SK2982002A3 - 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 a pharmaceutical preparation for female contraception and to a method of 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 relates to contraception. In particular, it relates to the use of mesoprogestins for the manufacture of a medicament for contraception in women, a pharmaceutical composition for contraception in women, and a method of contraception in women, comprising administering to women in need of contraception as a contraceptive an effective amount of mesoprogestin.

BACKGROUND OF THE INVENTION

Various pharmaceutical preparations are available for oral contraception in women.

The most common form of oral contraceptives are pills that combine estrogen and progestin, so-called combined oral contraceptives. In all, the progestin acts to block the release of gonadotropin (inhibition of ovulation), the estrogenic component providing endometrial control to reduce uterine bleeding from penetration.

Alternatively, there are contraceptives that contain only progestin. However, progestin-only formulations (= "progesterone-only pili = POP") have a more diverse spectrum of side effects than the combination formulations, especially the greater incidence of breakthrough bleeding. As a result, combination formulations are currently preferred as oral contraceptives (Sheth et al., Contraception, 25: 243, (1982)).

Antiprogestins (also called "progesterone antagonists or" antigestagens) are a group 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 from binding to the receptor. When administered in the luteal phase of the menstrual cycle, RU 486 induces vaginal bleeding.

Either inhibition of the ovulatory menstrual cycle or delayed endometrial maturation has been demonstrated in the art. In primate models, one injection of antiprogestin RU 486 (5 mg / kg im) in the late follicular phase or once weekly oral dose of 25 mg RU 486 has been shown to prevent ovulation (Collins et al., J. Clin. Endocrinol. Metab. 1986 , 63: 1270-1276; Danforth et al., Contraception 1989; 40: 195-200).

Using various research protocols that differed in regimen and dose, several groups of scientists 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. Clin. Endocrinol. Metab. 1987, 65: 1135-1140 (Luukkainen et al., Fertil. Steril. 1988, 19: 961-963).

Also, ovulatory inhibitory activity of other progesterone antagonists such as RU 486 (Zelinski-Wooten, MB, Slayden, OD, Chwalisz, K., Hess, DL, Brenner, RM, Stouffer, RL (1998a) was demonstrated. low-dose of the antiprogestin ZK 137 316: Establishment of a regiment that permits normal menstrual cyclicity. Hum Reprod 13: 256-267).

Therefore, several anti-ovulation strategy approaches have been proposed to achieve contraception by progesterone antagonists.

Contraceptive procedures have also been described in which RU 486 acts by inhibiting implantation.

In the so-called "LH + 2 treatment" (Swahn et al., The Luteal Effect of RU 486 Administration During The Early Luteal Phase On Bleeding Pattern, Hormonal Parameters And Endometrium, Human Reproduction 5, 4: 402-408 (1990)) days after the occurrence of LH peak (LH = luteinizing hormone), a single dose of RU 486 inhibiting ovulation. Thus, the active compound is administered only after ovulation in the luteal phase of the menstrual cycle (luteal contraception).

A contraceptive method using competitive progesterone antagonists is described in International Patent Application WO 93/23020. Progesterone antagonists achieve a dose lower than the ovulation inhibiting dose and the abortive dose, in women contraception by inhibiting implantation, preferably after oral administration. This method does not adversely affect the menstrual cycle in women and is free from the risk of miscarriage of a previously implanted fertilized egg or fetus. Administration of the progesterone antagonist occurs at least once in the follicular phase of the woman's menstrual cycle (i.e., prior to ovulation). The preferred frequency of administration is daily or at regular intervals of several days, e.g. once a week or 3 or 4 days apart between each administration of the active compound.

WO 94/18982 discloses a method of inhibiting a fertilized egg comprising administering an antiprogestin in an amount inhibiting fertilization to an ovulating mammal. This is insufficient to prevent the ovulation or regularity of the mammalian ovarian menstrual cycle. The preferred method of dosing is daily.

the amount is for violation

SUMMARY OF THE INVENTION

According to one aspect of the present invention, mesoprogestins are used as an ingredient in the manufacture of a medicament for contraception (contraceptives) in women.

They can be used either as the only pharmaceutically active ingredient of female contraceptives or can be used together with estrogens.

According to one aspect of the invention, mesoprogestins, either alone or in combination with estrogens, are used in regular, cyclic dosing regimens. That is, mesoprogestins are administered in identical and repeated application cycles while contraception is desired.

The cycle begins with the administration of mesoprogestin or a mesoprogestin / estrogen containing dosage unit, followed by additional dosage units daily. Each cycle is terminated by a period when no active drug units (no pill days) are administered or placebo is administered.

Alternatively, in the case of mesoprogestin / estrogen administration, the administration cycle may be terminated by further administration of a estrogen-only dosage unit.

The new dosing cycle begins on the first day after the end of the "no pill or placebo phase", respectively, or after the administration of estrogen-only dosage units.

In all cases, Day 1 of the first application cycle is the first day of bleeding the menstrual cycle of a woman on which contraceptive therapy begins.

mesoprogestin alone, units containing continuously throughout

One embodiment of administration provides administration of the drug mesoprogestin up to a maximum of 180 days.

With daily treatment (1 to 25 mg mesoprogestin / day), reversible amenorrhoea is induced and maintained. The effect of the contraceptive is induced by the effect of mesoprogestin on the endometrium (endometrial suppression). As a result, the endometrium is not ready for implantation of the fertilized egg. To achieve the effect of the contraceptive, it is sufficient to administer mesoprogestin at doses preventing nidation. The dose of mesoprogestin may also be a dose to achieve the effect of the contraceptive and to induce and maintain amenorrhoea.

Preferably, mesoprogestin alone is administered for a maximum of 3 months (this allows to control the reliability of the contraceptive).

Compared to other contraceptive regimens that use progestins, only the administration regimen described above results in a better bleeding regimen. A lower incidence of breakthrough bleeding is observed compared to a minipill (progesterone pill only) and a progestin-filled subcutaneous implant (Norplant).

Methods using a progesterone antagonist as described in WO 93/23020 and WO 94/18982 maintained a normal cycle.

Another embodiment of administering mesoprogestin alone is continuous over a period of more than 3 months, for example 1 to 3 years. Since mesoprogestin suppresses endometrial growth and prevents endometrial vessel fragility, it can be used chronically. In addition, a chronic but reversible amenorrhoea state is achieved.

A further embodiment of the administration of mesoprogestin alone provides administration of dosage units comprising mesoprogestin until day 21, 22, 23, 24 or 25, followed by either a period of 7, 6, 5, 4 or 3 days during which no active compound is administered. or followed by the administration of 7, 6, 5, 4 or 3 placebo pills to complete the 28-day cycle. The next day of the following cycle, administration of the mesoprogestin containing dosage unit, etc., begins.

In this latter mode of administration, mesoprogestin acts as a progestin by blocking ovulation and amenorrhea induction, and triggering bleeding from the slope. Penetration bleeds are not induced. Gradient bleeding is caused by mesoprogestin-induced endometrial transformation. Therefore, in this embodiment, the mesoprogestin should be administered, at least in the luteal phase of the menstrual cycle of a woman, in an ovulation inhibiting dose.

A variant of the latter embodiment (not claimed) is the administration of dosage units containing mesoprogestin at a dose that inhibits ovulation exclusively during the luteal phase of the menstrual cycle of the woman (no administration in the follicular phase).

Amenorrhea-inducing doses of mesoprogestins can be determined by a method known to those skilled in the art, for example in clinical studies.

In general, the daily dose of mesoprogestin is in the range of 1 to 25 mg.

When estrogen is administered in addition to mesoprogestin, both active ingredients are administered from day 1 (see above) to day 21, 22, 23, 24 or 25 of the woman's menstrual cycle, followed by either period 7, 6, 5, 4 or 3 days during which no active compound is administered or followed by administration of 7, 6, 5, 4 or 3 estrogen-only dosage units or followed by administration of 7, 6, 5, 4 or 3 placebo pills, in respectively to complete the 28-day application cycle. The next day of the following cycle, administration of the mesoprogestin / estrogen containing dosage unit, etc. begins.

Estrogen is used in a daily amount of 10 to 30 μg of ethinyl estradiol or a biologically equivalent amount.

Mesoprogestins can be used sequentially with a progestin (sequential method). In this contraceptive regimen, the mesoprogestin component prevents breakthrough bleeding that is usually associated with chronic progestin therapy. The progestin component at the dose used in the so-called "mini-pill mode" is

Ί administered over a period of 30-180 days, while the mesoprogestin component is administered over a period of 1-30 days.

Menstrual bleeding may or may not occur during mesoprogestin treatment. However, sequential progestin / mesoprogestin therapy results in a significantly reduced incidence of unplanned bleeding.

Regular cyclic application optionally in combination with estrogen, Figure 2.

mesoprogestin regimens are shown in detail in

The use of mesoprogestins in a discontinuous acyclic dosing regimen is use as so-called "pills as needed, to be administered only around the time of sexual intercourse for which contraception is desired. Preferably, the administration takes place before sexual intercourse ("drug condom"). For details see WO 93/23020.

Another aspect of the invention relates to a pharmaceutical combination product (composition) comprising mesoprogestin together with an estrogen.

Another aspect of the invention relates to a pharmaceutical combination product (composition) comprising mesoprogestin together with a progestin.

Yet another aspect of the invention relates to a pharmaceutical composition for female contraception comprising in unit dosage form a daily dose of mesoprogestin.

All aspects of the pharmaceutical composition of the invention are apparent from claims 25 and 38.

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

The above compounds, for example J867 [4- [173-methoxy-17a8]

- (methoxymethyl) -3-oxoestra-4,9-dien-1H-yl] benzaldehyde- (IE) -oxime] and J912 [4- [17β-methyl-17α- (methoxymethyl) -3-oxoestra-4], 9-dien-lip-yl] benzaldehyde (IE) -oxime] (both see DE 43 32 283) and J900 [4- [173-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene- lipyl-benzaldehyde- (IE) - [O- (ethoxy) carbonyl) oxime], J912 [4- [173-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-lipyl] benzaldehyde- (IE) - (O-acetyl) oxime] and J956 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-lip-yl] benzaldehyde- (IE) - [0 ( ethylamino) carbonyl] oxime] (all DE 43 32 284) are described as having strong antiprogestagenic and significantly reduced anti-glucocorticoid activity compared to RU 486. In addition, these compounds are reported to have (indirectly) antiestrogenic properties, which is reflected by a reduced uterine weight in guinea pigs with ongoing cycles.

These effects would promise a particularly advantageous effect on pathologically modified tissues in which estrogens stimulate growth (endometrious foci, myomas, etc.).

The description of these applications does not concern the use of new compounds for contraception in women or pharmaceutical preparations for this purpose.

Also, in these applications, there is no mention of the progestogenic activity of the compounds, which is advantageous for indication as a contraceptive claimed herein.

In addition, these applications do not mention what effective dose is to be used to treat any condition mentioned herein.

According to the invention, mesoprogestins are defined as compounds having both agonistic and antagonistic activity at the progesterone receptor (PR) in vivo. As progestins and antiprogestins, mesoprogestins show high binding affinity for PR. However, mesoprogestins exhibit different pharmacodynamic properties when compared to either progestins or antiprogestins.

The presence of mesoprogestin progesterone agonist activity, as measured in commonly used in vivo bioassays, is a key feature of this new PRM family. However, this activity remains lower than that of progesterone in the dose to maintain the plateau of the dose-response curve. Mesoprogestins have failed to maintain pregnancy in pregnant rodents with ovariectomy, such as mice and rats.

In the classical bioassay, the McPhail assay, which determines progestagenic and antiprogestagenic effects in rabbits (Selye H., Textbook of Endocrinology, 1947, pp. 345-346), progesterone achieves a maximum McPhail score of 4 (as defined). However, treatment with mesoprogestin without progesterone achieves a McPhail score that is higher than the score at any dose of RU 486, i. above 0.5 to 1.0, more preferably 2.0 to 3.0, but is clearly less than 4 in the plateau of the dose-response curve at clinically relevant doses for the claimed indications (ie 0.01 mg to 30 mg / rabbit ).

The capacity of mesoprogestins to antagonize progesterone function is also tested in the McPail assay using a dose of progesterone that induces a McPhail score between 3 and 4.

Mesoprogestin inhibits the effect of progesterone to a significant degree, but the maximum inhibition is below the maximum that can be achieved with RU 486 or other pure antiprogestin (e.g. onapristone).

Thus, mesoprogestins stabilize PR function at moderate levels of activity, providing a reason for new clinical applications in gynecological therapy. A corresponding functional state cannot be achieved by treatment with progestins or antiprogestins.

DETAILED DESCRIPTION OF THE INVENTION

Pharmacological results demonstrating the utility of mesoprogestins in the claimed indications

The PR antagonist and agonist properties of mesoprogestins were assessed in estrogen-initiated rabbits in the Selye McPhail assay (Textbook of Endocrinology, 1947, pp. 345346).

A) Evaluation of PR agonist properties of mesoprogestins in rabbit (Figure 1A)

Progestagenic activity J867, J956, J1042 [4- [173-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-lip-yl] benzaldehyde (1E) - [0- (ethylthio) carbonyl] oxime (German patent application 19809

845.6)] and RU 486 (dose range: 0.003 to 100 mg / rabbit) were evaluated in adolescent rabbits initiated by estradiol after 4 days of subcutaneous (s.c.) treatment in the absence of progesterone. The progestogenic effect of mesoprogestins was observed at doses equal to or greater than 0.03 mg / rabbit. Progesterone induced endometrial transformation at doses equal to or greater than 0.1 mg with a maximal effect at 1 mg / rabbit (approximate McPhail score 4). None of the mesoprogestins tested (J1042, J867, J956) achieved the maximum effect of progesterone. J956 showed a biphasic response in this assay with a maximum effect on McPhail score of 1.5 at a dose of 0.3-1 mg / rabbit.

B) Evaluation of PR antagonistic properties of mesoprogestins in rabbit (Figure 1B)

Similarly, the antiprogestagenic activity of J867, J956, J1042 and RU 486 (dose range: 0.001 to 100 mg / rabbit) was evaluated in adolescent rabbits initiated by estradiol after 4 days of subcutaneous (s.c.) treatment in the presence of progesterone (1 mg / rabbit s.c.). The first antiprogestagenic effect of mesoprogestins and RU 486 was observed at a dose of 0.3 to 1 mg / rabbit (McPhail index O = no transformation, 4 = complete transformation). The antiprogestagenic activity of mesoprogestins at higher clinically relevant doses (i.e. 3 to 30 mg / rabbit) was lower than the RU 486 dose.

In a guinea pig model that allows a good prediction of the effect on humans in abortion-inducing ability (abortive activity) (Elger W, Beier S, Chwalisz K, Fähnrich M, Hasan SH, Henderson D, Neef G , Rohde R. (1986): Studies on the action of progesterone antagonists (J Steroid Biochem 25: 835-845), mesoprogestins J867, J912, J956, J1042 induced maximal abortion rates at doses up to 100 mg / kg / day 20%.

C) evaluation of abortive effects

Physiological basis:

Guinea pig is considered to be a relevant model of human pregnancy and birth (Elger W., Fähnrich M., Beier S., Ching SS, Chwalisz 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, Fähnrich M, GrUndel M, Heermann J, Malmendier A, Laurent D, Puri CP, Singn MM, Hasan SH, Becker H. (1992) Evaluation of antifertility activities of antigestagens in animal model In: Puri CP and Van Look PFA (eds), Current Concepts in Fertility Regulation and Reproduction, Wiley Eastern Limited, New Dehi, pp. 303-328,

Elger, W., Faehnrich, M., Beier, S., Qing, SS, Chwalisz, 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, Gaeld RE (1990). Studies in laboratory-conditioning and laboratory effects of antiprogesterones in animal model. Ln: Garfield RE (eds), Norwell 153-175). The mechanism of anti-drug-induced abortion in this species is the onset of labor and ultimate expulsion of the fetus. Abortive effects in rats during very early pregnancy express inhibitory effects on nidation rather than initiation of uterine contractions. Studies in a rat model lead to an "over-evaluation of the potential of antiprogestins to terminate pregnancy in humans." In contrast, in the guinea pig model, irrespective of antiprogestin doses, there is a high proportion of still ongoing pregnancies, similar to the human situation (Elger et al., Current Concepts in Fertility Regulation and Reproduction, supra). In addition, there is a strong synergism between antiprogestins and prostaglandins in both humans and guinea pigs regarding the induction of labor (see the articles above and Elger W., Beier S. (1983). Prostaglandins and Antigestagens fur den Schwangerschaftsabbruch). (German Patent DE 333745012, Van Look P., Bygdeman M. (1989). Antiprogestational Steroids: A New Dimension in Human Fertility Regulation. Oxford Reviews of Reproductive Medicine 11: 2-60).

Evaluation of labor inducing activity (see Figure 2):

Pregnant guinea pigs were treated on day 43 and 44 of pregnancy and observed until day 50 of gestation. The effects of the various treatments are shown in Table 1 and Figure 2. Typically, this model is characterized in that fetal expulsion occurs several days after treatment. It can be observed that mesoprogestins had a much lower abortive activity compared to RU 486. The following abortive activity order was found: RU486> J956> J867, J912> J1042. The differences with respect to abortive activity appear to be qualitative only. It is not possible to increase the low abortive activity of mesoprogestin using higher doses.

Table 1

Relative Binding Activity (RBA) and ED50 Abortive Activity Studies in Pregnant Rats and Guinea Pigs

compound RBA (%) # Abortive activity ED50 (mg / animal / day, s.c.) PR ¹ GR ² lab. rat ³ guinea pig ⁴ RU 486 506 685 0, 98 * 3, 8 onapristone 22 39 1.71 * ca 3 J867 302 78 0.65 * > 100 J956 345 154 0, 64 * 20 J912 162 16 0.36 > 100 J1042 164 42 > 10 »100

# by Kaufmann, β-progesterone = 100%, ² dexamethasone = 100% ³ treatment days 5-7 of pregnancy, day 9 treatment, ⁴ treatment days 43-44, pregnancy day 50. * SAS software, probit procedure.

The mesoprogestin for the present invention is preferably selected from the group consisting of J867, J956, J1042.

Other preferred mesoprogestins are

4- [17β-Hydroxy-17α- (ethoxymethyl) -3-oxoestra-4,9-bromo-11β-yl] benzaldehyde (IE) -oxime,

4- [17β-methoxy] 17α- (ethoxymethyl) -3-oxoestra-4,9-benzo-11β-yl] benzaldehyde (IE) -oxime,

4- [173-hydroxy-17α- (chloromethyl) -3-oxoestra-4,9-benzo-11β-yl] benzaldehyde (IE) -oxime,

4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene-13-

-yl] benzaldehyde (IE) - (O-methyl) oxime (all DE 43 32 283), and

4- [173-methoxy-17a-methoxymethyl) -3-oxo-estra-4,9-όίέη-11β14

-yl] benzaldehyde (E) - [O- (phenylamino) carbonyl] oxime,

4- [17β- (methoxy-17a- (methoxymethyl) -3-oxoestra-4,9-tetrahydro-11β-yl) benzaldehyde (IE) - [propionyl] oxime,

4- [17β-π-α-γ-17α- (methoxymethyl) -3-oxoestra-4,9-diene-1β-

-yljbenz aldehyde- (IE) - [benzoyljoxím (all DE 43 32 284). Quantity per daily dose is in the range 1 to 25 mg mesoprogestin. Like estrogens are for purposes of the invention suitable all of them estrogenically active compound.

Estrogens that can be used in the practice of the present invention are, for example, ethynyl estradiol, 17β-estradiol and also its esters such as estradiol-3-benzoate, estradiol-17-valerate, -cypionate, -undecylate, -enanthate and / or or other estradiol esters (see 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 conjugated estrogens.

Estradiol, ethinylestradiol and estrone-3-sulfamates, for example estrone-N, N-dimethylsulfamate, estrone-N, N-diethylsulfamate, ethinylestradiol-3-Ν, N-dimethylsulfamate, ethinylestradiol-3-Ν, N-diethylsulfamate ethinylestradiol-3-Ν, N-tetramethylene sulfamate, estrone sulfamate, estradiol-3-sulfamate, estradiol-3-Ν, Ν-dimethylsulfamate, ethynilestradiol-3-sulfamate, all of which are prodrugs for the corresponding 3-hydroxy-allyl compounds (W. Elger , J. Steroid Biochem Molec. Biol., Vol. 55, No. 3/4, 395403, 1995, DE 44 29 398 A1 and DE 44 29 397 A1) can also be used in the pharmaceutical composition of the invention.

Suitable progestins useful in the present invention are all compounds that are suitable for use in oral contraceptives for their progestin activity. A list of examples of these compounds can be found in B. Runnebaum et al., &Quot; Female Contraception: Update and Trends, Springer-Verlag, Berlin, 1988, pages 64-90, 109-121, 122-128 and 129-140. Preferred progestins in the field of the present invention are gestodene, progesterone, levonorgestrel, cyproterone acetate, chlorormadinone acetate, drospirenone (dihydrospirorenone), norethisterone, norethisterone acetate, norgestimate, desogestrel or 3ketodesogestrel. In an embodiment comprising a progestin of the invention, the progestin is present in a dosage form suitable for oral administration, particularly as a tablet, coated tablet, capsule or pill. In this case, the progestin is formulated in a manner analogous to the production of progestins for hormonal contraception using the adjuvants generally used for this purpose. The daily unit dosage form of progestin contains a dose of 0.6-6.0 mg levonorgestrel, 2-20 mg cyproterone acetate, 0.3-3.0 mg gestodene or 0.2-2.0 mg desogestrel, or an amount of other progestin that is active. identical with these doses.

The determination of the amount of different progestins, representing a dose with equivalent effect, is carried out according to known methods, further details can be found, for example, in two articles "Problems of DoseFinding: Sex Hormones", F. Neumann et al. in "Arzneimittelforschung [Drug Research] 27, 2a, 296-318 (1977), and also" Aktuelle Entwicklungen in der Hormonalen Kontrazeption [Current Developements in Hormonal Contraception], H. Kuhl in "Gynecologists [Gynecologists] 25: 201-240 ( 1992).

According to all embodiments of the invention, the mesoprogestin may be present in unit dosage forms intended for daily oral administration.

Estrogen may also be present in daily oral unit dosage forms.

If the unit dosage forms of mesoprogestin are adapted for administration over a period of 7 days, these dosage forms may be advantageous in the form of a unit dosage form to be administered once a week.

In such a unit dosage form to be administered once weekly, the mesoprogestin may advantageously be prepared in a formulation that results in a delayed release of the active ingredient.

Delayed release of mesoprogestin can be achieved, for example, by formulating a dosage unit to be administered orally, such as a composite tablet, or by providing a dosage unit to be administered orally, with the package disintegrating over time, as is known to the skilled person.

By derivatisation, for example by esterification of the free hydroxy group of the active precursor, the mesoprogestin used in the manufacture of the medicament of the invention may also achieve a longer half-life than that of the precursor. As a result, long-term exposure is also achieved.

For the purposes of the present invention, the formulation of mesoprogestin and optionally estrogen is performed as usual, as is already known for the formulation of these compounds for their individual uses, as described for J867 in DE 43 32 283 and for estrogen treatment, for example Cyclo-Progyn.

Reference is also made to the information contained in these prior art documents.

In addition to oral administration of estrogen and mesoprogestin, it is also possible. administer one or both of the components transdermally, for example by a skin patch, which is best known for the administration of estrogen (Climara Patch).

In addition, administration may be accomplished using an intrauterine drug release system (see Mirena), but this variant is not preferred in the practice of the present invention.

Administration of one or both of the ingredients formulated in a depot preparation (system) is also possible.

Finally, all of the above types of administration can be combined. For example, the estrogen may be administered transdermally through a skin patch, and the progesterone antagonist may be administered daily orally or once or more as a depot preparation.

The estrogen is contained in a daily unit dosage form of the invention in an amount of 10 to 30 µg of ethinyl estradiol or a biologically equivalent amount of another estrogen.

In the pharmaceutical composition of the invention, the mesoprogestin is contained in each unit dosage form preferably in an amount that, when used for a predetermined period of time, is sufficient to cause amenorrhoea.

In a preferred embodiment of the pharmaceutical composition of the invention, the mesoprogestin is contained in each daily unit dosage form in an amount equivalent to 1 to 25 mg of J867.

Bioequivalent doses of mesoprogestin can be determined by the McPhail assay.

The package comprising the pharmaceutical composition of the invention is prepared such that, in addition to one or two of the mesoprogestin and estrogen components, in the appropriate intended dosage form (orally in the form of pills, coated tablets, etc.) in blister packs as may be suitable for mesoprogestin and / or estrogen or estrogen as a skin patch, and mesoprogestin in the form of pellets of coated tablets or the like in a blister or capsule, as a depot to be administered once), the package also containing instructions for use of the pharmaceutical preparation (package leaflet) ).

Claims (38)

Use of mesoprogestins as an ingredient in the manufacture of a medicament for female contraception. Use of mesoprogestins according to claim 1 without the participation of any other pharmaceutically active compound. Use according to claim 1 or 2 of mesoprogestin in a regular cyclic dosing regimen. The use of claim 3, wherein the administration of mesoprogestin is from day 1 to a maximum of day 180, wherein day 1 counts the first day of bleeding the menstrual cycle of the woman. The use of claim 4, wherein the daily amount of mesoprogestin is selected to induce and maintain amenorrhea. The use of claim 5, wherein the administration of mesoprogestin is from day 1 to at least day 21 and up to day 25, and day 1 counts the first day of the woman's menstrual cycle bleeding. The use of claim 6, wherein the daily amount is selected to provide reversible amenorrhoea. Use according to any one of the preceding claims 1 to 12 7, wherein the mesoprogestin is J867, J912, J956, J1042. Use according to any one of the preceding claims 1 to 9 8, wherein the daily dose of mesoprogestin is 1 to 25 mg. Use according to claims 1 and 3 to 9, wherein estrogen is used as a further component for the manufacture of a medicament. The use according to claim 10, wherein the other component is ethinyl estradiol, estradiol, estradiol ester or 17β-ethynyl estradiol 3-sulfamate or 17β-estradiol. Use according to claim 10 or 11, wherein the daily dose of the additional estrogen component is 10 to 30 gg of ethinyl estradiol or a biologically equivalent amount of another estrogen. The use of any one of the preceding claims, wherein the medicament is formulated for oral administration. Use according to any one of claims 1 to 12, wherein the medicament is formulated as an intrauterine system. Use according to claim 10, 11 or 12, wherein at least one of the mesoprogestin and the other estrogen component is formulated for oral administration. Use according to claim 10, 11 or 12, wherein at least one of the mesoprogestin and the other estrogen component is formulated as an intrauterine system. The use of claim 2 in a discontinuous acyclic delivery mode. The use of claim 17, wherein the mesoprogestin-containing medicament is administered "as needed, when contraception is currently required for one occasion." The use of claim 18, wherein the administration is for a period of up to 4 days. Use according to claim 19, wherein at least the first administration is carried out for a period of up to 4 days prior to intercourse in which contraception is required. The use of claim 20, wherein the administration is performed once and before sexual intercourse. 22. A pharmaceutical composition comprising mesoprogestin and estrogen. The pharmaceutical composition of claim 22, wherein the mesoprogestin is selected from the group consisting of J867, J912, J956, J1042. 24. The pharmaceutical composition of claim 22, wherein the estrogen is ethinyl estradiol, estradiol, estradiol ester, or 173-ethynyl estradiol 3-sulfamate or 17β-estradiol. 25. A pharmaceutical preparation for female contraception comprising daily dosage units of mesoprogestin, said dosage units being provided for a maximum of 180 days. A pharmaceutical composition according to claim 25, characterized in that up to 7 placebo dosage forms or other measure to indicate 7 days "without pills" are subsequently provided in continuous succession to mesoprogestin. A pharmaceutical composition according to claim 26 which provides 21, 22, 23, 24 or 25 unit dosage forms with a daily dose of mesoprogestin and 7, 6, 5, 4 or 3 dosage forms with placebo or other measures for indication 7. , 6, 5, 4 or 3 days "without pills. Pharmaceutical preparation according to claim 26 or 27, characterized in that in addition to dosage units comprising mesoprogestin, dosage units containing estrogen are provided. The pharmaceutical composition of claim 28, wherein the mesoprogestin and estrogen are in conventional dosage units. 30. The pharmaceutical composition of claim 28, wherein the mesoprogestin and estrogen are present in separate dosage units. 31. A pharmaceutical composition comprising daily dosage units of mesoprogestin and estrogen or mixtures of estrogens, wherein the dosage units are provided for administration over 21, 22, 23, 24, or 25 days, and thereafter, in continuous sequence thereto. mesoprogestin / estrogen units, 7, 6, 5, 4 or 3 dosage units containing only an estrogen or estrogen mixture are provided, so that together dosage units for administration over 28 days are provided. 32. The pharmaceutical composition of claim 31, wherein the mesoprogestin and estrogen are in conventional dosage units. 33. The pharmaceutical composition of claim 31, wherein the mesoprogestin and estrogen are present in separate dosage units. The pharmaceutical composition of any one of claims 25 to 33, wherein the mesoprogestin is J867, J912, J956, J1042. Pharmaceutical preparation according to any one of the preceding claims 28 to 34, characterized in that the estrogen is ethynyl estradiol, estradiol, estradiol ester or 17β-ethynyl estradiol 3-sulfamate or 17β-estradiol. A pharmaceutical preparation according to any one of the preceding claims 25 to 35, characterized in that the daily dosage unit contains 1 to 25 mg of mesoprogestin. Pharmaceutical preparation according to any one of the preceding claims 28 to 33, 35 to 36, characterized in that the daily dosage unit contains 10 to 30 µg of ethinylestradiol or a biologically equivalent amount of another estrogen. A pharmaceutical composition according to any one of claims 25 to 37, wherein the daily dosage unit comprises an amount of mesoprogestin inducing and maintaining amenorrhea. 1/3 Fig. IBΑ, IB Progesterone-like effect of the PR-modulators (upper figure IA) and progesterone antagonist (lower figure IB) on the uterus of adolescent-initiated estrogen-initiated rabbits (McPhail test) mg / animal / day O-vehicle-α-progesterone-^ -1,7486 -t-JSGt --- J956 -A-J1042 Fig. 2 2/3 PP zqWool · max. 180th day Day 1 max. 180. Day 1 day ("No pill" sáaisi *, or other placebo (max. 7 <3 days) δ ^^ 'ΓΚ ^ ββ'ΑητίτπββΙτη ^^^ · "no pill" el <= + -> - placebo (max. 7 days) etc. . 1 day Day 21 to Day 25. Day 28. Without pill * ai ± o placebo 7, 6, 5, 4 or 3 days • ‘MéSCDroaésánS. No pills * l.day “no pill * etc.” 21-25. Day 28: Day 5: Day 5: 3x; ' ^} H ί! l · · U} HJJ ·, · lEstroaeni; ! I> .j ;;; i »;:. ·,:;: S t. ! U.IISii.äiÍÍi ί l.deň Oi <i. ·· _φ ... ω: ·: «,: · Street; 1 day Day 21 to Day 25 H (1 ^ 25 ^ E £ lín§J: i! i! iLijU: i H u 111 i i !; ! Siii i! L <! i ·: j | I ih U ¹ i Day 1 mesaprcgestin dvtesgpreq esaa2; u * ✓. i !. s 11 íEstroaenií '/ i μ ^ ΠΕΠΗΡΕίΗΓ • ^? IIIIIII; s !! h: IIU! Íí 7 R 6 -5, .4 ^ 5: •> »: -x ABOUT ·. .n ·: o> ´ u: <S: l: <l: l?: l: Í: OleŠÓDrQäeŠiiní ......... ί i · I '' I i · ^{5 j :: 1 '11 t} t ^; ί 11 ii> l ' ⁵ ·': Π ii 11 ^'11 · ¹ » ¹ ' ¹ '··: ·''; · K · í; H · · ·: ·. H ijihi / n'Estrôrieni; Estrrogeril 1 H Iiii-chiiiii'HiIBiHiiii: i; H is HH i ii; í i !! sh í ;: ^! : '. ;; i! i ¹ 1! ^! H ^i:: 'I' · -1 · ::: '· :! í i;:! · {; i I j '1! j · · ii ::. · !; j.,. · I Day 28 Day 28 mesaprogestm 30 to 180 days and 1 to 30 days progestin meso- I progestin, etc. etc. Day 56. Day of mesaprocestin 30 to 180 days progestin Guinea pigs, treatment of 43 and abortion rates Fig. 3 Cumulative abort rate until day 50 on day 44 of pregnancy s.c. injections. (# 7 #) Cumulative abort rate (%) 2/7 * 0/7 0/7 16/21 1/7 0/7 13/14 4/7 1/7 0/7