Drug – bio-affecting and body treating compositions – Contraceptive – Female
Reexamination Certificate
1995-12-26
2002-03-26
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Contraceptive
Female
C514S170000, C514S171000, C514S182000
Reexamination Certificate
active
06362237
ABSTRACT:
This invention relates to the use of at least one compound with progesterone-antagonistic (PA) activity and at least one compound with antiestrogenic (AE) activity, each in a non-ovulation-inhibiting dosage in a single dosage unit, for the production of pharmaceutical agents for female contraception.
The pharmaceutical agents produced according to the invention exert their contraceptive action based on receptivity inhibition, by preventing nidation of a fertilized egg cell in the mucous membrane of the uterus, without ovulation or the cycle being disrupted.
Already all over the world, the use of oral contraceptives has developed into a business factor that cannot be ignored. Especially in view of the fact that the world population is continuing to shoot upward, further development of the hitherto proven methods for birth control is absolutely necessary.
The use of competitive progesterone antagonists in female birth control both in various animal species and in humans has been discussed for some years now, as can be found in the publications listed below, in which especially the use of RU 38 486 11&bgr;-[4-dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(1-propinyl)estra-4,9-dien-3-one; EP-A-0057115) has been cited in this connection:
Collins et al., Blockade of the Spontaneous Mid-Cycle Gonadotrophin Surge in Monkeys by RU 486; A Progesterone Antagonist or Agonist. J. Cli. Metab., 63: 1270-1276 (1986);
Croxatto, H. B., Salvatierra 1990 Cyclic Use of Anti-gestagens for Fertility Control. IIIrd International Symposium on Contraception, Heidelberg, Jun. 19-23, 1990;
Danford et al., Contraceptive Potential of RU 486 by Ovulation Inhibition. III. Preliminary Observations on Once Weekly Administration. Contraception 40: 195-200 (1989);
Kekkonen et al., Lähteoenmäki P 1990 Interference with Ovulation by Sequential Treatment with the Antiprogesterone RU 486 and Synthetic Progestin. Fertil Steril [Fertile Sterile] 53: 4747 (1990);
Puri et al., Gonadal and Pituitary Responses to Progesterone Antagonist ZK 98 299 During the Follicular Phase of the Menstrual Cycle in Bonnet Monkeys. Contraception 39(2): 227-243 (1989);
Puri et al., Contraceptive Potential of a Progesterone Antagonist ZK 98 734 {(Z)-11&bgr;-[4-(dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-hydroxy-1-propenyl)estra-4,9dien-3-one}: Effect on Folliculogenesis, Ovulation and Corpus Luteum Function in Bonnet Monkeys. In Moudgal et al., (eds) (1990).
The contraceptive effect of a progesterone antagonist is caused, on the one hand, by the ovulation-inhibiting action, and, on the other hand, by the direct effects on the endometrium.
In this connection, it should be mentioned that the dosage of a competitive progesterone antagonist that exerts an ovulation-inhibiting action depends very heavily on the respective competitive progesterone antagonist:
In the case of progesterone antagonists of the RU 486 type, these are little-dissociated compounds with a very strongly pronounced ovulation-inhibiting action.
Progesterone antagonists of the onapristone type are endometrium-specific (greatly dissociated) compounds that inhibit ovulation only at high dosages. Chronic treatment with such progesterone antagonists leads to retardation of the growth of the endometrium, in which case the ovarian and menstrual cycles are not disrupted. In the endometrium, this results in degeneration of endometrial glands and in compression of the stroma, so that the implantation of a fertilized egg is prevented (inhibition of receptivity).
The class of 11&bgr;-aryl- or 11&bgr;,19-arylene-substituted steroids is distinguished pharmacologically according to their strong progesterone- or glucocorticoid-antagonistic action. Thus, RU 468 can be used, on the one hand, to bring about a therapeutically-induced abortion (the human abortive dosage in combination with a prostaglandin is approximately 200-600 mg; EP-A 0 139 608), but also, on the other hand, via its antagonistic action on a glucocorticoid receptor, to treat Cushing's syndrome.
Another possible use of competitive progesterone antagonists for female birth control, the so-called “LH+2” treatment, is proposed by Swahn et al. [The Effect of RU 486 Administration During the Early Luteal Phase on Bleeding Pattern, Hormonal Parameters and Endometrium, Human Reproduction 5(4): 402-408 (1990)], by an ovulation-inhibiting RU 486 dosage unit being administered (luteal contraception) one time 2 days after the increase in the luteinizing hormone (LH) in the female menstrual cycle (this is generally on day 14, 15 or 16). Treatment with RU 486 in this portion of the menstrual cycle does not result in disruption of the cycle. At dosages above 1 mg/day, administration of RU 486 in other phases of the cycle results either in amenorrhea or in bleeding. This process has no practical importance, however, since determining the LH peak in a simple and precise manner still represents a problem.
Glasier et al. [Mefepristone (RU 486) Compared with High-Dose Estrogen and Progestogen for Emergency Postcoital Contraception, The New England J. of Med. 327: 1041-1044 (1992)] also describes the use of RU 486 for postcoital contraception (emergency postcoital contraception). The method shows a low level of side effects in addition to high effectiveness. An extension of the cycle occurred in a high percentage of women in this study. This effect can be attributed primarily to the antiovulatory action of RU 486.
In addition, WO 93/23020 describes that competitive progesterone antagonists in a dose that lies both below the abortive and ovulation-inhibiting dosage can be used for female birth control. Here, however, generally weekly or repeated and thus regular administration is necessary to achieve the desired effect.
EP-A 0 219 447 also describes what effects the daily administration of a progesterone antagonist triggers with respect to the endometrial differentiation state during the follicular phase or optionally also the luteal phase of the female cycle in a period of up to 4 days in a dosage of 10-200 mg. The changes in the endometrium that result in this connection are used with respect to the time of nidation for in vitro fertilization.
Batista et al. [Daily Administration of the Progesterone Antagonist RU 486 Prevents Implantation in the Cycling Guinea Pig. Am. J. Obstet. Gynecol. 165: 82-86 (1991)] also describes the use of RU 486 for female birth control, which in an ovulation-inhibiting dosage prevents nidation in guinea pigs by daily intake, precoitally and throughout the entire further cycle.
Kawano et al. [Effect of RU 486 on Glycogen Metabolism in Endometrium. Acta Obstetrica et Gynaecologica Japonica, 41: 1507-1511, (1989)] describes the influence of RU 486 at a dosage of 30 mg/kg of body weight on the endometrial glycogen metabolism in a rat model, so that successful egg implantation is disrupted. Administration is done, however, on day 2 or 4 of the pregnancy.
Hormonal control of implantation is species-dependent. In all mammals studied so far, the presence of ovarian progesterone is necessary for successful implantation. In the case of postcoitally ovariectomized rats and mice, which are substituted with progesterone, no implantation results, however, without the administration of estrogen (Finn C A, Porter D G [1975] Implantation of Ova [Chapter 6] and The Control of Implantation and the Decidual Reaction [Chapter 8]; In Finn C A and Porter [eds] The Uterus, Elek Science, London, pp. 57-73; 86-95). If estrogen is injected into this animal species, implantation of the blastocysts occurs immediately (delayed implantation model). These observations indicate that ovarian estrogen in the presence of progesterone induces implantation in rodents. It was already known that in guinea pigs and primates, ovarian estrogens are not essential for implantation. In the case of guinea pigs that were ovariectomized after mating, implantation takes place only after progesterone substitution (without additional
Chwalisz Kristof
Stöckemann Klaus
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
Webman Edward J.
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