Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1996-11-01
2001-05-01
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S171000, C514S178000, C514S179000, C514S180000, C514S843000
Reexamination Certificate
active
06225297
ABSTRACT:
This invention relates to a combination product that consists of individual dosage units of a competitive progesterone antagonist and, in addition, sequentially provided individual dosage units of a compound with gestagenic action, as well as its use for the production of contraceptives based on the inhibition of implantation (receptivity inhibition).
It is known that competitive progesterone antagonists (antigestagens=AG's), such as, e.g., RU 486 (mifepristones; 11&bgr;-[(4-N,N-dimethylamino)-phenyl]-17&bgr;-hydroxy-17&agr;-propinyl-4,9(10)-estradien-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 RU 486 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 RU 486 and Synthetic Progestin. Fertility and Sterility, 53/4, 747-750; 4) Ledger W. L. et al. (1992): Inhibition of Ovulation by Low Dose Mifepristone (RU 486). Human Reproduction, 7/7, 945-950; 5) Nieman L. K. et al. (1987): The Progesterone Antagonist RU 486: A New Potential New Contraceptive Agent. The New England Journal of Medicine, 316/4, 187-1991].
The implantation of a fertilized egg can also be prevented by AG's (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 C. P. et al. (1990): Effects of a Progesterone Antagonist, Ilopristone, On Induction of Menstruation, Inhibition of Nidation, and Termination of Pregnancy in Bonnet Monkeys. Biology of Reproduction, 43, 437-443; 8) Ishwad P. C. 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 M. C. et al. (1992): Delayed Endometrial Maturation Induced by Daily Administration of the Antiprogestin RU 486: A Potential New Contraceptive Strategy. AM. J. Obstet. Gynecol. 167/1, 60-65].
It should be possible to use AG's as contraceptives because of their ovulation-inhibiting action [3), 4), 5)] or implantation-inhibiting action [6), 7), 8), 9)]. The use of competitive progesterone antagonists in a non-ovulation-inhibiting as well as a non-abortion-inducing dose for the. production of oral contraceptives is described in International Patent Application WO-A 93/23020.
In addition, for gynecological applications, initial clinical studies have shown that AG's can be used for the treatment of endometriosis and leiomyomata uteri [10) Kettel L. M. et al. (1991): Endocrine Responses to Long-Term Administration of the Antiprogesterone RU 486 in Patients with Pelvic Endometriosis. Fertility and Sterility, 56/3, 402-407; 11) Kettel L. M. et al. (1993): Long-Term, Low-Dose RU 486 in the Treatment of Endometriosis. Meeting of the Society of Gynecological Investigation 1993, Abstract S-136; 12) Murphy A. A. et al. (1993): Regression of Uterine Leiomyomata in Response to the Antiprogestin RU 486, J. Clin. Endocrinol. Metab., 76/2, 513-517].
The findings of these studies indicate that in the case of chronic treatment with AG's over the entire menstrual cycle, but also in the case of treatment during specific cycle phases with AG's, the elimination of the progesterone action during the luteal phase of the cycle can lead to displacement or lengthening of the cycle with cessation of menstruation (amenorrhea) or weakened menstruation [8), 9), 10)].
Menstruation, however, means natural protection for the endometrium. In the normal menstrual cycle, in the follicle phase (proliferation phase) proliferation of the endometrium occurs under the action of estrogens. Subsequently, growth inhibition of the endometrium that is caused by progesterone takes place with conversion into a secretorily active endometrium in the luteal phase (secretion phase). At the end of this phase, menstruation of the endometrium occurs, during which portions of this tissue are shed.
If, however, during treatment with a competitive progesterone antagonist, the action of progesterone on the endometrium is completely blocked in the luteal phase, the proliferative influence of the estrogens on the endometrium predominates. In addition to stopping the conversion into a secretory endometrium and the thus deficient [10)] subsequent bleeding (induction of amenorrhea) or reduced bleeding [(8)] because of the so-called “unopposed estrogen effect,” long-term stimulation of the endometrium can result [13) Murphy A. A. et al. (1993): Endometrial Effect of a Long-Term, Low-Dose Administration of RU 486 in Cycling Women. Meeting of the Society of Gynecological Investigation 1993, Abstract S-138].
This can increase the risk of an endometrium hyperplasia or the development of an endometrial carcinoma [14) Galle P. C. and McRae M. A. (1992): Amenorrhea and Chronic Anovulation. Finding and Addressing the Underlying Cause. Postrad. Med., 92/2, 255-260; 15) Johansson ED. et al. (1981): Unopposed Endogenous Estrogens and the Incidence of Cancer in Female Reproductive Organs. Acta Obstet. Gynecol. Scand. Suppl., 101, 17-20].
The object of this invention is to improve the already known use of competitive progesterone antagonists for contraception based on receptivity inhibition in such a way that the undesirable actions do not occur or occur only to a slight extent during continuous treatment with competitive progesterone antagonists, such as, e.g., persistent amenorrhea, endometrial hyperplasia, etc., so that more efficient and more reliable treatment as well as better cycle control are ensured.
This object is achieved by the product according to the invention that contains in combination in a packaging unit individual dosage units of a competitive progesterone antagonist and individual dosage units of a gestagen for its sequential, oral administration, in which each individual dosage unit that contains the competitive progesterone antagonist contains the latter in a non-ovulation-inhibiting as well as non-abortion-inducing amounts.
The endometrium is transformed by the sequential administration of a gestagen during the pause in treatment with the competitive progesterone antagonist and converted into a secretorily active endometrium and thus prepared for bleeding—induced by the subsequent administration of the antigestagen.
A contraceptive method with sequential treatment with antigestagens for ovulation inhibition, followed by gestagen, has already been described [3)]. The dose that inhibits ovulation depends to a great extent on the species in question and for, e.g., RU 486 is 2-5 mg in women [Ledger W. L. et al., 4)].
In the contraceptively active combination product that is proposed according to the invention, the competitive progesterone antagonist is to be administered in a dose that is not ovulation-inhibiting. In this case, the progesterone antagonist inhibits, i.a., the development of endometrial glands, which must function in order for the implantation of a fertilized egg in the uterus to occur (thus inhibiting the receptivity of the endometrium), but does not interfere with ovulation. As a result, impairment of the ovarian cycle is avoided. After the receptive phase of the endometrium in the normal cycle, which is inhibited by competitive progesterone antagonists, the endometrium is again prepared by the gestagen—corresponding to the normal cycle in the luteal phase—for bleeding that is induced by the progesterone antagonists that are administered after the administration of gestagen (see Diagram 1).
In the normal cycle, two phases are distinguished: the proliferation phase
Chwalisz Kristof
Stockemann Klaus
Millen White Zelano & Branigan
Raymond Richard L.
Schering Akitiengesellschaft
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