CN1384748A - Mesoprogestins (progesterone receptor modulators) as 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

Mesoprogesterone (progesterone receptor modulator) as an ingredient in female contraceptives

The present invention relates to the field of contraception. More particularly, the present invention relates to the use of mesoprogestin for the preparation of female contraceptive medicines, and to pharmaceutical preparations for female contraception, and to female contraceptive methods for administering an effective amount of mesoprogestin to women wishing to prevent pregnancy.

Different pharmaceutical preparations are available for oral contraception in women.

The most common form of oral contraception is a pill that combines estrogen and progesterone, the so-called combined oral contraceptive formulation. Apparently, the progesterone acts to block the release of gonadotropins (ovulation inhibition); the estrogenic component provides endometrial control to reduce breakthrough bleeding.

Alternatively, there are contraceptive formulations that contain only progesterone. However, progesterone-only formulations (=progesterone-only pills=POP) had a more variable side effect profile than combined formulations, in particular more breakthrough bleeding. Therefore, combination formulations are the preferred oral contraceptives used today (Sheth et al., Contraception, 25:243 (1982)).

Antiprogestins (also known as "progesterone antagonists" or "antiprogestins") are compounds that block progesterone receptors. For example, RU 486 (mifepristone) is a progesterone receptor antagonist RU 486 binds to the progesterone receptor and produces a block of progesterone binding to its receptor.RU 486 induces vaginal bleeding when administered during the luteal phase of the menstrual cycle.

The prior art has demonstrated either inhibiting the ovulatory menstrual cycle, or delaying endometrial maturation. In a primate model, a single injection of the antiprogesterone RU 486 (5 mg/kg i.m.) or a once-weekly oral dose of RU 486 at a dose of 25 mg has been shown to prevent ovulation in the post-follicular phase (Collins et al., J. Clin. Endocrinol. Metab. 1986 , 63: 1270-1276; Danforth et al., Contraception 1989, 40: 195-200).

Using various regimens and dosage regimens, several research groups have demonstrated that RU486 also suppresses 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). Ovulation inhibitory activity of progesterone antagonists other than RU 486 has also been demonstrated (Zelinski-Wooten, M.B., Slayden, O.D., Chwalisz, K., Hess, D.L., Brenner, R.M., Stouffer, R.L. (1988a) Chronic treatment of female cyclingrhesus monkeys with low-dose of the antiprogestins (ZK 137 316: Establishment of a regimen that permits normal menstrual cyclicity. Hum Report 13: 259-267).

Therefore, several approaches have been suggested for antiovulatory strategies to achieve contraception with progesterone antagonists.

A method of contraception in which RU 486 works by inhibiting implantation has also been described. In the so-called "LH+2" treatment (Swahn et al., "The luteal effect of RU 486 administration during the early luteal phase onbleeding pattern, hormonal parameters and endometrium", Human Reproduction 5, 4: 402-408 (1990)), in LH 2 days after the onset of peak (LH = luteinizing hormone), an ovulation-inhibiting dose of RU 486 was administered once. The active compound is administered in this way only after the ejaculation time in the luteal phase of the menstrual cycle (luteal phase contraception).

WO 93/23020 discloses contraceptive methods using competitive progesterone antagonists. Progesterone antagonists achieve female contraception by inhibiting implantation at lower than their ovulation-inhibiting and abortive doses, preferably after oral administration. The method does not adversely affect the woman's menstrual cycle and does not risk aborting a previously implanted fertilized egg or fetus. Progesterone antagonists should be administered at least once during the follicular phase of a woman's menstrual cycle (ie, before ovulation). A preferred dosing frequency is daily or at regular intervals of several days, eg weekly or with an interval of 3 or 4 days between each administration of the active compound.

WO 94/18982 teaches a method of inhibiting the fertilization of oocytes comprising administering a fertilization inhibiting amount of an antiprogestin to an ovulating mammal. This amount is insufficient to prevent the mammal from ovulating or to interfere with the regularity of its ovarian menstrual cycle. The preferred frequency of dosing is once daily.

According to one aspect of the present invention, mesoprogesterone is used as an ingredient in the preparation of a medicament for female contraception. They are either used as the single drug active ingredient in female birth control pills, or they can be used with estrogen.

According to one aspect of the invention, mesoprogestins are administered alone or in combination with estrogens in a regular, periodic dosing regimen. This means that mesoprogestins are administered in equal and repeated dosing cycles for as long as contraception is desired.

The cycle begins with the administration of a dosage unit containing mesoprogesterone or mesoprogesterone/estrogen, followed by further daily administration of dosage units thereof. Periods were completed with either no active dosage unit ("pill-free" days) or placebo administration.

Alternatively, in the case of mesoprogesterone/estrogen administration, the dosing cycle may be completed by further administration of a dosage unit containing only estrogen. A new cycle of application was started on the first day after the end of the "pill-free" or placebo period, respectively, or after the period of administration of estrogen-only dosage units.

In all cases, Day 1 of the first dosing cycle was the first bleeding day of a woman's menstrual cycle on which contraceptive treatment was initiated.

One embodiment of administering only mesoprogesterone provides for administering a dosage unit containing mesoprogesterone up to day 180. Under continuous daily treatment (1 to 25 mg mesoprogesterone/day), reversible amenorrhea was induced and maintained. The contraceptive effect is due to the endometrial action of mesoprogesterone (endometrial suppression). Therefore, the endometrium is not prepared for the implantation of a fertilized egg. For contraceptive effect, mesoprogesterone is sufficient to prevent implantation. Doses of mesoprogesterone can also be ovulatory, but this is not necessary to achieve contraceptive effect and induce and maintain amenorrhea.

Preferably, mesoprogesterone-only administration occurs for up to 3 months (this allows testing the contraceptive reliability of the method).

The dosing regimen described above resulted in a better bleeding behavior compared to other contraceptive regimens using only progesterone. Fewer breakthrough bleedings were observed compared with minipills (progesterone-only pills) and progesterone-loaded subcutaneous implants (D-norgestrel implants).

With the use of progesterone antagonists as disclosed in WO 93/23020 and WO 94/18982, the normal cycle was maintained.

A next embodiment in which mesoprogesterone alone is administered is continued over 3 months, eg 1 to 3 years. Since mesoprogesterone inhibits endometrial growth and prevents endometrial vascular fragility, it can be used long term. In addition, a state of prolonged but reversible amenorrhea is achieved.

In a next embodiment where only mesoprogesterone is administered, the dosage unit containing mesoprogesterone is administered for up to 21, 22, 23, 24 or 25 days, followed by, or over a period of 7, 6, 5, 4 or 3 days , no active compound, or placebo pills for 7, 6, 5, 4, or 3 days to complete the 28-day cycle. On the following day, a dosage unit containing mesoprogesterone, etc. is administered to start the next cycle.

In the last-mentioned dosing regimen, mesoprogesterone acts like progesterone by blocking ovulation and inducing amenorrhea and causing withdrawal bleeding. Does not induce breakthrough bleeding. Bleeding subsided due to mesoprogesterone-induced endometrial transformation. Thus, in this embodiment, an ovulation inhibiting dose of mesoprogesterone must be administered at least during the luteal phase of the female's menstrual cycle.

A variation of the last mentioned embodiment (not yet claimed) is to administer only the ovulation inhibiting dose of the mesoprogesterone-containing dosage unit during the luteal phase of the female's menstrual cycle (no administration during the follicular phase).

The amenorrhea-inducing dose of mesoprogesterone can be determined by methods known to those skilled in the art, eg, in clinical research. In general, the daily dose of mesoprogesterone is 1 to 25 mg.

If estrogen is given in addition to mesoprogesterone, both active ingredients are given from day 1 (see above) to day 21, 22, 23, 24, or 25 of the woman's menstrual cycle, followed by, or on day 7, 6 , 5, 4, or 3 days with no active compound, or with estrogen-only dosage units for 7, 6, 5, 4, or 3 days, or with placebo for 7, 6, 5, 4, or 3 days pills, thereby completing the 28-day long dosing cycle. On the following day, a dosage unit containing mesoprogesterone/estrogen etc. is administered to start the next cycle.

The daily amount of estrogen is 10 to 30 μg ethinyl estradiol or its bioequivalent amount.

Mesoprogesterone can be used sequentially with progesterone. In this contraceptive regimen, the mesoprogesterone component prevents breakthrough bleeding commonly associated with long-term progesterone therapy. The progesterone component is administered for 30 to 180 days in doses used in the so-called "low dose oral contraceptive pill regimen" and the mesoprogesterone is administered for 1 to 30 days.

During mesoprogesterone therapy, menstrual bleeding may or may not occur. However, the number of unscheduled bleedings was significantly reduced as a result of progesterone/mesoprogesterone sequential therapy.

Figure 2 details the regular, periodic dosing regimen of mesoprogesterone, optionally in combination with estrogen.

The use of mesoprogestins in a discontinuous, non-periodic dosing regimen is as a so-called demand pill, which has to be given only around the time point of intercourse where contraception is desired. Preferably, it is administered prior to intercourse ("medicated condoms"), see WO 93/23020 for details.

Another aspect of the present invention relates to a drug combination product (composition) comprising a mesoprogesterone and an estrogen.

Another aspect of the present invention relates to a drug combination product (composition) containing mesoprogesterone and progesterone.

A further aspect of the present invention relates to a pharmaceutical formulation for female contraception comprising a daily dosage unit of mesoprogesterone.

All aspects of the pharmaceutical formulation of the invention are evident in claims 25 to 38.

As mesoprogestins, i.a. the compounds disclosed in DE 43 32 283 and DE 43 32 284 are suitable for the purpose of the present invention.

These aforementioned compounds, such as J 867 [4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E) -oxime] and J912[4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-oxime]( Both see DE 43 32 283) and J 900 [4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzene Formaldehyde-(1E)-[O-(ethoxy)carbonyl]oxime], J 914[4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9- Dien-11β-yl]benzaldehyde-(1E)-(O-acetyl)oxime] and J 956 [4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestradiol -4,9-dien-11β-yl]benzaldehyde-(1E)-[O-ethylamino]carbonyl]oxime] (all see DE 43 32 284) is described as having strong anti-progestin-conjugated activity and Compounds with significantly reduced antiglucocorticoid activity compared to RU 486. Furthermore, it is mentioned that these compounds have (indirect) antiestrogenic properties, which are reflected by a decrease in uterine weight in cyclic guinea pigs. These effects should predict a particularly favorable effect on pathologically altered tissues (endometriotic lesions, fibroids, etc.) in which estrogen stimulates growth.

The disclosures of these applications do not pertain to the use of new compounds for female contraception or to pharmaceutical preparations for this purpose.

Furthermore, in these applications there is no mention at all of the compound's progesterogenic activity, which would be advantageous for contraception for the indications claimed herein.

According to the present 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 to PR. However, mesoprogestins display different pharmacokinetic properties compared to progestins or antiprogestins. The presence of progesterone agonistic activity in mesoprogestins, as determined in commonly used in vivo bioassays, represents a key property of this new class of PRMs. However, this activity remained lower than that of progesterone in the plateau of the dose-response curve. Mesoprogesterone fails to maintain pregnancy in ovariectomized pregnant rodents such as mice and rats.

In the classic biochemical analysis, the McPhail test evaluates the combined progesterone and anti-progestin effects in rabbits (Selye H., Textbook of Endocrinology, 1947, 345-346 pages), and the maximum McPhail value (McPhail score) produced by progesterone ( By definition) is 4. However, treatment with mesoprogesterone in the absence of progesterone results in higher McPhail values compared to RU 486 at any dose, i.e. higher than 0.5-1.0, preferably 2.0-3.0, but for the claimed indication At clinically relevant doses (ie, 0.01 mg-30 mg/rabbit), values at the plateau of the dose-response curve were significantly lower than 4.

In the McPhail test, the ability of mesoprogestins to antagonize progesterone function is also tested using progesterone doses that induce McPhail values between 3 and 4. Mesoprogestins largely inhibit the effects of progesterone, but the maximal inhibition is lower than that induced by available RU 486 or other pure antiprogestins such as onapristone.

Thus, mesoprogesterone stabilizes PR function at a moderately active level, providing a rationale for new clinical applications in gynecological therapy. The corresponding functional status cannot be achieved with progestins or antiprogestins. Demonstrating the pharmacological results of mesoprogesterone in the claimed indication

According to Selye (Textbook of Endocrinology, 1947, pp. 345-346), the PR antagonistic and agonistic properties of mesoprogesterone were evaluated in the McPhail test in estrogen-primed rabbits. A) Evaluation of the PR agonistic properties of mesoprogesterone in rabbits (Fig. 1A)

Evaluation of J 867, J 956, J 1042 [4-[17β-methoxy-17α-(methoxymethyl )-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-[O-(ethylthio)carbonyl]oxime] (German patent application 198 09 845.6)] and RU 486 (dose range: 0.003-100mg/rabbit) binding progesterone activity. At doses equal to or higher than 0.03 mg/rabbit, a progestin-binding effect of mesoprogesterone was observed. At doses equal to or higher than 0.1 mg, progesterone-induced endometrial transformation reached a maximal effect at a dose of 1 mg/rabbit (McPhail value approximately 4). None of the mesoprogestins tested (J 1042, J 867, J 956) achieved maximal progesterone effects. J 956 showed a biphasic response in this test, with a McPhail value of 1.5 for its maximal effect at doses of 0.3-1 mg/rabbit. B) Evaluation of the PR antagonistic properties of mesoprogesterone in rabbits (Fig. 1B)

Similarly, J 867, J 956, J 1042 and RU 486 (dose range : 0.001-100mg/rabbit) anti-progesterone activity. The first antiprogestogen effect of mesoprogesterone and RU 486 was observed with doses of 0.3-1 mg/rabbit (McPhail index 0=no conversion, 4=complete conversion). At higher clinically relevant doses (i.e., 3-30 mg/rabbit), the anti-conjugated progesterone activity of mesoprogesterone was lower than that of RU 486.

In the guinea pig model that is predictive of the effect in humans with respect to abortive activity (Elger W, Beier S., Chwalisz K, Föhnrich M, Hasan SH, Henderson D, Neef G, Rohde R (1986): Studies On the mechanism of action of progesterone antagonists.JSteriod Biochem 25:835-845), mesoprogesterone J 867, J 912, J 956, J 1042 at most 100mg/kg/day lead to a maximum 20% abortion rate. C) Assessing the physiological context of abortion effects:

The guinea pig is considered a relevant model of human pregnancy and parturition (Elger W, Föhnrich M, Beier S, Quing 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, Fhnrich M, Gründel M, Heermann J, Malmendier A, Laurent D, PuriCP, Singh MM, Hasan SH, Becker H(1992).Evaluation of antifertility activities of antigestagens inanimal model.In: Puri CP and Van Look PFA (edited), Current Concepts in Fertility Regulation andpeproduction. Wiley Eastern Limited, New Delhi, 303-328; Elger w, Faehnrich M, Beier S, Qing SS, ChwaliszK (1986). in pregnant guinea pigs.Contraception6:47-62; Elger W, Chwalisz K, Faehnrich M, Hasan SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE(1990).Studies on labor-conditioning and labor-inducing effects of antiprogesterones in animal model. In: Garfield RE (ed.), Norwell, pp. 153-175). In this species, the abortive mechanism of antiprogestins is the initiation of labor and eventual expulsion of the conceptus. Abortive effects in rats during very early pregnancy reflect inhibition of implantation rather than initiation of uterine contractions. Studies in rat models lead to "overestimates" of antiprogestins' ability to terminate human pregnancy. In contrast, in the guinea pig model, independent of the dose of the antiprogesterone, there was a high rate of ongoing pregnancy similar to that in humans (Elger et al., Current Concepts in Fertility Regulation and Peproduction cited above). In addition, there is a strong synergy between antiprogestins and prostaglandins in both humans and guinea pigs with regard to the induction of parturition (see above cited literature and Elger W, Beier S (1983). Prostaglandine und Antigestagene für den Schwangerschaftsabbruch (Prostaglandins and antigestagens for pregnancy termination). German patent DE 3337450 12; Van Look P, Bygdeman M (1989). Antiprogestational steroids: a new dimension in human fertility regulation. Oxford reviews of ed2m1: reproductive261). Evaluation of labor-inducing activity: Figure 3

Pregnant guinea pigs were treated on days 43 and 44 of gestation and observed until day 50 for pregnancy. See Table 1 and Figure 3 for the effects of various treatments. A delay of several days after treatment for expulsion to occur is common for this model. It can be seen that mesoprogesterone has a much lower abortive activity compared to RU 486. The following order of abortive activity was found: RU 486 > J956 > J 867, J 912 > J 1042. The difference in abortion activity appears to be a difference in quality. It is not possible to overcome the low abortive activity of mesoprogestins by using higher doses. Table 1: Relative binding activity (RBA) and

_ED50 compound RBA(%)# Abortive Activity ED ₅₀ (mg/animal/day, sc) PR ¹ GR ² Rat ³ guinea pig ⁴ RU 486 506 685 0.98 ^* 3.8 Onapristone twenty two 39 1.71 ^* ca 3 J 867 302 78 0.65 ^* >100 J 956 345 154 0.64 ^* 20 J 912 162 16 0.36 >100 J 1042 164 42 >10 ＞＞100 #: By Caufmann; ¹ progesterone = 100%, ² dexamethasone = 100%, ³ treatment on days 5-7 of gestation, autopsy on day 9, ⁴ treatment on days 43-44 of gestation, cadaver on day 50 Anatomy, ^* SAS, Probabilistic Methods

The mesoprogesterone used in the present invention is preferably selected from J 867, J 912, J 956, J 1042.

A further preferred mesoprogesterone is [4-[17β-hydroxy-17α-(ethoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-oxime ; 4-[17β-methoxy-17α-(ethoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-oxime; 4-[17β -Hydroxy-17α-(chloromethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-oxime; 4-[17β-methoxy-17α-( Methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-(O-methyl)oxime (all see DE 43 32 283) and 4- [17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-(O-phenylamino)carbonyl]oxime ; 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-[propionyl]oxime; 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestro-4,9-dien-11β-yl]benzaldehyde-(1E)-[benzoyl]oxime ( All see DE 43 32 284).

The daily dose is 1-25 mg mesoprogesterone.

As estrogens, all estrogenicly active compounds are suitable for the purposes of the present invention. · Estrogens that can be used within the scope of the present invention are, for example, ethinyl estradiol, 17β-estradiol

Diols and their esters such as estradiol-3-benzoate, estradiol-17-pentanoate, -cyclo

cypionate, -undecanoate, -enanthate and/or other estradiol

Alcohol 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 conjugated estradiol. · Estradiol-, ethinylestradiol- and estrone-3-sulfamate, e.g. estrone-N,N-di

Methyl sulfamate, estrone-N, N-diethyl sulfamate, ethinyl estradiol-3-

N,N-dimethylsulfamate, ethinylestradiol-3-N,N-diethylsulfamate,

Ethinyl estradiol-3-N, N-tetramethylene sulfamate, estrone sulfamate, estradiol

Alcohol-3-sulfamate, estradiol-3-N, N-dimethylsulfamate, ethinylestradiol

Alcohol-3-sulfamate, all of which represent the precursors of the corresponding 3-hydroxy compounds

Medicine (W.Elger etc., in J.Steroid Biochem.Molec.

Biol., Vol. 55, Issue 3/4, 395-403, 1995; DE 44 29 398 A1

and DE 44 29 397 A1), they can also be used in the pharmaceutical agent of the present invention

middle.

As progestins useful in the present invention, all compounds suitable for use in oral contraceptives due to their progestogenic activity are suitable. An exemplary listing of such compounds is found in B. Runnebaum et al., "Female Contraception: Update and Trends," Springer-Verlag, Berlin, 1988, 64-90, 109-121, 122-128 and 129-140. Preferred progestins within the scope of the present invention are gestodene, progesterone, levonorgestrel, cyproterone acetate, chlormadinone acetate, drospirenone (dihydrospironolactone), acetylene norethindrone acetate, norethisterone, desogestrel, or 3-ketodesogestrel. In progesterone-containing embodiments of the invention, the progesterone is present in a dosage form suitable for oral administration, ie in the form of a tablet, coated tablet, capsule or pill. In this case, progesterone formulations are carried out in a manner analogous to the preparation of progesterone for hormonal contraception, using adjuvants conventionally used for this purpose. Daily dosage units of progesterone containing 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 equivalent to these doses The amount of other progesterone.

Doses corresponding to the effects of the various progestins are determined according to known methods; for further details see, for example, the two documents "Probleme der Dosisfindung: Sexual hormone [problems of Dose-Finding: Sex Hormones]"; F. Neumann et al. [Drug Research]" 27, 2a, 296-318 (1977) and "Aktuelle Entwicklungen in der hormonealen Kontrazeption [Current Developments in Hormonal Contraception]"; H. Kuhl in "Gynkologe [Gynecologists]" 25:201-240 (1992 ).

According to all embodiments, the mesoprogesterone may be present in a dosage unit for daily oral administration.

Estrogens may also be present in daily oral dosage units.

If dosage units of the mesoprogesterone are provided for administration over a period of 7 days, these dosage units may advantageously be in the form of dosage units which can be administered once a week.

In such dosage units for once-weekly administration, the mesoprogesterone should preferably be formulated to result in a delayed release of the active ingredient.

For example, delayed release of mesoprogesterone can be achieved by formulating the dosage unit as a combination tablet for oral administration, or by providing the dosage unit for oral administration with a timed disintegration coating, as is known to those skilled in the art. of.

The mesoprogestins used in the preparation of the pharmaceutical formulations of the invention may also have a longer half-life than their precursors by derivatization in effective precursors, eg esterification of free hydroxyl groups. Thus, a longer-lasting effect can also be achieved.

For the purposes of the present invention, the formulation of mesoprogesterone and optionally estrogen is carried out in a completely conventional manner, as is known for the formulation of these compounds when used alone, as described in DE 43 32 283 for J 867 , and for estrogen therapy, eg Cyclo-Progynova.

In particular, reference is also made to the information contained in the prior art literature.

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

Alternatively, an intrauterine delivery system (c.f. Mirena) can be used for administration, but this variant is not preferred within the scope of the present invention.

It is also possible to administer one or both components in a depot formulation.

Finally, all above-mentioned types of administration can be combined. For example, the estrogen may be administered transdermally using a skin patch, and the progesterone antagonist may be administered orally once daily or in a depot formulation one or more times.

According to the invention, the amount of estrogen contained per daily dosage unit is 10 to 30 [mu]g ethinyl estradiol or a bioequivalent amount of other estrogens.

In the pharmaceutical preparations according to the invention, the mesoprogesterone contained in each daily dosage unit is preferably used in such an amount that it is sufficient for amenorrhea to occur when used for the desired length of time.

In a preferred embodiment of the pharmaceutical preparation according to the invention, each daily dosage unit contains an amount of mesoprogesterone corresponding to 1 to 25 mg J 867.

Bioequivalent doses of mesoprogesterone can be evaluated in the McPhail test.

Packs containing the pharmaceutical preparations according to the invention are prepared in such a way that, in addition to progesterone and estrogen in one or both components of the respectively intended administration form (pills, coated tablets, etc. oral forms in blister packs, possibly applicable In addition to mesoprogesterone and/or estrogen, or estrogen as a skin patch, mesoprogesterone in the form of pills, coated tablets, etc., in blisters or capsules or depots for single administration), said packaging Instructions for using the pharmaceutical preparation are also included (package insert).

Claims (38)

1. middle progesterone is as the purposes of preparation female contraception with the composition of medicine.

2. the purposes of the middle progesterone of claim 1 does not wherein relate to any other medicines reactive compound.

3. the purposes of claim 1 or 2 middle progesterone is used in rule, the cyclical administration scheme.

4. the purposes of claim 3, it is characterized in that since the 1st day to giving middle progesterone at the most on the 180th day, wherein be calculated as hemorrhage first day of menstrual cycle of female on the 1st day.

5. the purposes of claim 4, in wherein selecting progesterone every day amount to bring out and to keep amenorrhea.

6. the purposes of claim 5 is characterized in that giving in the 25th day since the 1st day at least the 21 day and at the most middle progesterone, wherein is calculated as hemorrhage first day of menstrual cycle of female on the 1st day.

7. the purposes of claim 6 wherein selects measure to realize reversible amenorrhea every day.

8. the purposes of the arbitrary claim in the aforementioned claim 1 to 7, wherein middle progesterone is J 867, J 912, J 956, J 1042.

9. the purposes of the arbitrary claim in the aforementioned claim 1 to 8, dosage every day of progesterone is 1 to 25mg in it is characterized in that.

10. claim 1 and 3 to 9 purposes is characterized in that using estrogen as the supplementary element that is used to prepare medicine.

11. the purposes of claim 10 is characterized in that supplementary element is ethinylestradiol, estradiol, estradiol ester, or the 3-sulfamate of 17 β-ethinylestradiol or 17 beta estradiols.

12. the purposes of claim 10 or 11 is characterized in that supplementary element estrogenic every day of dosage is 10 to 30 μ g ethinylestradiols or other estrogenic bioequivalence.

13. the purposes of the arbitrary claim in the aforementioned claim 1 to 12 is characterized in that pharmaceutical formulation with orally give.

14. the purposes of the arbitrary claim in the aforementioned claim 1 to 12 is characterized in that pharmaceutical formulation is become uterine system.

15. claim 10,11 or 12 purposes is characterized in that middle progesterone and the supplementary element estrogen at least a prescription in the two with orally give.

16. claim 10,11 or 12 purposes is characterized in that middle progesterone and the supplementary element estrogen at least a uterine system of filling a prescription in the two.

17. the purposes of claim 2 is used in discontinuous, the aperiodicity dosage regimen.

18. the purposes of claim 17, the medicine of progesterone in wherein containing according to demand time a time when in fact wishing to practise contraception.

19. the purposes of claim 18, wherein administration time is 4 days at the most.

20. the purposes of claim 19, wherein the administration first time in time of 4 days at the most is before the sexual intercourse of hope contraception.

21. the purposes of claim 20 wherein only is administered once and administration before sexual intercourse.

22. progesterone and estrogenic pharmaceutical composition in containing.

23. the pharmaceutical composition of claim 22, wherein middle progesterone is selected from chemical compound J 867, J 912, J 956, J 1042.

24. the pharmaceutical composition of claim 22, wherein estrogen is ethinylestradiol, estradiol, estradiol ester, or the 3-sulfamate of 17 β-ethinylestradiol or 17 beta estradiols.

25. comprise in progesterone every day dosage unit female contraception pharmaceutical preparation, 180 days dosage unit at the most wherein is provided.

26. the pharmaceutical preparation of claim 25 in its relaying behind the progesterone, provides at the most 7 days placebo or the indication measure of 7 days no pills at the most is provided.

27. the pharmaceutical preparation of claim 26 wherein provides the dosage unit and 7,6,5,4 or 3 days placebo or indicate the measure of 7,6,5,4 or 3 days no pills every day of progesterone in 21,22,23,24 or 25 days.

28. the pharmaceutical preparation of claim 26 or 27 wherein except the dosage unit that contains middle progesterone is provided, also provides and contains estrogenic dosage unit.

29. the pharmaceutical preparation of claim 28, wherein middle progesterone and estrogen are comprised in the common dosage unit.

30. the pharmaceutical preparation of claim 28, wherein middle progesterone and estrogen are comprised in the isolating dosage unit.

31. comprise the pharmaceutical preparation of dosage unit every day, described every day dosage unit contain in progesterone and estrogen or estrogen mixture, wherein provide these dosage units with administration 21,22,23,24 or 25 days, and its relaying after progesterone/estrogen dosage unit, provides the dosage unit that only contained estrogen or estrogen mixture in 7,6,5,4 or 3 days to provide administration 28 days accumulated dose unit in these.

32. the pharmaceutical preparation of claim 31, wherein middle progesterone and estrogen are comprised in the common dosage unit.

33. the pharmaceutical preparation of claim 31, wherein middle progesterone and estrogen are comprised in the isolating dosage unit.

34. the pharmaceutical preparation of the arbitrary claim in the aforementioned claim 25 to 33, wherein middle progesterone is J 867, J 912, J 956, J 1042.

35. the pharmaceutical preparation of the arbitrary claim in the aforementioned claim 28 to 34, wherein estrogen is ethinylestradiol, estradiol, estradiol ester, or the 3-sulfamate of 17 β-ethinylestradiol or 17 beta estradiols.

36. the pharmaceutical preparation of the arbitrary claim in the aforementioned claim 25 to 35, wherein every day, dosage unit contained progesterone in 1 to 25mg.

37. the pharmaceutical preparation of the arbitrary claim in the aforementioned claim 28 to 33,35 and 36, wherein every day, dosage unit contained other estrogen of 10 to 30 μ g ethinylestradiols or bioequivalence.

38. the pharmaceutical preparation of the arbitrary claim in the aforementioned claim 25 to 37, wherein every day, dosage unit contained the middle progesterone of the amount of bringing out amenorrhea and keeping amenorrhea.

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