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Methods of Contraception Verfahren Zur Empfängnisverhütung Methodes De Contraception

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Methods of Contraception Verfahren Zur Empfängnisverhütung Methodes De Contraception Europäisches Patentamt *EP000792152B1* (19) European Patent Office Office européen des brevets (11) EP 0 792 152 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 31/565, A61P 15/18, of the grant of the patent: A61P 15/00 14.04.2004 Bulletin 2004/16 // (A61K31/565, 31:565) (21) Application number: 95940773.5 (86) International application number: PCT/US1995/015131 (22) Date of filing: 21.11.1995 (87) International publication number: WO 1996/015794 (30.05.1996 Gazette 1996/25) (54) METHODS OF CONTRACEPTION VERFAHREN ZUR EMPFÄNGNISVERHÜTUNG METHODES DE CONTRACEPTION (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL EP-A- 0 659 432 WO-A-93/21926 PT SE WO-A-93/21927 WO-A-95/17194 WO-A-95/26730 (30) Priority: 22.11.1994 US 343383 • GUIAN CHEN, JUN RONG HUANG, JAMES (43) Date of publication of application: MAZELLA, LINDA TSENG: "Long-term effects of 03.09.1997 Bulletin 1997/36 progestin and RU 486 on prolactin and synthesis in human endometrial stromal cells" HUMAN (73) Proprietor: BALANCE PHARMACEUTICALS, INC. REPRODUCTION, vol. 4, no. 4, 1989, pages Pacific Palisades, CA 90272 (US) 355-358, XP000944177 • FERTILITY AND STERILITY, Vol. 53, No. 4, (72) Inventors: issued April 1990, KEKKONEN R. et al., • SPICER, Darcy V. "Interference With Ovulation by Sequential Pasadena, CA 91103 (US) Treatment With the Antiprogesterone RU486 and • PIKE, Malcolm Cecil Synthetic Progestin", pages 747-750, Long Beach, CA 90803 (US) XP000569448 • DANIELS, John R. • FERTILITY AND STERILITY, Vol. 60, No. 4, Pacific Palisades, CA 90272 (US) issued October 1993, KEKKONEN R. et al., "Sequential Regimen of the Antiprogesterone (74) Representative: Grünecker, Kinkeldey, RU486 and Synthetic Progestin for Stockmair & Schwanhäusser Anwaltssozietät Contraception", pages 610-615, XP000569447 Maximilianstrasse 58 80538 München (DE) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 792 152 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 792 152 B1 2 Description with exposure to the progestogen. [0007] PCT Patent Applications WO 93/21926 and [0001] This invention relates to methods useful for 93/21927 to Hodgen describes the protracted adminis- contraception in mammals, especially human females. tration of a progestogen, with administration of an anti- More particularly, the present invention is directed to 5 progestational compound on the 28th or 30th day of the contraceptive methods and methods of treating benign treatment cycle. The contraceptive compositions de- gynecological disorders which are effective for reducing scribed by Hodgen provides for an even greater number exposure to progestational agents. of days of exposure to the progestogen component than [0002] The first progestogen antagonist synthesized in the normal menstrual cycle. and tested was RU 486 [RU 38466; 17-hydroxy- 10 [0008] The breast has a tightly regulated pattern of 11-(4-dimethylaminophenyl)-17-(prop-1-ynyl)estra- growth primarily under the control of steroid hormones. 4,9-dien-3-one; beta-[(4-N,N-dimethylamino)-phenyl]- The effects of steroid hormones on the normal breast 17β-hydroxy-17α-propynyl-4,9(10)-oestradiene-3-one; are increasingly well understood. Estrogen induces mefepristone]. Mefepristone has high affinity for the pro- some breast epithelial proliferation, but estrogen and gesterone receptor, with predominantly antiprogesta- 15 progesterone together produce even greater cell prolif- tional effects. Mefepristone is known to have growth-in- eration [Pike, M.C. et al., Epidemiol. Rev. 15:17-35 hibitory effects in breast cancer cells in in vitro and in (1993)]. In non-pregnant premenopausal women the vivo preclinical studies and in human clinical trials [Klijn, breast epithelium undergoes repetitive periods of cell J. G. M. et al. Cancer Research 49:2851- 2856 (1989)]. proliferation and cell loss secondary to cyclic ovarian ac- Other antiprogestational agents have been synthesized 20 tivity. In the terminal duct lobular unit (TDLU) of the pre- and tested including ZK 98.299 (onapristone) and ZK menopausal breast, cell proliferation is low during the 112,993, which also have antitumor efficacy [Michna, H. follicular phase of the menstrual cycle. Following ovula- et al., J. Steroid Biochem. Molec. Biol. 43:203-210 tion, progesterone is produced by the corpus luteum and (1992)]. TDLU cell proliferation increases two- to three-fold over [0003] Mefepristone is known to be useful as a med- 25 follicular levels [Pike et al. (1993), supra]. Consistent ical abortifacient (because of its antiprogestational ac- with the breast cell proliferation rates, the size and tivities) and as a postcoital contraceptive. Mefepristone number of terminal ductules peak during the late-luteal has been evaluated as a potential contraceptive agent phase [Longacre, T.A. & Barlow, S.A., Am. J. Surg. Path. using several schedules. A single dose of mefepristone 10:382-393 (1986)]. If fertilization and pregnancy do not late in the menstrual cycle may be a useful contraceptive 30 ensue, progesterone levels fall, the rate of breast cell approach [Nieman. L. K. et al., N. Engl. J. Med. 316: division decreases, and a wave of cell death by apop- 187-191 (1987)]. tosis follows the peak in cell proliferation [Anderson, T. [0004] Protracted (i.e., 3 month) administration of 100 J. et al., Br. J. Cancer 46:376-382 (1982)]. mg per day mefepristone alone to premenopausal wom- [0009] Proliferating cell populations are more suscep- en has been shown to inhibit ovulation and ovarian pro- 35 tible to carcinogenic effects, and the rise in cancer risk gesterone production, while maintaining early follicular associated with cell proliferation is secondary to an in- phase levels of estradiol, estrone and testosterone [Ket- creased chance of mutation and loss of tumor suppres- tel, L. M. et al. Fertil. Steril. 56:402-407 (1991)]. These sor genes [Preston-Martin, S. et al., Cancer Res. 50: effects may be mediated through a progesterone ago- 7415-7421 (1990)]. Thus, breast cancer risk would be nist effect of mefepristone on the hypothalamic-pituitary 40 predicted to increase the greatest during periods of ex- unit, although other mechanisms are possible. posure to both estrogen and progestogen, as in the pre- [0005] Several new regimens of progesterone antag- menopausal period or in women receiving combined onists and progestins have been described. One such oral contraceptives (COCs); less during periods of ex- regimen [Kekkonen, R. et al, Fertil. Steril. 53:747-750 posure only to estrogen, as in postmenopausal women (1990)] consists of 25 mg of mefepristone on days 1 to 45 receiving estrogen replacement therapy (ERT) or in 14 of a 28-day treatment cycle followed by norethister- obese postmenopausal women; and least during peri- one on days 15 to 24 of the cycle. A subsequent report ods of exposure to very low levels of both hormones, as describes a regimen consisting of 25 mg of mefepris- in non-obese postmenopausal Asian women. tone on days 1 to 21 of a 31-day treatment cycle followed [0010] The heretofore-identified regimens comprising by norethisterone 5 mg per day or medroxyprogester- 50 administration of an antiprogestational agent in se- one acetate 5 mg per day taken on days 22 to 31 [Kek- quence with a progestogen are thus not entirely satis- konen, R. et al., Fertil. Sterril. 60:610-615 (1993)]. factory. In particular, they result in exposure to pro- [0006] These administration sequences are designed gestogens for a period of time similar to a norma men- to mimic the physiological secretion of steroids in the strual cycle, and to a similar or greater amount of pro- menstrual cycle, with a progestational steroid adminis- 55 gestational action. As such, they may result in a breast tered over a 10 day period following 14 to 21 days of cancer risk similar to or possibly greater than that of a administration of the progestogen antagonist. With such normal ovulating woman. a regimen, approximately 30% of days are associated [0011] U.S. Patent No. 5,211,952 describes adminis- 2 3 EP 0 792 152 B1 4 tration of a progestational agent every two months to six [0019] It is further preferred that said antiprogesta- months, with administration of a gonadotropin hormone tional agent is selected from the group consisting of releasing hormone and an estrogen. mefepristone, onapristone, ZK 112.993, Org 31710, Org [0012] EP-A-0659 432 discloses a sugar-coated dos- 33628, Org 31806, lilopristone, trilostane, epostane, age unit characterized in that it contains a composition 5 azastene and cyanoketone. comprising a steroid having two hydrogen atoms at po- [0020] It is also preferred that said antiprogestational sition 3 of the steroid skeleton, and a process for the agent is selected from the group consisting of mefepris- preparation of said dosage unit. tone, onapristone and ZK 112.993. [0013] WO-A-95-17194 discloses a composition and [0021] Furthermore, it is preferred that said first peri- use of it for a contraceptive comprising an estrogen se- 10 od of time is two to three months. lected from estradiol and ethinylestradid and a gestagen [0022] In addition, it is preferred that the second pe- selected from a group comprising levonorgestrel and riod of time is ten days to fifteen days. desogestrel, inter alia during a total period of time of [0023] Finally, it is preferred that the second period of 23-24 days. The individual dosage formulation contains time immediately follows or immediately precedes the a constant amount of estrogen and gestagen (see Ab- 15 first period of time.
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