrual cycle.

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