CZ2002707A3 - Use of mesoprogestins (modulators of progesterone receptors) as a component for preparation of woman 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

Technical field

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, the so-called combined oral contraceptives. Apparently, the progestin acts by blocking 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 preparations (= "progesterone-only pili = POP") had a more diverse spectrum of side effects than the combination products, in particular a higher incidence of breakthrough bleeding. As a result, the combination formulations are the currently preferred oral contraceptives used (Sheth et al., Contraception, 25: 243, (1982)).

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Antiprogestins (also called progesterone antagonists or "antigestagens") are a group of compounds that block the progesterone receptor. For example, RU 486 (mifepristone) is an receptor-receptor antagonist.

RU 486 binds to the progesterone receptor.

progesterone and blocks progesterone binding 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 prior art. In primate models, one injection of antiprogestin RU 486 (5 mg / kg im) in the late follicular phase or once weekly with an 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: 195200).

Using different 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, 49: 961-963).

The ovulatory inhibitory activity of progesterone antagonists other than RU 486 has also been shown (Zelinski-Wooten, MB, Slayden, OD, Chwalisz, K., Hess, DL, Brenner, RM, Stouffer, RL (1998a)). low-dose of the antiprogestin ZK 137 316: Establishment of a regimen that permits normal menstrual cyclicity. Hum Reprod 13: 259-267).

Thus, several anti-ovulatory strategy approaches have been devised to achieve contraception by a progesterone antagonist.

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

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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)), 2 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 contraceptives in women by inhibiting implantation, preferably after oral administration. This method does not adversely affect the menstrual cycle in women and is without the risk of aborting 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, eg, once a week or 3 to 4 days apart, between each administration of the active compound.

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

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SUMMARY OF THE INVENTION

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

They can be used either as one 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 as long as contraception is desired.

The cycle begins with the administration of mesoprogestins or a mesoprogestin / estrogen containing dosage unit, followed by daily dosage units. 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 an 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 a woman's menstrual cycle bleeding at which contraceptive therapy begins.

One embodiment of mesoprogestin alone provides administration of mesoprogestin-containing dosage units up to a maximum of day 180. During continuous daily treatment (1 to 25 mg mesoprogestin / day) it is induced and • 1

99 9 9 • · reversible amenorrhoea maintained. The effect of the contraceptive is induced by the effect of mesoprogestins 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 mesoprogestins may also be an ovulation inhibiting dose, but this is not essential to achieve the effect of the contraceptive and to induce and maintain amenorrhea.

Preferably, administration of the mesoprogestins alone takes place for a maximum of 3 months (this makes it possible to control the reliability of the contraceptive).

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

For methods using progesterone antagonists as described in WO 93/23020 and WO 94/18982, a normal cycle was maintained.

Another embodiment of the administration of mesoprogestins alone is continuous over a period of more than 3 months, for example 1 to 3 years. Because mesoprogestin inhibits endometrial growth and prevents endometrial vessel fragility, it can be used chronically. In addition, a chronic but reversible amenorrhea is achieved.

Another provides mesoprogestins comprising embodiments of administering the mesoprogestin dosage units alone by day 21, 22, 23, 24, or 25, followed by either a period of 7, 6, 5, 4, or 3 days during which no active is administered. the compound or followed by administration of 7, 6, 5, 4 or 3 placebo pills to complete the cycle.

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28 days long. The next day of the next cycle begins the administration of the mesoprogestin containing dosage unit, etc.

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

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

The doses of amenorrhea inducing mesoprogestins can be determined by a method known to the person skilled in the art, for example in clinical studies.

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

When estrogen is administered in addition to mesoprogestins, 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 next cycle begins the administration of the mesoprogestin / estrogen containing dosage unit, etc.

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

Mesoprogestins can be used sequentially with progestin (sequential method). In this contraceptive mode • · · ·

The mesoprogestin component prevents bleeding from penetration, which is usually associated with chronic progestin therapy. The progestin component at the dose used in the so-called mini-pill regimen is administered for a period of 30-180 days, while the mesoprogestin component is administered for a period of 1-30 days.

Menstrual bleeding may or may not occur during mesoprogestin therapy. However, as a result of sequential treatment with progestin / mesoprogestin, the incidence of unplanned bleeding is significantly reduced.

Regular cyclic mesoprogestin delivery regimens, β 'optionally in combination with estrogen, are shown in detail in Figure 2.

The use of mesoprogestins in a discontinuous acyclic dosing regimen is use as a so-called "pill as needed" to be administered only around the time of sexual intercourse for which contraception is required. 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, daily doses of mesoprogestins.

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

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

The above compounds, for example J867 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-lip-yl] benzaldehyde (1E) -oxime] and J912 [4- [17β-hydroxy-17a] - (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (1E) -oxime] (both see DE 43 32 283) and J900 [4- [17β-methoxy-17α- (methoxymethyl)] -3-oxoestra-4,9-dien-lip-yl] benzaldehyde (1E) - [O- (ethoxy) carbonyl] oxime], J914 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra] -4,9-dien-β-yl] benzaldehyde- (1E (O-acetyl) oxime) and J956 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene-lip-] yl] benzaldehyde- (1E) - [O- (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 be have (indirectly) anti-estrogenic properties, which is reflected through reduced uterine weight in guinea pigs with ongoing cycles.

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

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

Also, in these applications no mention is made of the progestagenic activity of the compounds, which is advantageous for the indication as contraceptives claimed herein.

In addition, these applications do not mention what active 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 on the progesterone (PR) receptor in vivo. As progestins and antiprogestins, mesoprogestins show a high fc

binding affinity for PR. But compared to either progestins or antiprogestins, they exhibit pharmacodynamic properties.

mesoprogestins different

The presence of progesterone dose dependence and maintenance of pregnancy mesoprogestin 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 response curve. Mesoprogestins have failed in ovariectomized pregnant rodents 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. 345346), progesterone reaches a maximum McPhail score of 4 (by definition). However, mesoprogestin treatment without progesterone achieves a McPhail score that is higher than the score at any dose of RU 486, ie above 0.5 to 1.0, more preferably 2.0 to 3.0, but is clearly less than 4 in the plateau curve dose-response relationships 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 a McPhail test using a dose of progesterone that induces a McPhail score between 3 and 4. Mesoprogestin inhibits the progesterone effect to a significant degree, but the maximum inhibition is below the maximum achievable with RU 486 or other pure antiprogestin (eg, onapristone).

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

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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 evaluated in estrogen-initiated rabbits in the McPhail's Selye test (Textbook of Endocrinology, 1947, pp. 345-346).

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

Progestagenic activity J867, J956, J1042 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-lip-yl] benzaldehyde (IE) - [0- (ethylthio) carbonyl] oxime (German patent application 198 09 845.6)] and RU 486 (dose range: 0.003 to 100 mg / rabbit) were evaluated in adolescent rabbits initiated by estradiol after 4 days of subcutaneous (sc) treatment in the absence of progesterone. The progestagenic 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 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 two-phase response in this assay with a maximum effect on McPhail score of 1.5 at a dose of 0.3-1 mg / rabbit.

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B) Evaluation of PR antagonistic properties of mesoprogestins in rabbits (Figure IB)

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 mg / rabbit (McPhail index 0 = 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 terms of abortion-inducing ability (abortive activity) (Elger W, Beier S, Chwalisz K, Fahnrich M, Hasan SH, Henderson D, Neef G, Rohde R ( J Steroid Biochem 25: 835-845), mesoprogestins J867, J912, J956, J1042 produced a maximum abort rate of 20% at a dose of up to 100 mg / kg / day.

(C) evaluation of abortive effects

Physiological basis:

Guinea pig is considered a relevant model of human pregnancy and birth (Elger W, Fahnrich 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, Fahnner M, Grundel M, Heermann J, Malmendier A, Laurent D, Puri CP, Singh MM, Hasan SH, Becker H. (1992). · Ί · · · · · ·. Z z z z z z z z · z z z z · z · · · · · · · In: Puri CP and Van Look PFA (eds), Current Concepts in Fertility Regulation and Reproduction, Wiley Eastern Limited, New Delhi, pp. 303328, 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 on labor-conditioning and labor-inducing effects of antiprogesterones in animal model. In: Garfield RE (eds), Norwell. 153-175). The mechanism of antiprogestin-induced abortions in this species is the onset of labor and the ultimate expulsion of the fetus. Abortive effects in rats during very early pregnancy express nidation inhibitory effects rather than initiation of uterine contractions. Studies in a rat model lead to an over-evaluation of the potential of antiprogestins to terminate human pregnancy. In contrast, in the guinea pig model regardless of the antiprogestin dose, there is a high proportion of still-going 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 human and guinea pigs in terms of labor induction (see the articles above and Elger W, Beier S (1983). 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).

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4

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Assessment of labor inducing activity (see Figure 2):

Pregnant guinea pigs were treated on day 43 and 44 of gestation 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 by the ejection of the fetus several days after treatment. It can be observed that mesoprogestins had much lower abortive activity compared to RU486. The following order of abortive activity was found: RU486> J956> J867, J912> J1042. The differences with respect to abortive activity seem to be only qualitative. It is not possible to increase the low abortive activity of mesoprogestins using higher doses.

Table 1

Study of Relative Binding Activity (RBA) and ED50 Abortive Activity 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 48 6 506 685 0, 98 * 3, 8 Onapriston 22nd 39 1,71 * ca 3 J867 302 78 0.65 * > 100 J956 345 154 0,64 * 20 May J912 162 16 0.36 > 100 J1042 164 42 > 10 »100

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

The mesoprogestin for the present invention is preferably selected from the group consisting of J867, J912, J956, J1042.

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Other preferred mesoprogestins are 4- [17β-hydroxy-17α- (ethoxymethyl) -3-oxoestra-4,9-dien-lip-yl] benzaldehyde (IE) -oxime,

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

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

4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (IE) - (O-methyl) oxime (all DE 43 32 283) a

4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (IE) - [O- (phenylamino) carbonyl] oxime,

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

4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde (IE) - [benzoyl] oxime (all DE 43 32 284).

The amount per daily dose is in the range of 1 to 25 mg of mesoprogestins.

All estrogenic active compounds are suitable as estrogens for the purposes of this invention.

Estrogens that can be used in the practice of the present invention are, for example, ethinyl estradiol, 17β-estradiol as well as esters thereof, 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-N, N-dimethylsulfamate, φφφφφ φ * · φφφφ · φ φφφφφ · φφ φ · · φ «* · ♦ 9 Φ

Inyl Ethyloestradiol-3-N, N-diethylsulfamate, ethinylestradiol-3-Ν, N-tetramethylenesulfamate, estronsulfamate, estradiol-3-sulfamate, estradiol-3-N, N-dimethylsulfamate, estradiol-3-N, Diet-diethylsulfamate, ethinylestradiol-3-sulfamate, all of which are drug precursors for the corresponding 3-hydroxy compounds (W. Elger et al., In J. Steroid Biochem. Molec. Biol., Vol. 55, No. 3/4, 395) -403, 1995, DE 44 29 398 A1 and DE 44 29 397 A1) may 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., 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, chlormadinone acetate, drospirenone (dihydrospirorenone), norethisterone, norethisterone acetate, norgestimate, desogestrel or 3-ketodesogestrel. In an embodiment comprising a progestin of the invention, the progestin is present in a dosage form suitable for oral administration, in particular as a tablet, coated tablet, capsule or pill. In this case, the progestin formulation is produced in a manner analogous to the production of progestins for hormonal contraception using adjuvants, which are generally used for this purpose. Daily unit dosage form of progestin 0.6-6.0 mg levonorgestrel, 2-20 mg

0.3-3.0 mg gestodene or 0.2-2.0 mg contains a dose of cyproterone acetate, desogestrel, or an amount of other progestin that is equivalent to these doses.

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The determination of the amount of different progestins, representing a dose with equivalent effect, is carried out according to known methods, for further details see, for example, two articles of Probleme der Dosisfindung: Sexualhormon [Problems of Dose-Finding: Sex Hormones], F. Neumann et al. in Arzneimittelforschung [Drug Research] 27, 2a, 296-318 (1977), as well as Aktuelle Entwicklungen in der hormonalen Kontrazeption [Current Developments in Hormonal Contraception], H. Kuhl in Gynakologe [Gynecologists] 25: 201-240 (1992).

In all embodiments, 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 mesoprogestins are adapted for administration over a period of 7 days, the dosage forms may preferably be in the form of a unit dosage form to be administered once a week.

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

Delayed release of mesoprogestins 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 orally administered, with the package disintegrating over time, as is known to the skilled artisan.

By derivatisation, for example, by esterification of the free hydroxy group of the active precursor, the mesoprogestin used in the manufacture of the medicament according to the invention can also achieve a longer duration. The half-life of this precursor. As a result, longer-term exposure is also achieved.

For the purposes of the present invention, the formulation of mesoprogestin and optionally estrogen is carried out quite usually as is already known for the formulation of these compounds for their particular uses, as described for J867 in DE 43 32 283 and for the treatment of estrogens such as Cyclo-Progyn.

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

In addition to the oral administration of estrogen and mesoprogestin, it is also possible to administer one or both components transdermally, for example 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, estrogen may be administered transdermally through a skin patch, and the progesterone antagonist may be administered daily orally or one or more times as a depot preparation.

The estrogen is contained in the 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 for amenorrhea to occur.

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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.

Biologically equivalent mesoprogestins can be determined by the McPhail assay.

A package comprising a 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 pills, coated tablets, etc. in a blister or capsule, as a depot to be administered once), this pack also contains instructions for use of the pharmaceutical product (package leaflet) ).

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Claims (7)

PATENT CLAIMS 1/3 Use of mesoprogestins as a component for 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 mesoprogestins in a regular cyclic dosing regimen. Use according to claim 3, wherein the administration of the mesoprogestins is from day 1 to a maximum of day 180, wherein day 1 is calculated on the first day of a woman's menstrual cycle bleeding. The use of claim 4, wherein the daily amount of mesoprogestin is selected to induce and maintain amenorrhea. Use according to claim 5, wherein the administration of mesoprogestin occurs from day 1 until at least day 21 and at most day 25, wherein day 1 is calculated on the first day of a woman's menstrual cycle bleeding. Use according to claim 6, wherein the daily amount is selected so as to obtain reversible amenorrhea. Use according to any one of the preceding claims 1 to 7, wherein the mesoprogestin is J867, J912, J956, J1042. ** · »<♦ • 9 • · • 9 »• · 9 9 • 9 9 • 9 99 9 9 Use according to any one of the preceding claims 1 to 8, wherein the daily dose of mesoprogestins 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. Use according to claim 10, wherein the other component is ethinylestradiol, estradiol, estradiol ester or 17β-ethinylestradiol 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 μς of ethinylestradiol or a biologically equivalent amount of another estrogen. Use according to any one of the preceding claims, wherein the medicament is formulated for oral administration. Use according to any one of the preceding claims 1 to 12, wherein the medicament is formulated as an intrauterine system. Use according to claim 10, 11 or 12, estrogen when Yippee at least one of worded for mesoprogestins and oral administration next folders 16. Use according to claim 10, 11 or 12, when at least one of mesoprogestins and next folders estrogen Yippee worded as intrauterine system. The use of claim 2 in a discontinuous acyclic delivery mode. containing when ** ** · ♦ · · · 0 ♦ · 00 ** 0000 The use of the mesoprogestin of claim is administered 17, wherein the drug "as needed, contraception currently required for one occasion." The use of claim 18, wherein the administration is for a period of time up to 4 days. The use of claim 19, wherein at least the first administration over a period of up to 4 days is prior to sexual intercourse for which contraception is desired. The use of claim 20, wherein the administration is one time and prior to 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 17β-ethinylestradiol 3-sulfamate or 17β-estradiol. female contraceptive that contains unitary 25. A pharmaceutical composition for administering a daily dose of mesoprogestins, wherein unit dosage forms for a maximum of 180 days are provided. The composition according to claim 25, characterized in that subsequently in continuous fcfcfc fcfc fcfc fcfc fcfc fcfc fc fcfc fcfc fcfc fc fcfc < fcfc fcfcfc * 26. A pharmaceutical indicative of mesoprogestin sequence is provided by up to 7 placebo dosage forms or other measures to indicate 7 days' without pills. 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 indication to indicate 7, 6, 5, 4 or 3 days' without pills. A pharmaceutical composition according to claims 26 or 27, wherein, in addition to the unit dosage forms comprising mesoprogestin, unit dosage forms containing estrogen are provided. The pharmaceutical composition of claim 28, wherein the mesoprogestin and the estrogen are contained in conventional unit dosage forms. 30. The pharmaceutical composition of claim 28, wherein the mesoprogestin and estrogen are contained in separate unit dosage forms. 31. A pharmaceutical composition comprising unit dosage forms comprising daily doses of mesoprogestin and estrogen or a mixture of estrogens, wherein the dosage forms are provided for administration for 21, 22, 23, 24, or 25 days and wherein thereafter in continuous these mesoprogestin / estrogen dosage forms are provided with 7, 6, 5, 4 or 3 dosage forms containing only estrogen or a mixture of est ♦ · φ φ φ »» »» »» »» The oestrogens are provided so that, in total, unit dosage forms are provided for administration over a period of 28 days. ΦΦΦ ΦΦΦ ΦΦΦ rogen ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ rogen ΦΦΦ ΦΦΦ rogen takže 32. The pharmaceutical composition of claim 31, wherein the mesoprogestin and estrogen are contained in conventional unit dosage forms. 33. The pharmaceutical composition of claim 31, wherein the mesoprogestin and estrogen are contained in separate unit dosage forms. The pharmaceutical composition according to any one of the preceding claims 25 to 33, wherein the mesoprogestin is J867, J912, J956, J1042. A pharmaceutical composition according to any one of the preceding claims 28 to 34, wherein the estrogen is ethinyl estradiol, estradiol, estradiol ester or 17β-ethinylestradiol 3-sulfamate or 17β-estradiol. A pharmaceutical composition according to any one of the preceding claims 25 to 35, wherein the daily dosage unit form contains 1 to 25 mg mesoprogestins. 37. A pharmaceutical preparation according to any one of the preceding claims 28 to 33, 35 and 36, wherein the unit dosage form with a daily dose contains 10 to 30 gg of ethinyl estradiol or a biologically equivalent amount of other estrogens. * · 99 9 • 999 • 9 9 • 9999 W • · • 9 9 9999 The pharmaceutical of the preceding claims, wherein the unit amounts of the mesoprogestin preparation of any one of 25 to 37 characterized in that the daily dosage form comprises inducing and maintaining amenorrhea. ftft ftft ftft ftft ftft ftft ftft ftft 7 ^ teot - W ft ftftftft