EP0844880A2

EP0844880A2 - Contraceptive combined preparation, kits containing the same and contraceptive method using this combined preparation

Info

Publication number: EP0844880A2
Application number: EP96928467A
Authority: EP
Inventors: Klaus Stöckemann; Ulrich Koch; Kristof Chwalisz
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1995-08-17
Filing date: 1996-08-16
Publication date: 1998-06-03
Also published as: WO1997006807A3; US20050064031A1; ZA966995B; DE19531936A1; WO1997006807A2; JPH11511157A; AU6821796A

Abstract

A multiple-phase combined preparation contains at least 28 daily dosing units. The first phase with at least the first 21 daily dosing units contains a dose of a competitive progesterone antagonist sufficient to inhibit ovulation during this first phase. The second phase includes 5 to 28 daily dosing units that each contain a gestagen. Also disclosed is a package containing this combined preparation (contraceptive kit) and a contraceptive method that uses this combined preparation.

Description

Combination preparation for contraception, containing kits and one

Method using this

The present invention relates to a multi-phase combination preparation containing at least 28 daily dosage units: with a first phase of at least 21 first daily dosage units, containing a competitive progesterone antagonist in a dosage that inhibits ovulation during the first phase just named; and a second phase of 5 to 28 daily dosage units, in which each dosage unit of this second phase contains a progestogen, as well as a corresponding package (contraceptive kit) containing this combination preparation and a contraceptive method which uses the above combination preparation.

It is known that competitive progesterone antagonists (Antigestagene = AG ^' s) such as RU486 (Mifepristone; 11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-diene -3-one) are able to inhibit ovulation in various animal species and in women [1) Uilenbroek J.TH.J (1991): Hormone concentrations and ovulatory response in rats treated with antiprogestagens. Journal of Endocrinology, 129, 423-429; 2) Danforth R. et al (1989): Contraceptive Potential of RU486 by ovulation inhibition: III. Preliminary Observations on once weekly administration, Contraception, 40/2, 195-200; 3) Kekkonen R. et al. (1990): Interference with ovulation by sequential treatment with the antiprogestin RU486 and synthetic progestin. Fertility and Sterility, 53/4, 747-750; 4) Ledger WL. et al. (1992): Inhibition of ovulation by low dose mifepristone (RU486). Human Reproduction, 7/7, 945-950; 5) Nieman LK. et al. (1987): The progesterone antagonist RU486: A new potential new contraceptive agent. The New England Journal of Medicine, 316/4, 187-1991].

It is also known that AGs prevent the implantation of a fertilized egg (implantation inhibition); [6) Glassier A. et al. (1992): Mifepristone (RU 486) compared with high dose estrogen and progesterone for emergency postcoital contraception: New England Journal of Medicine, 8/15; 1041; 7) Puri CP. et al. (1990): Effects of a progesterone antagonist, lilopristone, on induction of menstruation, inhibition of nidation, and termination of pregnancy in bonnet monkeys. Bioiogy of Reproduction, 43, 437-443; 8) Ishwad PC et al. (1993): Treatment with a progesterone antagonist ZK 98 299 delays endometrial development without blocking ovulation in bonnet monkeys. Contraception, 48, 57-70; 9) Batista MC. et al. (1992): Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: A potential new contraceptive strategy. AT THE. J. Obstet. Gynecol. 167/1, 60-65].

These findings indicate that antigestagens can be used as contraceptives based on inhibition of ovulation or implantation.

The first clinical studies for gynecological applications have also shown that AGs can be used for the treatment of endometriosis and leiomyomata uteri [10) Kettel LM. et al. (1991): Endocrine responses to iong-term administration of the antiprogesterone RU 486 in patients with pelvic endometriosis. Fertility and Sterility, 56/3, 402-407; 1 1) Kettel LM et al. (1993): Long-term, low-dose RU486 in the treatment of endometriosis. Meeting of the Society of Gynecological Investigation 1993, Abstract S-136; 12) Murphy AA et al. (1993): Regression of uterine leiomyomata in response to the antiprogestin RU486, J. Clin. Endocriπol. Metab., 76/2, 513-517].

The findings from these studies indicate that chronic treatment with AG's over the entire menstrual cycle, but also treatment during certain cycle phases with AG's, due to the abolition of the progesterone effect during the luteal phase of the cycle, leads to a shift or Prolongation of the cycle can occur with a lack of monthly bleeding (amenorrhea) or weakened menstruation [8), 9), 10)].

Both the endometrium and the hypothalamic-pituitary-ovary

Axis come as target organs for a contraceptive approach with estrogens,

Gestagenπen, or their antagonists in question.

Estrogens alone can inhibit the gonadotropin increase necessary for ovulation via a negative feedback mechanism. In normal

Cycle modulates the estrogen rise during the follicular phase just before

Ovulation the increase in gonadotropin necessary for ovulation. Likewise, estrogens can be taken at high doses with the implantation of the fertilized

Interfering with (implication).

The role of progesterone in ovulation is not yet fully understood. Continuous administration of progestogens leads to an inhibition of gonadotropin secretion. In the normal cycle, progesterone appears to play an important role in ovulation. Recent studies have shown that the slight increase in progesterone shortly before ovulation appears to be of crucial importance.

The administration of a competitive progesterone antagonist (e.g. RU 486) at this point blocks ovulation. Simultaneous administration of progesterone cancels this effect [19) Batista M.C. et al., 1992: Evidence for a critical role of progesterone in the regulation of the midcycle gonadotropin surge and ovulation. Journal of Clinical Endocrinology and Metabolism 74: 565-570]. In addition to these effects, it is known that progesterone is involved in the enzymatic dissolution of the follicular wall and therefore plays a role in ovulation at the ovary level.

Furthermore, progesterone in the woman's cycle is of crucial importance for the secretory transformation of the endometium and for the preparation of the implantation of the fertilized egg.

On the basis of these findings, various contraceptives are conceivable. In conventional oral contraceptives, which usually consist of a combination of an estrogen and progestogen, both components together lead to an inhibition of ovulation.

Alternatively, there are contraceptives that contain only one progesterone component (progestagen only pill = POP); these are used primarily when side effects have occurred with conventional contraceptives (estrogen and progestogen) or in women who are at increased risk of thrombosis, for whom the estrogen component is held responsible [20) Gerstman et al., 1991, Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am.J. Epidemiol. 133: 32-37]. However, these POPs also have disadvantages. Thus, there is a significant increase in bleeding between POPs [21] Broome M., Fortherby K. (1990): Clinical expirience with the progesterone-only pill. Contraception 42: 489-494]. Also, the active principle in comparison to conventional OC ^'s is another; Not all women experience an inhibition of ovulation. In addition, in addition to a possible role of estrogens, progesterone is now also assigned an important role in the pathogenesis of breast cancer [22) King RJB (1990): A discussion of the roles of estrogen and progestin in human mammary carcinogenesis. J. Ster. Biochem. Molec. Biol. 39: 811 1-81; , 23) Paul C, Skeeg DCG, Spears GFS (1989): Depot medroxyprogesteron (Depo-Provera) and risk of breast cancer. Br. Med. J. 299: 759-762]. Although this is Some studies with progestogen supplements have not yet definitively proven this.

For the reasons mentioned above, it is therefore desirable to reduce the dosages of estrogen and progestogen in contraceptives.

There are three possibilities for using a competitive progesterone agonist in contraception, namely their use as an ovulation inhibitor, as a post-coital pill or as a luteal contraceptive.

Approaches to contraception with antigestagens for inhibiting ovulation with subsequent progestogen administration in the treatment cycle have been described [Kekkonen et al., (1990) Fertility and Sterility, 53 (4): 747-750 Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin , Bergink WO 94/04156]. Kekkonen et al. describes a discontinuous regimen in which 25 mg of mifepristone is administered daily from day 1-14 of the menstrual cycle followed by 3 mg of the progestogen norethisterone on days 15-24, followed by δday placebo administration. This regime was applied over 3 cycles. With the regime described there it was not possible to suppress the serum concentrations for FSH and LH. In addition, during progestogen administration, there was evidence in the first two cycles that ovulation and maturation of follicles had occurred. These results indicate that the one by Kekkonen et al. described regime does not provide sufficient contraceptive security and can therefore lead to unwanted pregnancies.

The regimen disclosed in the Bergink patent application comprises a continuous application of at least 5 days and at most 20 days of an anti-gestagen and then at least 10 days, but not more than 25 days of a gestagen. The preferred embodiment comprises the sequential administration of 14 days of an anti-gestagen and then the administration of 14 days of a gestagenπs. Even with such a regimen, ovulation is not inhibited with the desired reliability because the anti-gestagen phase is not long enough.

The object of the present invention is to provide a contraceptive product containing an antigestagen for inhibiting ovulation and inducing an amenorrhea with sequential administration of a progestogen for the preparation of a Bleeding, which provides the necessary contraceptive security through reliable ovulation inhibition from the first cycle and also allows a variable choice of cycle length.

This problem is solved by the provision of the multi-phase combination preparation described at the beginning.

In preferred embodiments of the multiphase combination preparation described at the outset, the first phase comprises:

21 to 28, maximum 77,

28

28 plus 7 or 28 plus a multiple of 7 first daily dosage units. and the second phase:

7 to 14 daily dosing units.

In a particularly preferred embodiment of the multiphase combination preparation, the first phase comprises 21 first daily dosage units and the second phase comprises 7 daily dosage units.

In a further particularly preferred embodiment of the multiphase combination preparation, the first phase comprises 23 or 24 first daily dosage units and the second phase 8, 7 or 6 daily dosage units, in such a way that the total number of daily dosage units of the first and second phases is 30 or 31 days added (so-called monthly pack).

In a further particularly preferred embodiment of the multiphase combination preparation, the first phase comprises 70 first daily dosage units and the second phase 14 daily dosage units. In a further particularly preferred embodiment of the multiphase combination preparation, the first phase comprises 63 first daily dosage units and the second phase comprises 7 daily dosage units.

The present invention further comprises a contraceptive kit containing at least 28 daily dosage units comprising: a first phase of at least 21 first daily dosage units containing, in each individual dosage unit, a competitive progesterone antagonist in a dosage that inhibits ovulation during the first phase just named; and a second phase of 5 to 28 separate daily dosage units, each dosage unit of the second phase containing a progestogen.

Preferred embodiments of the contraceptive kit are characterized in that the first phase:

21 to 28, maximum 77,

28

28 plus 7 or 28 plus a multiple of 7 first daily dosing units. and the second phase

7 to 14 daily dosage units.

In a particularly preferred embodiment of the contraceptive kit, the first phase comprises 21 first daily dosage units and the second phase 7 daily dosage units.

In a further particularly preferred embodiment of the contraceptive kit, the first phase comprises 23 or 24 first daily dosage units and the second phase 7 or 6 daily dosage units in such a way that the total number of daily dosage units of the first and second phases is 30 and 31 respectively Days supplemented (so-called monthly pack). -.-, ...-.... "PCT / EP96 / 03602 O 97/06807

In a further particularly preferred embodiment of the contraceptive kit, the first phase comprises 70 first daily dosage units and the second phase 14 daily dosage units.

In a further particularly preferred embodiment of the contraceptive kit, the first phase comprises 63 first daily dosage units and the second phase 7 daily dosage units.

In a further embodiment of the contraceptive kit according to the invention, the dosage units of the first and / or second phase are partially in periodically repeating subunits that are spatially and / or separated from one another by other markings. This enables variable handling of the initiation of the stopping bleeding.

The daily dosage units are preferably in subunits which can be separated from one another by perforations or other devices suitable for separation. In a particularly preferred embodiment of the invention, they are contained in separate subunits of 7 dosage units each.

Subunits are understood to mean any division or subdivision, such as that of a blister, in the case of several blisters or else the division within a blister; in between, all possible divisions or subdivisions are conceivable.

The division of the contraceptive kit facilitates the variable handling of initiating the bleeding, as described above, and the perforations allow the separate subunits to be separated from one another and the kit to be adapted to the individual regimen.

The invention further relates to a method for contraception in female mammals consisting of a sequential administration of at least 28 days: of at least 21 first daily dosage units during a first phase, containing a competitive progesterone antagonist in a dose that stimulates ovulation during the first phase just mentioned inhibits, and a second phase of 5 to 28 daily Dosieruπgseinheit, wherein each Dosieruπgseinheit, this second phase contains a progestogen.

All compounds which themselves or their metabolic products block the action of the progesterone at its receptor are suitable as competitive progesterone antagonists according to the present invention. The following are typical competitive progesterone antagonists:

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dieπ-3-one (Steroids 37 (1981), 361 -382),

1 1 ß- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (EP-A 0 190 759),

(Z) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one,

1 1 ß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3- one (RU486),

(Z) -9.11 α-Dihydro-17ß-hydroxy-17α- (3-hydroxy-1-propenyl) -6 '- (3-pyridinyl) -4Η- naphth [3', 2 ', 1': 10 , 9, 11] estra-4,9 (11) -dien-3-one,

(Z) -11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one,

4 ', 5'-dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2' (3'H) -furan] -3-one,

4 ', 5'-dihydro-1 1 ß- [4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2' (3'fy) -furan] -3-one,

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one as well

19, 11 β-bridged steroids from EP-A-0 283 428 and

10β-H steroids from EP-A-0 404 283. In a particularly preferred embodiment of the invention, the competitive progesterone antagonist is the compound (Z) -11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3 -on or a connection comparable in its profile.

This list is not exhaustive; other competitive progesterone antagonists described in the publications mentioned and those from publications not mentioned here are also suitable.

The competitive progesterone antagonists are tested on female cynomolgus monkeys for their ability to inhibit ovulation. For this purpose, the animals receive the respective test substance daily from day 2 to day 22 of the menstrual cycle, e.g. administered orally. The ovulation-inhibiting effect of the test substance in question is determined by determining the serum progesterone values, in particular on days 20 and 22 of the menstrual cycle, or by ultrasound examinations.

In the contraceptive combination preparation according to the invention, the competitive progesterone antagonist is to be administered in a dose which inhibits ovulation and induces amorrhea. This is e.g. for RU 468 2 mg / per woman / per day; for the other competitive progesterone antagonists, the amounts are in the range of 0.01-30 mg / per woman / per day.

The threshold dose of an ovulation-inhibiting competitive progesterone antagonist is determined in women in clinical trials by determining the serum progesterone values or by ultrasound examinations.

Following the phase of the endometrium which is receptive in the normal cycle and which is inhibited by competitive progesterone antagonists, the progestogen - in accordance with the normal cycle in the luteal phase - becomes the endometrium for a bleeding induced by the progesterone antagonist coming again after the progestogen administration prepared. According to the present invention, gestagens are all compounds which, because of their gestagenic activity, are suitable for use in oral contraceptives. A list of such connections can be found in B. Runnebaum et al., "Female Contraception: Up-date and Trends", Springer-Verlag, Berlin, 1988, pages 64-90, 109-121, 122-128 and 129-140.

In all embodiments of the invention, the gestagen is preferably selected from the group of compounds:

Gestoden,

Progesteroπ,

Levoπorgestrel,

Cyproterone acetate,

Chloromadin acetate,

Drospirenoπ (dihydrospirorenone),

Norethisterone,

Norethisterone acetate,

Norgestimate,

Desogestrel,

3-ketodesogestrel,

Selected dienogest or a mixture thereof.

In a particularly preferred embodiment, the progestin is in a daily dosage of:

0.02-0.6 mg levonorgestrel,

0.2-2.0 mg cyproterone acetate,

0.01-0.3 mg gestoden,

0.02-0.3 mg desogestrel or in a bioequivalent dose of another progestogen. In a particularly preferred embodiment, the gestagen gestoden is contained in a dosage of 0.02 to 0.075 mg.

During the administration of the antigestagens in an ovulation-inhibiting dose and in a dose inducing an amenorrhea, the endogenous progesterone is switched off, and the endogenous estrogen is reduced but not completely suppressed [10) Kettel LM. et al.]. Ovulation is inhibited and the endometrium is not converted to a bleeding endometrium, which leads to amenorrhea.

Blocking progesterone can lead to a protective effect on breast cancer. It has been described that antigestagens can inhibit the proliferation of normal mammary tissue and inhibit the growth of breast tumors experimentally induced in animals [Spitzer et al., (1995): Antiprogestin inhibit growth and stimulate differentitation in the normal mammary gland. Journal of Cellular Physiology 164: 1-8; Schneider et al. (1989): Antitumor activity of the progesterone antagonists ZK 98 299 and RU 38.486 in the hormone-dependent MXT mammary tumor model of the mouse and the DMBA- and NMU- induced mammary tumor model of the rat. Eur. J. Cancer Clin. Oncol. 25, 691-701]. Furthermore, it could be shown that if rats were treated with progesterone antibodies or with onapristone before the carcinogen was administered, the development of breast tumors can be inhibited.

After the respective administration of anti-gestagen, the bleeding is prepared with the help of a gestagen. Since antestagen treatment does not lead to complete suppression of the estrogens - the levels are comparable to those of the middle follicular phase [10) Kettel L.M. et al. ] - after ovulation inhibition in the receptive phase (only in this phase - if it is not inhibited - an implantation can take place) a progestogen can transform the progestogen and convert it into a secretively active endometrium and into a natural menstrual period Prepare the appropriate bleeding that is induced by continued progestogen treatment after progestogen administration.

The subsequent further treatment with a competitive progesterone antagonist (in an ovulation-inhibiting dose) simulates the natural decrease in progesterone (progesterone blockade) and triggers a menstruation in which parts of the endometrium are rejected. That this after anti-gestagen treatment - also in the presence of progesterone - possible was shown [Nieman LK. et al. (1987): The progesterone antagonist RU 486: A potential new contraceptive agent. The New England Journal of Medicine, 316/4, 187-191; Craxatto HB et al. (1985). The demonstration of antiprogestin effects of RU 486 when administered to the human during hCG-induced pseudopregnancy. In Bauiieu EE and Segal SJ (eds.). The Antiprogestin Steroid RU 486 and Human Fertility Control. Plenum Press, New York, pp 263-269; Kekkonen R. et al. (1993): Sequential regimen of the anti progesterone RU 486 and synthetic progestin for contraception. Fertility and Sterility 60: 610-615].

There are two phases in the normal cycle, the proliferation phase (follicular phase) and the secretion phase (luteal phase). In the follicular phase, estrogen-induced development of the secretory glands in the endometrium takes place in the normal menstrual cycle, while in the luteal phase the progestogen (progesterone) induces the secretory activity of the glands.

According to the present invention, the progesterone antagonist serves to inhibit ovulation; leads to an inhibition of both the development of endometrial glands during the follicular phase and the secretory conversion of the glands in the luteal phase, which are essential for successful implantation of the fertilized egg.

The sequential treatment with the gestagen ensures adequate cycle control.

With the proposed composition, the undesirable effects of possible monotherapy with a competitive progesterone antagonist (chronic amenrrohea and stimulation of the endometrium) can be prevented.

Schemes 1, 2, 3 and 4 exemplarily show various configuration options for the composition.

The progestogen to be administered sequentially to the competitive progesterone antagonist in the product according to the invention is at the earliest for administration from the 21st Day after the first administration of the competitive progesterone antagonist. The number of dosing units of the competitive progesterone antagonist to be administered and the number of dosing units containing progestin to be subsequently administered daily can be selected so that the menstrual bleeding triggered by the gestagen administration corresponds to the menstrual bleeding in an untreated cycle (Scheme 1).

The composition according to the invention can also contain the dosage units of the progestogen to be administered sequentially to the competitive progesterone antagonist in such a way that they are provided after a 2 x 28-day plus 14-day administration of the progesterone antagonist, the administration of the progestogen being 14 days (corresponds to the total duration 3 months) (Scheme 5)).

All conceivable cases are possible between these two limits (competitive progesterone antagonist over a period of 21 or 2 times 28 days plus 14 days), e.g. 3 times 21 days administration of the competitive progesterone antagonist, then 7 days progestogen administration (scheme 2) or also the administration of 23 or 24 days of the competitive progesterone antagonist, then 7 or 6 days progestogen administration (scheme 3).

Another possible variant provides for administration of 2 times 28 days plus 21 days of the competitive progesterone antagonist with subsequent 7-day gestagen administration (Scheme 4).

Examples:

1)

/ - 1st cycle - / 2nd cycle - / 3rd cycle day: day: day:

1 AG 21 / 22- - P— -28 / 1 AG 21/22 P- - 28/1 AG 21 / 22--

- -> bleeding -> bleeding etc.

P 28

- -> bleeding

2)

/. 1st cycle / 2nd cycle day: day: day:

1 AG- - 21/1 AG- - 21/1 AG 21/22 - P 28/1 AG- - 21 / 1-> bleeding _etc.

—AG 21/1 AG- - 21/22 - P- - 28> bleeding

AG stands for "competitive progesterone antagonist" and P for "progestogen" 3) so-called monthly preparation

/ 1st cycle - / - 2nd cycle

Day: Day: Day:

1 AG- - 23 or 24/24 or 25 - P - 30 / 1- - AG 23 or 24/24 or 25-

-> bleeding ./ 3rd cycle / etc.

... p. - 30/1 AG 23 or 24/24 or 25 - P 30

-—> bleeding -—> bleeding

4)

/. 1st cycle,. / -,

-I AG 28 / 1- -AG 28/1 AG 21/22 P 28/1 AG-> bleeding

ZCycle— etc.

- 28 etc.

5)

/ I. cycle _ /.,

Cycle - etc.

1 AG 28/1 AG 28/1 AG 14/15 P 28/1 -

-> bleeding _etc.

AG etc. Two studies in the Netherlands and Germany, France and the United Kingdom have shown that many women prefer to have less menstrual periods. The main reasons given were hygienic problems, monthly pains and psychological instability. The present invention enables women to determine the length of their cycle themselves. According to the present invention, any withdrawal bleeding can be postponed until after day 84. Since the women have different preferences, the present invention can meet the needs of women for a bi-monthly or alternatively 1/4 year cycle and thus the side effects associated with the menstrual period can be reduced accordingly.

The combination preparations or kits according to the invention containing these are particularly suitable for a prolonged menstrual cycle, since the chronic administration of antigestagens over the entire cycle, due to the abolition of the progesterone effect during the luteal phase, leads to a shift or extension of the cycle with the absence of monthly bleeding (amenorrhea) comes.

The special division of the contraceptive kit into subunits enables the variable handling of the initiation of the stopping bleeding. For example, the separate subunits can be easily separated from one another by perforations and thus optimally adapted to the individual regime.

With the help of the contraceptive kit, women can determine the length of their menstrual cycles themselves.

For example, the woman would take the contents of three 21-day blisters, which only contain dosage units of an antigestagens (Fig. 1)

Figure 1 o = anti-gestagen dosage unit and the content of a blister containing only dose units of a progestogen.

The number of gestagen-containing dosage units required for the transformation of the endometrium can be separated as subunits (Fig. 2).

Mon tue wed thu fri sat sun

• • • • • • •

_* • • • • • •

Figure 2. • = progestogen dosage unit = perforation

For example, if the woman decides to follow a 4-week regime, she will use the anti-gestagen blister with e.g. Use up 21 dragees first and then e.g. Take the gestagen dosing units for 7 days.

If she should opt for a longer cycle with less bleeding, she can consume two or three antigestagen blisters or subunits of 21 tablets containing a competitive progesterone antagonist one after the other and then the number of gestagen-containing dosage units required for the transformation of the endometrium (e.g. 7 days) Detach and ingest as a subunit.

Another exemplary embodiment ^"of the contraceptive kit could contain an anti-gestagen blister as shown in Figure 3 and a progestogen blister as shown in Figure 2. Here there are 42 dosage units of an anti-gestagen in a blister; the first 21 anti-gestagen-containing dosage units are not separated by perforations however, the subsequent 3 x 7 dosage units containing antestagen can be separated from one another by perforations (Fig. 3). MO Dl MI DO FR SA so ooooooooooooooooooooo

o o o o o o o

From education 3. o = anti-gestagen dosage units

- - = perforation

For example, if the woman opts for a 5-week cycle, she separates 21 + 7 dosage units containing antestagen from the blister and takes them one after the other. However, if the woman decides, for example, for a ^β- week cycle, she separates 21 + 7 + 7 dosage units containing antestagen from the blister and takes them one after the other. It then separates the number of gestagen-containing dosage units (eg 7 days) required for the transformation of the endometrium as a subunit from a gestagen blister as shown in Figure 2 and takes it. In a further embodiment of the contraceptive kit, as shown in FIG. 4, the anti-gestagen and the gestagen dosage units are in a blister.

MO TU WE TH FR SA SO o o o o o o o o o o o o o o

o o o o o o o

• • • • • • •

Figure 4. o = Anti-progestogen dosage unit = progestogen dosage unit = perforation The competitive progesterone antagonists according to the present invention can be applied locally, topically, enterally, transdermally or parenterally.

For the preferred oral application, tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable, which can be prepared in the usual way with the additives and carrier substances customary in galenics.

The competitive progesterone antagonist is formulated in the same way as is known, for example, for RU 486.

For local or topical use, for example, vaginal suppositories, vaginal gels, implants, vaginal rings or transdermal systems such as skin patches are suitable.

A unit dose contains about 2 mg of 11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 486) or a biologically equivalent amount of one other competitive progesterone antagonists.

If the competitive progesterone antagonist to be used according to the invention is applied by means of an implant, a vaginal ring or a transdermal system, these application systems must be such that they release a dose which is equivalent to the daily oral dose for the respective application form of the competitive progesterone antagonist (comparable Serum concentrations).

The dose of a competitive progesterone antagonist to be administered according to the invention lies in the ovulation-inhibiting and non-abortion-triggering dose range of the relevant progesterone antagonist and is sufficient to trigger an amenorrhea.

One-time administration should also mean that when using an application system that continuously releases the competitive progesterone antagonist, 0.01-30 mg are released each day.

The product according to the invention can also be designed such that the application of the individual dosage units of the competitive progesterone antagonist can take place every 4 to every 10 days, starting on any day before the time of ovulation in the first application cycle. This ensures contraceptive safety in the first application cycle (Bygdeman).

The time intervals between the doses of the individual dosage units should preferably be constant. In a further embodiment of the product according to the invention, the respective dosage units of the competitive progesterone antagonist are applied in such a way that they are applied once a week on the same weekday, for example on a Monday ("Monday morning").

The dose of the competitive progesterone antagonist when administered in 4 to 7 day intervals must be selected such that converted to a daily dosage, the respective dosage contains 4 to 7 times the active ingredient, so that an amount of active ingredient corresponding to the daily dosage is released per day.

The weekly application schedule on the same weekday ensures a high level of income security.

The product according to the invention can also provide for the application of the individual dosage units of the competitive progesterone antagonist daily, every second or every third day; the amount of active ingredient per dosage must then be increased accordingly.

The progestin is present in the product according to the present invention in a dosage form suitable for oral administration, namely as a tablet, dragee, capsule or pill.

The gestagen is formulated in a manner analogous to the preparation of gestagens for hormonal contraception using the auxiliaries customary for this.

Known methods are used to determine effective dose amounts of different gestagens; Further details can be found, for example, in the two articles "Dose Finding Problems: Sex Hormones"; F. Neumann et al. in "Drug Research" 27, 2a, 296-318 (1977) and "Current Developments in Hormonal Contraception"; H. Kühl in "Gynecologist" 25: 231-240 (1992).

Claims

claims

1. A multi-phase combination preparation containing at least 28 daily dosage units:

with a first phase of at least 21 first daily dosage units, containing a competitive progesterone antagonist in a dosage that inhibits ovulation during the first phase just named; and

a second phase of 5 to 28 daily dosage units, wherein each dosage unit of this second phase contains a progestogen.

2. A multi-phase combination preparation according to claim 1, wherein the first phase comprises 21 to 27 first daily dosage units.

3. A multi-phase combination preparation according to claim 1, wherein the first phase comprises at least 28 and at most 77 first daily dosage units.

4. A multi-phase combination preparation according to claim 1, wherein the first phase comprises 28 first daily dosage units.

5. A multi-phase combination preparation according to claim 1, wherein the second phase comprises 7 to 14 daily dosage units.

6. A multi-phase combination preparation according to claim 1, wherein the first phase comprises 21 first daily dosage units and the second phase 7 daily dosage units. 7. A multi-phase combination preparation according to claim 1, wherein the first phase 23 or 24 first daily Dosieruπgseinheit and the second phase 8,

Includes 7 or 6 daily Dosieruπgseinheit, so that the total number of daily dosage units of the first and the second phase to 30 or 31 days.

8. A multi-phase combination preparation according to claim 1, wherein the first phase comprises 70 first daily dosage units and the second phase comprises 14 daily dosage units.

9. A multi-phase combination preparation according to claim 1, wherein the first phase comprises 63 first daily dosage units and the second phase comprises 7 daily dosage units.

10. A multi-phase combination preparation according to claim 1, wherein the competitive progesterone antagonist from the group of compounds:

17α-ethynyl-17ß-hydroxy-1 1 ß- (4-methoxyphenyl) estra-4,9-dien-3-one

11 β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

(Z) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one

1 1 ß- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

(Z) -9.1 1 α-dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) -6 '- (3-pyridinyl) -4Η- naphth [3', 2 ', 1': 10.9, 11] estra-4.9 (11) -dien-3-one

(Z) -1 1 ß- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one

4 ', 5'-Dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2'(3'i4) furan] -3-one 4 ', 5'-Dihydro-1 1 ß- [4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2'(3'H) -furan] -3-one

11 β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one

or a mixture thereof is selected.

11. A multi-phase combination preparation according to claim 1, wherein the progestogen from the group of compounds

Gestoden,

Progesterone,

Levonorgestrel,

Cyproterone acetate,

Chlormadinone acetate,

Drospirenone (dihydrospirorenone),

Norethisterone,

Norethisterone acetate,

Norgestimate,

Desogestrel,

3-ketodesogestrel,

Dienogest or a mixture thereof is selected.

12. A multi-phase combination preparation according to claim 1, wherein the progestogen in a daily dosage

0.02-0.6 mg levonorgestrel,

0.2-2.0 mg cyproterone acetate,

0.01-0.3 mg gestoden,

0.02-0.3 mg desogestrel or in a bioequivalent dose of another progestogen.

13. A multi-phase combination preparation according to claim 1, wherein the progestogen is gestodene in a dosage of 0.02 to 0.075 mg.

14. A multi-phase combination preparation according to claim 1, wherein the competitive progesterone antagonist (Z) -11 ß- [4-

(Dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one in a dosage of 0.01 -5 mg.

15. A contraceptive kit containing at least 28 daily dosing units with:

a first phase of at least 21 first daily dosage units, containing in each individual dosage unit a competitive progesterone antagonist in a dosage that inhibits ovulation during the first phase just named; and

a second phase of 5 to 28 separate daily dosage units, in which each dosage unit of the second phase contains a progestogen.

16. A contraceptive kit according to claim 15, wherein the first phase comprises 21 to 27 first daily dosage units.

17. A contraceptive kit according to claim 15, wherein the first phase comprises at least 28 and a maximum of 77 first daily dosage units.

A contraceptive kit according to claim 15, wherein the first phase comprises 28 first daily dosage units.

19. A contraceptive kit according to claim 15, wherein the second phase comprises 10 to 25 daily dosage units.

20. A contraceptive kit according to claim 15, wherein the first phase comprises 21 first daily dosage units and the second phase 7 daily dosage units.

21. A contraceptive kit according to claim 15, wherein the first phase comprises 23 or 24 first daily dosage units and the second phase 8, 7 or 6 daily dosage units so that the total number of daily dosage units of the first and second phases is 30 or 31 days added.

22. A contraceptive kit according to claim 15, wherein the first phase comprises 70 first daily dosage units and the second phase 14 daily dosage units.

23. A contraceptive kit according to claim 15, wherein the first phase comprises 63 first daily dosage units and the second phase 7 daily dosage units.

24. A contraceptive kit according to claim 15, wherein the competitive progesterone antagonist from the group of the compounds:

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one

11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

(2) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one

1 1 ß- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (Z) -9,11-dihydro-α 17-hydroxy-17α- (3-hydroxy-1 -propenyl) -6 '- (3-pyridinyl) -4Η- naphth [3', 2 ^', 1': 10 , 9,11] estra-4,9 (11) -dien-3-one

(Z) -11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one

4 ', 5'-Dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2' (3'H) -furan] -3-one

4 ', 5'-Dihydro-1 1 ß- [4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2' (3'H) -furan] -3-one

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one

or a mixture thereof is selected.

25. A contraceptive kit according to claim 15, wherein the progestogen is from the group of compounds

Gestoden, Progesteron, Levonorgestrel, Cyproteronacetat, Chlσrmadinoπacetat, Drospirenoπ (Dihydrospirorenon), Norethisteroπ, Norethisteronacetat, Norgestimate, Desogestrel, 3-Ketodesogestrel, Dienogest or a mixture thereof is selected.

26. A contraceptive kit according to claim 15, where the progestin in a daily dose

0.02-0.6 mg levonorgestrel,

0.2-2.0 mg cyproterone acetate,

0.01-0.3 mg gestoden,

0.02-0.3 mg desogestrel or in a bioequivalent dose of another progestogen.

A contraceptive kit according to claim 15, wherein the gestagen is gestodene in a dosage of 0.02 to 0.075 mg.

28. A contraceptive kit according to claim 15, wherein the competitive progesterone antagonist (Z) -11 ß- [4-

29. A conceptual kit containing at least 28 daily dosage units:

with a first phase of at least 21 separate first daily dosage units, containing a competitive progesterone antagonist in a dosage that inhibits ovulation during the first phase just named; and

a second phase of 5 to 28 separate daily dosage units, wherein each dosage unit of the second phase contains a progestogen, the respective dosage units being at least partially in periodically repeating subunits which are spatially and / or separated from one another by other markings, which in the dosage units located in the first phase comprises at least 21 daily dosage units in a kit, and the daily dosage units in the second phase comprise at least 7 daily dosage units.

30. A contraceptive kit according to claim 29, wherein the individual subunits can be separated from one another by perforations or other devices suitable for separation.

31. Contraceptive kit according to one of claims 29 or 30, wherein the separate subunits each contain 7 dosage units.

32. Contraceptive kit according to one of claims 29 to 31, wherein the separate subunits of the first phase each contain 7 dosage units.

33. A method of contraception in female mammals consisting of sequential administration for at least 28 days:

at least 21 first daily dosage units during a first phase, containing a competitive progesterone antagonist in a dose that inhibits ovulation during the first phase just mentioned, and

a second phase of 7 to 28 daily dosage units, in which each dosage unit, this second phase contains a progestogen.

34. A method of contraception in female mammals according to claim 33, wherein 21 to 27 first daily dosage units are administered during the first phase.

35. A method of contraception in female mammals according to claim 33, wherein at least 28 and a maximum of 77 first daily dosage units are administered during the first phase.

36. A method of contraception in female mammals according to claim 33, wherein 28 first daily dosage units are administered during the first phase.

37. A method of contraception in female mammals according to claim 33, during the second phase 7 to 14 daily dosage units are administered.

38. A method of contraception in female mammals according to claim 33, wherein the first phase comprises 21 first daily dosage units and the second phase comprises 7 daily dosage units.

39. A method of contraception in female mammals according to claim 33, wherein the first phase comprises 23 or 24 first daily dosage units and the second phase 8, 7 or 6 daily dosage units so that the total number of "daily dosage units of the first and second Phase extended to 30 or 31 days.

40. A method of contraception in female mammals according to claim 33, wherein the first phase comprises 70 first daily dosage units and the second phase comprises 14 daily dosage units.

41. A method of contraception in female mammals according to claim 33, wherein the first phase comprises 63 first daily dosage units and the second phase comprises 7 daily dosage units.

42. A method of contraception in female mammals according to claim 33, wherein the competitive progesterone antagonist from the group of compounds:

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one

11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propinyi) estra-4,9-dien-3-one

(2) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-diene-3-oπ

11β- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-oπ

(Z) -9.11 α-dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) -6 ^, - (3-pyridinyl) -4 ^, H-naphth [3 ', 2', 1 ' : 10,9,11] estra-4,9 (11) -dien-3-one

(2) -11β- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en-3-one

4 ', 5 ^, -Dihydro-1 1 ß- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2'(3'H) -furan] -3-one

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one

or a mixture thereof is selected.

43. A method of contraception in female mammals according to claim 33, wherein the progestogen is from the group of compounds

Gestoden,

Progesterone,

Levonorgestrel,

Cyproterone acetate, Chlormadinone acetate, drospirenone (dihydrospirorenone), norethisterone, norethisterone acetate, norgestimate, desogestrel, 3-ketodesogestrel, dienogest or a mixture thereof is selected.

44. A method of contraception in female mammals according to claim 33, wherein the progestin is in a daily dosage

0.02-0.6 mg levonorgestrel,

0.2-2.0 mg cyproterone acetate,

0.01-0.3 mg gestoden,

0.02-0.3 mg desogestrel or in a bioequivalent dose of another progestogen.

45. A method of contraception in female mammals according to claim 33, wherein the progestogen is gestodene in a dosage of 0.02 to 0.075 mg.

46. A method of contraception in female mammals according to claim 33, wherein the competitive progesterone antagonist (Z) -1 1 ß- [4-