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~" ' MM II II II MM Mill Ml II MM II J European Patent Office _ _ _ B« © Publication number: 0 309 263 B1 Office_„. europeen des brevets

EUROPEAN PATENT SPECIFICATION

© Date of publication of patent specification: 09.03.94 © Int. CI.5: A61 K 31/565

© Application number: 88308840.3

@ Date of filing: 23.09.88

© Hormone composition and use.

© Priority: 24.09.87 CA 547743 © Proprietor: JENCAP RESEARCH LIMITED 24.09.87 CA 547744 354 Walmer Road Toronto, Ontario M5R 2Y4(CA) @ Date of publication of application: 29.03.89 Bulletin 89/13 @ Inventor: Casper, Robert F., 6-240 Eaton North Toronto General Hospital, 200 Elizabeth © Publication of the grant of the patent: Street 09.03.94 Bulletin 94/10 Toronto, Ontario M5G 2C4(CA)

© Designated Contracting States: AT BE CH DE ES FR GB GR IT LI LU NL SE © Representative: Jones, Helen Marjorie Mer- edith et al (se) References cited: Gill Jennings & Every, EP-A- 0 253 607 DE-A- 2 253 916 Broadgate House, DE-A- 2 645 307 FR-A- 2 589 735 7 Eldon Street GB-A- 2 096 462 US-A- 3 568 828 London EC2M 7LH (GB) US-A- 4 291 028 US-A- 4 292 315

Rote Llste, 1987, Editlo Cantor, Aulendorf, Wurttemberg, DE, no. 75 157

Rote Llste, 1987, Editio Cantor, Aulendorf, Wurttemberg, DE, no. 75 154, no. 75 156

00 Unlisted Drugs., vol. 38, no. 1, January 1986, US CO p. 2, Chatham, N.J., CO CM Chemical Abstracts, vol. 83, 1975, no. 72528q o> o CO 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). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) EP 0 309 263 B1

Med. Akt. 8 (1982), p. 418

New England J. of Medicine, 304 (March 5) 1981, pp. 560-563

Unlisted Drugs, vol. 22, no. 10, October 1970, p. 149

Unlisted Drugs, vol. 25, no. 10, October 1973, p. 160

Unlisted Drugs, vol. 26, no. 11, November 1974, p. 170

Unlisted Drugs, vol. 28, no. 2, Febr. 1976, p. 26

Current thep. Res. 12 (1970) 4, 177 & WB 1970, 11, 20

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Description of to the less potent estrone. A complex interaction occurs between This invention is concerned with a hormone and or progestin in the human en- replacement formulation which employs a combina- dometrium with the progestins acting as anti-es- tion of estrogen and progestin and wherein a short 5 trogens. Estrogen and progestin interactions are period of relatively dominant estrogenic activity al- also dynamic. For example, estrogen administration ternates with a short period of relatively dominant increased the concentration of both estrogen and progestagenic activity for hormonal replacement progestin receptors to peak levels, 7 times above therapy for menopausal or castrate women. baseline, within 3 days (see Ekert, R.L. and Kat- In the luteal phase of the menstrual cycle, io zenellenbogen, B.S. Human Endometrial Cells in serum progesterone levels increase and pro- Primary Tissue Culture: Modulation of the Pro- gesterone mediated secretory changes occur in the gesterone Receptor Level by Natural and Synthetic uterine endometrium. The presence of pro- In Vitro, J. Clin Endocrinol Metab. gesterone receptors has been shown to be a nec- 52:699, 1981). A three-fold increase in receptor essary prerequisite for progesterone action in the 75 concentrations occurred within one day. Normal endometrium (see Walters, M.R. and Clark, J.H. physiologic levels of progesterone in the first 3 Relationship between the quantity of progesterone days of the luteal phase resulted in a rapid and receptors and the antagonism of estrogen-induced significant decrease in estrogen receptor number uterotropic response Endocrinology 105:382, 1979) (see Kreitmann-Gimbal, B., Bayard, F., Nixon, W.E. and it is well documented that estrogen priming in 20 and Hodgen, G.D. Patterns of Estrogen and Pro- the follicular phase of the cycle is responsible for gesterone Receptors in Monkey Endometrium Dur- the development of both estrogen and pro- ing the Normal Menstrual Cycle, 35:471, gesterone receptors (see Bayard, F., Damilano, S., 1980). Exogenous administration of progesterone to Robel, P. and Baulien, E.E. Cytoplasmic and nu- cynomolgous macaques significantly suppressed clear estradiol and progesterone receptors in hu- 25 estrogen receptors within 1 to 2 days (see West, man endometrium, J. Clin Endocrinol Metab. N.B. and Brenner, R.M. Progesterone-Mediated 46:635, 1978). On the other hand, progesterone Suppression of Estradiol Receptors in Cynomol- exerts a negative feedback effect on its own recep- gous Macaque Cervix, Endometrium and Oviduct tor (see Tseng, L. and Gurpide, E. Effects of pro- During Sequential Estradiol-Progesterone Treat- gestins on estradiol receptor levels in human en- 30 ment, J. Biochem. 22:29, 1985) and dometrium, J. Clin Endocrinol Metab. 41:402, medroxy-progesterone acetate was able to signifi- 1975) and also acts to downregulate endometrial cantly suppress progestin receptor levels in estrogen receptors possibly by induction of an es- premenopausal women within 4 hours (see trogen receptor regulatory factor (see Leavitt, Neumannova M., Kauppila, A., Kivinen, S. and W.W., Okulicz, W.C., McCracken, J.A., Schramm, 35 Vihko, R. Short-Term Effects of , W.S. and Robidoux, W.F. Jr. Rapid recovery of Medroxy-progesterone Acetate, and Their Combi- nuclear estrogen receptor and oxytocin receptor in nation on Receptor Kinetics and 17beta-Hydrox- the ovine uterus following progesterone withdrawal, ysteroid Dehydrogenase in Human Endometrium, J. Steroid Biochem. 22:686, 1985). Obstet. Gynecol. 66:695, 1985). In contrast, pro- These physiologic changes can be reproduced 40 gesterone withdrawal in the presence of constant pharmacologically as shown by the induction of estrogen levels has been shown to result in rapid estrogen and progestin receptors in post- (6 to 12 hours) recovery of nuclear estrogen recep- menopausal women by the administration of ethinyl tors in sheep endometrium, associated with an estradiol (see Kreitmann, B., bugat, R. and Bayard, estrogen induced biological response, i.e. produc- F. Estrogen and Progestin Regulation of the Pro- 45 tion of oxytocin receptors (see Leavitt, W.W., gesterone Receptor Concentration in Human En- Okulicz, W.C., McCracken, J.A., Schramm, W.S. dometrium, J. Clin Endocrinol Metab. 49:926, and Robidoux, W.F. Jr. Rapid recovery of nuclear 1979). Neumannova et al (see Short-Term Effects estrogen receptor and oxytocin receptor in the of Tamoxifen, Medroxy-progesterone Acetate, and ovine uterus following progesterone withdrawal, J. Their Combination on Receptor Kinetics and 50 Steroid Biochem. 22:686, 1985). A similar phenom- 17beta-Hydroxysteroid Dehydrogenase in Human enon occurs in pregnant guinea pigs when es- Endometrium, Obstet. Gynecol. 66:695, 1985) have trogen levels rise relative to progesterone levels also demonstrated that administration of medroxy- prior to parturition (see Alexandrova, M. and Soloff, progesterone acetate in estrogen-primed women M.S. Oxytocin receptors and parturition in the guin- decreases the concentration of endometrial pro- 55 ea pig, Biol. Reprod. 22:1106, 1980). gestin receptors while at the same time increasing Therefore, it appears that estrogen acts to the activity of 17beta-hydroxysteroid de- stimulate both estrogen and progestin receptor hydrogenase, an enzyme which is responsible for concentrations and to induce sensitivity of the en-

3 3 EP 0 309 263 B1 4 dometrium to both estrogen and progestin. Pro- makes these pills vulnerable to drug interactions or gesterone or progestin exerts an anti-estrogen ac- missed pills which may lead to breakthrough ovula- tion by decreasing estrogen receptors and by in- tion. The beginning of the package is the critical creasing 17beta-hydroxysteroid dehydrogenase ac- time in terms of breakthrough ovulation since the tivity in endometrial tissue. However, it appears that 5 user has just completed a 7 day drug-free interval the stimulatory effects of progesterone on human during which follicular development may begin. endometrial function are of short duration probably Even if does not occur, breakthrough because of a self-provoked downregulation of pro- ovulation can lead to poor cycle control. gestin receptors and estrogen receptors. For exam- Estrogen replacement therapy is warranted in ple, the effect of progesterone on 17beta-hydrox- io menopausal women for several reasons. Estrogen ysteroid dehydrogenase peaks at 3 days and is replacement will relieve hot flushes and this relief then followed in 2 to 3 weeks by suppression of the of flushes and night sweats improves sleep pat- enzyme (see Whitehead, M.I., Townsend, P.T., terns and contributes to the patient's general feel- Pryse-Davies, J. et al. Effects of estrogens and ing of well-being (see Campbell S., Whitehead M.I. progestins on the biochemistry and morphology of is Estrogen therapy and the menopausal syndrome. the postmenopausal endometrium, N. Engl, J. Med In Clinics in Obstetrics and Gynecology: Volume 4. 305:1599, 1981). The Menopause. Edited by R.B. Greenblatt, J.W.W. Currently on the market there are a number of Studd, London, W.B. Saunders, 1977, pages 31-47; contraceptive formulations which can be classified Erlik Y., Tataryn I.V., Meldrum D.R. et al. Associ- readily into several general types. The first of these 20 ation of waking episodes with menopausal hot are known as monophasic formulations. These con- flushes. JAMA 24:1741, 1981). Estrogen replace- tain a constant amount of estrogen and progestin. ment protects against postmenopausal loss of cal- Nuisance side effects with these pills depend on cium from the skeleton, especially from vertebral the balance between the estrogen and progestin bodies, preventing crush fractures and loss of body component of the pill. For example, with a rela- 25 height (see Lindsay R., Hart D.M., Forrest, C. et al. tively dominant progestin pill, the formulation will, Prevention of spinal osteoporosis in oophorec- over time, result in a depletion of both estrogen tomized women. Lancet 2:1151, 1980). Several and progestin receptors. The result which might be studies have now reported that long-term estrogen expected is an understimulated or atrophic en- therapy is also associated with a reduction in the dometrium which may eventually cause either on- 30 incidence of classical osteoporotic fractures of the pill amenorrhea or breakthrough bleeding or spot- forearm and hip (see Hutchinson, T.A., Polansky, ting due to poor epithelialization. On the other S.M., Finestein, A. Postmenopausal estrogens pro- hand, with a relatively dominant estrogenic prep- tect against fractures of hip and distal radius. Lan- aration, it is possible that prolonged use could cet 2:706, 1979; Paganini-Hill, A., Ross, R.K., Ger- result in endometrial growth with the development 35 kins, V.R., et al. A case control study of meno- of unsupported fragile stroma and subsequent pausal estrogen therapy in hip fractures. Annals of spotting or breakthrough bleeding. Internal Medicine 95:28, 1981; Weiss N.S., Ure Newer formulations known as triphasics have C.L., Ballard J.H. et al. Decreased risk of fractures varying levels of estrogen and progestin; in most of the hip and lower forearm with postmenopausal cases consisting of relatively constant levels of 40 use of estrogen. New England Journal of Medicine estrogen with a step-wise increase in progestin 303:1195, 1980). Another beneficial effect of long- throughout the cycle. This pattern of estrogen and term estrogen use is the reduction of the risk of progestin administration results in a relatively domi- death from ischemic heart disease probably me- nant estrogenic formulation at the beginning of the diated by changes in blood lipoprotein concentra- package with increasing progestagenic activity to- 45 tions (see Ross R.K., Paganini-Hill A., Mack T.M. et ward the end of the package. Endometrial stability al. Menopausal estrogen therapy and protection may be better with these pills since the estrogenic from ischemic heart disease. Lancet 1:858, 1981). activity at the beginning of the package induces Estrogen replacement has also been shown to im- both estrogen and progestin receptors making the prove the vascularity and health of the vaginal endometrium sensitive to the increased levels of 50 mucosa and urinary tract. The only major risk fac- progestin towards the end of the package. The tor associated with estrogen administration in the progestin activity produces denser, more stable doses required to relieve menopausal symptoms, is endometrial stroma although the relatively long du- hyperstimulation of the endometrium and an in- ration of progestin exposure, toward the end of the creased risk of endometrial cancer (see Cramer package, may still lead to decreased estrogen and 55 D.W., Knapp R.C. Review of epidemiologic studies progestin receptors and activity. A significant prob- of endometrial cancer and exogenous estrogen. lem with this type of formulation is the low dose of Obstetrics and Gynecology 54:521, 1979; Shapiro steroids at the beginning of the package which S., Coughman D.W., Sloan D., et al. Recent and

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past use of conjugated estrogens in relation to osteoporosis in oophorectomized women. Lancet adenocarcinoma of the endometrium. New England 2:1151, 1980). However, concerns have been ex- Journal of Medicine 303:485, 1980). pressed about the potential adverse effects of pro- Estrogens predispose to cancer of the en- gestin in suppressing high density lipoprotein cho- dometrium by stimulating cell mitosis and prolifera- 5 lesterol concentrations (see Hirvonen E., Malkonen tion and increasing the levels of DNA synthesis and M., Manninen V. Effects of different nuclear estradiol receptors in the endometrium (see on lipoproteins during postmenopausal replace- Whitehead M.I., Townsen P.T., Pryce-Davies J., et ment therapy. New England Journal of Medicine al. Effects of estrogens and progestins on the bio- 304:560, 1981). This cholesterol fraction appears to chemistry and morphology of the postmenopausal io have a protective effect against ischemic heart endometrium. New England Journal of Medicine disease and atherosclerosis. The lowering of HDL 305:599, 1981; Whitehead M.I., Townsen P.T., cholesterol by progestin could negate the long- Pryce-Davies J., et al. Actions of progestins on the term beneficial effects of estrogen in reducing the morphology and biochemistry of the endometrium incidence of myocardial infraction. Other side ef- of postmenopausal women receiving low dose es- 15 fects of progestins include acne, breast tenderness, trogen therapy. American Journal of Obstetrics and depression and irritability (see Barranco V.P. Effect Gynecology, 142:791, 1982). of dominant and estrogen dominant oral The addition of a progestin for 13 days each contraceptives on acne. Cutis 14:384, 1974; Royal month has been demonstrated to protect the en- College of General Practioners. Oral Contraceptives dometrium from these stimulatory effects of es- 20 and Health: An Interim Report. New York: Pitman, trogen (see Gambrill R.D., Jr., Massey F.M., 1974). Since the side effects of progestins appear Castaneda et al. Use of the challenge to be dose dependent, the dose of progestin used test to reduce the risk of endometrial cancer. Ob- with postmenopausal estrogen replacement should stetrics and Gynecology 55:732, 1980; Studd be the minimum necessary to achieve endometrial J.W.W., Thorn M.H., Patterson M.E.L., Wade-Evans 25 protection, (see Padwick M.L., Pryce-Davies J., T. The prevention and treatment of endometrial Whitehead M.I. A simple method for determining pathology in postmenopausal women receiving ex- the optimal dosage of progestin in postmenopausal ogenous estrogens. In: Pasetto N., Paoletti R., Arm- women receiving estrogens. New England Journal bus J.L., Editors. The menopause and post- of Medicine 315:930, 1986). menopause. Lancester MPT Press. 127,1980). 30 The biological effects of both estrogen and The addition of a progestin protects the en- progestin in target tissues such as the en- dometrium by reducing nuclear estradiol receptor dometrium are dependent on the levels of estrogen concentration and thereby decrease nuclear es- and progestin receptors. Both estrogen and pro- trogen bioavailability resulting in an antimitotic ef- gestins exert a modulating influence on the levels fect and lowering DNA synthesis. Progestins also 35 of their own receptors. For example, in the luteal increase the activity of endometrial estradiol-l7beta- phase of the menstrual cycle, serum progesterone dehydrogenase, an enzyme which metabolizes es- levels increase and progesterone mediated secre- tradiol to estrone, a less potent estrogen (see tory changes occur in the uterine endometrium. Whitehead M.I., Townsen P.T., Pryce-Davies J. Ef- The presence of progesterone receptors has been fects of estrogens and progestins on the biochem- 40 shown to be a necessary prerequisite for pro- istry and morphology of the postmenopausal en- gesterone action in the endometrium (see Walters dometrium. New England Journal of Medicine. M.R. and Clark J.H. Relationship between the 305:1599, 1981; King R.J.B., Townsen P.T., Sittle quantity of progesterone receptors and the antago- N.C., et al. Regulation of estrogen and pro- nism of estrogen-induced uterotropic response. En- gesterone receptor levels in epithelium and stroma 45 docrinology 105:382, 1979) and it is well docu- from pre and postmenopausal endometria. Journal mented that estrogen priming in the follicular phase of Steroids and Biochemistry, 16:21, 1982; Gurpide of the cycle is responsible for the development of E. Enzymatic modulation of hormonal action at the both estrogen and progesterone receptors (see Ba- target tissue. Journal of Toxicology and Environ- yard F., Damilano S., Robel P. and Baulieu E.E. mental Health, 4:249, 1978). The addition of pro- 50 Cytoplasmic and nuclear estradiol and pro- gestin to estrogen replacement therapy may also gesterone receptors in human endometrium. Jour- result in an increase in bone mass when started nal Clinical Endocrinology and Metabolism 46:635, within 3 years of the menopause (see Nachtigall 1978). On the other hand, progesterone exerts a L.E., Nachtigall R.H., Nachtigall R.D., et al. Es- negative feedback effect on its own receptor (see trogen replacement therapy: A 10 year prospective 55 Tseng L. and Gurpide E. Effects of progestins on study in relationship to osteoporosis. Obstetrics estradiol receptor levels in human endometrium. and Gynecology 53:277, 1979; Lindsay R., Hart Journal Clinical Endocrinology and Metabolism D.M., Forrest C, et al. Prevention of spinal 41:402, 1975) and also acts to downregulate en-

5 7 EP 0 309 263 B1 8 dometrial estrogen receptors possibly by induction stetrics and Gynecology. 90:171, 1983), of an estrogen receptor regulatory factor (see The present invention provides a hormone re- Leavitt W.W., Okulicz W.C., McCracken J.A., placement product containing estrogen and pro- Schramm W.S. and Robidoux W.F., Jr. Rapid re- gestin as a combined preparation for administering covery of nuclear estrogen receptor and oxytocin 5 a plurality of unit dosages of a relatively dominant receptor in the ovine uterus following progesterone estrogen activity combination and for administering withdrawal. Journal Steroid Biochemistry 22:686, a plurality of unit dosages of a relatively dominant 1985). progestin activity combination in which the unit Current hormonal replacement consists of con- dosages are arranged for the administration to a tinuous (daily or cyclic) (example day 1-25 of each io female in need of hormone replacement therapy month) estrogen administration with the addition of continuously and consecutively alternately of a a progestin for 10-13 days (example days 13-25) number of unit dosages of the relatively dominant each month. This type of replacement regimen is estrogen activity combination and of a number of effective in preventing menopausal symptoms and unit dosages of the relatively dominant progestin at the same time, protects the endometrium against is activity combination, each said number of unit dos- the development of hyperplasia or adenocarcino- ages consisting of 1 to 5 unit dosages. ma. However, the cyclic administration of a pro- Each of said numbers of unit dosages is pref- gestin leads to a scheduled withdrawal bleed or erably 2 to 4 and most preferably 3 unit dosages. period in 65-75% of women (see Hellberg D., Nils- The product may be presented in the form of son S. Comparison of a triphasic es- 20 packages each containing 20 to 35 unit dosages. tradiol/ acetate preparation with and The female treated by the invention by hor- without estriol component in the treatment of cli- mone replacement therapy is for instance of child macteric complaints; Maturitas 5:233, 1984; bearing age or older in whom ovarian estrogen and Christensen M.S., Hagen C, Christiansen C, Tran- progesterone production has been interrupted ei- sbol I. Dose response evaluation of cyclic estro- 25 ther because of natural menopause, surgical, radi- gen/gestagen in postmenopausal women: Placebo ation or chemical ovarian ablation of extirpation or controlled trial of its gynecologic and metabolic premature ovarian failure. actions. American Journal of Obstetrics and Gyne- The invention also provides the new use of cology. 144:873, 1982). This withdrawal bleeding is estrogen and progestin in the manufacture of the usually not welcomed by the patient and can lead 30 new product. to problems with compliance. Also because the Thus, in the present disclosure, a formulation is progestin administration is preceded by up to 13- described that is better able to protect the en- 16 days of unopposed estrogen therapy with en- dometrium against the estrogen related risk of en- dometrial proliferation and estrogen and progestin dometrial hyperplasia and adenocarcinoma with a receptor induction, it is possible that a high dose of 35 lower dose of progestin by administering progestin progestin is required to antagonize these effects for a short period of time alternating with a short resulting in a greater chance of side effects and period of absent or reduced progestin. It has been adverse metabolic effects. Newer continuous low demonstrated that a protective effect of progestin is dose estrogen and progestin regimens for hor- related to the duration of administration with 12-13 monal replacement may avoid the problem of with- 40 days per month appearing to be the minimum drawal bleeding (see Magos A.L., Brincatt M., required for greatest protection. The present for- O'Dowd T., et al. Amenorrhea and endometrial mulation administers a low dose of progestin inter- atrophy following continuous oral estrogen and pro- mittently throughout the month for a minimum of gestogen therapy in postmenopausal women. 15 days exposure. Maturitas 6:145, 1984). However, daily administra- 45 The present invention provides a pharmaceuti- tion of a progestin in these regimens induces de- cal preparation for administration to a female of pletion of both estrogen and progestin receptors child bearing age or older in whom ovarian es- resulting in endometrial atrophy which may be as- trogen and progesterone production has been inter- sociated with breakthrough bleeding. Since abnor- rupted either because of natural menopause, sur- mal bleeding in a postmenopausal woman is known 50 gical, radiation, or chemical ovarian ablation or ex- to be associated with endometrial carcinoma, it tirpation or premature ovarian failure, which com- must be investigated by endometrial sampling for prises a plurality of unit dosages, each unit dosage hypertrophy usually by D&C. Daily administration for continuous consecutive daily administration and of a progestin also raises the concern that the comprising combinations of estrogen and progestin favourable effects of estrogen on HDL cholesterol 55 selected from a combination with relatively domi- metabolism will be adversely affected with a fall in nant estrogen activity and a combination with rela- HDL cholesterol (see Notelovitz M., Gudat J.C., tively dominant progestin activity, with a plurality of Ware M.D., Dougherty M.C. British Journal of Ob- dominant estrogen dosages being alternated with

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plurality of dominant progestin dosages, and each ethinyl estradiol, mestranol and quinestranol. Par- unit dosage also comprising a pharmaceutically ticularly of interest are 17alpha- and acceptable inert carrier when required. esters and ethers thereof. The preferred estrogen In another aspect, the invention provides the is 17alpha-ethinylestradiol. The natural estrogens use of estrogen and progestin in a method of 5 may include, for example, conjugated equine es- manufacture of a product for use in a method of trogens, 17-beta-estradiol, estradiol valerate, es- hormonal replacement therapy for administration to trone, piperazine estrone sulphate, estriol, estriol a female in need of such treatment, in particular to succinate and polyestrol phosphate. a female of child bearing age or older to whom The progestin component may be any pro- ovarian estrogen and progesterone production has io gestationally active compound. Thus, the progestin been interrupted either because of natural meno- may be selected from progesterone and its deriva- pause, surgical, radiation, or chemical ovarian abla- tives such as, for example, 17-hydroxy pro- tion or extirpation or premature ovarian failure, gesterone esters, 19-nor-17-hydroxy progesterone which comprises administering continuously and esters, 17alpha-ethinyltestosterone and derivatives consecutively, in daily sequence, alternately of a is thereof, 17alpha-ethinyl-19-nor- and number of relatively dominant progestin activity derivatives thereof, norethindrone, norethindrone unit dosages and of a number of the dominant acetate, ethynodiol diacetate, , estrogen activity unit dosages, each said number of medroxy-progesterone acetate, norethynodrel, al- unit dosages consisting of 1 to 5 unit dosages. lylestrenol, lynoestrenol, fuingestanol acetate, The hormonal replacement formulation of the 20 , norgestrienone, dimethiderome, present invention results in the absence of with- , , laevo-, d-nor- drawal bleeding; intermittent increases in estrogen gestrel, dl-norgestrel, d-17alpha-acetoxy-13beta- activity; and stimulation of endometrial growth and ethyl-1 7alpha-ethinyl-gon-4-en-3-one oxime, progestin receptors. This makes the endometrium , , and more sensitive to subsequent progestin activity 25 . Preferred progestins are norethin- which limits growth by decreasing estrogen recep- drone, d-norgestrel and norgestimate. tors and increasing 17beta-hydroxysteroid de- In the invention, the plurality of dosages may hydrogenase. Interaction of progestin with pro- comprise from one to five unit dosages, but prefer- gestin receptors induces secretory changes in the ably three unit dosages are employed. Thus, in a endometrium which results in a denser stroma and 30 preferred form of the invention, three unit dosages endometrial stability. A return to relatively dominant of relatively dominant estrogen activity are alter- estrogenic activity then again stimulates estrogen nated with three unit dosages of relatively dominant and progestin receptors and renews endometrial progestin activity. sensitivity to progestin. This push/pull activity Generally, the quantities of estrogen and pro- keeps endometrial activity with a narrow range de- 35 gestin incorporated in the formulation of the inven- pending on the number of days of estrogenic and tion are dependent on the type of estrogen or progestagenic activity and maintains a stable en- progestin selected. However, the quantities em- dometrium resulting in the absence of break- ployed are generally less than those used in the through or withdrawal bleeding. currently marketed formulations for reasons men- This hormonal replacement formulation allows 40 tioned earlier. In the present formulation, the es- better progestational effects with less progestin. trogen level is kept constant, while the progestin With current formulation the dose of progestin is level is adjusted up or down to produce the re- significantly decreased compared with a prepara- quired estrogen or progestin dominance. The se- tion containing constant daily administration of a lection of quantity is dependent on the type of progestin. A total steroid dosage is achieved which 45 estrogen or progestin since each hormone has its is similar to or even lower than that of the present own specific activity. cyclic method of administering estrogen and pro- Typically in the hormone replacement formula- gestin for hormonal replacement therapy of ovarian tions, the amount of estrogen per unit dose may failure. A reduction in progestin dosage results in range from a minimum of about 0.3 mg of estrone less negative impact on HDL cholesterol levels. 50 sulphate or its equivalent to a maximum of about HDL cholesterol is increased by estrogen and de- 2.5 mg of estrone sulphate or its equivalent. The creased by progestin. amount of progestin per unit dosage may range The estrogens which may be employed as a from a minimum of 0 mg to a maximum of about 5 component in the regimens of this invention may mg of norethindrone or its equivalent. (These be any of those conventionally available. Typically, 55 amounts generally refer to oral dosages.) the estrogen may be selected from the group com- Some preferred combinations include the fol- prising synthetic and natural estrogens. The syn- lowing: thetic estrogens may be sleeted from, for example,

7 11 EP 0 309 263 B1 12

1. Three units dosages of 0.75 mg piperazine packaged in accordance with the chosen regimen. estrone sulphate alternating with three unit dos- In the oral form of the formulation, the unit ages of 0.75 mg of piperazine estrone sulphate dosages are preferably produced in the form of a with 0.35 mg of norethindrone. pharmaceutical kit or package, with the daily dos- 2. Three unit dosages of 0.75 mg piperazine 5 ages arranged for proper sequential administration. estrone sulphate and 0.15 mg of norethindrone Thus, in another aspect, the present invention also alternating with three unit dosages of 0.75 mg of provides a pharmaceutical package which contains piperazine estrone sulphate and 0.35 mg of combination-type unit dosages in multiple dosage norethindrone. units in a synchronized, fixed sequence, wherein The above combinations may also be grouped io the sequence or arrangement of the dosage units into three's and four's, starting with either three or corresponds to the stages of daily administration. four day groups and ending with the other. For the This can be known as a multi-preparation pack. hormone replacement therapy it may be advanta- Preferably, such packages are in the form of a geous for the groups of dominant estrogen activity transparent package with twenty-eight dosage units combination to comprise one more unit dosage is arranged sequentially. than the dominant progestin activity combination Preferably the tablets containing the hormones unit dosages, or vice versa, for instance the num- are different colours or shapes. Data indications bers in the groups being 2 and 3 or 3 and 4. may be provided on the packaging. The packaging The formulations of the invention may be ad- may be a tube or box or a strip. The box may be ministered orally, preferably in tablet form, paren- 20 circular, square, or otherwise shaped with the tab- teral^, sublingually, transdermal^, intravaginally, lets being accommodated separately therein for intranasally or buccally. The method of administra- ease of administration. Date indications may ap- tion determines the types of estrogens and pro- pear adjacent each tablet corresponding with the gestins useful in the formulation, as well as the days on which each tablet is to be taken. Some amounts per unit dosage. 25 indication of the sequence in which the tablets are Methods for transdermal administration includ- to be taken preferably appears on the packaging ing the associated methods for manufacturing such regardless of its form. systems are well known in the art. In this connec- In the following examples, specific embodi- tion, reference may be had to U.S. Patents Nos. ments of the present invention are set forth. These 4,752,478, 4,685,911, 4,438,139 and 4,291,014. 30 are meant to be illustrative of the invention. All Generally speaking, the formulations are pre- parts and percentages are by weight, unless in- pared according to conventionally known proce- dicated otherwise. dures in accordance with the method of administra- Examples Illustrating the Hormone-Replace- tion. Thus, the active ingredients are prepared ac- ment Therapy. cording to known methods in a pharmaceutically 35 acceptable form for administration. These ingre- EXAMPLE 1 dients, in their required quantities are combined with the appropriate pharmaceutical carriers such Three-day phases of unit dosages of 0.75 mg as additives, vehicles and/or flavour ameliorating piperazine estrone sulphate alternating with three- substances. These substances may be referred to 40 day phases of unit dosages of estrone sulphate as diluents, binders and lubricants. Gums, starches 0.75 mg and NET 0.35 mg given continuously and and sugars are also common terms. Typical of orally. these types of substances or excipients are phar- maceutical grades of mannitol, lactose starch, mag- EXAMPLE 2 nesium stearate, sodium saccharin, talcum, cel- 45 lulose, glucose, sucrose, carbonate Three-day phases (unit dosages of estrone sul- and the like. The active ingredient(s) may comprise phate 0.75 mg and norethindrone 0.15 mg) al- from about 0.01% by weight to about 99.99% by ternating with three-day phases of estrone sulphate weight of the total formulation and the remainder 0.75 mg and norethindrone 0.35 mg given continu- comprises the pharmaceutically acceptable carrier. 50 ously and orally. The percentage of active ingredient(s) may vary according to the delivery system or method of EXAMPLE 3 administration and is chosen in accordance with conventional methods known in the art. Three-day phases of oral micronized 17beta- Thus, the active ingredients are compounded 55 estradiol 1 mg alternating with three-days of with the chosen carrier and in for example the case 17beta-estradiol 1 mg and norethindrone .35 mg of a tablet form, placed in a tablet molding appara- given continuously. tus to form the tablets which are subsequently

8 13 EP 0 309 263 B1 14

EXAMPLE 4 Claims Claims for the following Contracting States : Three-day phases of transdermal 17beta-es- AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE tradiol (100 ug/day) alternating with three-days of transdermal 17beta-estradiol (100 ug/day) and tran- 5 1. A hormone replacement preparation containing sdermal norethindrone (.35 mg/day) given continu- estrogen and progestin as a combined prep- ously. aration in which a plurality of unit dosages are arranged for the continuous and consecutive EXAMPLE 5 administration to a female in need of hormone io replacement alternately of a number of rela- Three-day phases of estrone sulphate 1 .25 mg tively dominant estrogen activity unit dosages alternating with three-day phases of estrone sul- and of a number of relatively dominant pro- phate 1.25 mg and norethindrone 0.35 mg given gestin activity unit dosages, each said number continuously and orally. of unit dosages consisting of 1 to 5 unit dos- 15 ages. EXAMPLE 6 2. A preparation according to claim 1 wherein the Three-day phases of estrone sulphate 1 .25 mg female to be treated is of child bearing age or alternating with three-day phases of estrone sul- older in whom ovarian estrogen and pro- phate 1.25 mg and norethindrone 0.5 mg given 20 gesterone production has been interrupted ei- continuously and orally. ther because of natural menopause, surgical, radiation or chemical ovarian ablation or ex- EXAMPLE 7 tirpation or premature ovarian failure.

One-day or two-day alternating phases using 25 3. A preparation according to claim 1 or 2 in the unit dosages set forth in Examples 1 and 2 which each said number of unit dosages con- given continuously and orally. sists of 2 to 4 unit dosages.

EXAMPLE 8 4. A preparation according to any preceding 30 claim in which each said number of unit dos- Three-day phases of estrone sulphate 0.75 mg ages consists of 3 unit dosages. alternating with three-day phases of estrone sul- phate 0.75 mg and norgestimate 0.050 mg given 5. A preparation according to any preceding continuously and orally. claim in which unit dosages are administered 35 orally, parenterally, sublingually, transdermal^, EXAMPLE 9 intravaginally, intranasally or buccally.

Three-day and four-day phases of each of the 6. A preparation according to claim 5 in which combinations as set forth in Examples 1 and 2, unit dosages are administered orally. starting with either a 3- or 4-day phase and given 40 continuously and orally. 7. A preparation according to claim 5 in which unit dosages are administered transdermally. EXAMPLE 10 8. A preparation according to any preceding Two-day and three-day phases of each of the 45 claim in which the estrogen is selected from combinations as set forth in Examples 1 and 2, synthetic estrogens, selected from 17alpha- starting with either a 2- or 3-day phase and given ethinylestradiol and esters and ethers thereof, continuously and orally. ethinyl estradiol, mestranol and quinestranol Our co-pending divisional application is direct- and from natural estrogens selected from con- ed to related contraceptive uses of the cyclic dos- 50 jugated equine estrogens, 17beta-estradiol, es- age regimen described herein and claimed for use tradiol valerate, estrone, estrone sulphate, in hormone replacement therapy. piperazine estrone sulphate, estriol, estriol suc- cinate and polyestrol phosphate.

55 9. A preparation according to claim 8 in which the estrogen is sleeted from estrone sulphate, piperazine estrone sulphate and 17beta es- tradiol.

9 15 EP 0 309 263 B1 16

10. A preparation according to any preceding 16. A preparation according to claim 14 or 15 in claim in which the progestin is selected from which the unit dosages are for administration in progesterone, 17-hydroxy progesterone esters, alternating groups of three of each type of 19-nor-17-hydroxyprogesterone esters, 17al- hormone-containing unit dosage. pha-ethinyl-testosterone, and derivatives there- 5 of 17alpha-ethinyl-19-nor-testosterone and de- 17. A preparation acording to claim 12 or 13 in rivatives thereof, norethindrone, norethindrone which each said number is 3 and in which the acetate, ethynodiol diacetate, dydrogesterone, relatively dominant estrogen activity combina- acetate, norethynodrel, tion dosages contain 1 mg 17-beta estradiol , lynoestrenol, acetate io and the relatively dominant progestin activity medrogestone, norgestrienone, , combination dosages contain 1 mg 17-beta ethisterone, cyproterone, cyproterone acetate, estradiol and 0.35 mg norethindrone and each levo-norgestrel, d-norgestrel, dl-norgestrel, d- is administered orally. 1 7alpha-acetoxy-1 3beta-ethyl-1 7alpha-ethinyl- gon-4-en-3-one oxime, gestodene, nor- is 18. A preparation according to claim 12 or 13 in gestimate and desogestrel. which each said number is 3 and in which the relatively dominant estrogen activity combina- 11. A preparation according to claim 10 in which tion unit dosage contains 0.75 mg estrone sul- the progestin is norethindrone or norgestimate phate and the relatively dominant progestin or progesterone. 20 activity combination unit dosage contains 0.75 mg estrone sulphate and 0.050 mg nor- 12. A preparation according to any preceding gestimate each administered orally. claim in which the amount of estrogen per unit dosage ranges from a minimum of about 0.3 19. A preparation according to claim 12 or 13 in mg to a maximum of about 5.0 mg of 25 which each said number is 3 and in which the piperazine estrone sulphate or its equivalent relatively dominant estrogen activity combina- dosage in another synthetic or natural estrogen tion unit dosage contains 1 .25 mg estrone sul- and the amount of progestin per unit dosage phate and the relatively dominant progestin may range from a minimum of about 0.0 mg to combination contains 1 .25 mg estrone sulphate a maximum of about 5.0 mg of norethindrone 30 and either 0.35 mg or 0.5 mg norethindrone or its equivalent in a synthetic or natural pro- each administered orally. gestin. 20. A preparation according to claim 12 or 13 in 13. A preparation according to claim 12 in which which each said number is 1, 2, 3 or 4 and in the amount of estrogen per unit dosage ranges 35 which the relatively dominant estrogen activity from 0.3 mg to 2.5 mg of piperazine estrone combination contains 0.75 mg estrone sulphate sulphate or its equivalent. and 0.15 mg norethindrone and the relatively dominant progestin activity combination con- 14. A preparation according to claim 12 or 13 in tains 0.75 estrone sulphate and 0.35 mg which the unit dosages are for oral administra- 40 norethindrone each administered orally. tion and each said number is 1, 2, 3 or 4 and the relatively dominant estrogen activity com- 21. A preparation according to claim 12 or 13 in bination unit dosages contain 0.75 mg which the unit dosages are for transdermal piperazine estrone sulphate and the relatively administration and are for administration in al- dominant progestin activity combination unit 45 ternating three day periods of 17beta-estradiol dosages contain 0.75 mg piperazine estrone at 0.1 mg/day and three day periods of 17beta- sulphate and 0.35 mg norethindrone. estradiol at 0.1 mg/day plus norethindrone at 0.35 mg/day. 15. A preparation according to claim 12 or 13 in which the unit dosages are for oral administra- 50 22. Use of estrogen and progestin in a method of tion and each said number is 1, 2, 3 or 4 and manufacturing a product characterised in that in which the dominant estrogen combination the product is for hormone replacement ther- unit dosages contain 0.75 mg piperazine es- apy and contains estrogen and progestin as a trone sulphate and 0.15 mg norethindrone and combined preparation for administering to a the dominant progestin combination unit dos- 55 female in need of continu- ages contain 0.75 piperazine estrone sulphate ously and consecutively alternately of a num- and 0.35 mg norethindrone. ber of relatively dominant estrogen activity unit dosages and of a number of relatively domi-

10 17 EP 0 309 263 B1 18

nant progestin activity unit dosages, each said mal^. number of unit dosages consisting of 1 to 5 unit dosages. 8. Use according to any preceding claim in which the estrogen is selected from synthetic es- 23. Use according to claim 22 which is for admin- 5 trogens, selected from 17alpha-ethinylestradiol istration to a female of child bearing age or and esters and ethers thereof, ethinyl estradiol, older in whom ovarian estrogen and pro- mestranol and quinestranol and from natural gesterone production has been interrupted ei- estrogens selected from conjugated equine es- ther because of natural menopause, surgical, trogens, 17beta-estradiol, estradiol valerate, es- radiation or chemical ovarian ablation or ex- io10 trone, estrone sulphate, piperazine estrone sul- tirpation or premature ovarian failure. phate, estriol, estriol succinate and polyestrol phosphate. 24. Use according to claim 22 or 23 in which the product has the further features as defined in 9. Use according to claim 8 in which the estrogen any of claims 3 to 21 . is is sleeted from estrone sulphate, piperazine estrone sulphate and 17beta estradiol. Claims for the following Contracting States : ES, GR 10. Use according to any preceding claim in which the progestin is selected from progesterone, 1. Use of estrogen and progestin in a process of 20 17-hydroxy progesterone esters, 19-nor-17- manufacturing a product characterised in that hydroxy- progesterone esters, 17alpha-ethinyl- the product is for hormone replacement ther- testosterone, and derivatives thereof 17alpha- apy and contains estrogen and progestin as a ethinyl-19-nor-testosterone and derivatives combined preparation for administering to a thereof, norethindrone, norethindrone acetate, female in need of hormone therapy continu- 25 ethynodiol diacetate, dydrogesterone, medrox- ously and consecutively alternately of a num- yprogesterone acetate, norethynodrel, al- ber of relatively dominant estrogen activity unit lylestrenol, lynoestrenol, dosages and of a number of relatively domi- medrogestone, norgestrienone, dimethisterone, nant progestin activity unit dosages, each said ethisterone, cyproterone, cyproterone acetate, number of unit dosages consisting of 1 to 5 30 , d-norgestrel, dl-norgestrel, d- unit dosages. 1 7alpha-acetoxy-1 3beta-ethyl-1 7alpha-ethinyl- gon-4-en-3-one oxime, gestodene, nor- 2. Use according to claim 1 wherein the female to gestimate and desogestrel. be treated is of child bearing age or older in whom ovarian estrogen and progesterone pro- 35 11. Use according to claim 10 in which the pro- duction has been interrupted either because of gestin is norethindrone or norgestimate or pro- natural menopause, surgical, radiation or gesterone. chemical ovarian ablation or extirpation or pre- mature ovarian failure. 12. Use according to any preceding claim in which 40 the amount of estrogen per unit dosage ranges 3. Use according to claim 1 or 2 in which each from a minimum of about 0.3 mg to a maxi- said number of unit dosages consists of 2 to 4 mum of about 5.0 mg of piperazine estrone unit dosages. sulphate or its equivalent dosage in another synthetic or natural estrogen and the amount 4. Use according to any preceding claim in which 45 of progestin per unit dosage may range from a each said number of unit dosages consists of minimum of about 0.0 mg to a maximum of 3 unit dosages. about 5.0 mg of norethindrone or its equivalent in a synthetic or natural progestin. 5. Use according to any preceding claim in which unit dosages are suitable for administration 50 13. Use according to claim 12 in which the amount orally, parenterally, sublingually, transdermal^, of estrogen per unit dosage ranges from 0.3 intravaginally, intranasally or buccally. mg to 2.5 mg of piperazine estrone sulphate or its equivalent. 6. Use according to claim 5 in which unit dos- ages are suitable for administration orally. 55 14. Use according to claim 12 or 13 in which the unit dosages are for oral administration and 7. Use according to claim 5 in which unit dos- each said number is 1, 2, 3 or 4 and the ages are suitable for administration transder- relatively dominant estrogen activity combina-

11 19 EP 0 309 263 B1 20

tion unit dosages contain 0.75 mg piperazine 21. Use according to claim 12 or 13 in which the estrone sulphate and the relatively dominant unit dosages are for transdermal administration progestin activity combination unit dosages and are for administration in alternating three contain 0.75 mg piperazine estrone sulphate day periods of 17beta-estradiol at 0.1 mg/day and 0.35 mg norethindrone. 5 and three day periods of 17beta-estradiol at 0.1 mg/day plus norethindrone at 0.35 mg/day. 15. Use according to claim 12 or 13 in which the unit dosages are for oral administration and 22. A process of manufacturing a product charac- each said number is 1, 2, 3 or 4 and in which terised in that the product is for hormone re- the dominant estrogen combination unit dos- io placement therapy and contains estrogen and ages contain 0.75 mg piperazine estrone sul- progestin as a combined preparation for ad- phate and 0.15 mg norethindrone and the ministering to a female in need of hormone dominant progestin combination unit dosages therapy continuously and consecutively alter- contain 0.75 piperazine estrone sulphate and nately of a number of relatively dominant es- 0.35 mg norethindrone. 15 trogen activity unit dosages and of a number of relatively dominant progestin activity unit 16. Use according to claim 14 or 15 in which the dosages, each said number of unit dosages unit dosages are for administration in alternat- consisting of 1 to 5 unit dosages. ing groups of three of each type of hormone- containing unit dosage. 20 23. A process of manufacturing a hormone re- placement product comprising estrogen and 17. Use according to claim 12 or 13 in which each progestin, comprising the steps of selecting an said number is 3 and in which the relatively amount of estrogen and an amount of pro- dominant estrogen activity combination dos- gestin suitable for providing a relatively domi- ages contain 1 mg 17-beta estradiol and the 25 nant estrogen activity unit dosage, mixing each relatively dominant progestin activity combina- of the estrogen and progestin of the relatively tion dosages contain 1 mg 17-beta estradiol dominant estrogen activity dosage with a phar- and 0.35 mg norethindrone and each is admin- mceutical carrier, selecting an amount of es- istered orally. trogen and progestin suitable for providing a 30 relatively dominant progestin activity unit dos- 18. Use according to claim 12 or 13 in which each age, mixing each of the estrogen and progestin said number is 3 and in which the relatively of the relatively dominant progestin activity dominant estrogen activity combination unit dosage with a pharmaceutical carrier, and dosage contains 0.75 mg estrone sulphate and packaging the unit dosages in an arrangement the relatively dominant progestin activity com- 35 for administering continuously and consecu- bination unit dosage contains 0.75 mg estrone tively alternately of a number of relatively sulphate and 0.050 mg norgestimate each ad- dominant estrogen activity unit dosages and of ministered orally. a number of relatively dominant progestin ac- tivity unit dosages, each said number of unit 19. Use according to claim 12 or 13 in which each 40 dosages consisting of 1 to 5 unit dosages. said number is 3 and in which the relatively dominant estrogen activity combination unit 24. A process according to claim 23 in which the dosage contains 1 .25 mg estrone sulphate and unit dosages are molded to form tablets and the relatively dominant progestin combination the tablets are packaged in a transparent pack- contains 1.25 mg estrone sulphate and either 45 age each comprising twenty-eight dosage units 0.35 mg or 0.5 mg norethindrone each admin- arranged in a fixed sequence. istered orally. 25. A process according to claim 24 in which the 20. Use according to claim 12 or 13 in which each package includes date indications adjacent said number is 1, 2, 3 or 4 and in which the 50 each tablet each indicating the day on which relatively dominant estrogen activity combina- the corresponding tablet is to be taken. tion contains 0.75 mg estrone sulphate and 0.15 mg norethindrone and the relatively domi- 26. A process according to any of claims 22 to 25 nant progestin activity combination contains in which the product is for administration to a 0.75 estrone sulphate and 0.35 mg norethin- 55 female who is of child bearing age or older in drone each administered orally. whom ovarian estrogen and progesterone pro- duction has been interrupted either because of natural menopause, surgical, radiation or

12 21 EP 0 309 263 B1 22

chemical ovarian ablation or extirpation or pre- wahlt aus 17a-Ethinylestradiol und dessen mature ovarian failure. Estern und Ethern, Ethinylestradiol, Mestranol und Chinestranol, und aus naturlichen Ostroge- 27. A process according to any of claims 22 to 26 nen, ausgewahlt aus konjugierten Pferdeestro- which has the further features defined in any of 5 genen, 17/3-Ostradiol, Ostradiolvalerianat, claims 3 to 21 . Ostron, Ostronsulfat, Piperazin-estronsulfat, Ostriol, Ostriolsuccinat und Polyestrolphosphat. Patentanspruche Patentanspruche fur folgende Vertragsstaaten 9. Praparat nach Anspruch 8, bei dem das Ostro- : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE io gen ausgewahlt ist aus Ostronsulfat, Piperazin- estronsulfat und 17/3-Ostradiol. 1. Praparat zum Hormonersatz, das Ostrogen und Progestin als ein Kombinationspraparat enthalt, 10. Praparat nach irgendeinem der vorhergehen- bei dem eine Menge Dosierungseinheiten kon- den Anspruche, bei dem das Progestin ausge- tinuierlich und aufeinanderfolgend angeordnet 15 wahlt ist aus Progesteron, 17-Hydroxyproge- sind zur Verabreichung abwechselnd einer An- steronestern, 1 9-Nor-1 7-Hydroxyprogesterone- zahl Dosierungseinheiten mit relativ dominanter stern, 17a-Ethinyltestosteron und dessen Deri- Ostrogenaktivitat und einer Anzahl Dosierungs- vaten, 17a-Ethinyl-19-nortestosteron und des- einheiten mit relativ dominanter Progestinaktivi- sen Derivaten, Norethisteron, Norethisteronace- tat an eine Frau, die Hormonersatz benotigt, 20 tat, Ethynodioldiacetat, Dydrogesteron, Me- wobei eine jede Anzahl Dosierungseinheiten droxyprogesteronacetat, Norethynodrel, Allyle- aus 1 bis 5 Dosierungseinheiten besteht. strenol, Lynoestrenol, Chingestanolacetat, Me- drogeston, Norgestrienon, Dimethisteron, Ethi- 2. Praparat nach Anspruch 1 , wobei eine Frau im steron, Cyproteron, Cyproteronacetat, Lavo- gebarfahigen Alter oder alter behandelt wird, 25 Norgestrel, d-Norgestrel, dl-Norgestrel, d-17a- bei der die Produktion von Ostrogen und Pro- Acetoxy-1 3/3-ethyl-1 7a-ethinyl-gon-4-en-3-on- gesteron in den Ovarien entweder aufgrund oxim, Gestoden, Norgestimat und Desogestrel. der naturlichen Menopause, wegen chirurgi- scher, bestrahlungsbedingter oder chemischer 11. Praparat nach Anspruch 10, bei dem das Pro- Entfernung oder Extirpation der Eierstocke 30 gestin Norethisteron oder Norgestimat oder oder wegen verfruhten Versagens der Eier- Progesteron ist. stocke unterbrochen ist. 12. Praparat nach irgendeinem der vorhergehen- 3. Praparat nach Anspruch 1 oder 2, bei dem den Anspruche, bei dem die Menge Ostrogen eine jede Anzahl Dosierungseinheiten aus 2 35 pro Dosierungseinheit zwischen einem Mini- bis 4 Dosierungseinheiten besteht. mum von ungefahr 0,3 mg und einem Maxi- mum von ungefahr 5,0 mg Piperazin-estronsul- 4. Praparat nach irgendeinem der vorhergehen- fat oder dessen Aquivalentdosierung eines an- den Anspruche, bei dem eine jede Anzahl Do- deren synthetischen oder naturlichen Ostro- sierungseinheiten aus 3 Dosierungseinheiten 40 gens liegt, und die Menge Progestin pro Do- besteht. sierungseinheit zwischen einem Minimum von ungefahr 0,0 mg und einem Maximum von 5. Praparat nach irgendeinem der vorhergehen- ungefahr 5,0 mg Norethisteron oder dessen den Anspruche, bei dem die Dosierungseinhei- Equivalent eines synthetischen oder naturli- ten oral, parenteral, sublingual, transdermal, in- 45 chen Progestins liegen kann. travaginal, intranasal oder bukkal verabreicht werden. 13. Praparat nach Anspruch 12, bei dem die Men- ge Ostrogen pro Dosierungseinheit zwischen 6. Praparat nach Anspruch 5, bei dem die Dosie- 0,3 mg und 2,5 mg Piperazinestronsulfat oder rungseinheiten oral verabreicht werden. 50 dessen Equivalent liegt.

7. Praparat nach Anspruch 5, bei dem die Dosie- 14. Praparat nach Anspruch 12 oder 13, bei dem rungseinheiten transdermal verabreicht wer- die Dosierungseinheiten zur oralen Verabrei- den. chung bestimmt sind und eine jede Anzahl 1, 55 2, 3, oder 4 ist und die Dosierungseinheiten 8. Praparat nach irgendeinem der vorhergehen- mit einer Kombination mit relativ dominanter den Anspruche, bei dem das Ostrogen ausge- Ostrogenaktivitat 0,75 mg Piperazin-estronsul- wahlt ist aus synthetischen Ostrogenen, ausge- fat enthalten und die Dosierungseinheiten mit

13 23 EP 0 309 263 B1 24

einer Kombination relativ dominanter Proge- 21. Praparat nach Anspruch 12 oder 13, bei dem stinaktivitat 0,75 mg Piperazin-estronsulfat und die Dosierungseinheiten zur transdermalen 0,35 mg Norethisteron enthalten. Verabreichung und zur Verabreichung in alter- nierenden Dreitagesphasen mit 0,1 mg/Tag 15. Praparat nach Anspruch 12 oder 13, bei dem 5 17/3-Ostradiol und Dreitagesphasen mit 0,1 die Dosierungseinheiten zur oralen Verabrei- mg/Tag 17/3-Ostradiol plus 0,1 mg/Tag Noret- chung bestimmt sind und eine jede Anzahl 1, histeron bestimmt sind. 2, 3, oder 4 ist und bei der die Dosierungsein- heiten mit einer Kombination mit dominanter 22. Verwendung von Ostrogen und Progestin in Ostrogenaktivitat 0,75 mg Piperazin-estronsul- io einem Verfahren zur Herstellung eines Erzeug- fat und 0,15 mg Norethisteron enthalten und nisses, dadurch gekennzeichnet, dal3 das Er- die Dosierungseinheiten mit einer Kombination zeugnis zur Hormonersatztherapie bestimmt ist dominanter Progestinaktivitat 0,75 mg Pipera- und Ostrogen und Progestin als Kombinations- zin-estronsulfat und 0,35 mg Norethisteron ent- praparat enthalt, zur kontinuierlichen und auf- halten. 15 einanderfolgenden Verabreichung abwechselnd einer Anzahl Dosierungseinheiten mit relativ 16. Praparat nach Anspruch 14 oder 15, bei dem dominanter Ostrogenaktivitat und einer Anzahl die Dosierungseinheiten jeder Art der hormon- von Dosierungseinheiten mit relativ dominanter haltigen Dosierungseinheit zur Verabreichung Progestinaktivitat an eine Frau, die Hormoner- in alternierenden Dreiergruppen vorliegen. 20 satz benotigt, wobei eine jede Anzahl Dosie- rungseinheiten aus 1 bis 5 Dosierungseinheiten 17. Praparat nach Anspruch 12 oder 13, bei dem besteht. eine jede Anzahl 3 ist, und bei dem die Dosie- rung mit einer Kombination mit relativ domin- 23. Verwendung nach Anspruch 22 zur Verabrei- anter Ostrogenaktivitat 1 mg 17/3-Ostradiol ent- 25 chung an eine Frau im gebarfahigen Alter oder halten und die Dosierung mit einer Kombina- alter, bei der die Produktion an Ostrogen und tion relativ dominanter Progestinaktivitat 1 mg Progesteron in den Ovarien entweder aufgrund 17/3-Ostradiol und 0,35 mg Norethisteron ent- der naturlichen Menopause, wegen chirurgi- halten und jeweils oral verabreicht werden. scher, bestrahlungsbedingter oder chemischer 30 Entfernung oder Extirpation der Eierstocke 18. Praparat nach Anspruch 12 oder 13, bei dem oder wegen verfruhten Versagens der Eier- eine jede Anzahl 3 ist, und bei dem die Dosie- stocke unterbrochen ist. rungseinheit mit einer Kombination mit relativ dominanter Ostrogenaktivitat 0,75 mg Ostron- 24. Verwendung nach Anspruch 22 oder 23, bei sulfat enthalt und die Dosierungseinheit mit 35 der das Erzeugnis die weiteren in irgendeinem einer Kombination mit relativ dominanter Pro- der Anspruche 3 bis 21 definierten Kennzei- gestinaktivitat 0,75 mg Ostronsulfat und 0,050 chen hat. mg Norgestimat enthalt, jeweils oral verab- reicht. Patentanspruche fur folgende Vertragsstaaten 40 : ES, GR 19. Praparat nach Anspruch 12 oder 13, bei dem eine jede Anzahl 3 ist, und bei dem die Dosie- 1. Verwendung von Ostrogen und Progestin in rungseinheit mit einer Kombination mit relativ einem Verfahren zur Herstellung eines Erzeug- dominanter Ostrogenaktivitat 1,25 mg Ostron- nisses, dadurch gekennzeichnet, dal3 das Er- sulfat enthalt und die Kombination mit relativ 45 zeugnis zur Hormonersatztherapie bestimmt ist dominanter Progestinaktivitat 1,25 mg Ostron- und Ostrogen und Progestin als Kombinations- sulfat und entweder 0,35 mg oder 0,5 mg praparat enthalt, zur kontinuierlichen und auf- Norethisteron enthalt, jeweils oral verabreicht. einanderfolgenden Verabreichung abwechselnd einer Anzahl Dosierungseinheiten mit relativ 20. Praparat nach Anspruch 12 oder 13, bei dem 50 dominanter Ostrogenaktivitat und einer Anzahl eine jede Anzahl 1, 2, 3 oder 4 ist, und bei Dosierungseinheiten mit relativ dominanter dem die Kombination mit relativ dominanter Progestinaktivitat an eine Frau, die Hormoner- Ostrogenaktivitat 0,75 mg Ostronsulfat und satz benotigt, wobei eine jede Anzahl Dosie- 0,15 mg Norethisteron enthalt und die Kombi- rungseinheiten aus 1 bis 5 Dosierungseinheiten nation mit relativ dominanter Progestinaktivitat 55 besteht. 0,75 mg Ostronsulfat und 0,35 mg Norethiste- ron enthalt, jeweils oral verabreicht. 2. Verwendung nach Anspruch 1, wobei die zu behandelnde Frau eine Frau im gebarfahigen

14 25 EP 0 309 263 B1 26

Alter oder alter ist, bei der die Produktion von Norgestrel, d-Norgestrel, dl-Norgestrel, d-17a- Ostrogen und Progesteron in den Ovarien ent- Acetoxy-1 3/3-ethyl-1 7a-ethinyl-gon-4-en-3-on- weder aufgrund der naturlichen Menopause, oxim, Gestoden, Norgestimat und Desogestrel. wegen chirurgischer, bestrahlungsbedingter oder chemischer Entfernung oder Extirpation 5 11. Verwendung nach Anspruch 10, bei der das der Eierstocke oder wegen verfruhten Versa- Progestin Norethisteron oder Norgestimat oder gens der Eierstocke unterbrochen ist. Progesteron ist.

3. Verwendung nach Anspruch 1 oder 2, bei der 12. Verwendung nach irgendeinem der vorherge- eine jede Anzahl Dosierungseinheiten aus 2 io henden Anspruche, bei der die Menge Ostro- bis 4 Dosierungseinheiten besteht. gen pro Dosierungseinheit zwischen einem Mi- nimum von ungefahr 0,3 mg und einem Maxi- 4. Verwendung nach irgendeinem der vorherge- mum von ungefahr 5,0 mg Piperazin-estronsul- henden Anspruche, bei der eine jede Anzahl fat oder dessen Aquivalentdosierung eines an- Dosierungseinheiten aus 3 Dosierungseinheiten 15 deren synthetischen oder naturlichen Ostro- besteht. gens liegt, und die Menge Progestin pro Do- sierungseinheit zwischen einem Minimum von 5. Verwendung nach irgendeinem der vorherge- ungefahr 0,0 mg und einem Maximum von henden Anspruche, bei der die Dosierungsein- ungefahr 5,0 mg Norethisteron oder dessen heiten zur oralen, parenteralen, sublingualen, 20 Equivalent eines synthetischen oder naturli- transdermalen, intravaginalen, intranasalen chen Progestins liegen kann. oder bukkalen Verabreichung geeignet sind. 13. Verwendung nach Anspruch 12, bei der die 6. Verwendung nach Anspruch 5, bei der die Menge Ostrogen pro Dosierungseinheit zwi- Dosierungseinheiten zur oralen Verabreichung 25 schen 0,3 mg und 2,5 mg Piperazin-estronsul- geeignet sind. fat oder dessen Equivalent liegt.

7. Verwendung nach Anspruch 5, bei der die 14. Verwendung nach Anspruch 12 oder 13, bei Dosierungseinheiten zur transdermalen Verab- der die Dosierungseinheiten zur oralen Verab- reichung geeignet sind. 30 reichung bestimmt sind und eine jede Anzahl 1, 2, 3, oder 4 ist und die Dosierungseinheiten 8. Verwendung nach irgendeinem der vorherge- mit einer Kombination mit relativ dominanter henden Anspruche, bei der das Ostrogen aus- Ostrogenaktivitat 0,75 mg Piperazin-estronsul- gewahlt ist aus synthetischen Ostrogenen, aus- fat enthalten und die Dosierungseinheiten mit gewahlt aus 17a-Ethinylestradiol und dessen 35 einer Kombination mit relativ dominanter Pro- Estern und Ethern, Ethinylestradiol, Mestranol gestinaktivitat 0,75 mg Piperazin-estronsulfat und Chinestranol, und aus naturlichen Ostroge- und 0,35 mg Norethisteron enthalten. nen, ausgewahlt aus konjugierten Pferdeestro- genen, 17/3-Ostradiol, Ostradiolvalerianat, 15. Verwendung nach Anspruch 12 oder 13, bei Ostron, Ostronsulfat, Piperazin-estronsulfat, 40 der die Dosierungseinheiten zur oralen Verab- Ostriol, Ostriolsuccinat und Polyestrolphosphat. reichung bestimmt sind und eine jede Anzahl 1, 2, 3, oder 4 ist und bei der die Dosierungs- 9. Verwendung nach Anspruch 8, bei der das einheiten mit einer Kombination mit dominanter Ostrogen ausgewahlt ist aus Ostronsulfat, Pi- Ostrogenaktivitat 0,75 mg Piperazin-estronsul- perazin-estronsulfat und 17/3-Ostradiol. 45 fat und 0,15 mg Norethisteron enthalten und die Dosierungseinheiten mit einer Kombination 10. Verwendung nach irgendeinem der vorherge- dominanter Progestinaktivitat 0,75 mg Pipera- henden Anspruche, bei der das Progestin aus- zin-estronsulfat und 0,35 mg Norethisteron ent- gewahlt ist aus Progesteron, 17-Hydroxyproge- halten. steronestern, 1 9-Nor-1 7-Hydroxyprogesterone- 50 stern, 17a-Ethinyltestosteron und dessen Deri- 16. Verwendung nach Anspruch 14 oder 15, bei vaten, 17a-Ethinyl-19-nortestosteron und des- der die Dosierungseinheiten jeder Art hormon- sen Derivaten, Norethisteron, Norethisteronace- haltiger Dosierungseinheit zur Verabreichung in tat, Ethynodioldiacetat, Dydrogesteron, Me- alternierenden Dreiergruppen vorliegen. droxyprogesteronacetat, Norethynodrel, Allyle- 55 strenol, Lynoestrenol, Chingestanolacetat, Me- 17. Verwendung nach Anspruch 12 oder 13, bei drogeston, Norgestrienon, Dimethisteron, Ethi- der eine jede Anzahl 3 ist, und bei der die steron, Cyproteron, Cyproteronacetat, Lavo- Dosierung mit einer Kombination relativ domin-

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anter Ostrogenaktivitat 1 mg 17/3-Ostradiol ent- stin umfaBt, das die Schritte umfaBt: Auswah- halten und die Dosierung mit einer Kombina- len einer Menge Ostrogen und einer Menge tion relativ dominanter Progestinaktivitat 1 mg Progestin, die geeignet sind, eine Dosierungs- 17/3-Ostradiol und 0,35 mg Norethisteron ent- einheit mit relativ dominanter Ostrogenaktivitat halten und jeweils oral verabreicht werden. 5 zu liefern, Mischen des Ostrogens und des Progestins der Dosierungseinheit mit relativ 18. Verwendung nach Anspruch 12 oder 13, bei dominanter Ostrogenaktivitat jeweils mit einem der eine jede Anzahl 3 ist, und bei der die pharmazeutischen Trager, Auswahlen einer Dosierungseinheit mit einer Kombination mit Menge Ostrogen und Progestin, die geeignet relativ dominanter Ostrogenaktivitat 0,75 mg io sind, eine Dosierungseinheit mit relativ domin- Ostronsulfat enthalt und die Dosierungseinheit anter Progestinaktivitat zu liefern, Mischen des mit einer Kombination mitrelativ dominanter Ostrogens und des Progestins der Dosierungs- Progestinaktivitat 0,75 mg Ostronsulfat und einheit mit relativ dominanter Progestinaktivitat 0,050 mg Norgestimat enthalt, jeweils oral ver- jeweils mit einem pharmazeutischen Trager, abreicht. is und Verpacken der Dosierungseinheiten in ei- ner Anordnung zur kontinuierlichen und aufein- 19. Verwendung nach Anspruch 12 oder 13, bei anderfolgenden Verabreichung abwechselnd der eine jede Anzahl 3 ist, und bei der die einer Anzahl Dosierungseinheiten mit relativ Dosierungseinheit mit einer Kombination mit dominanter Ostrogenaktivitat und einer Anzahl relativ dominanter Ostrogenaktivitat 1,25 mg 20 Dosierungseinheiten mit relativ dominanter Ostronsulfat enthalt und die Kombination mit Progestinaktivitat, wobei eine jede Anzahl Do- relativ dominanter Progestinaktivitat 1,25 mg sierungseinheiten aus 1 bis 5 Dosierungsein- Ostronsulfat und entweder 0,35 mg oder 0,5 heiten besteht. mg Norethisteron enthalt, jeweils oral verab- reicht. 25 24. Verfahren nach Anspruch 23, bei dem die Do- sierungseinheiten zu Tabletten geformt werden 20. Verwendung nach Anspruch 12 oder 13, bei und die Tabletten in eine transparente Verpak- der eine jede Anzahl 1, 2, 3 oder 4 ist, und bei kung gepackt werden, wobei jede Packung 28 der die Kombination mit relativ dominanter Dosierungseinheiten umfaBt, die in einer be- Ostrogenaktivitat 0,75 mg Ostronsulfat und 30 stimmten Folge angeordnet sind. 0,15 mg Norethisteron enthalt und die Kombi- nation mit relativ dominanter Progestinaktivitat 25. Verfahren nach Anspruch 24, bei dem die Pak- 0,75 mg Ostronsulfat und 0,35 mg Norethiste- kung Datumsangaben neben jeder Tablette be- ron enthalt, jeweils oral verabreicht. sitzt, die jeweils den Tag angeben, an dem die 35 jeweilige Tablette einzunehmen ist. 21. Verwendung nach Anspruch 12 oder 13, bei der die Dosierungseinheiten zur transdermalen 26. Verfahren nach irgendeinem der Anspruche 22 Verabreichung in alternierenden Dreitagespha- bis 25, bei dem das Erzeugnis zur Verabrei- sen mit 0,1 mg/Tag 17/3-Ostradiol und Dreita- chung an eine Frau im gebarfahigen Alter oder gesphasen mit 0,1 mg/Tag 17/3-Ostradiol plus 40 alter bestimmt ist, bei der die Produktion von 0,1 mg/Tag Norethisteron bestimmt sind. Ostrogen und Progesteron in den Ovarien ent- weder aufgrund der naturlichen Menopause, 22. Verfahren zur Herstellung eines Erzeugnisses, wegen chirurgischer, bestrahlungsbedingter dadurch gekennzeichnet, dal3 das Erzeugnis oder chemischer Entfernung oder Extirpation zur Hormonersatztherapie bestimmt ist und 45 der Eierstocke oder wegen verfruhten Versa- Ostrogen und Progestin als Kombinationspra- gens der Eierstocke unterbrochen ist. parat enthalt, zur kontinuierlichen und aufein- anderfolgenden Verabreichung abwechselnd 27. Verfahren nach irgendeinem der Anspruche 22 einer Anzahl Dosierungseinheiten mit relativ bis 26, das die weiteren in irgendeinem der dominanter Ostrogenaktivitat und einer Anzahl 50 Anspruche 3 bis 21 definierten Kennzeichen Dosierungseinheiten mit relativ dominanter hat. Progestinaktivitat an eine Frau, die Hormoner- satz benotigt, wobei eine jede Anzahl Dosie- Revendicatlons rungseinheiten aus 1 bis 5 Dosierungseinheiten Revendicatlons pour les Etats contractants besteht. 55 suivants : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 23. Verfahren zur Herstellung eines Erzeugnisses zum Hormonersatz, das Ostrogen und Proge-

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1. Preparation hormonale substitutive contenant polyestrol. un oestrogene et un progestatif sous la forme d'une preparation associee dans laquelle une 9. Preparation selon la revendication 8, dans la- pluralite de doses unitaires sont congues pour quelle I'oestrogene est selectionne parmi le I'administration continue et consecutive chez 5 sulfate d'estrone, le sulfate d'estrone-piperazi- une femme necessitant une substitution hor- ne et le 17/3-estradiol. monale, par alternance, d'un certain nombre de doses unitaires a activite oestrogenique re- 10. Preparation selon I'une des revendications pre- lativement dominante et d'un certain nombre cedentes, dans laquelle le progestatif est se- de doses unitaires a activite progestative relati- io lectionne parmi la progesterone, les esters de vement dominante, chacun desdits nombres 17-hydroxyprogesterone, les esters de 19-nor- de doses unitaires consistant en 1 a 5 doses 17-hydroxyprogesterone, la 17a-ethinyltestoste- unitaires. rone et ses derives, la 17a-ethinyl-19-nortes- tosterone et ses derives, la norethisterone, 2. Preparation selon la revendication 1, dans la- 15 I'acetate de norethisterone, le diacetate d'ethy- quelle la femme a traiter est en age de pro- nodiol, la dydrogesterone, I'acetate de me- creer ou plus agee et sa production ovarienne droxyprogesterone, le norethynodrel, I'allyles- d'oestrogene et de progesterone a ete inter- trenol, le , I'acetate de quingestanol, rompue soit a la suite d'une menopause natu- la medrogestone, la norgestrienone, la dime- relle, soit a la suite d'une ablation ou d'une 20 thisterone, I'ethisterone, la cyproterone, I'aceta- extirpation ovarienne chirurgicale, par rayons te de cyproterone, le levo-norgestrel, le d- ou produits chimiques, soit a la suite d'une norgestrel, le dl-norgestrel, le d-17a-acetoxy- insuffisance ovarienne precoce. 1 3/3-ethyl-1 7a-ethinylgon-4-ene-3-one oxime, le gestodene, le norgestimate et le desoges- 3. Preparation selon la revendication 1 ou 2, dans 25 trel. laquelle chacun desdits nombres de doses uni- taires consiste en 2 a 4 doses unitaires. 11. Preparation selon la revendication 10, dans laquelle le progestatif est la norethisterone ou 4. Preparation selon I'une quelconque des reven- le norgestimate ou la progesterone. dications precedentes, dans laquelle chacun 30 desdits nombres de doses unitaires consiste 12. Preparation selon I'une des revendications pre- en 3 doses unitaires. cedentes, dans laquelle la quantite d'oestroge- ne par dose unitaire est comprise entre un 5. Preparation selon I'une quelconque des reven- minimum d'environ 0,3 mg et un maximum dications precedentes, dans laquelle les doses 35 d'environ 5,0 mg de sulfate d'estrone-piperazi- unitaires sont administrees par voie orale, pa- ne ou une dose equivalente d'un autre oestro- renteral, sublinguale, percutanee, intravagina- gene synthetique ou naturel et la quantite de le, intranasale ou buccale. progestatif par dose unitaire peut etre compri- se entre un minimum d'environ 0,0 mg et un 6. Preparation selon la revendication 5, dans la- 40 maximum d'environ 5,0 mg de norethisterone quelle les doses unitaires sont administrees ou de son equivalent en progestatif syntheti- par voie orale. que ou naturel.

7. Preparation selon la revendication 5, dans la- 13. Preparation selon la revendication 12, dans quelle les doses unitaires sont administrees 45 laquelle la quantite d'oestrogene par dose uni- par voie percutanee. taire est comprise entre 0,3 mg et 2,5 mg de sulfate d'estrone-piperazine ou son equivalent. 8. Preparation selon I'une quelconque des reven- dications precedentes, dans laquelle I'oestro- 14. Preparation selon la revendication 12 ou 13, gene est selectionne parmi les oestrogenes de 50 dans laquelle les doses unitaires sont desti- synthese selectionnes parmi le 17a-ethinyles- nees a I'administration orale et chacun desdits tradiol et ses esters et ethers, I'ethinylestradiol, nombres est 1 , 2, 3 ou 4, et les doses unitaires le mestranol et le quinestranol et parmi les de I'association a activite oestrogenique relati- oestrogenes naturels selectionnes parmi les vement dominante contiennent 0,75 mg de sul- oestrogenes equins conjugues, le 17/3-estra- 55 fate d'estrone-piperazine et les doses unitaires diol, le valerate d'estradiol, I'estrone, le sulfate de I'association a activite progestative relative- d'estrone, le sulfate d'estrone-piperazine, I'es- ment dominante contiennent 0,75 mg de sulfa- triol, le succinate d'estriol et le phosphate de te d'estrone-piperazine et 0,35 mg de norethis-

17 31 EP 0 309 263 B1 32

terone. mg de sulfate d'estrone et 0,35 mg de nore- thisterone, I'une et I'autre administrees par 15. Preparation selon la revendication 12 ou 13, voie orale. dans laquelle les doses unitaires sont desti- nees a I'administration orale et chacun desdits 5 21. Preparation selon la revendication 12 ou 13, nombres est 1, 2, 3 ou 4 et dans laquelle les dans laquelle les doses unitaires sont desti- doses unitaires de I'association a dominance nees a I'administration percutanee et a I'admi- oestrogenique contiennent 0,75 mg de sulfate nistration en alternance par periodes de 3 jours d'estrone-piperazine et 0,15 mg de norethiste- de 17/3-estradiol a raison de 0,1 mg/jour et par rone et les doses unitaires de I'association a io periodes de 3 jours de 17/3-estradiol a raison dominance progestative contiennent 0,75 mg de 0,1 mg/jour et de norethisterone a raison de de sulfate d'estrone-piperazine et 0,35 mg de 0,35 mg/jour. norethisterone. 22. Emploi d'un oestrogene et d'un progestatif 16. Preparation selon la revendication 14 ou 15, is dans un procede de preparation d'un produit, dans laquelle les doses unitaires sont desti- caracterise en ce que le produit est destine a nees a I'administration en groupes alternants I'hormonotherapie substitutive et contient un de 3 pour chaque types de dose unitaire oestrogene et un progestatif sous la forme contenant une hormone. d'une preparation associee destinee a I'admi- 20 nistration chez une femme necessitant une 17. Preparation selon la revendication 12 ou 13, hormonotherapie, de fagon continue et conse- dans laquelle chacun desdits nombres est 3 et cutive, par alternance d'un certain nombre de dans laquelle les doses de I'association a acti- doses unitaires a activite oestrogenique relati- vite oestrogenique relativement dominante vement dominante et d'un certain nombre de contiennent 1 mg de 17/3-estradiol et les doses 25 doses unitaires a activite progestatique relati- de I'association a activite progestative relative- vement dominante, chacun desdits nombres ment dominante contiennent 1 mg de 17/3- de doses unitaires consistant en 1 a 5 doses estradiol et 0,35 mg de norethisterone, I'une et unitaires. I'autre etant administrees par voie orale. 30 23. Emploi selon la revendication 22, lequel est 18. Preparation selon la revendication 12 ou 13, destine a I'administration chez une femme en dans laquelle chacun desdits nombres est 3 et age de procreer ou plus agee dont la produc- dans laquelle la dose unitaire de I'association a tion ovarienne d'oestrogene et de progestero- activite oestrogenique relativement dominante ne a ete interrompue soit a la suite d'une contient 0,75 mg de sulfate d'estrone et la 35 menopause naturelle, soit a la suite d'une dose unitaire de I'association a activite proges- ablation ou extirpation ovarienne chirurgicale, tative relativement dominante contient 0,75 mg par rayons ou par produits chimiques, soit a la de sulfate d'estrone et 0,050 mg de norgesti- suite d'une insuffisance ovarienne precoce. mate, I'une et I'autre administrees par voie orale. 40 24. Emploi selon la revendication 22 ou 23, dans lequel le produit presente les autres caracteris- 19. Preparation selon la revendication 12 ou 13, tiques definies dans I'une quelconque des re- dans laquelle chacun desdits nombres est 3 et vendications 3 a 21 . dans laquelle la dose unitaire de I'association a activite oestrogenique relativement dominante 45 Revendicatlons pour les Etats contractants contient 1 ,25 mg de sulfate d'estrone et I'asso- suivants : ES, GR ciation a dominance progestative relative contient 1,25 mg de sulfate d'estrone et soit 1. Emploi d'un oestrogene et d'un progestatif 0,35 mg, soit 0,5 mg de norethisterone, I'une dans un procede de preparation d'un produit, et I'autre administrees par voie orale. 50 caracterise en ce que le produit est destine a I'hormonotherapie substitutive et contient un 20. Preparation selon la revendication 12 ou 13, oestrogene et un progestatif sous la forme dans laquelle chacun desdits nombres est 1 , 2, d'une preparation associee destinee a I'admi- 3 ou 4 et dans laquelle I'association a activite nistration, chez une femme necessitant une oestrogenique relativement dominante contient 55 hormonotherapie, de fagon continue et conse- 0,75 mg de sulfate d'estrone et 0,15 mg de cutive, par alternance d'un certain nombre de norethisterone et I'association a activite pro- doses unitaires a activite oestrogenique relati- gestative relativement dominante contient 0,75 vement dominante et d'un certain nombre de

18 33 EP 0 309 263 B1 34

doses unitaires a activite progestative relative- ters de 17-hydroxyprogesterone, les esters de ment dominante, chacun desdits nombres de 19-nor-17-hydroxyprogesterone, la 17a-ethinyl- doses unitaires consistant en 1 a 5 doses testosterone et ses derives, la 17a-ethinyl-19- unitaires. nortestosterone et ses derives, la norethistero- 5 ne, I'acetate de norethisterone, le diacetate 2. Emploi selon la revendication 1 , dans lequel la d'ethynodiol, la dydrogesterone, I'acetate de femme a traiter est en age de procreer ou plus medroxyprogesterone, le norethynodrel, I'ally- agee et sa production ovarienne d'oestrogene lestrenol, le lynestrenol, I'acetate de quingesta- et de progesterone a ete interrompue soit a la nol, la medrogestone, la norgestrienone, la di- suite d'une menopause naturelle, soit a la suite io methisterone, I'ethisterone, la cyproterone, d'une ablation ou extirpation ovarienne chirur- I'acetate de cyproterone, le levo-norgestrel, le gicale, par rayons ou par produits chimiques, d-norgestrel, le dl-norgestrel, le d-17a-acetoxy- soit a la suite d'une insuffisance ovarienne 1 3/3-ethyl-1 7a-ethinylgon-4-ene-3-one oxime, precoce. le gestodene, le norgestimate et le desoges- 15 trel. 3. Emploi selon la revendication 1 ou 2, dans lequel chacun desdits nombres de doses uni- 11. Emploi selon la revendication 10, dans lequel taires consiste en 2 a 4 doses unitaires. le progestatif est la norethisterone ou le nor- gestimate ou la progesterone. 4. Emploi selon I'une quelconque des revendica- 20 tions precedentes, dans lequel chacun desdits 12. Emploi selon I'une quelconque des revendica- nombres de doses unitaires consiste en 3 do- tions precedentes, dans lequel la quantite ses unitaires. d'oestrogene par dose unitaire est comprise entre un minimum d'environ 0,3 mg et un 5. Emploi selon I'une quelconque des revendica- 25 maximum d'environ 5,0 mg de sulfate d'estro- tions precedentes, dans lequel les doses uni- nepiperazine ou une dose equivalente d'un au- taires conviennent a I'administration par voie tre oestrogene synthetique ou naturel et la orale, parenteral, sublinguale, percutanee, in- quantite de progestatif par dose unitaire peut travaginale, intranasale ou buccale. etre comprise entre un minimum d'environ 0,0 30 mg et un maximum d'environ 5,0 mg de nore- 6. Emploi selon la revendication 5, dans lequel thisterone ou son equivalent en progestatif les doses unitaires conviennent a I'administra- synthetique ou naturel. tion par voie orale. 13. Emploi selon la revendication 12, dans lequel 7. Emploi selon la revendication 5, dans lequel 35 la quantite d'oestrogene par dose unitaire est les doses unitaires conviennent a I'administra- comprise entre 0,3 mg et 2,5 mg de sulfate tion par voie percutanee. d'estrone-piperazine ou son equivalent.

8. Emploi selon I'une quelconque des revendica- 14. Emploi selon la revendication 12 ou 13, dans tions precedentes, dans lequel I'oestrogene est 40 lequel les doses unitaires sont destinees a selectionne parmi des oestrogenes de syntha- I'administration orale et chacun desdits nom- se selectionnes parmi le 17a-ethinylestradiol et bres est 1 , 2, 3 ou 4 et les doses unitaires de ses esters et ethers, I'ethinylestradiol, le mes- I'association a activite oestrogenique relative- tranol et quinestranol et parmi des oestrogenes ment dominante contiennent 0,75 mg de sulfa- naturels selectionnes parmi les oestrogenes 45 te d'estrone-piperazine et les doses unitaires equins conjugues, le 17/3-estradiol, le valerate de I'association a activite progestative relative- d'estradiol, I'estrone, le sulfate d'estrone, le ment dominante contiennent 0,75 mg de sulfa- sulfate d'estrone-piperazine, I'estriol, le succi- te d'estrone-piperazine et 0,35 mg de norethis- nate d'estriol et le phosphate de polyestrol. terone. 50 9. Emploi selon la revendication 8, dans lequel 15. Emploi selon la revendication 12 ou 13, dans I'oestrogene est selectionne parmi le sulfate lequel les doses unitaires sont destinees a d'estrone, le sulfate d'estrone-piperazine et le I'administration orale et chacun desdits nom- 17/3-estradiol. bres est 1 , 2, 3 ou 4 et dans lequel les doses 55 unitaires de I'association a dominance oestro- 10. Emploi selon I'une quelconque des revendica- genique contiennent 0,75 mg de sulfate d'es- tions precedentes, dans lequel le progestatif trone-piperazine et 0,15 mg de norethisterone est selectionne parmi la progesterone, les es- et les doses unitaires de I'association a domi-

19 35 EP 0 309 263 B1 36

nance progestative contiennent 0,75 mg de 0,1 mg/jour et de norethisterone a raison de sulfate d'estrone-piperazine et 0,35 mg de no- 0,35 mg/jour. rethisterone. 22. Procede de preparation d'un produit, caracteri- 16. Emploi selon la revendication 14 ou 15, dans 5 se en ce que le produit est destine a I'hormo- lequel les doses unitaires sont destinees a notherapie substitutive et contient un oestroge- I'administration en groupes alternants de 3 ne et un progestatif sous la forme d'une prepa- pour chaque type de dose unitaire contenant ration associee destinee a I'administration chez une hormone. une femme necessitant une hormonotherapie, 10 de fagon continue et consecutive, par alternan- 17. Emploi selon la revendication 12 ou 13, dans ce d'un certain nombre de doses unitaires a lequel chacun desdits nombres est 3 et dans activite oestrogenique relativement dominante lequel les doses de I'association a activite oes- et d'un certain nombre de doses unitaires a trogenique relativement dominante contiennent activite progestative relativement dominante, 1 mg de 17/3-estradiol et les doses de I'asso- is chacun desdits nombres de doses unitaires ciation a activite progestative relativement do- consistant en 1 a 5 doses unitaires. minante contiennent 1 mg de 17/3-estradiol et 0,35 mg de norethisterone, I'une et I'autre 23. Procede de preparation d'un produit de substi- etant administrees par voie orale. tution hormonale comprenant un oestrogene et 20 un progestatif, comprenant les etapes consis- 18. Emploi selon la revendication 12 ou 13, dans tant a selectionner une quantite d'oestrogene lequel chacun desdits nombres est 3 et dans et une quantite de progestatif appropriees pour lequel la dose unitaire de I'association a activi- obtenir une dose unitaire a activite oestrogeni- te oestrogenique relativement dominante que relativement dominante, a melanger I'oes- contient 0,75 mg de sulfate d'estrone et la 25 trogene et le progestatif de la dose a activite dose unitaire de I'association a activite proges- oestrogenique relativement dominante avec un tative relativement dominante contient 0,75 mg excipient pharmaceutique, a selectionner une de sulfate d'estrone et 0,050 mg de norgesti- quantite d'oestrogene et de progestatif appro- mate, I'une et I'autre etant administrees par priee pour obtenir une dose unitaire a activite voie orale. 30 progestative relativement dominante, a melan- ger I'oestrogene et le progestatif de la dose a 19. Emploi selon la revendication 12 ou 13, dans activite progestative relativement dominante lequel chacun desdits nombres est 3 et dans avec un excipient pharmaceutique et a condi- lequel la dose unitaire de I'association a activi- tionner les doses unitaires selon une disposi- te oestrogenique relativement dominante 35 tion destinee a I'administration continue et contient 1 ,25 mg de sulfate d'estrone et I'asso- consecutive, par alternance, d'un certain nom- ciation a dominance progestative relative bre de doses unitaires a activite oestrogenique contient 1,25 mg de sulfate d'estrone et soit relativement dominante et d'un certain nombre 0,35 mg, soit 0,5 mg de norethisterone, I'une de doses unitaires a activite progestative relati- et I'autre etant administrees par voie orale. 40 vement dominante, chacun desdits nombres de doses unitaires consistant en 1 a 5 doses 20. Emploi selon la revendication 12 ou 13, dans unitaires. lequel chacun desdits nombres est 1 , 2, 3 ou 4 et dans lequel I'association a activite oestroge- 24. Procede selon la revendication 23, dans lequel nique relativement dominante contient 0,75 mg 45 les doses unitaires sont moulees pour former de sulfate d'estrone et 0,15 mg de norethiste- des comprimes et les comprimes sont presen- rone et I'association a activite progestative re- ted en un conditionnement transparent com- lativement dominante contient 0,75 mg de sul- prenant 28 doses unitaires disposees selon un fate d'estrone et 0,35 mg de norethisterone, ordre fixe. I'une et I'autre etant administrees par voie ora- 50 le. 25. Procede selon la revendication 24, dans lequel le conditionnement comprend des indications 21. Emploi selon la revendication 12 ou 13, dans de dates adjacentes a chaque comprime, indi- lequel les doses unitaires sont destinees a quant le jour auquel le comprime correspon- I'administration percutanee et a I'administration 55 dent doit etre pris. en alternance par periodes de 3 jours, de 17/3- estradiol a raison de 0,1 mg/jour et, par perio- 26. Procede selon I'une quelconque des revendi- des de 3 jours, de 17/3-estradiol a raison de cations 22 a 25, dans lequel le produit est

20 37 EP 0 309 263 B1 38

destine a I'administration chez une femme en age de procreer ou plus agee dont la produc- tion ovarienne d'oestrogene et de progestero- ne a ete interrompue soit a la suite d'une menopause naturelle, soit a la suite d'une 5 ablation ou extirpation ovarienne chirurgicale, par rayons ou produits chimiques, soit a la suite d'une insuffisance ovarienne precoce.

27. Procede selon I'une quelconque des revendi- 10 cations 22 a 26, lequel possede les caracteris- tiques supplementaires definies dans I'une quelconque des revendications 3 a 21 .

75

20

25

30

35

40

45

50

21