Composition and method to prevent conception

 

(57) Abstract:

Usage: the invention relates to medicine and relates to a method of inhibiting ovulation in women. Effect: the invention provides effective inhibition of ovulation without the risk of negative side effects. The invention: the invention is that for the prevention of conception in women of childbearing age prescribed for administration of melatonin in a daily dose of 2 to 1000 mg per 70 kg of body weight or composition containing a mixture of melatonin at 2 - 1000 mg and progestogen in the amount of 7.5 to 2500 mg, or a mixture of melatonin and estrogen in the amount of 2 to 100 mg, or a mixture of melatonin, a progestogen and estrogen on various schemes. There are also sets of drugs in various combinations for the prevention of conception in women. 11 C. and 19 C.p. f-crystals.

The invention relates to a method of inhibiting ovulation in women. More specifically the invention relates to a method of inhibiting ovulation by injection inhibiting ovulation amounts of melatonin. Optional melatonin is combined with gestagenna and/or estrogenic agent.

Research and development in the field of conception for people who skirts, diaphragms, intrauterine devices and condoms and oral contraceptives to one or more steroid hormones (Mashkovsky M. D. Drugs 1 o'clock, M.: Medicine, 1987, S. 594-595). Were developed highly effective contraceptives for oral administration and is currently more than fifty million women worldwide use oral contraceptives. Usually oral contraceptives are prepared in the form of a combination of estrogen and progestogen (also known as progestin). In some schemes medication, known as combinational circuits, consistent dose of estrogen and progestogen are introduced daily during the period of introduction. Other schemes use the medicinal product referred to as interleaved scheme, the amount of estrogen or progestogen, or both increases or decreases during the menstrual cycle. Some alternate modes provide two-phase or two-phase control (U.S. patent N 3969502). Other schemes provide a three-stage or three-phase combination of components. (U.S. patents NN 4628051, 4390531). The third type of scheme administration of medication is also known under trade entered contraception interact on the Central nervous system, and tissue in the urinary tract by inhibiting the reproductive function. The principal localization steps are the hypothalamus and the pituitary gland, in order to prevent the release of luteinizing hormone (LH) in intermenstrual cycle and thus prevent ovulation. Basal concentrations of LH and follicle-stimulating hormone (FSH) and estradiol levels and progesterone plasma from using oral contraceptives suppressed (reduced). Essentially these contraceptives are causing changes in the levels of hormones that simulates levels caused by pregnancy. These conventional oral contraceptives take a minimum of 21 days of the female cycle, and in some cases all of 28-30 days cycle.

Oral contraceptives also have a direct effect on the genitourinary tract. They change the structure and physico-chemical composition of the endometrium and the consistency of the cervical mucus, thus altering the ability of the uterus for implantation of the Mature egg.

It was shown that oral contraceptives have other advantages than termination of pregnancy. It has been shown that women taking oral p the deposits in the organs of the pelvis, ectopic pregnancy, vnutrisutochnogo cancer and benign breast diseases. Most importantly, contraceptive combination type responsible for reducing the incidence of ovarian cancer. Oral contraceptives also facilitate for common menstrual disorders, including irregular menstruation, premenstrual stress, excessive blood loss and cramping.

The use of traditional oral contraceptives, however, associated with some risk. This risk, which includes a higher chance of suffering from pulmonary veins, coronary heart disease, cerebrovascular disease and hypertension, which are, apparently, largely due to the estrogenic component (typically levonorgestrel or mestranol) contraceptive means. The risk of disease in any of these States, as it was found, primarily limited to women aged over 35 years old, especially women smokers older than 35 years. Women who take estrogen, may also suffer other negative side effects, including gastrointestinal disorders, nausea, increased with oral contraceptives, have developed an oral contraceptive containing only one or more POCs as an active ingredient. These contraceptives, however, as it was found, usually less effective than contraceptives containing both estrogen and progestogen. One common side effect that affects women taking the oral contraceptive pill, which contains one of progestogen is breakthrough bleeding during menstrual cycle.

In view of these drawbacks and negative side effects caused by the use of traditional oral contraceptives, it took the development of new contraceptives. Thus the aim of the present invention is to develop a method against conception, which would be highly effective, given the advantages and eliminate the negative effects associated with currently used contraception. The aim of the invention is also a method of reducing cases of breast cancer in women.

In accordance with this invention describes a method of preventing conception in women destroydialog age by introducing melt the genome and/or estrogen. In the preferred implementation of the contraceptive method according to the invention is administered in oral dosage form. In accordance with the present invention is also described a method of preventing breast cancer in women by introducing effective doses of melatonin.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that synthesizes and secretes the pineal gland. The exact role of this hormone to date not yet determined. Studies have shown that injection of melatonin Golden Syrian hamsters at a certain specific time of day has an inhibitory effect on the development of the gonads, the weight of the testes in males and ovulation in females.

Female rats, injected with melatonin at a certain time of day, also showed the inhibition of ovulation. Thus it has been shown that melatonin has a primary inhibitory effect on the gonads of different species of rodents. A similar effect, however, is not observed in other mammalian species, injected melatonin. More specifically the melatonin sheep (Kennway, A. J. et al., J. Reproductive Fertifit 73 859, 1951; Reppert, S. N. et al., Endari, 104 : 295, 1979) did not lead to direct changes in their reproductive physiology. Introduction of exogenous Mel is a major depression, in pharmokinetics purposes (Waldhauser, F., Neuroendocrino logy 39 : 307, 313, 1984), in connection with the rhythms of sleep - Wake and the phenomenon of "Jet - lag", maintainer flights on jets associated with changing time zones.

The invention is based on the discovery that pharmacological doses of melatonin, administered daily women, selectively inhibit the normal secretion of luteinizing hormone in the middle of the intermenstrual period sufficient to prevent ovulation. The present invention is directed to a method of preventing conception in women in the reproductive period by introducing the woman melatonin in doses effective to prevent ovulation by suppressing the release of luteinizing hormone, which occurs prior to ovulation and is required for it.

The invention is directed also to a method of preventing the occurrence of breast cancer in women. It was found that pharmacological melatonin prevents the formation of 7,12-dimethylbenzanthracene (DMBA), called adenocarcinoma in different species of rodents. It was also found that women with oestrogen receptor positive breast cancer have low night concentration multimillions doses of melatonin to prevent the formation of cells in the breast tissue, which may appear during the menstrual cycle. It is theoretically possible that that education, if it continues for a long period of time, can lead to tumor development and that the administration of melatonin to stabilize the growth of the cells so that there is a balanced number of cells in the breast tissue in each reproductive cycle.

As used in the description, the term melatonin encompasses also the analogs of melatonin, which are inhibitory effect when administered to women. Such analogs of melatonin include 6-formulatory, 5-oxitriptan, 5-methoxyindol and 5 methoxytryptamine. Other such analogs of melatonin include compounds described in U.S. patents NN 4087444, 4614807 listed in the bibliographic reference.

Melatonin (or similar melatonin) administered daily in doses sufficient to suppress women using melatonin, the normal release of luteinizing hormone and thereby preventing ovulation. In General, the melatonin is administered in amounts in the range of 2 to 1000 mg per day per 70 kg of body weight of women taking melatonin. Preferably 30 to 500 mg of melatonin daily.

Melatonin can be entered Carmignano period in the cycle, which immediately precedes the normal day of ovulation women, enough to achieve the contraceptive action. Ovulation typically occurs on the fourteenth day of the cycle or alternate between the ninth and the seventeenth day of the female cycle. This mode is preferred for administration of melatonin. The type of the selected mode may influence the amount of injected daily melatonin. The number provided for each day of dosing, may vary from the selected method of administration.

Melatonin can be administered to women orally, parenterally or in the form of the implant. Introduction most typically, if melatonin is made in oral dosage form, such as capsules, pills, suspensions or solutions. Preferred capsules or tablets. Capsules can be prepared by mixing the compound with a pharmaceutically acceptable carrier and then filling gelatin capsules with the mixture in accordance with conventional procedure for the preparation of dosage forms. Alternative melatonin can be mixed with one or more lubricants, such as acid or magnesium stearate, improves taste substances, dispersing elements, vkliuceateli tablets melatonin can be mixed with lactose, corn starch and sucrose, and then compressed into tablets.

Alternative oral introduction melatonin may be introduced parenterally or in the form of a solid implant. For parenteral administration melatonin prepared in injectable dosages of a solution or suspension of the hormone in a physiologically acceptable diluent with a pharmaceutical carrier. The carrier may include water or oil, and optionally also contain a surfactant, or other pharmaceutically acceptable additive. Suitable oils include oils of animal, vegetable and synthetic origin, including walnut, soybean, corn, sesame, castor and mineral oils. Preferred liquid carriers include water, saline, aqueous solutions of sugars and glycols, such as polyethylene glycol or polypropylenglycol.

Melatonin can also be entered in the form of the implant, which is prepared in a way that provides prolonged release melatonin. To prepare the implant, it is necessary to compress melatonin in small cylinders and place them in the shell of a physiologically acceptable material, such as decaying body or porous polyethlene of the present invention, the melatonin is administered in combination with a progestogen. Progestogen is added for induction of cyclic bleeding, similar to cyclic menstrual bleeding, and benefits associated with the introduction of POCs in traditional contraception. Any progestogen-active compound is useful for use as progestogenic components in the present invention. Appropriate POCs include the progestogen and its derivatives. Currently, the preferred POCs are norethindrone (i.e., 19-nor-17-ethinyl-17-hydroxy-4-androsten-3-one) and norgestrel (13-ethyl-17-ethinyl-17-oxygen-4-EN-3-one). Other POCs include formation-acetate (i.e., the acetate of 6-chloro-17-oxepin-4,6-diene-3,20-dione), norethynodrel (17-ethinyl-17-exists-5(10)- ene), medroxyprogesterone acetate (17-acetoxy-6-methyl-pregn-4-ene-3,20-dione), megestrol acetate (17-acetoxy-6-methylpregna-4,6-diene-3,20-dione), lynestrenol (17-ethinyl-17-hydroxy-variety-4-ene), hingeston (3 cyclopentyloxy-pregna-3,5-Dien-20-one), norethindrone acetate (17-acetoxy-17-ethinyl-variety-4-EN-3-one), acetate ethynodiol (3 , 17 diacetoxy-17- -ethinyl-variety-4-ene), dimethisterone (17-hydroxy-6-methyl-17-(1 - PROPYNYL)-androst-4-EN-3-one) and levonorgestrel.

Several schemes introduction are suitable for the t to be within 21 days following injection melatonin without a progestogen within seven days. In the second scheme, the administration of medication melatonin and progestogen is administered for 21 days and then stop the introduction of compounds for approximately seven days.

In the third scheme of the administration of medication melatonin is administered in approximately 5 to 14 days, followed by the introduction of progestogen within approximately 7 - 14 days in total to get about 21 days. Neither melatonin nor progestogen is not injected into the remaining seven days of the cycle. The fourth mode includes the introduction of placebo during the first five days, then the melatonin for about 3 - 7 days with subsequent introduction of a progestogen to twenty-one days of medication. Again, neither melatonin nor progestogen is not injected into the remaining seven days of the cycle.

In another scheme, the administration of medication progestogen taken for 21 days. Melatonin is administered in combination with a progestogen within 1 to 7 days, preferably 3 to 5 days) intermenstrual cycle just before a normal day of ovulation using drugs women. After 21 days of progestogen is not administered within about seven days. As noted above, traditional only one dose of progestogen within 21 - 28 days had no effective contraceptive action. Adding melatonion funds usually introduced in the amount of 7.5 - 2500 μg per day, preferably in the range of 7.5 to 600 mcg per day. Most preferably the progestogen in the amount of 7.5 to 250 micrograms per day. The actual number of progestogen entered in each daily dose will depend on specifically selected progestogen, its relative efficiency, and the selected route of administration. For example, with smaller amounts more active progestogen can achieve the same result that large quantities are less active progestogen. As noted above, the amount of progestogen may also vary depending on the way of introduction, usually a lower dose with the introduction of the implant or by intravenous injection than by oral administration.

In any of the above schemes the introduction of drugs in those days, when injected melatonin and progestogen, both the active ingredient is usually mixed and injected together, although they can also be entered separately.

In an alternate implementation of the present invention in any scheme of injection of melatonin or melatonin and progestogen can be added a small amount of estrogen. Estrogen may be added, if desired, to stabilize melatonin p is Any traditional estrogen may be applied as appropriate components of the contraceptive compositions according to the present invention. Preferred estrogen at the present time are the following compounds: levonorgestrel (i.e. 17-ethinyl-3,17-dixisti-1,3,5(10)-triene) and mestranol (17-ethinyl-17 - hydroxy-3-petoksista-1, 3,5 (10)-triene). Other suitable estrogens include estradiol (3,17-deoxy-östra-1,3,5 (10)-triene, estriol (3,16 , 17 - trioxi-östra-1,3,5 (10)-triene), estrone (3-hydroxy-östra-1,3,5(10)-triene-17-one), diethylstilbestrol, chinatravel (3 cyclopentyloxy-16 , 17 - deoxy-östra-1,3,5(10)-triene) and estrone sulfate. Estrogen can be administered daily for 21 days of a 28-day cycle at any schema drug administration, described above, but preferably before the normal day of ovulation. In General, the estrogen is administered in the amount of 2 to 100 mg per day and preferably in the range of 10 to 50 μg per day. As with progestogen, the actual amount of estrogen in the daily dose will depend on the specific estrogen and its relative activity. Levonorgestrel, for example, has twice as higher activity in comparison with mestranol. Because of the negative side effects caused by estrogen, it is desirable to use the minimum number of estrogen needed for stabilization used melatonin. Estrogen may be the second scheme, the estrogen is administered at the beginning of the female cycle for about 5 - 13 days followed by administration of melatonin within 1 to 7 days (preferably 3-5 days) to a normal day of ovulation, then injected progestogen within approximately 21 days of treatment.

In another implementation of the present invention melatonin can enter as a "morning after" pill either as such or in combination with estrogen and/or progestogen. In this implementation, the melatonin is administered in a daily dose of about 100 mg to 10000 mg, preferably in a dose of at least 2000 mg for 1 to 5 days postcoitus period. If melatonin is administered in combination with a progestogen and/or estrogen, progestogen is administered in a daily amount within 10 to 20 mg and the estrogen is administered in a daily dose in the range of 2.5 - 25 mg

In the preferred implementation of this invention contraceptives according to the invention is administered in oral dosage form, preferably in the form of pills or capsules, they can be packaged in any manner suitable for quick access and use. Preferably they are Packed in the form of a pharmaceutical kit or package in which there are daily single dosage form or arranged in alternating sequence, allowing p is positive cycle. Suitable kits or packages include a set of plastic bubble containing a single pill or 21 or 28 pills, depending on the selected schema drug administration, in the shell of a flexible plastic. The bubbles are sealed in a plastic wrapper, which you can break and release the pill while squeezing the bubble. On the first day of medication, which is usually the first day after cessation of bleeding from the last menstrual period, the first pill from the sequence, whether it contains a contraceptive pill or placebo, removed from their individual packaging and take. The next pill in the sequence take on another day and so continues until the empty packaging. The following start packing on the seventh day following the female cycle. Explanations and instructions can be applied to a packaged kit for guidance of the user by treatment with oral contraceptives.

As noted above, it was also found that the administration of melatonin in quantities taken in the above schemes may be effective for prevention of breast cancer. This discovery ol the tion according to the invention, contains melatonin as a contraceptive. In addition, melatonin and containing melatonin compositions can be entered postmenopausal women as a way to prevent breast cancer. Melatonin is desirable to introduce postmenopausal women in a daily dose of 2 to 1000 mg, as described above. Progestogen and/or estrogen can be combined with melatonin and put in the quantities and on the schemes described above, to prevent breast cancer.

Example 1. Contraceptive efficacy of melatonin was studied on the patient, the initials of which S. B., born September 21, 1950. This patient was observed in the normal pre-oscillation of luteinizing hormone and peak follicle-stimulating hormone, followed postovulation increase of progesterone.

In each of the three cycles, the patient received nutrivene 300 mg of melatonin at physiological glucose in saline solution from the ninth day of her cycle for six consecutive days.

The data show three cycles, in which the melatonin leads to suppression of the normal pre-release of luteinizing hormone from the patient. These data confirmed the ion estradiol and a significant reduction in levels of progestogen. Suppression of luteinizing hormone is a sufficient indication that the patient was absent ovulation in any of the three months, which was administered melatonin.

Example 2. The concentration of luteinizing hormone, follicle-stimulating hormone, progesterone and estradiol in the plasma of the patient was measured daily for three menstrual cycles. Determined the average concentration of each hormone for each day of the cycle. The average peak concentration of luteinizing hormone patient amounted to 295 ng/ml and the average peak concentration of follicle-stimulating hormone was equal to 410 ng/ml the Average level of progesterone in the peak phase of her cycle was 14.5 ng/ml and the average peak concentration of estradiol equal to 0.6 ng/ml Peak of luteinizing hormone, the patient appeared on the fifteenth day of her cycle.

The patient was administered intravenous injection of 500 mg of melatonin in glucose in saline solution every day from 7 to 12 days of her cycle. The concentrations of the four hormones in the plasma of the patient measured during this cycle, as before. The melatonin was found to affect the concentration of hormones in the following way: the peak concentration of luteinizing hormone in plasma was equal to 110 ng/nnye indicate that the patient has not come ovulation during this cycle; studies have shown that the peak concentration of luteinizing hormone at least 250 ng/ml necessary for occurrence of ovulation.

Example 3. A woman with a normal menstrual cycle is 28 days with 3-5 days of moderate menstrual bleeding ( 50 ml blood loss) received intravenous injection of 350 mg of melatonin in glucose in saline for seven consecutive days, starting on the 8th day of her cycle. 14 - 28 days of her cycle she was treated orally with 0.75 mg of norethindrone per day. Concentrations of luteinizing hormone, follicle stimulating hormone, progesterone and estradiol in the blood was measured daily during her cycle. Ovulation has not occurred during this cycle (peak concentration of luteinizing hormone in plasma was 115 ng/ml). There was a minimal loss of blood component 15 ml.

Example 4. A woman with a normal menstrual cycle is 30 days (on the twelfth day of ovulation) received intravenous injection of 200 mg of melatonin in glucose in saline solution every 7 - 10 days of your cycle. Ovulation has not occurred in this cycle, although the level of luteinizing hormone in the blood, as it was us who stimuliruyuscyego hormone in the plasma during this cycle was normal for her, progesterone was slightly depressed, and the concentration of estradiol in the plasma during the cycle was normal.

Example 5. In a clinical study of five women were administered melatonin in gelatin capsules. Melatonin was administered in a daily dose in the range of 30 - 1000 mg. Preliminary evaluation shows satisfactory absorption of melatonin from the gastrointestinal tract without negative side effects (such as diarrhea or vomiting).

1. The way to prevent conception in women of childbearing age, including the introduction of hormonal preparations in a dose sufficient to prevent ovulation, characterized in that as a hormonal drug is administered melatonin in a daily dose of 2 to 1000 mg per 70 kg of body weight of women, mainly in the dose of 30 to 500 mg per 70 kg of body weight.

2. The method according to p. 1, wherein the melatonin is administered in combination with a progestogen, and the daily dose of melatonin is 2 - 1000 mg per 70 kg and a daily dose of progestogen is 7.5 - 2500,0 μg per 70 kg of body weight women, and the progestogen is chosen from the group comprising norethindrone, norgestrel, chlormadinone-acetate, norethynodrel, medroxyprogesterone acetate, acetate megestrol, lynestrenol, Hing is tives such as those that includes the introduction of every day for about 21 days combination of melatonin and a progestogen, followed by the introduction within approximately 7 days of daily melatonin without a progestogen.

4. The method according to p. 2, characterized in that daily enter approximately 21 days combination of melatonin and a progestogen and during the next 7 days not enter neither melatonin nor progestogen.

5. The method according to p. 2, characterized in that it includes a daily injection of melatonin for 5 to 14 days, followed by daily introduction of progestogen within 7 to 14 days with a total time of injection 21 days with the subsequent abolition of the introduction of drugs within 7 days.

6. The method according to p. 2, characterized in that it includes the introduction of a placebo daily for about 5 days, the melatonin next 3 to 7 days and the introduction of a progestogen for about 9 to 13 days prior to the General period of introduction about 21 days followed about 7 days, during which neither melatonin nor progestogen-do not enter.

7. The method according to p. 2, characterized in that it includes the introduction of progestogen within 1 to 7 days prior to the normal day of ovulation women.

8. The method according to p. 1, wherein the melatonin is administered in the op is a gene selected from the group including etinilestradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, chinatravel sulfate and estrone.

9. The method according to p. 8, wherein the daily dose of melatonin is 30 - 500 mg per 70 kg body weight and the dose of estrogen it is thought that is 10 to 50 μg per 70 kg of body weight.

10. The method according to p. 8, characterized in that melatonin and progestogen is administered in combination with estrogen it is thought that, with a daily dose of melatonin is 2 - 1000 mg per 70 kg of body weight of the patient, and the estrogen it is thought that is chosen from the group comprising ethinylestradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol and sulphate Astron.

11. The method according to p. 10, characterized in that it includes the introduction of estrogen it is thought that about 5 - 13 days, followed by administration of melatonin within 1 to 7 days up to a normal day of ovulation women and the subsequent daily introduction of progestogen during the overall period of introduction about 21 days.

12. The method according to p. 10, wherein the daily dose of melatonin is from about 2 to 1000 mg per 70 kg of body weight, daily dose of progestogen is 7.5 - 2500,0 mcg 70 kg and a daily dose of estrogen it is thought that - 2 - 100 μg per 70 kg of body weight.

13. The method according to PP. 1, 2, 8 and 10, characterized in that evenno in a physiologically suitable medium.

15. The method according to PP.1, 2, 8 and 10, characterized in that the drugs administered in the form of an implant.

16. The method according to PP.1, 2, 8 and 10, characterized in that use similar melatonin with inhibiting ovulation action, instead of melatonin.

17. Composition for the prevention of conception in women of childbearing age, containing hormones, characterized in that as hormonal drugs it contains a mixture of melatonin in an amount of about 2 to 1000 mg and a progestogen in an amount of 7.5 - 2500,0 mg, while the progestogen can be represented by norethindrone, norgestrel, chlormadinone-acetate, acetate megestrol, lynestrenol, hinestrosa, acetate, norethindrone, acetate ethynodiol, levonorgestrel and dimethisterone.

18. Composition for the prevention of conception in women of childbearing age, containing hormones, characterized in that as hormonal drugs it contains a mixture of melatonin at 2 - 1000 mg of estrogen it is thought that in the amount of 2 to 100 mg, with estrogen it is thought that can be represented by ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, hinestrosa and estrone sulfate.

19. Composition for TVET as hormonal drugs it contains a mixture of melatonin 2 - 1000 mg of a progestogen in an amount of 7.5 - 2500,0 mg and estrogen it is thought that in the amount of 2 to 100 mg, with progestogen may be provided by norethindrone, norgestrel, chlormadinone-acetate, acetate megestrol, lynestrenol, hinestrosa, norethindrone acetate, acetate ethynodiol, levonorgestrel and dimethisterone, and the estrogen it is thought that - ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, hinestrosa and estrone sulfate.

20. Oral contraceptive set containing approximately 21 daily dose contraceptive effective combination of melatonin and a progestogen and about 7 daily doses of contraceptive effective amount of melatonin.

21. Oral contraceptive set containing approximately 21 daily dose contraceptive effective combination of melatonin and a progestogen.

22. Oral contraceptive set containing approximately 5 - 14 daily doses of contraceptive effective amount of melatonin and approximately 7 - 14 day dose contraceptive effective amount of a progestogen, which provides a total of approximately 21 daily dosage.

23. Oral contraceptive set containing prima daily doses of birth control effective amounts of progestogen, for this purpose there are approximately 21 daily dose.

24. Oral contraceptive set for women, containing about 21 - 28 daily doses of about 7.5 - 2500,0 micrograms of the progestogen and about 1 to 7 daily dose contraceptive effective amount of melatonin, while melatonin is administered concurrently with progestogen during the days immediately preceding the normal day of ovulation women.

25. Oral contraceptive set for women, containing approximately 5 - 13 daily doses of estrogen it is thought that about 1 to 7 daily doses of melatonin and about 6 to 15 daily doses of progestogen, which provides a total of approximately 21 daily dose, with daily doses of estrogen it is thought that attended, beginning with the first day of the period of introduction, followed by a reception daytime doses of melatonin and then daily doses of progestogen and estrogen it is thought that, melatonin and progestogen provided in contraceptive effective combination.

26. Oral dose pack including 1 - 5 daily doses of approximately 1,000 to 20,000 mg of melatonin.

27. Set under item 26, characterized in that it contains 1 to 5 daily doses approximately 5,000 - 10,000 mg of melatonin.

28. Set under item 26 or 27, characterized in that it further soderzhanie on PP. 17 to 19, characterized in that instead of melatonin use similar melatonin with inhibiting ovulation activity.

 

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