Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the use of at least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (A ⁇ ) activity, in each case in non-ovulation-inhibiting dosage in a single dose unit, for the production of medicaments for female contraception.
• PA progesterone-antagonistic
• a ⁇ anti-estrogenic
• the medicaments produced according to the invention develop their contraceptive effect on the basis of the receptivity inhibition by preventing a fertilized egg from implanting in the uterine mucosa without disturbing the ovulation or the cycle.
• the contraceptive effect of a progesterone antagonist is due on the one hand to the ovulation-inhibiting effect and on the other hand to direct effects on the endometrium.
• RU 486-type progesterone antagonists are poorly dissociated compounds with a strong ovulation-inhibiting effect.
• Progesterone antagonists of the onapristone type are endometrium-specific (strongly dissociated) compounds that only inhibit ovulation at high doses. Chronic treatment with such progesterone antagonists leads to growth retardation of the endometrium, whereby the ovarian and menstrual cycle is not disturbed. In the endometrium, endometrial glands degenerate and the stroma is compressed, so that the implantation of a fertilized egg is prevented (inhibition of receptivity).
• RU 468 can be used for a therapeutically induced termination of pregnancy (the human abortive dose in combination with a Prostaglandin is 200-600 mg; EP-A 0 139 608), but on the other hand can also be used for the therapy of Cushing's syndrome due to its antagonistic effect on the glucocorticoid receptor.
• EP-A 0 219 447 describes the effects of daily administration of a progesterone antagonist during the follicular or, optionally, also the luteal phase of the female cycle in a period of up to 4 days in one dose of 10-200 mg with respect to the endometrial differentiation state.
• the resulting changes in the endometrium are used for in vitro fertilization with regard to the time of nidation.
• the hormonal control of the implantation depends on the species. In all mammals examined so far, the presence of ovarian progesterone is necessary for successful implantation. In postcoital ovariectomized rats and mice that are substituted with progesterone, there is no implantation without estrogen administration (Finn CA, Porter DG [1975] Implantation of ova [Chapter 6] and The control of implantation and the decidual reaction [Chapter 8] ; In Finn CA and Porter [eds] The Uterus, Elek Science, L.ondon, pp 57-73; 86-95). If estrogen is injected into these animal species, the blastocyst is immediately implanted (delayed implantation model).
• ovarian estrogen induces rodent implantation in the presence of progesterone. It was already known that in guinea pigs and primates, ovarian estrogens are not essential for implantation. In guinea pigs that were ovariectomized after mating, the implantation only takes place after progesterone substitution (without additional estrogen treatment) (Deansley R [1972] Retarded embryonic development and pregnancy termination in ovariectomized guinea pigs: progesterone deficiency and decidual collapse; J Reprod Fert [1972 ] 28: 241-247).
• DE-A 42 13 005 shows the use of aromatase inhibitors for contraception in female primates of reproductive age in a dosage at which the menstrual cycle of the female primate remains essentially unaffected.
• Aromatase inhibitors block the biosynthesis of estrogens from their metabolic precursors.
• the absolute amount of the daily doses required for the contraceptive effect depends entirely on the type of aromatase inhibitor used. For highly active aromatase inhibitors, the daily doses are usually between about 0.05 to about 30 mg. With less active aromatase inhibitors, the daily doses can also be higher.
• the present invention has for its object to provide a preparation for endometrial contraception (inhibition of endometrial receptivity, post-coital use, "need pill”), which does not show the undesirable side effect mentioned above and at the same time a higher contraceptive Security as the separate application of the corresponding individual components.
• a “need pill” is to be understood as an orally administered medicament which prevents a conception when it is preferably used once and precoitally as required.
• Such an agent, produced using only a competitive progesterone antagonist, is described in the unpublished German patent application P 44 38 820.9.
• At least one compound with progesterone-antagonistic (PA) and at least one compound with anti-estrogenic (A ⁇ ) activity are used together for the production of medicaments for female contraception.
• Agent containing at least one compound with antigestagenic and at least one compound with anti-estrogenic activity, in particular for induction of birth and termination of pregnancy and for the treatment of gynecological disorders, and the use of at least one compound with antigestagenic and at least one compound with anti-estrogenic activity for the production of medicaments for the indicated indications are already the subject of EP-A 0 310 541.
• compositions for post-coital fertility control which contain a competitive progesterone antagonist (antigestagen) and a progesterone and estrogen synthesis blocker, have already been described in US Pat. No. 4,670,426.
• Typical representatives of the competitive progesterone antagonist to be used are fluocrnolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17 acetal with acetone and IIß- [4- (dimethylamino) phenyl] -17ß- hydroxy-17 ⁇ - (l-propynyl) estra-4,9-dien-3-one (RU 38 486) and equivalent derivatives mentioned.
• the typical content is between 20 and 50 mg.
• Examples of the progesterone and estrogen synthesis blocker are aminoglutethimide, 4 ⁇ , 17 ⁇ -dimethyl-17ß-hydroxy-3-oxo-4 ⁇ , 5-epoxy-5 ⁇ -androstan-2-carbonitrile, 20.25-
• Diazocholesterol and compounds with equivalent activity are listed in a dose of 300 to 1000 mg.
• the composition must be used as early as possible within the first week after sexual intercourse over a period of 3 days; it is best to continue treatment for 2 to 6 days.
• the prevention of nidation and thus pregnancy is achieved by the synergistic effect when the two components of the composition are used together, with a success rate of the order of 90% or more.
• the main advantages of the present invention lie not least in the low dosage of the active ingredients, on the one hand due to the possible reduction in the effective amounts required for monotherapy due to the synergistic effect, and on the other hand through the use of lower, non-ovulation-inhibiting dosages.
• the cyclicality of the female menstrual cycle is in no way impaired (as caused by ovulation-inhibiting substances such as RU 486) and the organism is not burdened by unnecessarily high amounts of the competitive progesterone antagonist or the anti-estrogen.
• progesterone antagonist / anti-estrogen combination offers safe contraception, ie the regular use of such a medication (daily, regularly every 3 to 7 days) prevents the blastocyst from implanting without affecting the cycle. Furthermore, the contraceptive security is increased after a one-time, needs-based precoital intake regardless of the intake day in the cycle ("need pill") or after postcoital treatment.
• estrogen deprivation Due to the dose reduction of the anti-estrogen, estrogen deprivation is not to be expected. In this way, an endometrium-selective effect of the anti-estrogen can be achieved and an unfavorable effect due to estrogen deprivation on other organs, for example on the bone, can be avoided.
• the weight ratio of both components in the new drug can be varied within wide limits. Both the same amounts of PA and A ⁇ and an excess of one of the two components can be used. PA and A ⁇ are used together, separately, simultaneously in a weight ratio of essentially 50: 1 to 1:50, preferably 25: 1 to 1:25, and in particular 10: 1 to 1:10. Co-administration is preferred. PA and A ⁇ can preferably be applied in combination in one dose unit.
• the two components can be applied once a day or intermittently every 3-6 days over the entire cycle. They can also be used once precoitally (as required; "pill on demand") regardless of the time of the menstrual cycle or postcoitally. In the case of precoital use, the progesterone antagonist is dosed higher, but below the ovulation-inhibiting dose.
• progesterone receptor progestogen receptor
• progesterone antagonists All compounds which competitively block the effect of progesterone on the progestogen receptor (progesterone receptor) and which do not show their own progestogen activity are possible as competitive progesterone antagonists; the blockage can be brought about by the substance administered itself or by its metabolites.
• the competitive progesterone antagonists are preferably endometrium-specific (dissociated) compounds which at most have weak antiovulatory activity.
• Non-dissociated progesterone antagonists can also be used, in which case their Dosage is below the ovulation-inhibiting dose.
• the following steroids are possible:
• typical examples of competitive progesterone antagonists to be used according to the invention are: IIß- [4- (dimethylamino) phenyl] -17 ⁇ -hydroxy-17ß- (3-hydroxypropyl) -13 ⁇ -estra-4,9-dien-3-one (EP-A-0 129 499);
• the latter PAs are of the dissociated type, in which changes in the endometrium are observed at a certain threshold dose, while the ovulation (central effect) is not inhibited.
• the quotient of the ovulation-inhibiting and abortive dose (dissociation factor) can serve as a measure of the dissociation. Dissociated PAs are preferred in the context of the present invention.
• the competitive progesterone antagonists can, for example, be applied locally, topically, enterally, transdermally or parenterally.
• 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.
• vaginal suppositories, vaginal gels, implants, vaginal rings, intrauterine release systems (IUDs) or transdermal systems such as skin patches are suitable.
• One unit dose contains about 0.25 to 50 mg of llß- [4- (dimethylamino) phenyl] - 17 ⁇ -hydroxy-17ß- (3-hydroxypropyl) -13 ⁇ -estra-4,9-dien-3-one or a biologically equivalent Amount of another competitive progesterone antagonist. Effective amounts are determined in the niditation inhibition test on guinea pigs (treatment day 1-7 post coitum).
• the pharmaceutical agent produced according to the invention is applied by means of an implant, a vaginal ring, an IUD or a transdermal system, these application systems must be designed in such a way that the dose of the competitive progesterone antagonist released by them daily in this range of 0.25 to 50 mg lies.
• the dose of a competitive progesterone antagonist to be applied according to the invention can be in the non-ovulation-inhibiting and non-abortion-triggering dose range of the progesterone antagonist in question.
• the most suitable compounds having an anti-estrogen effect are estrogen antagonists (competitive anti-estrogens).
• Estrogen antagonists according to the present invention can either be derived from steroids or be non-steroidal compounds.
• Estrogen antagonists according to the present invention are only to be understood as those compounds which act as selectively as possible, i.e. which essentially only inhibit the effect of estrogens and / or lower their concentration. The estrogen antagonists work by displacing estrogen from the receptor.
• estrogen antagonists All common compounds with a competitive anti-estrogenic effect on the receptor can be considered as estrogen antagonists. They can be used in approximately the same amounts as the estrogen antagonists already on the market, that is to say the daily dose is about 5-100 mg for tamoxifen or the biologically equivalent amount of another estrogen antagonist.
• non-steroidal estrogen antagonists are: (Z) -N r N-dimethyl-2- [4- (1,2-diphenyl-l-butenyl) phenoxy] ethanamine (tamoxifen), l- [2- [4- (3,4-dihydro-6-methoxy-2-phenyl-l-naphthalinyl) phenoxy] ethyl] pyrrolidine hydrochloride ( ⁇ afoxidin), ⁇ .
• steroidal estrogen antagonists which may also be used are, for example: 17 ⁇ -ethynyl-11 ⁇ -methylestra-1,3,5 (10) -triene-3,17ß-diol and 16ß-ethyltra-1,3,5 (10) -triene-3, 17ß-diol,
• estrogen antagonists which act particularly strongly and as selectively as possible on the endometrium (for example tamoxifen, ifenafoxidin, 7 ⁇ - [9 - [(4, 4,5,5, 5-pentafluoropentyl) sulfinyl] nonyl] estral , 3,5 (10) -triene-3,17 ⁇ -diol).
• the threshold dose for endometrium-selective action is determined in ovariectomized, estradiol-substituted rats. Mitotic activity serves as a parameter (proliferation marker: PC ⁇ A).
• the threshold dose is the amount of the estrogen antagonist at which only an effect on the uterus, namely an inhibition of the estrogen-induced proliferation of the endometrium, is observed.
• Aromatase inhibitors in connection with progesterone antagonists can also be used as anti-estrogens according to the present invention.
• Aromatase inhibitors suppress the synthesis of estrogens from their precursors.
• the use of estrogen antagonists is preferred over that of aromatase inhibitors in any case, since the estrogen antagonists reduce the serum Do not affect estrogen concentration
• An A ⁇ dose unit contains 0.01-100 mg tamoxifen or a biologically equivalent amount of another anti-estrogenic compound.
• Progesterone antagonistic and anti-estrogenic compounds can e.g. B. locally, topically, enterally or parenterally.
• the progesterone antagonist and the anti-estrogen are preferably used in a common dosage unit.
• Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
• Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives mentioned above, can also be pressed separately into a two-layer tablet.
• Example 5 the active compounds according to the invention, each with half of the additives mentioned above, can also be pressed separately into a two-layer tablet.
• the solution is filled into an ampoule
• Tablet press is manufactured. If appropriate, the active compounds according to the invention, each with half of the additives indicated above, can also be pressed separately into a two-layer tablet.
• the experiments were carried out on intact guinea pigs with a normal cycle. Treatment started on day 1 post coitum. The animals were treated with vehicle (benzyl benzoate / castor oil) or the tamoxifen in a dose of 0.3, 1, 3 mg / day animal or the progesterone-antagonistically active compound onapristone (0.3, 1.0, 3.0 mg / Day / animal), each alone, or treated with a combination of both compounds. The substances were applied subcutaneously. The number of implantation sites on day 12 post coitum serves as a parameter.
• Tamoxifen 0.5 mg leads to a significant increase in effectiveness (synergism).
• Receptivity inhibition means a complete avoidance of

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