Method of contraception among women of reproductive age who have not attained premenopause

 

(57) Abstract:

The present invention relates to the field of medicine and relates to a method of contraceptive composition comprising an estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0.015-0.02 mg of ethinylestradiol; gestagen selectable from 0.05 to 0.075 mg of gestodene, of 0.075-0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-keto-desogestrel, 0.1 to 0.3 mg of drospirenone, 0.1-0.2 mg of cyproterone, 0,2-0,3 mg norgestimate and 0.35-0.75 mg norethisterone, by introducing its dosage forms for 23 or 24 days, beginning with the first day of the menstrual cycle, with the next 5 or 4 days without pills or taking pills without drugs for a total of 28 days in a cycle of introduction, and individual dosage forms contain within all 23 or 24 days constant amount of estrogen/gestagen. The proposed method can improve the control cycle, lower doses of hormones. 2 C. and 14 C.p. f-crystals, 2 Il.

The present invention relates to a joint application of estrogen and gestagen for obtaining single-phase combination preparation for oral contraception and the corresponding containing this single-phase combined product packaging.

Combivent Germany 2546062) or marvelon (Marvelon; posted a description of unaccepted application for patent in Germany 2361120). These drugs consist of twenty-one containing a biologically active substance (estrogen/gestagen) dosing units and seven do not contain biologically active substances coated tablets (containing no drug pills; placebo). Daily injected dose, respectively, are equally high (so-called single-phase drugs), and during the whole time of admission and during a break in reception or while receiving placebo causes the desired contraceptive effect. In the case of most drugs 7-day break in reception of containing a biologically active substance dosing units, until recently, was considered necessary in order to cause reliable bleeding and thus to achieve satisfactory control of the loop.

There are other drugs that contain more than 21 containing estrogen and gestagenna biologically active substance dosing units, and where a break in the reception part (Ijzerman, Pasquale) or fully (Kuhl) overlaps the reception containing estrogen dosing units. It is possible that the data contained otherwise in peroral the data by estrogen, preferably estradiol.

From European patent A-0491438 and 0491415 already known low-dose three-phase combination of drugs for hormonal contraception, which contain 21-24, respectively, 24 daily estrogen/gestagen-dosing units. According to the instructions of the European patent A-0491438 first of all, starting with day 1 of the menstrual cycle, take placebo provided for additions to the overall 28-day cycle, or primarily provide interval without taking pills, and without receiving any contraceptive steroids.

Combined preparation for replacement therapy and contraception for women before menopause (starting around the 40 th year of life) is known from European patent A-0253607. This combination product contains estrogen from the group consisting of 17-estradiol, ethinylestradiol and mestranola and gestagen from the group consisting of levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel and norethindrone. Thus, the selected composition should ease hormonal irregularities in the transition phase premenopause and facilitate problems (diseases), due to hormonal changes women's argarine still necessary in this age of contraceptive protection.

The development of new oral contraceptives for women in the age at which they are able to produce offspring, before premenopausal, in the last twenty years were characterized primarily by lower doses of estrogen and progestogen.

The reduction of the daily dose of the hormone is associated with the expectation to minimize the frequency of occurrence of undesirable side effects. Meanwhile collected epidemiological data confirm the desired trend towards better tolerability of low-dose drugs in the calculation of cardiovascular complications ((1.) Thorogood M, Oral Contraceptives and Cardiovascular Disease: An Epidemiologic Overview; Pharmacoepidemiology and Drug Safety, T. 2; c. 3-16 (1993); (2. ) Gerstman centuries, Piper J. M., D. Tomita K., Ferguson, W. J., Stadel B. V., F. Lundin E; Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease, Am JE, T. 133, N 1, 32-36 (1991); (3.) Lidegaard O, Oral contraception and rist of a cerebral thromboembolic attack: results of a case-control study; BMJ T. 306, 956-63 (1993); (4.) Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study; BMJ, T. 292, (1986); (5.) Mishell D. R. , Oral Contraception: Past, Present, and Future Perspectives; Int. J. Fertil, 36 Suppl., 7-18 (1991)).

It is assumed that primarily between high doses of estrogen and random cardiovascular disease there is a connection. Extreme reduction of the daily dose of estrogen, however,vka oral contraceptives predominantly called gestagenna component, also estrogenic component makes a significant contribution to the Central depressive effect and ovarian suppression (suppression of ovulation). Moreover, the daily dose of estrogen should not exceed the area limit doses to provide satisfactory control cycle (Der Frauenarzt; 34, 7, 793 (1993)).

Existing on the market contained in oral contraceptive means the lowest dose of estrogen is 20 mcg of ethinyl estradiol in combination with 150 micrograms of desogestrel (mercilon). Although the control cycle with this drug compared to drugs with a higher dose of estrogen according to the expectation of somewhat worse, high intake of mercilon indicates minor clinical relevance of this shortcoming. Clinically important problem, however, is made coincident in the case of various studies, the observation of a more minor ovarian suppression provided containing 20 mcg ethinyl estradiol drug. Obviously, at this very low dose of estrogen in the case of many women come to the maturation of the follicles, which can be detected by ultrasound, sootvetstvenno the vonorgestrel; Acta Obstet Gynecol Scand Suppl. 88: 17-21 (1979); (7.) Mall-Haefeli, M., Werner-Zodrow I., P. R. Huber, Klinische first experiences mit Mercilon and Marvelon unter besonderer Beruckaichtigung der ovary-Funktion; Geburfsh. und Frauenheilk, 51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); (8.) Strobel E. , Behandluilg mit oralen Kontrazeptiva; Fortschr. Med. 110 Jg. No. 20 (1992); (9. ) Letter to Editor, Contraception 45: 519-521 (1992); (10.) Teichmann A. T. , K. Brill, Can Dose Reduction of Ethinylestradiol in OCs jeopardize Ovarian Suppression and Cycle Control, Abstract Book, VIIIth World Congress on Human Reproduction, Bali, Indonesia (1993)).

Carried out the determination of hormones show that we are talking about functional cells gradulate membrane of the ovarian follicles, which secrete 17-estradiol. Any lack (absence) in women receiving with distinct ovarian activity, therefore, with streventname follicles can lead to a rapid increase in the production of gonadotropin. Thus, the prerequisites for ovulation. Assessment approximately one-third of women over the years, regularly takes oral contraceptives (Gynpress, I, Jahrgang, No. 3, 1990). The risk of pregnancy so especially in the case of deficiencies (lack of) reception when using drugs with 20 µg of ethinyl estradiol high.

The present invention is to obtain improved single-phase combined drug capable of producing offspring of the same is Rogen and gestagen, with low estrogen in each individual dosage unit, however, it is also low in all of the hormones in the cycle of administration of the medicine.

Currently, it is found that the pronounced ovarian suppression without frequent Satriani follicles at a low daily dosage of estrogen, low overall amount of estrogen, and low overall number of hormones on the cycle of the medicinal product use can be achieved through the use of a composition comprising an estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0,015-0,020 mg ethinyl estradiol, and gestagen selected from 0.05 to 0.075 mg of gestodene, of 0.075-0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg of 3-keto-desogestrel, 0.1 to 0.3 mg of drospirenone, 0.1-0.2 mg of cyproterone, of 0.2-0.3,mg norgestimate and 0.35-0.75 norethisterone; to obtain a dosage form for the purpose of contraception for women in the age at which you can produce offspring that have not yet reached premenopause, by administering a dosage form for 23 or 24 days, starting with day 1 of the menstrual cycle (first day of menstrual bleeding), followed by 5 or 4 days without taking pills with the medication or not containing/P> Individual dosage forms during all 23 or 24 days must contain a constant amount of estrogen/gestagen.

The concept of "premenopause" and "menopause" in the framework of the present invention are used in the sense commonly accepted definition; see, for example, "The Controversial Climacteric"; P. A. van Keep and others, ed. MTP Press (1981), for example, S. 9.

The daily dose of the hormone in it support at a very low level, while the usual 21-day admission is extended for two or three days. In the remaining 5 or 4 day cycle is preferably introduced placebo, to avoid lack of acceptance, or 5 or 4 days without taking medicines.

According to a preferred variant implementation of the present invention, it refers to the application of a composition comprising an estrogen selected from 2.0 to 6.0 mg of 17-estradiol and at 0.020 mg ethinylestradiol and a progestogen selected from 0.06 to 0.075 mg of gestodene, 0,100-0.125 mg of levonorgestrel, of 0.10-0.15 mg of desogestrel, of 0.10-0.15 mg of 3-keto-desogestrel, 0.25 to 0.30 mg of drospirenone, 0.1-0.2 mg of cyproterone, 0,2-0,3 mg norgestimate and 0.50 to 0.75 mg norethisterone; to obtain a dosage form for the purpose of contraception, as described above.

Further, the present invention relates to single-phase is inity, depending on the circumstances, containing estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0,020 mg etinilestradiol, and gestagen selected from 0.06 to 0.075 mg of gestodene, 0,100-0.125 mg of levonorgestrel, of 0.10-0.15 mg of desogestrel, of 0.10-0.15 mg of 3-keto-desogestrel, 0.25 to 0.30 mg of drospirenone, 0.1-0.2 mg of cyproterone, 0,2-0,3 mg norgestimate and 0.50 to 0.75 mg norethisterone; and

b) 5 or 4 not containing medicinal pills or other indications to show that a daily intake of 23 or 24 dosage units should follow 5 or 4 days without taking pills or taking pills without drugs.

Other proposed according to the invention forms implementation follow from the features of dependent claims.

According to the present invention is particularly preferred combination product contains 23 dosing units.

Particularly preferred contain 23 dosing unit single-phase combined preparation containing 20 micrograms ethinylestradiol and 75 micrograms of gestodene in each dosage unit and 5 pills without medicines or other indications to show that in the last 5 days of the menstrual cycle does not impose any dosing the following exercise with ethinyl estradiol as the estrogen and gestodene as representative of the class of possible according to the invention gestagen.

23-day admission 20 mcg of ethinyl estradiol in combination with 75 mg gestodene compared with the 21-day intake leads to stronger ovarian suppression. In a double-blind experience when using limiting values in healthy women with normal ovarian function groups of 30 subjects receive a combined preparation or once a day for 21 or 23 days and within 7, respectively, 5 days placebo (to ensure that the study of nature, double-blind experience).

Processing begins after ovulation, without processing, precycle, the first day of menstrual bleeding subsequent cycle and release it as a whole for three cycles of treatment. The study finished finished cycle without treatment.

Ovarian suppression determine, guided by the height of endogenous levels of 17-estradiol and the value of the follicular structures. The results show that the level of 17-estradiol admission within 23 days of the test drug lower (p < 0.05) as compared with taking drugs for 21 days (Fig. 1).

In accordance with these data the number of women with Mature follicles more clearly when taken 21 is, the ri immutable low daily dose, causes much greater ovarian suppression. Proposed according to the invention and the combined drug, thereby, achieve efficiency, known so far for drugs with daily content of 30 μg of ethinyl estradiol, although the daily (daily) dose ethinyl estradiol at 33% lower and total dose for the cycle is 27% less.

The advantages to be implemented within 23 days of a combined preparation for oral contraception compared with conventional 21-day preparations with less than 30 mcg of ethinyl estradiol can be characterized as follows.

1. Significantly lower rate of development of follicles in cases of administering the drug to women (to a maximum of 13% in the case of women who receive a 23-day drug, compared with 40% in the case of women who receive a 21-day drug). This means greater contraceptive reliability 23-day drug, especially when the previous lack of reception. The danger of "breakthrough ovulation" less.

2. The emergence of large follicles with a diameter of more than 30 mm is extremely rare. The development of ovarian cysts in 23-day drug compared with the 21-day drug is the pause.

4. Endogenous levels of 17-estradiol in the case of a predominant part of drug-23-day drug women well controlled suppressed. Clinical symptoms as voltage (tonosi) Breasts, premenstrual syndrome and bleeding disorders, which are reduced to high and strongly fluctuating levels of estrogen, in the case of a 23-day of the drug are observed with a distinctly lower frequency.

Summarizing, we can say that extended to two (or three) days of receiving containing in each daily dosage unit 20 mcg ethinylestradiol drugs can lead to the aforementioned advantages without the necessity to increase the daily dose is still widely used level of 30 micrograms of ethinyl estradiol.

The above advantages, in particular the best suppression of maturation of follicles, can be achieved according to the present invention using single-phase combined drug. Compared with the multi-phase preparation phase the preparation has the following advantages:

1) easier prigotovlenoy;

2) no random obmerivanie pills by reason of non-compliance receive sequence;

3) easier, you can achieve changes menst the dosing unit blister card (Blister), does not need to provide a label for the treatment of attention on the sequence of reception.

The formulation of estrogen and progestogen for proposed according to the invention of the application or proposed according to the invention combined drug carry out fully the same way as is already known for normal oral contraceptives with duration of treatment 21 days of biologically active substances, as, for example, Hemavan (Femovan; ethinylestradiol/gestodene) or microgynon (Microgynon; ethinyl estradiol/levonorgestrel).

Containing proposed according to the invention combined product packaging is also similar in structure to the packages already known commercially available oral contraceptives, with the deviation that instead of the usual 21 containing the active constituent parts dosing units now have 23 or 24 such dosage units and 5 or 4 pills without medicines, or, however, contain other suitable indications that 5 or 4 days you need to fill up to continue receiving containing a biologically active substance dosing units.

However, you need to make a reference to prevalently amounts of ethinyl estradiol and 17-estradiol, on the one hand, and various gestagens, as levonorgestrel, desogestrel, 3-keto-desogestrel and gestodene, on the other hand.

For further details on defining dosing equivalents of various biologically active substances need to refer to "Probleme der Dosisfindung: Sexualhormone"; F. Neumann et al. in "Arzneimittelforschung" (Drug Research) 27, 2a, 296-318 (1977), and "Aktuelle Entwicklungen in der hormonalen Kontrazeption"; H. Kuhl in Gynakologe" 25: 231-240 (1992).

1. Method of contraception among women of reproductive age who have not attained premenopause, characterized in that the dosage form composition comprising an estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0,015-0,020 mg ethinyl estradiol, and gestagen selected from 0.05 to 0.075 mg of gestodene, of 0.075-0.125 mg of levonorgestrel, 0.06 to 0.15 mg of desogestrel, 0.06 to 0.15 mg 3-ketodesogestrel, 0.1 to 0.3 mg of drospirenone, 0.1 - 0.2 mg of cyproterone, 0,2-0,3 mg norgestimate and 0.35-0.75 mg norethisterone, administered for 23 or 24 days, starting with the first day of the menstrual cycle, with the next 5 or 4 days without taking pills or taking pills that do not contain drugs within 28 days of the cycle injection.

2. The method according to p. 1, characterized in that as estrogen use levonorgestrel.

3. The method according to p. 1, otlichit as progestogen use gestodene.

5. The method according to PP.1, 2 or 3, characterized in that as progestogen use levonorgestrel.

6. The method according to PP.1, 2 or 3, characterized in that as progestogen use tsiproteronatsetat or drospirenone.

7. The method according to p. 1, wherein the administered dosage form comprising an estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0,020 mg ethinyl estradiol; and gestagen selected from 0.06 to 0,075 of gestodene 0,100-levonorgestrel 0.125, 0.10 to 0.15 desogestrel, 0,10-0,15 mg 3 ketodesogestrel, 0.25 to 0.30 mg of drospirenone, 0.1-0.2 mg of cyproterone, 0,2-0,3 mg norgestimate and 0.50 to 0.75 mg norethisterone.

8. The method according to p. 1, wherein the estrogen is administered in a dose of 20 micrograms of ethinyl estradiol, or the equivalent dose of 17-estradiol and a progestogen is administered in a dose of 75 µg of gestodene or equivalent dose of levonorgestrel, cyproterone or drospirenone.

9. The method of oral contraception in women of reproductive age who have not attained premenopause, characterized in that injected a) 23 or 24 dosage units, as the case may be, containing estrogen selected from 2.0 to 6.0 mg of 17-estradiol and 0,020 mg ethinyl estradiol; and gestagen selected from 0.06 to 0,075 of gestodene 0,100-levonorgestrel 0.125, 0.10 to desogestrel 0.15, 0.10 testerone and b) 5 or 4 pills, not containing medicines, daily intake of 23 or 24 dosage units should follow 5 or 4 days without taking pills or taking pills that do not contain drugs.

10. The method according to p. 9, characterized in that as estrogen use levonorgestrel.

11. The method according to p. 9 or 10, characterized in that as progestogen use gestodene.

12. The method according to p. 9 or 10, characterized in that as progestogen use levonorgestrel.

13. The method according to p. 9 or 10, characterized in that as progestogen use tsiproteronatsetat or drospirenone.

14. The method according to p. 9, wherein the estrogen is administered in a dose of 20 mcg of ethinyl estradiol or equivalent dose of 17-estradiol and a progestogen is administered in a dose of 75 µg of gestodene or equivalent dose of levonorgestrel, cyproterone or drospirenone.

15. The method according to PP.9-13, characterized in that the take 23 dosing units and 5 pills that do not contain drugs, during the last 5 days of the menstrual cycle does not impose any dosing unit or taking pills that do not contain drugs.

16. The method according to Auden, and 5 pills that do not contain drugs, during the last 5 days of the menstrual cycle does not impose any dosing unit or taking pills that do not contain drugs.

 

Same patents:

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, placed in spatial terms separately in one packing unit and retrieved separately daily dosing units, and the first hormonal component as hormonal biologically active substance contains a combination of estrogen and at least sufficient to suppress ovulation dosage gestagenna the drug either in-phase or multi-phase execution, and the second hormonal component as hormonal biologically active substance contains only one estrogen drug, and the first hormonal component covers 23 or 25, and the second hormonal component covers 4-10 daily dosing units, daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and synthetic estrogen, and the total number of daily dosing
The invention relates to the field of medicine

The invention relates to substituted derivatives of 19-norpregnane, methods of producing these compounds and pharmaceutical compositions containing them

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation for hormonal contraception

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, placed in spatial terms separately in one packing unit and retrieved separately daily dosing units, and the first hormonal component as hormonal biologically active substance contains a combination of estrogen and at least sufficient to suppress ovulation dosage gestagenna the drug either in-phase or multi-phase execution, and the second hormonal component as hormonal biologically active substance contains only one estrogen drug, and the first hormonal component covers 23 or 25, and the second hormonal component covers 4-10 daily dosing units, daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and synthetic estrogen, and the total number of daily dosing
The invention relates to veterinary medicine, in particular to the means of regulating sexual activity dogs and cats, specifically to compositions based on synthetic progestogen - megestrol acetate

The invention relates to medicine
The invention relates to medicine and agriculture, in particular to a method of extraction of biologically active compounds from plant material
The invention relates to the field of medicine

The invention relates to the field of pharmaceutical industry, namely the method of production of pharmaceutical dosage units

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation for hormonal contraception

The invention relates to the field of medicine and relates to a pharmaceutical combination preparation of the two, Packed in spatial terms separately in the same packaging unit, intended for oral administration at a time sequentially hormonal components, which consist, depending on the circumstances, placed in spatial terms separately in one packing unit and retrieved separately daily dosing units, and the first hormonal component as hormonal biologically active substance contains a combination of estrogen and at least sufficient to suppress ovulation dosage gestagenna the drug either in-phase or multi-phase execution, and the second hormonal component as hormonal biologically active substance contains only one estrogen drug, and the first hormonal component covers 23 or 25, and the second hormonal component covers 4-10 daily dosing units, daily dosage units of the first hormonal component does not contain a combination of biogenic estrogen and synthetic estrogen, and the total number of daily dosing

The invention relates to medicine, in particular to pulmonology

The invention relates to a sulphamate derivatives derivatives of 1,3,5(10)-estratriene General formula (I), where R1- COR3, -COOR4, -CONR5R6, -SO2R4or-SO2NR5R6where R3and R4independently C1- C5alkyl, C3- C6cycloalkyl or phenyl, R5and R6independently C1- C5alkyl; R2is a hydrogen atom or a C1- C5alkyl; R7and R8independently a hydrogen atom or a C1- C5alkoxygroup; R9and R10is a hydrogen atom or together a methylene group; R11- R13independently a hydrogen atom or hydroxyl group, optionally esterified physiologically acceptable inorganic or organic acids, or R12and R13quinil to 5 carbon atoms and R8, R11and R12independently located in theor-position
Up!