Regimens gestagen-antigestagen

 

Proposed: a new continuous contraceptive regimens, new contraceptive kits, providing a continuous flow of progestogen and antigestagen in a woman's body, the method of production thereof and method for the treatment of bleeding due to taking a progestogen. As continuous contraceptive regimens and component similar set of proposed connection with mixed profile gestagennoy antigestagen properties, in particular mifepristone (RU 486), onapristone or Org 33628. The invention allows to prevent irregular intermenstrual bleeding when taking contraceptive and does not lead to permanent functional cysts of the ovary. 6 C. and 12 C.p. f-crystals, 2 tab.

This invention relates to a contraceptive kit (delivery system drug), including means (a) for the daily administration of the progestogen and the means (b) for receiving antigestagen providing a regimen of contraceptive that does not contain estrogen, i.e., the type of progestogen only.

For some time it was known that contraceptive can be achieved by oral administration of sufficient amounts of progestogen woman reproductive (getordprop due to bleeding, changes in the duration of the menstrual cycle and amenorrhea, preferred. In addition, it is preferable to use contraceptive schemes that minimize the amount of estrogen and gestagen. Drugs that meet many of these requirements are disclosed in WO 93/21927, which describes contraceptive scheme that does not contain estrogen, and an active, inhibiting ovulation ingredient is a drug belonging to the gestagen or gestagennouu tool. This tool combine, in particular with breaks, with antigestagens in an amount equivalent to from 10 to 250 mg RU 486 on the dose. Used scheme is a scheme where the progestogen is administered only levonorgestrel, except that on days 1, 30, 60, 90, 120, 150 and 180 a dose of antigestagen RU 486. In fact, this scheme is the scheme receive only progestogen, interrupted by the reception of antigestagen at the beginning of each cycle. Although this scheme represents a significant improvement compared with existing schemes, including the estrogens, the profile of bleeding is not perfect, because the light bleeding is repeated after a time interval, almost free from bleeding, and pactically way contraceptio for mothers breastfeeding, older women, women for whom estrogen is contraindicated in women who have high blood pressure, and women who develop headache type migraine, when receiving a combination tablets (i.e. tablets containing estrogen and gestagen component). See, for example, "Contraception for women over the age of 35", IPPF Medical Bulletin, 22: 3-4 (1988) and P. W. Howie "The progestogen-only pill", Brit. J. Obstet. Gynaecol., 92: 1001-2 (1985).

Although various schemes only gestagen described, they are associated with incomplete inhibition of ovulation and relatively high degrees of adverse outcome. Vessey et al. "Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness", Brit. J. Family Planning, 292: 526-30 (1986). It was suggested to increase the daily dose of progestogen in order to cause complete inhibition of ovulation, however, such an increase in the dose also increases the incidence of intermenstrual bleeding (i.e., "small selection"), which is certainly undesirable. E. Diczfalusy et al., Progestogens in Therapy, p. 150 (Raven Press, NY 1983). In addition, the reported high incidence of functional ovarian cysts in the application schema only gestagen, which resolved after discontinuation of contraceptive only gestagen. Fotherby, K. "The Progestogen-pill contraceptive only gestagen, which is more effective in inhibiting ovulation, however, without increasing the frequency of intermenstrual bleeding or not resulting in permanent functional cysts of the ovary. The solution to this problem by adding with intermittent antigestagen needs further development.

Unexpectedly, was found regimen contraceptive satisfying the above requirement, namely, that the gestagen is administered at a dose sufficient to inhibit ovulation, and enter antigestagen dose not affect ovulation, but sufficient to maintain good control over the cycle and almost completely stop the number of occurrence of secretions and bleeding, i.e., in General, a dose sufficient to prevent irregular bleeding and which leads to improved, more predictable and more acceptable picture of bleeding compared to regimen only progestogen with or without periodic reception of antigestagen.

Thus, this invention relates to a contraceptive kit of the type described in the opening paragraph, where these funds (a) and (b) are designed to be combined tool (s) for daily podkoren is shown in WO 93/21927, i.e., below the equivalent of 10 mg RU 486.

In addition, this invention includes pharmaceutical product (i.e., dosage units, or the package containing dosage units), the method of use of the product and method for producing a pharmaceutical product.

In addition, the invention includes a method of providing contraceptive, including the use of the woman above schemes.

The progestogen used in this invention are 3-keto-desogestrel (etonogestrel), desogestrel, gestodene, levonorgestrel, norgestrel and other gestagens, usually used for contraceptive. Desogestrel is the chemical name 13-ethyl-11-methylene-18,19-di-nor-17-pregn-4-EN-20-in-17-ol, and it is the preferred gestagen. Desogestrel believed to be metabolized in the body in 3-ketodesogestrel (etonogestrel). Preferably, the unit dose contains 75 micrograms of desogestrel or 3-ketodesogestrel, or a number of other progestogen with effect equivalent to the effect of 75 micrograms of desogestrel. On the basis of applied dose levonorgestrel, desogestrel and 3-ketodesogestrel are relatively similar gestagenna activity. Gestodene is approximately 1.5 times the strong who are the progestogen newer generation, a preferred example of which is the Org 30659 known from EP 210678, IUPAC chemical name of which is (17)-17-hydroxy-11-methylene-19-norpregna-4,15-Dien-20-in-3-one.

Antigestagen can be an inhibitor of the synthesis of progestogen, such as apistan, asisten or trilostane (Sheeple, Contraception 24, 289, 1981; Drugs of the Future 7, 661, 1982, van der Spuy et al., Contraception 35, 111, 1987; U.S. patent 3296255), or antagonist of the receptor progestogen, or any such pharmaceutical acceptable vehicle, which counteracts the normal biological activity of progestogen, such as antibodies or ligands that are able to communicate with a progestogen or progestogen receptor.

Suitable antigestagen is receptor antagonist progestogen. Such compounds are widely known, for example, from EP 277676, EP 289073, EP 321010, EP 549041, EP 582338 and numerous other publications. Good examples are the use of RU 486, Onapristone, Org 31710 [(611th17th)-11-(4-dimethylaminophenyl)-6-methyl-4', 5'-dihydrospiro [östra-4,9-Dien-17,2'-(3 N)-furan]-3-one] and Org 33628 [(1117th)-11-(4-acetylphenyl)-17,23-epoxy-19,24-Generala-4,9,20-trien-3-one] , all of which, in particular, acceptable practices in the of had been sufficient to prevent irregular bleeding. Preferably, this dose was low as possible. Thus, the daily dose of antigestagen usually chosen so that it was equivalent to a daily dose of the reference antigestagen RU 486 from 0.05 to 5 mg, and preferably from 0.1 to 2 mg For most antigestagens this usually means daily intake corresponding fixed dose. For example, in the case of Org 33628 and Org 31710, which are somewhat more potent antigestagen, the number of daily doses should generally be in the range of from 0.02 to 4 mg and preferably from 0.05 to 2 mg For average technicians obvious that in some cases it is preferable to choose a regimen of a drug to have the exposure (duration) antigestagen, which is equivalent to the above-mentioned daily dose comparison. This scheme can be determined by routine method based on the half-life period specified connection. For example, Org 33628, and RU 486 (with the corresponding periods of the half-life of approximately 15 h and 20 h) with the introduction of daily above low dose lead to corresponding daily exposure antigestagen, while Org 31710 (with period p is the accumulation level antigestagen. In order to achieve useful effects in the above-described continuous circuit with a low dose, Org 31710, you can enter every two days, and usually the number of doses are in the range of 0.05-5 mg of

The combined means (C) may include any number of daily pills containing a progestogen and antigestagen. In comparison with the known contraceptives only with a gestagen or without estrogen, the packaging of daily tablets free tablets containing only gestagen: essentially, all tablets include a combination of progestogen and antigestagen. In practice it is preferable to develop a set with at least 28 daily dosage units, as this is the normal length of menstrual cycle. In addition, you can enable both, as the gestagen and antigestagen, in a controlled release device, such as an implant or vaginal ring. It is also possible inclusion in IUD (intrauterine device). In principle, the combined means (C) for the introduction of a gestagen and antigestagen may contain two different forms for injection. It is preferable, however, that both substances were contained in the same dosage units for oral administration, which then education is activated (single or combined with either or both of the gestagen and antigestagen) separate active substance, having the desired mixed profile gestagennoy antigestagen properties. Such compounds are known, see, for example, Sobek et al. in ENDO'97, page 549 (Poster Sessions of the Endocrine Society, No. P3-452) and Wagner et al. in Proc.NatI.Acad. Sci.USA, Vol.93, pp.8739-8744 (1996).

The term "dosage unit" generally refers to physically discrete units suitable as a single dose for people, and each contains a predetermined amount of the active substance, designed to obtain the desired action, for example, tablets, pills, powders, suppositories, capsules, etc.,

Methods and compositions for obtaining such dosage units are well known to specialists in this field. For example, a conventional technology for tablets and pills containing the active ingredients described in reference literature, Gennaro et al., Remington''s Pharmaceutical Sciences, (18thed., Mack Publishing Company, 1990, see, in particular, Part 8: Pharmaceutical Preparations and Their Manufacture).

To obtain the dosage units such as tablets, assume the use of conventional additives, such as fillers, dyes, polymeric binder, etc. In General, any pharmaceutically acceptable additive, which does not interfere with the action of the active compounds, may be used in one or several of the Sabbath., derivatives of cellulose, etc., used in the right quantities. A preferred carrier is lactose. In addition, you can use a mixture of media.

A method of obtaining a set of this invention involves mixing predetermined amounts of progestogen (for example, desogestrel, 3-ketodesogestrel or mixtures thereof) and antigestagen (for example, Org 31710) with predefined amounts of fillers and the transformation mixture in dosage units containing a progestogen and antigestagen. Preferred kits contain, in the amount of at least 28 of the daily dosage units of contraceptives.

The transformation mixture in dosage unit typically includes compressing the mixture into a tablet, a filling of the capsules of the dried mixture or filling capsules with a damp mixture.

The preferred method of obtaining a pharmaceutical product in accordance with the invention includes the incorporation of the required doses of the contraceptive steroid (eg, desogestrel, 3-ketodesogestrel or mixtures thereof) into tablets using technologies such as tabletting technology wet granulate. Packaging containing dosage unit typically contains between 28 and 364 (13, mnogochastichnogo tools for oral administration, it should be emphasized that the contraceptive kit of the present invention differs from the known contraceptive kits type "progestogen-only" and, in fact, in addition, represents a significant improvement compared with those in which, in addition to the progestogen, in addition, apply antigestagen (i.e., more correctly described as "the scheme without estrogen"). Known regimens of the contraceptive of this type include multiphase combination of daily dosage units contraceptives containing only progestogen and daily dosage units contraceptives containing a progestogen and antigestagen. Further, in contrast to these well-known circuits, the present invention differs in that the schema does not contain any metered units with only gestagen, i.e. daily dosage units contraceptives form a continuous, single phase combination of a gestagen and antigestagen. This leads to a significant advantage in that you can enter significantly lower number of antigestagen in dosage unit, while receiving superior control over the cycle.

As mentioned above, the set under DNEVNOY tablets. It is possible for one, for example, progestogen to be in the form of a daily pill and the other in the form of the device is delayed (extended) release, such as the implant, intrauterine device or endovaginal product, such as a vaginal ring, or Vice versa. Just as in the case of daily pills, also in the case of other dosage forms, preferably, when the combined means (C) in accordance with this invention is in fact only one way, i.e. as the gestagen and antigestagen released from the same device slow release. The fact that the scheme of reception of contraceptive of the present invention is a continuous, single-phase regimen, creates great opportunities, from a technical point of view, to provide other ways of administration.

The ways to obtain slow release devices such as implants and vaginal rings known in the art. In this regard, refer to Jorge Heller Drug Delivery in the Plastics Age, in "Innovations in Drug Delivery", Tom Sam and Jasper Fokkens ed., pages 134-145. Preferred contraceptive implant is mentioned in EP 303306. A large number of designs vaginal number of the medicinal product, made in the form of a ring, which can be used in the present invention, includes at least one compartment comprising a core of a thermoplastic polymer containing at least gestagen and antigestagen in respect of, by weight, which allows immediate release of the specified polymer of both compounds in a physiologically required quantities. To this end, the gestagen is first dissolved in the polymer core with a relatively low degree of saturation, which preferably exceeds 1-6 times the amount, by weight, required to obtain the saturation concentration of the specified progestogen in the specified polymer core at 25oWith, and antigestagen first dissolved in the polymer core in a concentration that is below the concentration specified gestagenna compounds, and thermoplastic shell (outer layer), which is permeable to the gestagen and antigestagen.

In addition, this invention relates to a method of treatment. The method relates to the introduction of antigestagen women who, in consequence of the conventional regimens only progestogen, suffer extensive (extensive) and/or irregular bleeding. In this regard, izobreteniya, where antigestagen administered daily dose, calculated as the equivalent of RU 486, from 0.05 to 5 mg, and preferably from 0.1 to 2 mg in order to get a better controlled and more predictable picture of the bleeding.

In addition, in combination with the above, the invention relates to a new medical indication daily introduction of antigestagen. Thus, the invention also relates to the use of antigestagens for obtaining a medicinal product for treatment (by daily dose, equivalent dose of RU 486 from 0.05 to 5 mg) bleeding, resulting from the use of contraceptives on the basis of only progestogen.

Further the invention is illustrated by the following examples.

Example I This example relates to the production of a standard way of tablets A-F for a single daily administration. The basic composition of all tablets, in addition to the active substances, is a 6,500 mg of corn starch, 1,950 mg of povidone, 0,650 mg of stearic acid, 0,650 mg colloidal silicone 0,080 mg dl--tocopherol and 65,000 mg of lactose. Tablets are provided with a coating layer, containing 0.75 mg of hydroxypropylmethylcellulose, 0.15 mg of polyethylene glycol 400, 0,1125 mg of Digene and antigestagen. The number of active substances (in mg) are given in table. 1.

Each tablet is the only substance, inhibiting ovulation, is desogestrel.

Example II This example applies to tablets G-L for a single daily administration, having the same basic composition and the coating layer as in example I, and the number of active substances (in mg) are given in table. 2.

Each tablet is the only substance, inhibiting ovulation, is Org 30659.

Example III This example applies to a double-blind, placebo-controlled, statistical, clinical study conducted in one centre in which the tablets corresponding to a, C, E and F, enter 40 healthy female volunteers in order to investigate antigestagen at three different doses in continuous combined scheme in accordance with the invention. Subjects examined during the period of 180 days, with introduction (ingestion) medicines beginning with the first day of spontaneous menstruation. One group of 10 women receive only pills And (in combination with placebo), acting as a control group. Three groups of 10 women each of which receives a pill a day and the dose of Org 31710 through the day, and what's register bleeding or no bleeding).

Example IV This example is to test for inhibition of ovulation in the combined treatment of the gestagen and antigestagens on short-tailed monkey (Masasa Arctoides).

Scheme of the experiment. This test is used to assess the impact of combinations of progestogen (desogestrel) and antigestagen (Org 33628) on ovulation inhibitory activity and action control cycle after daily oral administration for 21 days. Adult monkeys-females, Masasa Arctoides, with at least 2 regular ovulatory estrous cycles (5-20 years of age, 5-17 kg) treated from day cycle 2-22. Cycle control, taking daily swabs from the vagina with fingering with cotton wool on the end. Consider that the first day of menstrual bleeding is day 1 of the cycle, and the experiment begins with a preprocessing of the control cycle. Blood samples taken twice a week during cycle processing and control cycles (pre-processing and post-processing) for determination of estradiol and progestogen that is used to assess the occurrence of ovulation.

Doses of the compounds. Compounds used oral; desogestrel take a dose of 4 mg/kg/day, Antipov the(levels above 1 ng/ml) during treatment is predictable in the case of inhibition of ovulation. The absence of oestradiol levels above 150 PG/ml during treatment indicates inhibiting the follicle Genesis.

Claims

1. Contraceptive kit comprising a means (a) for a daily injection of progestogen and the means (b) for the introduction of antigestagen, characterized in that the said means (a) and (b) are the combined means (C) for simultaneous daily long-acting progestogen and antigestagen, and the number of daily doses antigestagen below the equivalent of 10 mg RU 486.

2. Contraceptive set under item 1, characterized in that the means (a) for a daily injection of progestogen is intended for daily dose sufficient to inhibit ovulation, and the means (b) for daily administration antigestagen is intended for a daily dose, does not affect ovulation.

3. Contraceptive set under item 1, characterized in that a daily dose of antigestagen equivalent dose of RU 486 from 0.05 to 5 mg.

4. Contraceptive set under item 3, wherein the daily dose of antigestagen equivalent dose of RU 486 from 0.1 to 2 mg.

5. Contraceptive set under item 3 or 4, characterized in that it ensures that n is tives such as those that combined means (C) includes daily dosage units contraceptives containing a progestogen and antigestagen.

7. Contraceptive set under item 6, wherein the daily dosage units contraceptives are pills.

8. The contraceptive kit according to any one of the preceding paragraphs, wherein the gestagen is a desogestrel, gestodene or Org 30659, and antigestagen represents RU 486 or Org 33628.

9. Contraceptive set under item 3 or 4, characterized in that the combined means (C) includes take daily pills containing a progestogen, and a controlled release device containing antigestagen.

10. The contraceptive kit according to any one of paragraphs. 1-7, characterized in that the combined means (C) includes at least one active substance with a mixed profile gestagennoy antigestagen properties.

11. Contraceptive set under item 1, including tablets, containing inhibiting ovulation the amount of progestogen, and tablets containing antigestagen in an amount equivalent, relative to the in vivo antiprogesterone activity, the dose of RU 486 from 0.05 to 5 mg, and set konstruirovanie set p. 1, wherein antigestagen represents RU 486 or Org 33628, and each pill contains progestogen and antigestagen and should be applied daily.

13. Contraceptive kit comprising consecutive daily dosage units of contraceptives for oral administration, including dosage unit having as pharmaceutically active ingredients gestagen and antigestagen, characterized in that the consecutive daily dosage units contraceptives form a continuous, single phase combination of a gestagen and antigestagen.

14. Contraceptive set on p. 13, wherein the gestagen is a desogestrel, gestodene or Org 30659, and antigestagen represents RU 486 or Org 33628.

15. The method of obtaining the contraceptive kit according to any one of paragraphs. 1-8, 10 and 12-14, comprising mixing predetermined amounts of progestogen and antigestagen with predefined amounts of fillers and processing the mixture in dosage units, each includes a gestagen and antigestagen, and packaging, at least 28 of these dosage units in the set.

16. A method of treating krovotechenia.gotove administered daily at a dose equivalent dose of RU 486, from 0.05 to 5 mg.

17. The continuous contraceptive regimens, characterized in that it is a composition containing a progestogen and antigestagen, and dose antigestagen equivalent of 0.05-5 mg RU 486.

18. The continuous contraceptive regimens, characterized in that it is a compound with a mixed profile gestagennoy antigestagen properties.

Priority items: 14.11.1997 on PP. 1-9, 11-18; 08.05.1998 on PP. 10 and 19.

 

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