Combined preparation for contraception based on natural estrogens

 

(57) Abstract:

The invention relates to medicine, in particular to drugs for contraception. Combined preparation for contraception consists of many stages: the first stage of 2-4 daily doses, each daily dose of active substance is composed exclusively of natural estrogenos; the second stage - from 22-16 daily doses, each daily dose of the active substance contains a combination of at least one natural estrogen and at least one synthetic or natural gestagen; the third stage is from 2-4 daily doses, each daily dose of the active substance contains only natural extrogen; and a fourth step of 2-4 daily doses, each daily dose provides pharmaceutical pure placebo. The drug significantly improves the flow of cyclic bleeding and side effects are minimized or completely eliminated. 3 C.p. f-crystals.

The invention relates to medicine, in particular to drugs for contraception.

Oral contraceptives appeared on the market in the early 60s. Through the Currently available oral contraceptives with low-dose which mainly consist of one estrogenic component and one gestagenna component.

When this hormonal doses are available in various combinations and dosage in the form of combination products (single-phase products) or a systematic process (multi-stage) combined preparations (a systematic process of drugs) or sequentronic drugs (two specimens) for the period from 21 to 28 days.

Single-phase drugs (usually bearing the designation of the combined drugs) are characterized by a uniform appropriate dose of estrogen or progestogen in each daily dose.

Thanks to the simultaneous reception gestagenna component together with estrogen shares, from the first day of use of a combination of drugs have a high contraceptive reliability.

It is known that all forms of combination products will reliably suprimit ovulatory phase LH, so suppressed as ovulation and formation of corpus luteum (ELSTEN, V. et al.: Studies on low dose oral contraceptives: cervical mucus and plasma hormone echanges in relation to circulating d-norgestrel and 17 ethinyl estradiol contraceptlons.Fertil Steril 27: 892 (1976); Kontrazeption mil Hormonen. Hrsg.Taubert, H.-D. und Kuhl, H. Georg Thieme Verlag Stuttart/New York, (1965)) [l].

However, under the influence of GE is the emergence of intermediate bleeding primarily during the first cycle.

Modified combined and systematic process of preparations made so far in the two-phase (two drugs) and three phase (three drugs) versions. Two drugs are the drugs that are in the first phase of the reception contain conventional combined drugs reduced the dose of progestogen, which rises in the second phase (half cycle). When 21/22-day pilule mode, a lower dose of progestogen is given 11 days, while the dose of estrogen remains the same for the entire period of taking the drug.

It is known that the three drugs contain in the first days of their admission along with low-dose estrogen the low-dose progestogen, which for two steps rise up to the highest dosage of progestogen in the last 7 to 10 days, while the proportion of estrogen or remains the same or increases signalline and short-term within 5 to 6 days by analogy with the normal physiological cycle, with a three-stage drugs allow you to keep the total dose applied gestagen at a lower level than other oral contraceptives (CARLBORG, L. : Comparison of contraceptive acceptability of levonorgestr the Sabbath. [2] is the closest to the invention, as well as the proposed combination drug for contraception, consists of many steps.

Two drugs (sequentiae drugs) contain the first 7 - maximum of 11 days of pure estrogen component and only in the subsequent 10-maximum of 14 days applies estahanova share. Thus, the endometrium undergoes changes that correspond to the flow of the physiological cycle. Therefore, they ensure the implementation of very good cycle control.

It is known that sequentiae drugs reduce basal gonadotropin levels in the same way as a combination of drugs, and the level of FSH in all probability is suppressed more than the level of LH (AKTORIES.K. et al.: Die Beeinflussung des Ovarlalzykius durch verschledene Typen hormonaler Kontrazeptiva. Geburtshlife Frauenhellkunde 36: 318 (1976)) [3].

All is still known combination of drugs for oral contraceptive containing as component dracunculus L. levonorgestrel or three-metaliteracy mestranol. The latter is Podruga and metabolized in the body into estrogens. Levonorgestrel however, has several disadvantages and side effects. This synthetic estrogen though and quickly resorbed at Kish is e then the liver is changed chemically. This process also has a strong individual differences. This implies insufficient and individually divergent biological availability of ethinyl estradiol.

It is known that ethinylestradiol further acts as suicidal brake on the cytochrome P450 system (GUENGERICH, F. P.: Oxidation of.alpha-ethinylestradlol of human liver cytochrome P450. Moleo. Pliarmacol 33:500 (1988); BOECKER, R. et al.: In vitro interaction of contraceptive steroids with human liver cytochrome P-450 enzymes. Advances Contraception 7: 140 (1991)) [4] and thereby inhibits its own metabolism.

As the gestagen and other foreign bodies/medicines for the most part are on the same path of destruction in the course of metabolism, reapplying etinilestradiolo contraceptives can lead to accumulation of certain xenobiotics in the body. In addition, levonorgestrel has a tendency to cancerogenicity (ZHU.B.T. et al.: The carcinogenic activity ofethinyl estrogens 1st determined by both their hormonal characteristics and their conversion to catechol metabolltes. Endocrinol. i32: 577 (i993)) [5].

B as an alternative to ethinyl estradiol, described in patents Germany N 4104385 [6] and N 4224534 [7], is proposed through the use of natural estrogens.

Known from U.S. patent N 4.921.843 [8] contraceptive system, in which between the last hormonal neptuna system has the disadvantage of during the introduction of the placebo begins the maturation of follicles transfer.

Easy use of natural estrogens have not found so far any practical application. For example, according to TAUBERT AND KUL (Kontrazeption mi t Hormonen.Hrsg.Taubert.H.-D. und Kuhl, H. Georg Thieme Verlag Stuttgart/New York, (1995)') [9] the use of natural estradiol as the estrogenic component in oral contraceptives failed. While the use of only one gestagenna component gives a reliable contraceptive protection. Proliferation of the endometrium with estrogen is insufficient. It leads to anomalies in the area of bleeding, for example, to the intermediate bleeding until bloodless cycles.

There were numerous attempts to develop so-called "semi-subsistence pills" on the basis of natural estrogens (e.g micronized estradiol 17-b ether natural estradiol 17-b, conjugated estrogen, phytoestrogen and estrone, estriol and its derivatives). An example of this can be a combination of estradiol (estradiolvalerate 1 mg to 2 mg per 10 -11 days) with 33% intermediate bleeding (Hirvonen.E. et al.: Oral contracepive containing natural estradlol for premenopausal women. Maturitas 21: 27, (1995) [10] or a combination of estradiol (3 mg) and desogestre the sts and obsetricians, (1995)) [11].

In anticipation of this invention have conducted researches, the purpose of which was to be achieved through equal dosing of estradiol in the period of 28 days and equal dosing getragene on day 21 as well as using different dosing estradiol (2.0 mg, 4.0 mg and 2.0 mg to 7.14 and 7 days) and a stable dosage of progestogen in the period of 21 days acceptable control cycle. These studies have not succeeded, because the intermediate bleeding in 25% negligible differed from those that were mentioned in the above mentioned studies HIRVONEN and KALINKA BELINKA.X. (SCHLEUSSNER.E.: ] An die Jenapharm GmbH, (1995)) [12].

Summarizing, we can say that in all tested still modes failed to reach a satisfactory picture of the bleeding.

Therefore, the invention aims to offer a hormonal contraceptive, whose mode of application greatly improves the flow of cyclic bleeding, and contraceptively reliability combination between estrogen and gestagen remains, and side effects (probability of Carcinogenicity, the accumulation of xenobiotics) is minimized or completely eliminated.

This task is daily dose and each daily dose contains as active substance only natural estrogens;

- whose second stage consists of 22-16 daily doses and each daily dose contains as active substance a combination of at least one natural estrogen and at least one natural or synthetic progestogen;

- whose third stage consists of 2 to 4 daily doses and each dose contains as active substance exclusively natural estrogens and

- whose final stage consists of 2-4 doses and each daily dose contains as active substances in pharmaceutical clean placebo.

The preferred implementation is that the second stage is divided into two groups, the first group consists of 5-3 daily doses, and the second group of 17-13 doses. The content of progestogen at a daily dose of the second group is higher than in daily doses of the first group. The content of progestogen at a daily dose of the second group is equal to one and a half to three times greater than the content of progestogen at a daily dose of the first group.

The total number of daily doses is thus mainly 28. As a natural estrogen is suitable primarily estradiol, for example, 17B, connection estradiol type, for example, tragedy, and phytoestrogens. As progestogen used mainly derivatives of nortestosterone 19 as, for example, desogestrel, dienogest, gestodene and levonorgestrel is a progestogen-21 as, for example, medroxyprogesterone, chlormadinone as well as natural progesterone.

The object of the present invention is a combined preparation for contraception that consists of many steps. It differs from known drug [2] is that the first stage consists of 2 to 4 daily doses, each daily dose of active substance is composed exclusively of natural estrogens, the second step consists of 22-16 daily doses, each daily dose of the active substance contains a combination of at least one natural estrogen and at least one synthetic or natural gestagen, the third stage consists of 2 to 4 daily doses, each daily dose of the active substance contains only natural estrogens and each subsequent stage consists of 2-4. daily doses, each daily dose provides pharmaceutical pure placebo, while the second stage may consist of 2 groups of daily doses, prichastnyh gestagen in the second group exceeds the share in the first group, in addition, estrogenic active substance is estradiol, which after taking estradiol forms a connection esterdiol in the body, can be conjugated equine estrogen or phytoestrogens, or natural progesterone, medroxyprogesterone or other synthetic gestagen.

Invented a combined drug can be used together with conventional solid or liquid substances-media or together with diluents and is generally used in the pharmaceutical industry technical auxiliary substances in accordance with the desired method of application in the appropriate dosage, in a customary way.

For oral administration are primarily used tablets, pills, coated tablets or capsules of hard gelatin.

Combined product based on the invention is directed to the fact that in the first half of the cycle estrogen-gestagenna balance was much shifted in favor of the estrogenic component and, in particular phase was even done a complete rejection gestagenna substance. This mode allows you to continue to refuse excessive dosage of estrogen (more than 4 mg estradiol equivalent per day). Shortening the interval without taking up 2-takenaway phase 2 -4 days has no effect on the regular occurrence of the discharge bleeding, however, has an additional deterrent effect at the beginning of the growth of a potentially subsequent cycle. The latter was proven in studies based on a combination of estradiol and dienogest. The value of the ovarian follicles transfer, measured by sonography, never exceeded 10 mm

Invented by a combined preparation prevents at the beginning of the cycle of activity of enzymes estradiol-SS dehydrogenase and sulfotransferase stimulated gestagen, so that the transformation of natural estrogens such as estradiol SS less effective estrone probably to a lesser extent. Thus it is possible to ensure sufficient estrogenic effects on the endometrium and natural estrogens.

Invented combined product has a high contraceptive reliability. Thanks to the use of natural estrogens largely excluded accumulation of xenobiotics in the body as a consequence of the use of contraceptives. Natural estrogens are carcinogenic trend is unknown.

The use of the invention was largely demonstrated on some examples. This was especially proven improvement prohozhdenie-3 - 3 mg of estradiolvalerate/d;

days 4-7 - 2 mg of estradiolvalerate/d + 0,075 mg desogestrel/d;

days 8-23 2 mg of estradiolvalerate/d + 0,150 mg desogestrel/d;

days 24-25 - 1 mg of estradiolvalerate/d;

days 26-28 placebo.

The study was conducted on 101 to be tested in age from 18 to 25 years. The deadline of the drug were respectively 6 cycles. The average level intermediate bleeding fell (breakthrough bleeding and spotting) from 20.2 percent in the first round to 10.7 percent in the 6th round. While receiving the drug did not come any unwanted pregnancy. From 101 to be tested 57 were held on the 8th, 22nd and 24th day of the cycle radioimmunological measurement of the concentration of serum progesterone. Only one patient in the 4th round of the measured boundary data of 4.0 ng/ml progesterone. All other measured data were clearly below 2 ng/ml. This testified conducted by the inhibition of ovulation with the use of invented formula preparation.

Application example 2.

days 1-3 of 3 mg of micronized estradiol SS/d;

days 4-7 - 2 mg of micronized estradiol SS/d + 0,075 mg desogestrel/d;

days 8-23 2 mg of micronized estradiol 17c="ptx2">

In the second example, the application in contrast to the first estradiolvalerate was replaced micronized estradiol 17 SS. It will be less than in the first case, the number of subjects achieved similar results.

Application example 3.

days 1-3 - 2,50 mg conjugated equine estrogen (CEE)/d;

days 4-7 - 1.25 mg CEE/d + 1 mg dienogest/d;

days 8-23 - 1.25 mg CEE/d + 2 mg dienogest/d;

days 24-25 - 0,60 mg CEE/d;

days 26-28 placebo.

In the appropriate clinical study involved 87 women aged from 35 to 47 years. The length of treatment was 6 cycles. The share of intermediate bleeding (breakthrough bleeding and spotting) amounted to 15.7 percent in the first round, she fell during the subsequent techniques, respectively, each time by 7 percent. Additionally, the 17 women before taking the drug and in the last day of the 6th cycle of research was conducted oral test glucose tolerance. Any deviations in the concentration of insulin from the norm (2-25 mU/l) were observed. The relationship between insulin and glucose in all subjects at all stages of the measurement was normal. By the increase of pepcid "With". HbA 1C were no znachitelno increased compared with the control cycle. During oral tolerance test glucose only 3 subjects showed limited glucose tolerance.

Two of these subjects had overweight. The results show excellent tolerance metabolism invented contraceptive based on natural estrogens.

Application example 4.

days 1-3 - 2,50 mg conjugated equine estrogen CEE/d;

days 4-7 - 1.25 mg CEE/d + 150 mg micronized progesterone/d;

days 8-23 - 1.25 mg/ CEE/d + 300 mg micronized progesterone/d;

days 24-25 - 0,60 mg CEE/d;

days 26-2 - a placebo.

Instead dienogest in example 4 was applied as gestagennogo component micronized progesterone.

Application example 5.

days 1-3 of 3 mg of estradiolvalerate/d;

days 4-7 - 1 mg of estradiolvalerate/d + 0.010 ethinyl estradiol/d + 1 mg dienogest/d;

days 8-23 - 1 mg of estradiolvalerate/d + 0.010 ethinyl estradiol/d + 2 mg dienogest/d;

days 24-25 - 1 mg of estradiolvalerate/d;

days 26-28 placebo.

In the fifth example in comparison with the forthcoming examples on the steps 2 and 3 had 20 daily doses of 1 mg of natural estrogen, supplemented 0,010 mg synthetic estrogenicity preparation of 6 cycles in a row. Target parameters were the contraceptive reliability (Pearl - Index), behavior during cycle and compatibility. The results show a complete suppression of maturing follicles transfer (determining the level of progesterone in the blood, sonography) and excellent control cycle (the number of intermediate bleeding decreased from 12.1% in the first cycle to less than 6% in the last cycle of drug).

Thus, the result of this study testifies first of all very good cyclic stability of the drug.

1. Contraceptive combined preparation for multi-stage injection, containing estrogens and gestagens, characterized in that it contains as estrogen natural estrogen and progestogen - at least one synthetic and one natural gestagen in the following components: the first stage - 2 to 4 daily doses of estrogen; the second stage - 22 - 16 daily dose combination of estrogen and gestagen; third stage - 2 to 4 daily doses of estrogen; the fourth stage - 2 to 4 daily doses of placebo.

2. The drug under item 1, characterized in that it contains 2 groups of daily doses of a combination of estrogen and gestagen, with the first group of soul in the second group exceeds the share in the first group.

3. The drug under item 1 or 2, characterized in that the estrogenic active substance, which after taking estradiol forms a connection of estradiol in the body, is conjugated equine estrogen or fitoestragenom.

4. The drug under item 1, or 2, or 3, characterized in that the estrogen active ingredient is a natural progesterone, medroxyprogesterone or other synthetic gestagen.

 

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