LT5001B - Mesoprogestins (progesterone receptor modulators) as a component of female contraceptives - Google Patents

Abstract

The present invention relates to the use of mesoprogestins for the production of a pharmaceutical for female contraception, to the pharmaceutical preparation for female contraception administering effective amounts of a mesoprogestin in a female desiring contraception. Optionally the mesoprogestin can be used in combination with an estrogen. Mesoprogestins are defined as compounds possessing both agonistic and antagonistic activities at the progesterone receptor (PR) in vivo. They stabilize the function of PR at an intermediate level of agonistic and antagonistic. Corresponding functional states cannot be achieved with progestins or antiprogestins. J867, J912, J956 and J1042 are the mesoprogestins preferred according to the invention.

Description

The present invention is in the field of contraception. More specifically, it relates to the use of mesoprogestin in the manufacture of a medicament for female contraception, a pharmaceutical preparation for female contraception, and a female contraceptive, for the administration of effective amounts of mesoprogestin to a woman who wishes to prevent pregnancy.

Various pharmaceutical preparations are available for female oral contraception.

The most common form of oral contraceptive is a pill containing both estrogen and progestin, a so-called combined oral contraceptive. Progestin appears to act by blocking the release of gonadotropin (inhibition of ovulation); the estrogen component gives endometrial control by reducing bleeding outbreaks.

Alternatively, there are contraceptives containing progestin only. However, progestin-only formulations (= progestin-only pill = POP) have a broader range of side effects than combination formulations, especially larger bleeding outbreaks. Therefore, oral contraceptives that are more suitable for use today are combination preparations (Sheth et al., Contraception, 25: 243, (1982)).

Antiprogestins (also called "progesterone antagonists" or "antigestagens") are a class of compounds that block the progesterone receptor. For example, RU 486 (mifepristone) is a progesterone receptor antagonist. RU 486 binds to the progesterone receptor and blocks progesterone binding to this receptor. In the luteal phase of the menstrual cycle, RU 486 induces vaginal bleeding.

Previous work has shown either inhibition of the ovulatory menstrual cycle or delayed endometrial maturation. In a primate model, it was shown that both a single injection of antiprogestin RU 486 (5 mg / kg, i.m.) in the late follicular phase and a single oral dose of 25 mg RU 486 once a week prevented ovulation (Collins et al.,

J. Dyn. Endocrinol. Metab. 1986, 63, 270-1276; Danforth et al., Contraception 1989, 40: 195-200).

Using a variety of techniques that vary in regimens and dosages, several research groups have shown that RU 486 also inhibits ovulation in women (Shoupe et al., Am. J. Obstet. Gynecol. 1987, 157: 1421-1426; Liu et al., J. Dyn. Endocrinol. Metab. 1987, 65: 1135-1140; Luukkainen et al., Fertil. Steril. 1988, 49: 961-963). Ovulation inhibitory activity of progesterone inhibitors other than RU 486 has also been shown (Zelinski-Wooten, MB, Slayden, OD, Chwalisz, K., Hess, D.L., Brenner, R.M., Stouffer, R.L. (1998a) Chronic treatment of female cycling rhesus monkeys with low doses of antiprogestin ZK 137316: Establishment of a regiment that permits normal menstrual cyclicity. Hum. Reprod. 13: 256-267).

Thus, several antovulatory strategies for contraception using progesterone antagonists have been proposed.

A contraceptive strategy in which RU 486 works through implantation inhibition has also been described. In the so-called LH + 2 treatment (Swahn et al., "The Luteal Effect of RU 486 Administration during Early Luteal Phase on Bleeding Patients, Hormone Parameters and Endometrium, Human Reproduction 5, 4: 402-408 (1990)), A dose of RU 486 inhibiting ovulation is administered once for 2 days after the LH peak (LH = luteinizing hormone). The active compound is used only after ovulation in the luteal phase of the menstrual cycle (luteal contraception).

A method of contraception using competitive progesterone antagonists is described in WO 93/23020. At doses lower than ovulation inhibition and abortion at the progesterone antagonist, preferably contraception is achieved in women by inhibition of implantation. This method does not adversely affect the woman's menstrual cycle and there is no risk of having a previously implanted fertilized egg or fetus. The use of a progesterone antagonist occurs at least once in the follicular phase of a woman's menstrual cycle (i.e., prior to ovulation). The most appropriate frequency of use is daily or thereafter at regular intervals of several days, e.g. weekly, or every 3 or 4 days after a single administration of the active compound.

WO 94/18982 describes a method of inhibiting oocyte fertilization, which comprises administering to an ovulating mammal an amount of an antiprogestin that inhibits fertilization. This amount is not sufficient to prevent ovulation or disrupt the regularity of the mammalian menstrual cycle. Best to take daily.

In one aspect of the present invention, mesoprogestins are used as a component in the manufacture of a medicament for female contraception. They can be used either as a separate pharmaceutically active component in female contraceptives, or they can be used in combination with estrogen.

In one aspect of the present invention, mesoprogestins, alone or in combination with estrogens, are used in a regular cyclic administration regimen. This means that mesoprogestins are administered in uniform and repetitive cycles as long as pregnancy is avoided. The cycle starts with the administration of a mesoprogestin or mesoprogestin / estrogen-containing dosage unit, followed by daily administration of another dosage unit. Each cycle ends with a period of no active dosage unit (pills-free) or placebo. Alternatively, with mesoprogestin / estrogen, the cycle may be completed by continued use of estrogen-only dosage units. A new cycle of administration begins on the first day after the "pill-free" or placebo phase, respectively, or the phase in which only the estrogen-containing dosage units were used. In all cases, the first day of the first cycle is the first day of the woman's menstrual cycle where contraception begins.

One embodiment of mesoprogestin alone provides mesoprogestin dosage units for up to 180 days. Continuous daily administration (1 to 25 mg mesoprogestin / day) induces and maintains reversible amenorrhea. The contraceptive effect is due to the endometrial effects (inhibition of the endometrium) of mesoprogestin. This makes the endometrium unprepared for implantation of a fertilized egg. For contraceptive efficacy, administration of progestin at doses sufficient to prevent penetration is sufficient. Mesoprogestin dose may also inhibit ovulation, but it is not important to achieve a contraceptive effect and to achieve and maintain amoorrhea. It is best to use one mesoprogestin for a maximum of 3 months (this allows for the contraceptive reliability of the method to be tested). Compared to other progestogen-only contraceptive regimens, the administration regimen described above results in improved bleeding behavior.

Compared to the minipill (single progesterone pill) and the subcutaneous implants filled with progestin (Norplant), fewer outbreaks of bleeding were observed. Methods using a progestone antagonist as described in WO 93/23020 and WO 94/18982 maintain a normal cycle.

In another variant of mesoprogestin administration, the duration of use is continuous for more than 3 months, for example 1-3 years. Because mesoprogestin inhibits endometrial growth and prevents the fragility of endometrial vessels, it can be used permanently. In addition, chronic but reversible amenorrhea is achieved.

In another embodiment of mesoprogestin administration, mesoprogestin-containing dosage units are provided for up to 21, 22, 23, 24 or 25 days, followed by a period of 7, 6, 5, 4 or 3 days without any active compound, or 7, 6 , 5, 4, or 3 days of piacebo pills administration with a 28 day cycle. The next day, another cycle of mesoprogestin-containing dosage units begins, and so on. In this aforementioned mode of administration, mesoprogestin acts as a progestin by blocking ovulation and causing amenorrhea, and causes bleeding to be stopped. Sudden outbreaks of walking are not caused. Discontinuation bleeding is due to endoprosthetic changes due to mesoprogestin. Thus, in this embodiment, mesoprogestin should be administered at least in the luteal phase of the female menstrual cycle at doses that inhibit ovulation. not used).

Amenorrhoea-inducing doses may be determined by those skilled in the art, for example in clinical trials. Usually the daily dose of mesoprogestin will be in the range of 1-25 mg.

When estrogen is given in combination with mesoprogestin, the two active components are given between 1 (see above) and 21, 22, 23, 24 or 25 days of the woman's menstrual cycle, followed by periods of 7, 6, 5, 4 or 3 days, during which no active compound is administered, or a 7, 6, 5, 4, or 3 day piacebo pill administration period with a 28 day cycle. The next day, another cycle of mesoprogestin / estrogen-containing dosage units begins, and so on.

Estrogen is administered in an amount of 10 to 30 pg ethinyl estradiol or its bioequivalent daily intake.

Mesoprogestins may be used alternately with progestin. In this contraceptive regimen, the mesoprogestin component prevents bleeding outbreaks that are usually associated with continued progestin use. The dose of the so-called “mini-pill regimen” of the progestin component is given for 30-180 days and the mesoprogestin component is administered for 1-30 days. Menstrual bleeding may or may not occur during treatment with mesoprogestin. When using alternate progestin / mesoprogestin, the rate of unexpected bleeding is much lower.

Regular, cyclic mesoprogestin administration regimens, when required in combination with estrogen, are illustrated in detail in FIG.

The use of mesoprogestin in an intermittent, non-cyclic regimen is referred to as on-demand use, whereby the product is to be used only for the duration of sexual intercourse when contraception is desired. Pre-sexual use is recommended ("condom"). See details. WO 93/23020.

Yet another aspect of the present invention is a pharmaceutical product combination wherein mesoprogestin is co-administered with estrogen.

Yet another aspect of the present invention is a pharmaceutical product combination wherein the mesoprogestin is in combination with a progestin.

Yet another aspect of the present invention relates to pharmaceutical formulations for female contraception containing mesoprogestin daily dosage units.

All aspects of the pharmaceutical preparations of the present invention will be apparent from the claims 25-38.

Suitable mesoprogestins for the purposes of the present invention are the compounds described in DE 43 32 283 and DE 43 32 284.

The above compounds, such as J867 4- [17? -Methoxy-17? (Methoxymethyl) -3-oxoestra-4,9-diene-11? -Yl] benzaldehyde (1E) -oxime] and J912.

4- [17β-Hydroxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-ylbenzaldehyde (1E) -oxime (both DE 4332283) and J900 4- [17β-methoxy-17α- (methoxymethyl) ) 3-oxoestra-4,9-diene-11β-yl] benzaldehyde (1E) - [O- (ethoxy) carbonyl] oxime], J 914 4- [17β-methoxy-17α- (methoxymethyl) -3 -oxoestra-4,9-diene-11β-yl] benzaldehyde (1E) - (O -acetyl) -oxime] and J956 4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene- 11 p-yl] benzaldehyde- (1E) - [O (ethylamino) carbonyl] oxime] (all DE 4332284) are described as having potent antiprogestagenic activity and significantly reduced anti-glucocorticoid activity compared to RU486. In addition, it has been mentioned that these compounds have (indirect) anti-estrogenic properties, which are manifested in reduced uterine mass in a test in cyclic guinea pigs. These effects should reflect a particularly favorable effect on pathologically modified tissues in which estrogens stimulate growth (endometrial foci, myomas, etc.). There is nothing in the descriptions of these applications about the use of these new compounds for female contraception or about pharmaceutical preparations for this purpose. These applications also make no mention of the progestagenic activity of the compounds, which is desirable for the contraceptive indications mentioned herein. In addition, the aforementioned applications omit any active doses that should be used to treat these conditions.

According to the present invention, mesoprogestins are compounds having both agonistic and antagonistic effects on the progesterone receptor (PR) in vivo. Like progestins and antiprogestins, mesoprogestins show a high degree of connectivity to PR. However, mesoprogestins have different pharmacodynamic properties compared to either progestins or antiprogestins. The presence of progesterone agonist activity in mesoprogestins, as measured by commonly used in vivo biological assays, represents a key feature of this novel class of PRM. However, this activity remains below the plateau of progesterone in the dose-response curve. Mesoprogestans fail to maintain pregnancy in pregnant, ovariectomized females such as mice and rats.

In the classic bioassay, McPhail's test, which assesses progestagenic and antiprogestagenic effects in rabbits (Selye H., Textbook of Endocrinology, 1947, pp. 345-346), progesterone gives a maximum McPhail score of 4 (by definition). However, treatment with mesoprogestin in the absence of progesterone results in a McPhail score which is higher than the score at any dose of RU486, i.e. more than 0.5-1.0, preferably 2.0-3.0, but well below 4 on the dose-response curve at clinically appropriate doses for the above indications (i.e. 0.01 mg-30 mg / rabbit).

The McPhail assay also tested the ability of mesoprogestin to antagonize progesterone function using a dose of progesterone that produces a McPhail score within the range of 3-4. Mesoprogestin has a high degree of inhibition of the progesterone effect but the maximum inhibition is lower than the inhibition provided by RU486 or other pure antiprogestins (eg onapristone).

Therefore, mesoprogestins stabilize PR function at the level of intermediate activity, making them suitable for new clinical use in gynecological therapy. Corresponding functional states cannot be achieved with progestins or antiprogestins.

Pharmacological data demonstrating the utility of mesoprogestin for defined indications

The antagonistic and agonistic properties of mesoprogestin PR were evaluated using estrogen-primed rabbits in McPhail's test according to Selye (Textbook of Endocrinology, 1947, 345-346).

A) Evaluation of the agonist properties of mesoprogestin PR in a rabbit assay (Fig. 1A)

J867, J956, J1042 [4- [17β-Methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9 diene-1ip-yl] benzaldehyde (1E) - [O- (ethylthio) carbonyl] oxime (German Patent Application) 198 09 845.6)] and RU486 (dose range: 0.003-100 mg / rabbit) progestagenic activity was assessed using estradiol-primed rabbits, 4 days after subcutaneous (sc) administration in the absence of progesterone. The progestagenic effect of mesoprogestin was observed at doses of 0.03 mg / rabbit or higher. Progesterone induced endometrial changes at doses of 0.1 mg or greater, reaching a maximum at 1 mg / rabbit (approximate McPhail score of 4). None of the mesoprogestins studied (J 1042, J867, J956) achieved the maximum effect of progesterone. J956 showed a two-way response in this assay with a maximum McPhailO score of 1.5 at doses of 0.3-1 mg / rabbit.

B) Evaluation of PR antagonistic properties of mesoprogestins in a rabbit experiment (Fig. 1B)

Similarly, the antiprogestagenic activity of J867, J956, J1042 and RU486 (dose range: 0.001-100 mg / rabbit) was evaluated using estradiol-primed rabbits, 4 days after subcutaneous (sc) administration of progesterone (1 mg / rabbit, sc). ). The first antiprogestagenic effect of mesoprogestins and RU486 was observed at doses of 0.3-1 mg / rabbit. (McPhailO scores 0 = no change, 4 = complete change). The antiprogestagenic activity of mesoprogestins was higher than that of RU486 at higher clinical doses (3-30 mg / rabbit).

In a guinea pig model that predicts human exposure in terms of abortion-inducing activity (Elger W., Beier S., Chwalisz K., Fahnrich M., Hasan S.S., Henderson D., Neef G., Rohde R (1986): Studies on the mechanism of action of progesterone antagonists J. Steroid Biochem. 25: 835-845), mesoprogestins J867, J912, J956, J1042 at doses up to 100 mg / kg / day gave a 20% maximum abortion rate.

C) Evaluation of the effects of inducing abortion

Physiological justification:

Guinea pigs are considered an appropriate model for human pregnancy and childbirth (Elger W., Fahnrich M., Beier S., Quing S.S., Chwvalisz K. (1987) Endometrial and myometrial effects of progesterone antagonists in pregnant guinea pigs. Am. J. Obstet. Gynecol 157: 1065-1074; Elger W., Neef G., Beier S., Fahnrich M., Grundel M., Heermann J., Malmendier A., Laurent D., Puri CP, Singh MM, Hasan S.S., Becker. H (1992) Evaluation of antifertility activities of antigenic agents in an animal model In: Puri CP and Van Look PFA (eds), Current Concepts in Fertility Regulation and Reproduction, Wiley Eastern Limited, New Delhi, pp. 303-328; Elger W., Faehnrich M., Beier S., Qing S.S., Chwvalisz K. (1986) Mechanism of action of progesterone antagonists in pregnant guinea pigs, Contraception 6: 47-62; Elger W., Chwalisz K. Faehnrich M., Hasan SH, Laurent D., Beier S., Ottow E., Neef G., Garfield RE (1990) Studies on Laboratory Conditioning and Laboratory Induction Effects of Antiprogesterons in Anima l Model In: Garfield R. E. (eds), Norwell, pp. 153-175). The mechanism of abortion in these species is the onset of childbirth and eventually fetal displacement. The effect of inducing abortion in rats during very early gestation reflects the i’nhibitory effect on penetration rather than induction of uterine contractions. Studies in the rat model overestimate the ability of antiprogestins to terminate human pregnancy. In contrast, the guinea pig model produced a high percentage of subsequent pregnancies, independent of antiprogestin doses, similar to that in humans (see Elger W et al., Current Concepts in Fertility Regulation and Reproduction, cited above). In addition, both humans and guinea pigs show strong synergism between antiprogestins and prostaglandins in terms of childbirth (see articles cited above and Elger W., Beier S. (1983). Prostaglandins and Antigestagens for Pregnancy and Prostaglandins). German Patent DE 3337450 12; Van Look P., Bygderman M. (1989) Antiprogestational steroids: a new dimension in human fertility regulation (Oxford reviews of reproductive medicine 11: 260).

Evaluation of birth-inducing activity: FIG. 3.

Pregnant guinea pigs were exposed on day 43 and 44 of pregnancy and monitored until day 50 of pregnancy. the effects of the various effects are given in Table 1 and FIG. This model is characterized by the fact that emissions occur several days after exposure. It can be seen that mesoprogestins have a significantly reduced abortion-inducing effect compared to RU486. The following order of abortion activity was found: RU486> J956> J867, J912> J1042. The differences in abortion activity appear to be purely qualitative. However, this low abnormal activity of mesoprogestins cannot be avoided at higher doses.

Table ιυ: Relative Binding Activity (RBA) and Abortion Activity in ED ₅₀ Pregnant Rats and Guinea Pigs

The compound RBA (%) # Abortion activity ED ₅₀ (mg / animal, sc) PR ¹ GR ² rats ³ guinea pigs ⁴ RU486 506 685 0.98 * 3.8 onapristone 22nd 39 1.71 * about 3 J867 302 78 0.65 * > 100 J956 345 154 0.64 * 20th J912 162 16th 0.36 > 100 J1042 164 42 > 10 »100 # by Kaufmann; progesterone = 100%, ² c examethasone = 100%,

Exposure Day ³ : 5-7 Pregnancy Day, Autopsy on Day 9 Exposure Day ⁴ : 43-44 Pregnancy Day, Autopsy on Day 50 * SAS, probit technique.

Mesoprogestins for the present invention are preferably selected from the group of compounds J867, J912, J956, J1042.

Other suitable mesoprogestins include:

4- [17β-Hydroxy-17α- (ethoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) -oxime;

4- [17? -Methoxy-17? - (ethoxymethyl) -3-oxo-estra-4,9-diene-11? -Benzobenzaldehyde (1E) -oxime;

4- [17β-Hydroxy-17α- (chloromethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) -oxime;

4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - (O-methyl) oxime (all DE 43 32 283) and

4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - [O- (phenylamino) carbonyl] oxime;

4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - (propionyl) oxime;

4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - (benzoyl) oxime (all DE 43 32 284).

The daily dose of mesoprogestin is 1-25 mg.

As estrogens, all estrogen-active compounds are suitable for the purposes of the present invention.

Estrogens which may be used in the present invention include, for example, ethinyl estradiol, 17β-estradiol and its esters, such as estradiol-3-benzoate, estradiol-17-valerate, -cipionate, -undecylate, -enanthate and / or other estradiol esters. US-PS 2,611,773, US-PS 2,990,414, US-PS 2,054,271, US-PS 2,225,419 and US-PS 2,156,599) and estrogen conjugates.

• Estradiol, ethinyl estradiol and estrone-3-sulfamates, such as estrone-N, N-dimethyl sulfamate, estrone-N, N-diethyl sulfamate, ethinyl estradiol-3-Ν, dimethyl sulfamate, ethinyl estradiol-3-N, N-diethyl sulfamate, ethinyl estradiol. ,? -Tetramethylenesulfamate, estronsulfamate, estradiol-3-sulfamate, estradiol-3-N, N-dimethylsulfamate, estradiol-3-N, N-diethylsulfamate, ethinylestradiol-3-sulfamate; all of which are prodrugs of 3-hydroxy compounds (W. Elger et al., 1995, J. Steroid Biochem. Molec. Biol., Vol. 55, No.3 / 4, 395-403, 1995; DE 44 29 398 A1 and DE 44 29 397 A1) and may also be used in the pharmaceutical agent of the present invention.

The progestins of the present invention include all compounds which are suitable for use in oral contraceptives because of their progestin activity. A list of examples of such compounds is B. Runnebaum et al., "Female Contraception: Update and Trends", Springer-Verlag, Berlin, 1988, p. 64-90, 109-121, 122-128 and 129-140. Preferred progestins for the present invention are gestodene, progesterone, levonorgestrel, cyproterone acetate, chlormadinone acetate, drospirenone (dihydrospirorenone), norethisterone, norethisterone acetate, norgestimate, desogestrel or 3ketodesogestrel. In a progestin-containing embodiment of the present invention, the progestin is in a dosage form suitable for oral administration, namely a tablet, a coated tablet, a capsule or a pill. In this case, the progestin dosage form is prepared in the same way as the progestin for hormonal contraception using adjuvants that are commonly used for this purpose. The daily dosage unit of progestin contains 0.6-6.0 mg of levonogestrel, 2-20 mg of ciproterone acetate, 0.3-3.0 mg of gestodene or 0.22.0 mg of desogestrel, or other amount of progestin that is effective. equivalent to these doses.

Doses of various progestin equivalent effects were determined by known methods; other details can be found, for example, in two articles: "Probleme der Dosisfindung: Sexualhormone" F. Neumann et al. in "Arzneimittelforschung [Drug Research]" 27, 2a, 296-318 (1977), and "Current development of hormonal contraception", by H. Kuhl in "Gynacologist {Gynecologistsj" 25: 201-240 (1992). ).

In all embodiments, mesoprogestin may be presented in dosage units for daily oral administration.

Estrogen can also be taken in oral daily dosage units. If mesoprogestin dosage units are provided for 7 days, it is preferable that they be in the form of a unit dosage once a week. In such a dosage unit to be administered once a week, mesoprogestin should be formulated in such a manner as to provide delayed release of the active ingredient.

Delayed release of mesoprogestins may be achieved, for example, by formulating a dosage unit to be administered orally as a composite tablet or by providing a dosage unit to be administered orally with a gradual disintegration coating well known to those skilled in the art.

In the preparation of derivatives, for example by esterification of the free hydroxyl group in an effective precursor, the mesoprogestin used to produce the pharmaceutical agent of the present invention may also have a longer half-life than this precursor. This results in longer life.

For the purposes of the present invention, the dosage form of mesoprogestin and, where appropriate, estrogen is prepared in a manner similar to the known dosage forms of these compounds for their separate administration as described in DE 43 32 283 for J867 and for Cyclo-Progynova for example.

In particular, the information contained in the abovementioned documents must be indicated.

Apart from the use of oral estrogen and mesoprogestin, it is also possible to use one or both components transdermally, for example as patches on the skin, which are widely known for estrogen administration (Climara Patch).

In addition, an intrauterine excretion system (such as Mirena) may be used, but this embodiment is not preferred according to the present invention.

It is also possible to use both components in the form of a depot formulation.

After all, all of these uses can be combined. For example, estrogen may be administered transdermally via a skin patch, and a progesterone antagonist may be administered daily orally or once or more times in the form of a depot formulation.

The amount of estrogen in the daily dosage unit of the present invention is 10 to 30 pg ethinyl estradiol or a bioequivalent amount of other estrogen.

Preferably, the amount of mesoprogestin in each dosage unit of the pharmaceutical agent of the present invention is such that it is sufficient to produce amenorrhea at the indicated time.

In a particularly preferred embodiment of the pharmaceutical agent, mesoprogestin according to the present invention is present in each daily dosage unit and is present in an amount equivalent to 1-25 mg J867. Bioequivalent doses of mesoprogestin can be determined by McPhail's test.

The package containing the pharmaceutical preparation of the present invention is formulated so as to provide mesoprogestin and estrogen components (oral pills, coated tablets, etc., in a blister pack which may be suitable for mesoprogestin and / or estrogen) or estrogen as a patch on the skin. , while mesoprogestin in the form of pills, coated tablets, etc. in a blister pack or capsule as a depot to be administered once), it also contains instructions for use of the pharmaceutical agent (insert).

Claims (38)

DEFINITION OF INVENTION Use of mesoprogestins as a component in the manufacture of a medicament for female contraception. Use of mesoprogestins according to claim 1, characterized in that the mesoprogestins are used without any other pharmaceutically active compound. Use of mesoprogestin according to claim 1 or 2, characterized in that the mesoprogestins are used in regular, cyclic administration. 4. The use of claim 3, wherein the mesoprogestin is administered from day 1 to a maximum of 180 days, with day 1 being considered as the first day of bleeding in a woman's menstrual cycle. The use according to claim 4 wherein the daily amount of mesoprogestin is selected to cause and maintain amenorrhea. 6. The use according to claim 5, wherein the mesoprogestin is administered from day 1 to at least 21 days and at most 25 days, and day 1 is considered to be the first day of the woman's menstrual cycle. 7. The use according to claim 6, wherein the daily amount is selected to achieve reversible amenorrhea. Use according to any one of the preceding claims 1-7, characterized in that the mesoprogestin is J 867 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde. (1E) oxime], J 912 [4- [17β-hydroxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene-1-yl] benzaldehyde (1E) -oxime], J 956 [4- [ 17β-Methoxy-17α (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - [O- (ethylamino) carbonyl] oxime], J 1042 [4- [17β-methoxy- 17α- (Methoxymethyl) -3-oxoestra-4,9-diene-11β-yl] benzaldehyde (1E) - [O- (ethylthio) carbonyl] oxime]. Use according to any one of claims 1-8, wherein the daily dose of mesoprogestin is from 1 to 25 mg. Use according to claims 1 and 3 to 9, characterized in that estrogen is used as an additional component in the manufacture of a medicament. Use according to claim 10, characterized in that the additional component is ethinyl estradiol, estradiol, estradiol ester or 17β-ethynylestradiol or 17β-estradiol 3-sulfamate. 12. The use according to claim 10 or 11, wherein the daily dose of the additional component estrogen is from 10 to 30 µg of ethinyl estradiol or a bioequivalent amount of the other estrogen. Use according to any one of the preceding claims 1 to 12, characterized in that the medicament is prepared for oral administration. Use according to any one of the preceding claims 1 to 12, characterized in that the medicament is prepared for intrauterine administration. 15. The use according to claim 10, 11 or 12, wherein at least one or both of the mesoprogestin and the estrogen supplementary component are formulated for oral administration. 16. Use according to claim 10, 11 or 12, wherein at least one or both of the mesoprogestin and the estrogen component is prepared for intrauterine administration. 17. The use of claim 2, wherein the mesoprogestins are for use in an intermittent, non-cyclic administration. 18. The use of claim 17, wherein the mesoprogestin-containing medicament is used as needed when contraception is effectively administered once. Use according to claim 18, wherein the use is up to 4 days. 20. The use of claim 19, wherein at least the first administration for up to 4 days is prior to intercourse where contraception is desired. 21. The use of claim 20, wherein the administration is disposable and prior to sexual activity. 22. A pharmaceutical composition comprising mesoprogestin and estrogen. 23. The pharmaceutical composition of claim 22, wherein the mesoprogestin is selected from J 867 [4- [17? -Methoxy-17? (Methoxymethyl) -3-oxo-estra-4,9-diene-11? -Yl] benzo, dehyde. (1E) -oxime], J 912 [4- [17β-hydroxy-17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) -oxime], J 956 [4 - [17? -Methoxy-17? - (methoxymethyl) -3-oxoestra-4,9-diene-11? -? - benzaldehyde (1E) - [O- (ethylamino) carbonyl] oxime], J 1042 [4- [17? -Methoxy- Groups of 17α- (methoxymethyl) -3-oxoestra4,9-diene-11β-Ν] όβηζ3ΜβΙ ^ - (1E) - [O- (ethylthio) carbonyl] oxime]. 24. The pharmaceutical composition of claim 22, wherein the estrogen is ethinyl estradiol, estradiol, estradiol ester or 17β-ethinyl estradiol or 17β-estradiol 3-sulfamate. 25. A pharmaceutical preparation for female contraception, characterized in that it contains mesoprogestin daily dosage units and these dosage units are provided for a maximum of 180 days. 26. A pharmaceutical preparation according to claim 25, wherein up to 7 units of placebo or a means for marking off pills are provided alongside mesoprogestin. 27. A pharmaceutical preparation according to claim 26, wherein 21, 22, 23, 24 or 25 daily doses of mesoprogestin and 7, 6, 5, 4 or 3 placebo units or measures 7, 6, 5, 4 or 3 are provided. marked for pill-free days. 28. A pharmaceutical preparation according to claim 26 or 27, wherein in addition to mesoprogestin-containing dosage units, estrogen-containing dosage units are provided. 29. The pharmaceutical preparation of claim 28, wherein the mesoprogestin and estrogen are in the same dosage units. 30. A pharmaceutical preparation according to claim 28, wherein the mesoprogestin and estrogen are in separate dosage units. 31. A pharmaceutical preparation comprising dosage units of mesoprogestin and estrogen or a mixture of estrogens, wherein said dosage units are provided for 21, 22, 23, 24 or 25 days, wherein said mesoprogestin / estrogen dosage units are provided on 7, 6, 5, 4, or 3 dosage units containing estrogen or a mixture of estrogens alone, providing total dosage units for a 28 day period. 32. A pharmaceutical preparation according to claim 31, wherein the mesoprogestin and estrogen are in the same dosage units. 33. A pharmaceutical preparation according to claim 31, wherein the mesoprogestin and estrogen are in separate dosage units. 34. A pharmaceutical preparation according to any one of the preceding claims 25-33, wherein the mesoprogestin is J 867 [4- [17? -Methoxy-17? - (methoxymethyl) -3-oxo-estra-4,9-diene-11? -Yl] benzaldehyde - (1E) oxime], J 912 [4- [17β-hydroxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene 11β-yl] benzaldehyde (1E) -oxime], J 956 [4- [ 17β-Methoxy-17α (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - [O (ethylamino) carbonyl] oxime], J 1042 [4- [17β-methoxy] -17α- (methoxymethyl) -3-oxo-estra-4,9-diene-11β-yl] benzaldehyde (1E) - [O- (ethylthio) carbonyl] oxime]. 35. A pharmaceutical preparation according to any one of the preceding claims 28-34, wherein the estrogen is ethinyl estradiol, estradiol, estradiol ester or 17β-ethynylestradiol or 17β-estradiol 3sulfamate. 36. A pharmaceutical preparation according to any one of the preceding claims 25-35, wherein the daily dosage unit contains from 1 to 25 mg of mesoprogestin. 37. A pharmaceutical preparation according to any one of the preceding claims 28-33, 35 and 36, wherein the daily dosage unit contains from 10 to 30 µg of ethinyl estradiol or a bioequivalent amount of another estrogen. 38. A pharmaceutical preparation according to any one of the preceding claims 25-37, wherein the daily dosage unit comprises amenorrhea-inducing and amenorrhea-containing mesoprogestin. PR modulator-like effects of progesterone (top, Fig. 1A) and antagonistic effects of progesterone (bottom, Fig. 1B) in the uterus of estrogen-primed immature rabbits (McPhail's test)