DK174181B1 - Compsn. for hormone replacement therapy and contraception - comprises alternating dominant oestrogen activity with dominant progestagenic activity combinations of oestrogen and progestin - Google Patents

Abstract

Combined oestrogen and progestin prepn. comprises: (a) unit doses of dominant oestrogen activity; and (b) unit doses of dominant progestin activity. The oestrogen is natural or synthetic and is pref. 17-alpha-ethenybestradiol (Ia) or its esters or ethers, conjugated equine oestrogens, 17-beta-oestradiol (Ib), oestradiol valerate, oestrone, oestrone sulphate, piperazine oestrone sulphate (Ic) oestriol, oestriol succinate, polyoestrol phosphate, ethenyl oestradiol, menstranol or quinestranol. The progestin is progesterone, 17-hydroxy progesterone esters, 17-nor-17-hydroxy progesterone esters, 17alpha-ethinyl testosterone, 17alpha-ethinyl-10-nor-testosterone, or their derivs., norethindrone, norethindrone acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestrone, norgestrienone, dimethisterone, ethisterone, cyproterone, cyproterone acetate, levonorgestrel, d-norgestrel, dl-norgestrel, d-17-beta-acetoxy-13-beta-ethyl -17-alpha-ethinyl-gon -4-en-3-one oxime, gestodene, norgestimate or desogestrel and is esp. norethindrone (IIa) or norgestimate for contraceptives or progesterone for hormone replacement.

Description

in DK 174181 B1

The present invention relates to a hormone composition utilizing a combination of estrogen and progestin in which a short period of relatively dominant estrogen activity alternates with a short period of relatively dominant progestagen activity. The preparation is suitable for hormone-5 treatment of menopausal women or after surgery.

During the luteal phase of the menstrual cycle, serum progesterone concentrations are increased and progesterone-mediated secretory changes occur in the uterine endometrium. The presence of progesterone receptors has been shown to be necessary for progesterone action in the endometrium (see Walters, MR and Clark, J.H. "Relationship between the quantity of progesterone receptors and the antagonism of estrogen-induced uterotropic response" Endocrinology 105: 382, 1979), and it is well documented that priming in the follicular phase of the cycle is responsible for the development of both estrogen and progesterone receptors (see Bayard, F., Damilano, S., Robel, P. and Baulien, E.E. Cytoplasmic and nuclear estradiol and progesterone receptors in human endometrium, "J. Clin Endocrinol Metab. 46: 635, 1978). On the other hand, progesterone exhibits a negative feedback effect on its own receptor (see Tseng, L. and Gurpide, E. "Effects of progestins on estradiol receptor levels in human endometrium", J. Clin Endocrinol Metab. 41: 402, 1975) and also acts by downregulating endometrial estrogen receptors, possibly by introducing an estrogen receptor regulatory factor (see Leavitt, WW, Okulicz, WC,

McCracken, J.A., Schramm, W.S. and Robidoux, W.F. Jr. "Rapid recovery of nuclear estrogen receptor and oxytocin receptor in the ovary uterus following 25 progesterone withdrawal", J. Steroid Biochem. 22: 686.1985).

These physiological changes can be reproduced pharmaceutically as shown by the introduction of estrogen and progesterone receptors in postmenopausal women by administration of ethinyl estradiol (see Kreitmann, B., bugat, R. and 30 Bayard, F. "Estrogen and Progestin Regulation of the Progesterone Receptor Concentration in Human Endometrium, J. Clin Endocrinol Metab. 49: 926, 2 DK 174181 B1 1979). Neumannova et al. (see "Short-Term Effects of Tamoxifen, Medroxyprogesterone Acetate, and Their Combination on Receptor Kinetics and 17beta-Hydroxysteroid Dehydrogenase in Human Endometrium", Obstet.

Gynecol. 66: 695, 1985) have also shown that administration of medroxy-5 progesterone acetate in estrogen-primed women decreases the concentration of endometrial progestin receptors while simultaneously increasing the activity of 17β-hydroxysteroid dehydrogenase, an enzyme responsible for the metabolism of estradiol to the less powerful estrone.

10 A compound interaction occurs between estrogen and progesterone or progestin in the human endometrium with the progestins acting as anti-estrogens. Estrogen and progestion interactions are also dynamic. Eg. estrogen administration increased the concentration of both estrogen and progestin receptors to peak levels, 7 times above baseline, over 3 15 days (see Ekert, RL and Katzenellenbogen, BS "Human Endometrial Cells in Primary Tissue Culture: Modulation of the Progesterone Receptor Level by Natural and Synthetic Estrogens in Vitro ", J. Clin Endocrinol Metab. 52: 699, 1981). A threefold increase in receptor concentrations occurred over one day. Normal physiological concentrations of progesterone during the first 3 2 days of the luteal phase resulted in a rapid and substantial decrease in estrogen receptor number (see Kreitmann-Gimbal, B., Bayard, F., Nixon, W. E. and Hodgen, G. D. Patterns of Estrogen and Progesterone Receptors in Monkey Endometrium During the Normal Menstrual Cycle ", Steroids 35: 471, 1980).

Exogenous administration of progesterone to cynomolgous macaque significantly suppressed estrogen receptors over 1 to 2 days (see West, NB and Brenner, RM "Progesterone-Mediated Suppression of Estradiol Receptors in Cynomolgous Macaque Cervix, Endometrium and Oviduct During Sequential Estradiol Treatment, J. Steroid Biochem. 22:29, 1985, and medroxyprogesterone acetate were able to substantially suppress progestin receptor concentrations in premenopausal women over 4 hours (see Neumannova M., Kauppila, A., Kivinen, S., and Vihko, R.

3 DK 174181 B1 "Short-Term Effects of Tamoxifen, Medroxy-Progesterone Acetate, and Their Combination on Receptor Kinetics and 17beta-Hydroxysteroid Dehydrogenase in Human Endometrium", Obstet. Gynecol. 66: 695, 1985). In contrast, progesterone withdrawal in the presence of constant estrogen concentrations has been shown to result in rapid (6 to 12 hours) recovery of sheep estrogen nuclear estrogen receptors associated with an estrogen-induced biological response, namely production of oxytocin receptors (see Leavitt, W.W.,

Okulicz, W.C., McCracken, J.A., Schramm, W.S. and Robidoux, W.F. Jr. "Rapid recovery of nuclear estrogen receptor and oxytocin receptor in the ovary lo uterius following progesterone withdrawal", J. Steroid Biochem. 22: 686, 1985). A similar phenomenon occurs in pregnant guinea pigs when estrogen concentrations rise relative to pre-birth progesterone concentrations (see Alexandrova, M. and Soloff. M.S. "Oxytocin receptors and parturition in the guinea pig", Biol. Rep. 22: 1106,1980).

15

Therefore, estrogen appears to act by stimulating both estrogen-like progestin receptor concentrations and by introducing endometrial sensitivity to both estrogen and progestin. Progesterone or progestin exhibits an antiestrogenic effect by decreasing estrogen receptors and by increasing 17β-hydroxysteroid dehydrogenase activity in endometrial tissue. However, it appears that the stimulatory effects of progesterone on human endometrial function are of short duration, possibly due to a self-provoked down-regulation of progestin receptors and estrogen receptors.

Eg. peaks the effect of progesterone on 17β-hydroxysteroid dehydro-2 genase after 3 days and is then followed for 2 to 3 weeks by the suppression of the enzyme (see Whitehead, MI, Townsend, PT, Pryse-Davies, J. et al. "Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium ", N. Engl, J. Med. 305: 1599, 1981).

30 Currently, a number of contraceptive preparations are marketed, which can be easily classified into several general types. The first of these is known as mono-nophatic preparations. These contain a constant amount of estrogen and progestin. Annoying side effects of these pills depend on the balance between the pill's estrogen and progestin component. Eg. with a relatively dominant progestin pill, the preparation over time will result in the depletion of 5 estrogen and progestin receptors. This could be expected to result in an under-stimulated or atropic endometrium that could possibly cause either amenorrhea or breakthrough bleeding or spot bleeding despite pills due to poor epithelialization. On the other hand, with relatively predominantly estrogenic preparations, it is possible that prolonged use could result in endometrial growth, with the resultant development of unsupported light stroma and subsequent spot bleeding or breakthrough bleeding.

Newer preparations known as triphasic have varying concentrations of estrogen and progestin; in most cases, they consist of relatively constant amounts of estrogen with a gradually increasing amount of progestin throughout the cycle. This pattern of estrogen and progestin administration results in a relatively estrogen-dominated preparation at the beginning of the pack with increasing progestagen activity towards the end of the pack. Endome trial stability may be better with these pills as the estrogenic activity at the beginning of the package induces both estrogen and progestin receptors which make the endometrium sensitive to the increased concentrations of progestin towards the end of the package. Progestin activity produces denser, more stable endometrial stroma, although the relatively long duration of progestin exposure toward the end of the pack may still lead to a decrease in estrogen and progestin receptors and activity. A major problem with this type of preparation is the low dose of steroids at the beginning of the pack which makes these pills vulnerable to drug interactions or forgotten pills which can lead to breakthrough ovulation. The onset of packing is the critical part in breakthrough ovulation, as the user has just completed a 7-day drug-free period during which follicular development can begin. Although pregnancy does not occur,! 5 DK 174181 B1 breakthrough ovulation can lead to poor cycle control.

Estrogen replacement therapy is recommended for menopausal women for a variety of reasons, estrogen replacement will alleviate hot flushes, and this relief for heath-5 trips and night sweats improves sleep patterns and contributes to the general well-being of the patient (see Campbell S., Whitehead M. "Estrogen therapy and the menopausal syndrome" in Clinics in Obstetrics and Gynecology, Volume 4. "The Menopause," edited by RB Greenblatt, J. W. Studd, London, W. B. Saunders, 1977, pages 31-47; Erlik Y., Tataryn IV, Meldrum DR et al. "Associati-10 on of waking episodes with menopausal hot flushes ", JAMA 24: 1741,1981). Estrogen replacement protects against postmenopausal loss of skeletal calcium, especially from vertebrate bodies, preventing collapse fracture and loss of body weight (see Lindsay R., Hart D.M., Forrest, C. et al. "Prevention of spinal osteoporosis in oophorectomized women"). Lancet 2: 1151, 1980 (1980). Several studies have now reported that long-term estrogen therapy is also associated with a reduction in the incidence of classic forearm and hip osteoporo fractures (see Hutchinson, T.A., Plansky, S.M.,

Finestein, A. "Postmenopausal estrogens protect against hip and distal radius fractures", Lancet 2: 706, 1979; Paganini-Hill, A., Ross, R. K., Gerkins, 20 V. R., et al. "A case control study of menopausal estrogen therapy in hip fractures", Annals of Internal Medicine 95:28, 1981; Weiss N.S., Hours C.L., Ballard J.H. et al. "Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen", New England Journal of Medicine 303: 1195, 1980). Another useful effect of using estrogen over a longer period is the reduction of the risk of death due to ischemic heart disease, usually mediated by changes in blood lipoprotein concentrations (see Ross RK, Aganini-Hill A., Mack TM et al. " Menopausal estrogen therapy and protection from ischemic heart disease ", Lancet 1: 858, 1981). Estrogen replacement has also been shown to improve the vascularity and health status of the vaginal mucosa and urinary tract. The only major risk factor associated with estrogen administration in the doses required to alleviate menopausal symptoms is hyperstimulation of the endometrium and an increased risk of endometrial cancer, uterine cancer (see Cramer DW, Knapp RC "Review of epidemiologic studies of endometrial cancer and exogenous estrogen ", Obstetris and Gynecology 54: 521, 1979; 5 Shapiro S., Coughman D.W., Sloan D., et al." Recent and past use of conjugated estrogens in relation to endometrial adenocarcinoma ", New England Journal of Medicine 303: 485,1980).

Estrogens predispose to endometrial cancer by stimulating cell chemistry and proliferating and increasing the degree of DNA synthesis and nuclear estradiol receptors in the endometrium (see Whitehead MI, Townsen PT, Pryce-Davies J., et al. "Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium ", New England Journal of Medicine 305: 1599; Whitehead MI, Townsen PT, Pryce-Davies J., et al.

15 "Actions of progestins on the morphology and biochemistry of the endom triumph of postmenopausal women receiving low dose estrogen therapy", American Journal of Obstetrics and Gynecology, 141: 791, 1982).

The addition of a progestin for 13 days each month has been shown to protect the 20 endometrium from these stimulatory effects from estrogen (see Gambrille RD, Jr., Massey FM, Castaneda et al. "Use of the progestogen challenge test to reduce the risk of endometrial cancer ", Obstetrics and Gynecology 55: 732, 1980; Studd JWW, Thom MH, Patterson MEL, Wade-Evans T.

"The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens", in Pasetto N., Paoletti R., Armbus J.L., ed., "The menopause and postmenopause", Lancester MPT Press.

127.1980).

The addition of a progestin protects the endometrium by reducing nuclear estradiol receptor concentration and thereby reducing nuclear estrogen bioavailability, resulting in an antimitotic effect and reduction of DNA synthesis. The progestins also increase the activity of endometrial estradium in diol-17β dehydrogenase, an enzyme that metabolizes estradiol to estrone, a less potent estrogen (see Whitehead M.I., Townsen P.T., Pryce-Davies J.

"Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium", New England Journal of Medicine, 305: 1599, 1981; King Townsen P.T., Sittle N.C., et al. "Regulation of estrogen and progesterone receptor levels in epithelium and stroma from pre and postmenopausal endometria", Journal of Steroids and Biochemistry, 16:21, 1982; Gurpide E. "Enzymatic modulation of hormonal action at the target tissue", Journal of Toxicology and Environmental Health, 4: 249, 1978).

The addition of progestin to estrogen replacement therapy may also result in an increase in bone mass when starting within 3 years after the onset of menopause (see Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy "A 10 year prospective study in relationship to 15 osteoporosis ", Obstetrics and Gynecology 53: 277,1979; Lindsay R., Hart D. M., Forest C., et al." Prevention of spinal osteoporosis in oophorectomized women ", Lancet 2: 1151,1980). However, concerns have been expressed about the powerful side effects of progestin by suppressing high-density lipoprotein cholestrol concentrations (see Hirvonen E., Malkonen M., Manninen 20 V. "Effects of different progestogens on lipoproteins during postmenopausal replacement therapy", New England Journal of Medicine 304: 560 1981).

This cholesterol fraction appears to have a protective effect against ischemic heart disease and atherosclerosis. The reduction of HDL cholesterol with progestin could abrogate the long-term good effects of estrogen to reduce the incidence of myocardial infraction. Other side effects of progestins include acne, chest tightness, depression and irritability (see Barran-co VP "Effect of androgen dominant and estrogen dominant oral contraceptives on acne", Cutis 14: 384, 1974; Royal College of General Practioners "Oral Contraceptives and Health: An Interim Report ”, New York: Pitman, 30 1974). Since the side effects of progestin appear to be dose dependent, the dose progestin used in postmenopausal estrogen replacement therapy must be as small as possible to achieve endometrial protection (see Padwick ML., Pryce-Davies J., Whitehead M.A. simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens ",

New England Journal of Medicine 315: 930, 1986).

5

The biological effects of both estrogen and progestin in target tissues, such as the endometrium, are dependent on the amounts of estrogen and progestin receptors. Both estrogen and progestins exert a modulatory influence on the amount of their own receptors. For example, in the luteal phase of menstrual cyclone, serum progesterone concentrations decrease, and progesterone-mediated secretory changes occur in the uterine endometrium. The presence of progesterone receptors has been found to be a necessary prerequisite for progesterone action in the endometrium (see Walters MR and Clark JH, "Relationship between the quantity of progesterone receptors and the antagonism of estrogen-induced uterotropic response", Endocrinology 105: 382, 1979 ), and it is well documented that estrogen priming in the follicular phase of the cycle is responsible for the development of both estrogen and progesterone receptors (see Bayard F., Damilano S., Robel P., and Baulieu E. E. Cytoplasmic and nuclear estradiol and progesterone receptors in human endometrium ", Journal 20 Clinical Endocrinology and Metabolism 46: 635, 1978). On the other hand, progesterone exhibits a negative feedback effect on its own receptor (see Tseng L. and Gurpide E. "Effects of progestins on estradiol receptor levels in human endometrium", Journal Clinical Endocrinology and Metabolism 41: 402, 1975) and also works by down-regulate endometrial estrogen receptors, possibly by introducing an estrogen receptor regulatory factor (see Leavitt WW, Okulicz WC, McCracken JA, Schramm WS and Robidoux WF, Jr. "Rapid recovery of nuclear estrogen receptor and oxytocin receptor in the ovine uterus following progesterone withdrawal ", Journal Steroid Biochemistry 22: 686, 1985).

These physiological changes can be reproduced pharmacologically as shown by the introduction of estrogen and progestin receptors in postmenopausal women by administration of ethinyl estradiol (see Kreitmann B., Bugat R. and Bayard F. "Estrogen and progestin regulation of the progesterone. receptor concentration in human endometrium ", Journal Clinical Endocrinology and Metabolism 49: 926, 1979). Neumannova et al. 8se Short-term effects of tamoxifen, medroxyprogesterone acetate, and their combination on receptor kinetics and 17beta-hydroxysteroid dehydrogenase in human endometrium ", Obstetrics and Gynecology 66: 695, 1985) have also shown that administration of medroxyprogesterone acetate in estrogen-primed women 1 oon the endometrial progestin receptors while simultaneously increasing the activity of 17β-hydroxysteroid dehydroxygenase, the enzyme responsible for the metabolism of estradiol to the less potent estrone.

A complex interaction occurs between estrogen and progesterone or progestin in the human endometrium, where the progestins act as anti-estrogens. Estrogen and progestin interactions are also dynamic. Eg. estrogen administration increased the concentration of both estrogen and progestin receptors to peak concentrations, 7 times above baseline, over 3 days (see (Ekert RL and Katzenellenbogen BS "Human endometrial cells 20 in primary tissue culture: Modulation of the progesterone receptor level by natural and synthetic estrogens in vitro ", Journal Clinical Endocrinology and Metabolism 52: 699, 1981). A three-fold increase in receptor concentrations occurred over 1 day. Normal physiological concentrations of progesterone during the first 3 days of the luteal phase resulted in a rapid and significant decrease in estrogen receptor number (see Kreitmann-Gimbal B., Bayard F., Nixon W. E. and Hodgen G. D. "Patterns of estrogen and progesterone receptors in monkey endometrium during the normal menstrual cycle", Steroids 35: 471, 1980). of progesterone to cynomolgous macaque significantly suppressed estrogen receptors over 1 -2 days (see West 30 NB and Brenner R.M. "Progesterone-mediated suppression of estradiol receptors in cynomolgous macaque cervix, endometrium and oviduct during sequential estradiol-protesterone treatment", Journal Stroid Biochemistry 22:29, 1985), and medroxyprogesterone acetate was able to substantially suppress progestin receptors in premenopausal women over 4 hours (see Naumannova M., Kauppila A., Kivinen S., and Vihko R.

5 "Short-term effects of tamoxifen, medroxyprogesterone acetate, and their combination on receptor kinetics and 17beta-hydroxysteroid dehydrogenase in human endometrium, Obstetrics and Gynecology 66: 695, 1985). In contrast, progesterone removal in the presence of constant estrogen concentrations has been shown to result in rapid (6-12 hours) recovery of nuclear 1 o estrogen receptors in the sheep endometrium, associated with an estrogen-induced biological response, namely production of oxytocin receptors (see Leavitt WW,

Okulica W.C., McCracken J.A., Schramm W.S. and Robidoux W.F., Jr. "Rapid recovery of nuclear estrogen receptor and oxytocin receptor in the ovine uterus following progesterone withdrawal", Journal Steroids and Biochemistry 15 22: 686, 1985). A similar phenomenon occurs in pregnant guinea pigs when estrogen concentrations increase relative to progesterone concentrations before delivery (Biology and Reproduction 22: 1106, 1980).

Therefore, estrogen seems to act by stimulating both estrogen and progestin receptor concentrations and introducing hypersensitivity to the endometrium to both estrogen and progestin. Progesterone or progestin exhibits an antiestrogenic effect by decreasing the concentration of estrogen receptors and by increasing 17β-hydroxysteroid dehydrogenase activity in endometrial tissue. However, it appears that the stimulatory effects of 25 progesterone on human endometrial function are of short duration, probably due to a self-provoked down-regulation of progestin receptors (see Neu-mannova M., Kauppila A., Kivinen S. and Vihko R. " Short-term effects of tamoxifen, medroxyprogestrone acetate, and their combination on receptor kinetics and 17beta-hydroxysteroid dehydrogenase in human endometrium ", 30 Obstetrics and Gynecology 66: 695,1985; Whitehead MI, Townsen PT, Pryce-Davies J. et al. "Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium", New England Journal of Medicine. 305: 1599, 1981). Eg. peaks the effect of progesterone on 17β-hydroxysteroid dehydrogenase after 3 days, followed by 2-3 weeks of suppression of the enzyme (see Whitehead, MI, Townsend, PT, Pryse-Davies, J. et al. "Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium", New England Journal Medicine 305: 1599, 1981).

Ongoing hormonal replacement consists of continuous (daily or cyclic) lo (eg, day # 1-25 of each month) estrogen administration with the addition of a progestin for 10-13 days (eg day # 13-25) every month. This type of replacement therapy is effective in preventing menopausal symptoms while protecting the endometrium from the development of hyperplasia or adenocarcinoma. However, the cyclic administration of a progestin leads to a temporally determined withdrawal bleeding or menstruation for 65-75% of women (see Hellberg D. Nilsson S. "Comparison of a triphasic estradiol / norethisterone acetate preparation with and without estriol component in the treatment of climacteric complaints ", Maturitas 5: 233, 1984; Christensen M.S., Hagen C., Christiansen C., Transbol I." Dose response evaluation of 20 cyclic estrogen / gestations in postmenopausal women ";" Placebo controlled trial of its gynecologic and metabolic actions ", American Journal of Obstetrics and Gynecology. 144: 873, 1982). This withdrawal bleeding or break bleeding is usually not welcome for the patient and may lead to problems with understanding. Also, because progestin administration is preceded by up to 13-16 days of unopposed estrogen therapy with endometrial proliferation and estrogen and progestin receptor induction, a high dose of progestin may be required to antagonize these effects, resulting in greater risk of adverse effects and adverse metabolic effects. effects. Newer continuous low-dose estrogen and progestin treatments for hormonal replacement 30 may avoid the problem of withdrawal bleeding (see Magos AL, Brincatt M., O'Dowd T., et al. "Amenorrhea and endometrial atrophy following conti- 12 DK 174181 B1 nous oral estrogen and progestogen therapy in postmenopausal women ",

Maturitas 6: 145, 1984). However, daily administration of progestin in this way yields use of both estrogen and progestin receptors, resulting in endometrial atrophy which can be associated with pervasive bleeding.

5 Since abnormal bleeding in a postmenopausal woman is known to be associated with endometrial carcinoma, it must be examined by endometrial examination for hypertrophy, usually at D&C. Daily administration of progestin also raises the concern that the beneficial effects of estrogen on DHL cholesterol metabolism will be adversely affected by a decrease 10 in DHL cholesterol (see Notelovitz M., Gudat J.C., Ware M.D., Dougherty M.C.

British Journal of Obstetrics and Gynecology. 90: 171, 1983).

The present invention relates to a pharmaceutical composition for administration to a woman of childbearing age or to an elderly woman whose ovarian estrogen and progesterone production has been interrupted either due to natural menopause, surgery, radiation or chemical ovarian ablation or extirpation or premature ovarian failure, comprising multiple dosage units, each dosage unit for continuous administration day after day, comprising dosage units of estrogen and progestin selected from a combination of relatively dominant estrogen activity and a combination of relatively dominant progestin activity wherein 1-5 dominant estrogen doses are alternated with 1-5 dominant progestin doses, and each dosage unit also includes a pharmaceutically acceptable inert carrier as needed.

25

The preparation is suitable for hormonal replacement therapy for administration to a woman in need of such treatment, especially for a woman of childbearing age or an elderly woman whose ovarian estrogen and progesterone production has been interrupted either due to natural menopause, surgery, radiation 30 or chemical ovarian ablation or extirpation or premature ovarian failure by continuously or sequentially daily administering multiple daily dosage regimens.

units comprising combinations of estrogen and progestin, selected from a combination of relatively predominant estrogen activity and a combination of relatively predominant progestin activity, alternating multiple dosage units with predominant estrogen activity with multiple dosing units with 5 predominant progestin activity.

The reduction of progestin dose possible with the present invention results in a pill which also has good estrogenic effect. The preparation is therefore good for controlling acne, oily skin and hirsutism, and there is also less risk of amenorrhea during the pill period.

The hormone replacement composition of the invention results in the absence of withdrawal bleeding, intermittent increases in estrogen activity, and stimulation of endometrial growth and progestin receptors. This makes the endometrium more sensitive to subsequent progestin activity, leading to growth by decrease in estrogen receptors and increase of the 173-hydroxysteroid dehydrogenase. The interaction of progestin with progestin receptors introduces secretory changes in the endometrium, resulting in closer stroma and endometrial stability. A return to relatively dominant estrogen activity then in turn stimulates estrogen and progestin receptors and renews endometrial sensitivity to progestin. This push-pull activity keeps the endometrial activity within a narrow range depending on the number of days of estrogen and progestin activity and maintains a stable endometrium, resulting in the absence of bleeding and withdrawal bleeding.

This hormonal replacement preparation allows for better progestational effects with less progestin. With the present invention, the dose of progestin is substantially reduced compared to a composition containing a constant daily dose of progestin. A total steroid dosage is obtained which is equal to or even lower than that given with the currently used cyclic administration method for estrogen and progestin for hormonal replacement therapy in ovarian failure. A reduction in progestin dose results in less adverse effect on HDL cholesterol concentrations. HDL cholesterol has been shown to be protective against the development of atherosclerosis. The concentration of HDL cholesterol is increased by estrogen and decreased by progestin.

5

The estrogens which may be used as a component of the present invention may be any of the conventionally available. The estrogen can typically be selected from synthetic and naturally occurring estrogens. The synthetic estrogens may e.g. be ethinylestradiol, mestranol or qui-10 o nestranol. Of particular interest are 17α-ethinylestradiol and esters and ethers thereof. The preferred estrogen is 17α-ethinylestradiol. The natural estrogens can e.g. be conjugated equine estrogens, estradiol-17β, estradiol valerate, estrone, piperazine estrone sulfate, estriol, estriol succinate, desogestrel and polyestrol phosphate.

15

The progestin component may be any progestationally active compound. Thus, the progestin may be selected from progesterone and its derivatives, such as e.g. 17-hydroxyprogesterone esters, 19-nor-17-hydroxyprogesterone esters, 17α-ethinyl testosterone and derivatives thereof, 17α-ethinyl-19-nortestostosterone and its derivatives, norethindrone, norethindrone acetate, ethynodiol diacetate, didrogesterone, medroxy , allylestrenol, lynoestrenol, fusing estanol acetate, medrogestone, norgestrienone, dimethide-rum, ethisterone, cyproterone, levo-norgestrel, d-norgestrel, dl-norgestrel, d-17a-acetoxy-13p-ethyl-17a-ethinyl-gon-4-en -3-onoxime, cyproterone acetate, gestoden and norgestimate. Preferred progestins are norethindrone, d-norgestrel and norgestimate.

In the invention, the majority of doses may contain from 1 to 5 dosage units, but preferably 3 dosage units are used. In a preferred form of the invention, 3 dosage units with relatively dominant estrogen activity are alternated with 3 dosage units with relatively dominant progestin activity, etc. for a total of 21 or 24 dosage units. 4 or 7 hormone-free dosage units are incorporated so that the preparation corresponds to the natural 28-day menstrual cycle for the woman. These pills may contain a placebo or any other hormone-free drug. Examples of suitable alternative agents are vitamins such as an iron supplement. Where the total dosage units do not include multiples of three, an appropriate number of hormone-free dosage units may be incorporated to yield the total number of desired units.

Generally, the amounts of estrogen and progestin are incorporated into the composition of the invention depending on the type of estrogen or progestin selected. However, the quantities used are generally lower than those. used in the currently marketed preparations for the reasons mentioned above. In the present composition, the estrogen content is kept constant while the progestin content is adjusted up or down to achieve the desired estrogen or progestin dominance. The choice of amount depends on the type of estrogen or progestin used, as each hormone has its own specific activity.

The amount of estrogen per dosage unit in hormone replacement preparations 20 can typically be in the range of a minimum of approx. 0.3 mg oestrone sulphate or equivalent to a maximum of approx. 2.5 mg of estrone sulfate or equivalent.

The amount of progestin per dosage unit can range from 0 mg to approx. 5 mg norethindrone or equivalent.

Some preferred combinations are as follows: 1. 3 dosage units with 0.75 mg piperazine estrone sulfate alternating with 3 dosage units with 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.

30 2. 3 dosage units with 0.75 mg of piperazine estrone sulfate and 0.15 mg 16 alternatively with 3 dosage units with 0.75 mg of piperazine estrone sulfate and 0.35 mg of norethindrone.

The above compositions may also be grouped into three or four dosage units in each group starting with either 3 or 4 day groups and ending with the opposite.

The compositions of the invention may be administered orally, preferably in tablet form, parenterally, sublingually, transdermally, intravaginally, intranasally, or buccally. The method of administration determines the types of estrogens and progestins useful in the preparation, as well as the amounts per unit dose. dosage unit.

Methods of transdermal administration comprising associated methods for preparing such systems are well known in the art. In this connection, reference is made to U.S. Patent Nos. 4,752,478, 4,685,911, 4,438,139, and 4,291,014.

Generally, the compositions of the invention are prepared according to generally known procedures in accordance with the method of administration. Thus, the active ingredients are prepared by known methods in a pharmaceutically acceptable form for administration. These ingredients are combined in the desired amounts with the appropriate pharmaceutical carriers, such as additives, auxiliaries and / or flavor enhancers. These substances may be referred to as diluents, binders and lubricants. Gums, starches, and sugar varieties are also commonly expressed. Typical of these types of substances or excipients are pharmaceutical grades of mannitiol, lactose starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose and magnesium carbonate. The active ingredient (s) may be approx. 0.01% by weight 30 to approx. 99.99% by weight of the entire composition, the remainder being the pharmaceutically acceptable carrier. The percentage of the active ingredient (s) may vary according to the delivery system or method of administration and is selected according to conventional methods known in the art.

Thus, the active ingredients are compounded with the selected carrier and e.g. in the case of a tablet form, they are placed in tablet forming apparatus to form the tablets, which are then packaged according to the manner chosen.

In the oral form of the composition, the contraceptive agents are preferably prepared in the form of a pharmaceutical kit or package, wherein the daily doses are arranged for appropriate sequence administration. Thus, the present invention also discloses a pharmaceutical package containing the combination type contraceptives in multiple unit doses in a synchronized solid sequence wherein the sequence or arrangement of the dosage units corresponds to daily administration.

Such packs are preferably in the form of a transparent pack of 28 dosage units arranged sequentially and consisting of 21 or 24 tablets containing the combined estrogen / progestin preparation cyclically arranged in 20 order of intake and then with 7 or 4 placebo doses.

The placebo tablets and tablets containing the hormones preferably have different colors or shapes. Data indications can be given on the package.

The gasket may be a tube or box or strip. The box may be circular, square or of other form with the tablets placed separately therein for easy administration. Date indications may appear next to each tablet, corresponding to the days on which each tablet should be taken. Any indication of the order in which the tablets are to be taken is preferred on the package regardless of its form.

The following examples describe specific embodiments of the present invention.

EXAMPLE 1 3-day phases with dosage units 17a-ethinyl * estradiol (EE) 0.035 mg and norethindrone (NET) 0.5 mg alternate with 3-day phases with dosage units of EE 0.035 mg and NET 0.75 mg for a total of 7 phases (21 days or 21 dosage units) starting and ending with the NET 0.5 mg combination.

EXAMPLE 2 3-day phases (dosage units of (EE) 0.035 mg and (NET) 0.5 mg) alternating with 3-day phases with EE 0.035 mg and NET 0.35 mg starting and ending with the 0.5 mg combination.

EXAMPLE 3 2 day phases with dosage units of (EE) 0.035 mg alternating with dosage units of EE 0.035 mg and NET 0.35 mg starting and ending 2 o with the first dosage unit and running for a total of 24 days.

Example 4 3-day phases with dosage units of (EE) 0.035 mg and (NET) 0.5 mg alternating with EE 0.035 mg and NET 0.35 mg and continuous for a total of 24 days.

EXAMPLE 5 3-day and 4-day phases with each of the above combinations as set forth in Examples 1 and 2 starting with either 3- or 4-day phases and ending 5 with the opposite.

EXAMPLE 6 4 day and 3 day phases with each of the above prepared starting with 10 a 4 day dosing unit with 0.035 mg EE.

EXAMPLE 7 3-day and 4-day phases of each of the above compositions starting with 15 a 3-day phase with 0.035 mg NET and 0.035 mg EE and ending with a 4 day phase with 0.5 mg NET and 0.035 mg EE.

EXAMPLE 8 20 1 day alternating phases using the dosage units as set forth in Examples 1 and 2.

Example 9 25 2-day alternating phases ending or beginning with a single 3-day phase using the dosage units as set forth in Example 1 or 2.

EXAMPLE 10 3-day phases with (EE) 0.035 mg and levnonorgestrel (D-norgestre) 0.05 mg 30 E 174181 B1 alternating with 3-day phases with EE 0.035 mg and levnonorgestrel 0.075 mg.

EXAMPLE 11 3 day phases with EE 0.035 mg and norgestimate 0.05 mg alternating with EE 0.035 mg and norgestimate 0.075 mg.

Example 12 10 3 day phases with EE 0.035 mg and norgestimate 0.05 mg alternating with EE 0.035 mg and norgestimate 0.035 mg.

EXAMPLES 13 and 14 15

A preparation was administered to two women for a total of 3 periods to show that cycle control is acceptable in terms of breakthrough bleeding. The test composition consisted of 3 unit doses of 0.035 mg of 17α-ethinylestradiol and 0.5 mg of norethindrone alternating with 3 dosage units of 0.035 17α-20 0 ethinylestradiol and 0.75 mg of norethindrone in a total of 7 groups of 3 starting and ending with 0.5 mg. norethindrone.

EXAMPLE 13 A 23-year-old woman who did not give birth who had not taken any hormonal medication, including oral contraceptives, for 3 months, agreed to take the test composition of the invention for 2 periods. The patient was in good health and did not smoke. She had no contraindications to the use of oral contraceptives, and her menstrual cycle was regular. The patient started with the test preparation on day # 5 of her cycle (menstruation is calculated from day # 1) for 21 on each other on the following days (first cycle) followed by a 7 day interval which was free of hormone therapy, and then restarted on the sample for another 21 days (second cycle). In the first cycle, she had no bleeding or spot bleeding while taking the sample, and she had a withdrawal bleeding starting at 2 days in the hormone-free interval. The withdrawal bleeding lasted for 5 days and was easier than a normal menstrual period consisting of reddish-brown stain bleeding. There were no drawbacks associated with the withdrawal bleeding. In the second cycle, she was also free from bleeding and stain bleeding while taking the sample and again had a brownish, very slight withdrawal bleeding which began 2 days after stopping the sample preparation and lasted for 6 days. The patient did not observe any side effects during the two test cycles.

EXAMPLE 14 15

The patient was a healthy, 27-year-old unborn woman who was currently taking a commercially available oral contraceptive preparation containing 17α-ethinylestradiol and dl-norgestrel ("Triphasil" (trademark of Wyeth Pharmaceuticals)). The patient agreed to take the test preparation 20 according to the invention for one cycle. She started the trial after a 7-day hormone-free period after the last 'Triphasil' tablet. The trial was taken for 21 days followed by a 7-day free trial. The patient had no staining or bleeding during the period of taking the trial, and observed a withdrawal bleeding that began 2 25 days after stopping the sample, withdrawal bleeding lasted 4 days, was painless, and was of the same strength and color as a normal menstrual period for the patient, and had no side effects during the intake of the sample.

30 Both patients found the sample preparation to be acceptable for cycle control, side effects, and menstrual bleeding.

22 DK 174181 B1

The following examples show hormone replacement therapy.

EXAMPLE 15 3 day phases with unit doses of 0.75 mg of piperazine estrone sulfate alternating with 3 days phases with unit doses of estrone sulfate 0.75 mg and NET 0.35 mg were administered continuously and orally.

EXAMPLE 16 3-day phases (unit doses of estrone sulfate 0.75 mg and norethindrone 0.15 mg) alternating with 3-day phases of estrone sulfate 0.75 mg and norethindrone 0.35 mg are given continuously and orally.

EXAMPLE 17 3-day phases with oral micronized 17β-estradiol 1 mg alternating with 3 days phases with 173-estradiol 1 mg and norethindrone 0.35 mg given continuously.

EXAMPLE 18 3-day phases of transdermal 17β-estradiol (100 µg / day) alternating with 25 days of transdermal 17β-estradiol (100 µg / day) and transdermal norethindrone (0.35 mg / day) given continuously.

EXAMPLE 19 3-day phases with estrone sulfate 1.25 mg alternatively with 3-day phases with estrone sulfate 1.25 mg and norethindrone 0.35 mg given continuously and orally.

EXAMPLE 20 3-day phases with estrone sulfate 1.25 mg alternating with 3-day phases with estrone sulfate 1.25 mg and norethindrone 0.5 mg given continuously and orally.

Example 21 10 1-day and 2-day phases alternating using dosage units as set forth in Examples 13 and 14 are administered continuously and orally.

Example 22 15 3-day phases with estrone sulfate 0.75 mg alternating with 3-day phases with estrone sulfate 0.75 mg and norgestimate 0.050 mg given continuously and orally.

EXAMPLE 23 3 day and 4 day phases of each of the combinations as set forth in Examples 13 and 14 starting with either a 3 day or 4 day phase and given continuously and orally.

EXAMPLE 24 2 day and 3 day phases with each of the combinations as set forth in Examples 13 and 14 starting with either a 2 day or 3 day phase and 30 given continuously and orally.

Claims (16)

1. Pharmaceutical preparation for hormone therapy of women of childbearing age or older women whose ovarian estrogen and progesterone production has been discontinued either due to natural menopause, surgery, radiation or chemical ovarian ablation or extirpation or premature ovarian failure , characterized in that it comprises multiple dosage units for continuous and consecutive daily administration comprising combinations of estrogen and progestin selected from a combination of relatively 10 dominant progestin activity, with 1-5 dominant estrogen activity doses alternating with 1-5 dominant progestin activity doses, and each dosage unit comprises a pharmaceutically acceptable inert carrier when needed. Pharmaceutical composition according to claim 1, characterized in that estrogen nets are synthetic or natural and the progestin is any progestational active compound. Pharmaceutical composition according to claim 1, characterized in that estrogen is one of the following synthetic estrogens: ethinyl estradiol, mestranol and quinestranol. Pharmaceutical composition according to claim 1, characterized in that the estrogen is 17a-ethinyl-estradiol or an ester or an ether thereof. 25 Pharmaceutical composition according to claim 1, characterized in that the estrogen is natural and selected from conjugated equine estrogens, 17β-estradiol, estradiol valerate, estrone, estrone sulfate, piperazine estrone sulfate, estriol, estriol succinate and polyestrol phosphate. 30 DK 174181 B1 Pharmaceutical composition according to claim 1, characterized in that the progestin is selected from progesterone, 17-hydroxyprogesterone esters, 19-nor-17-hydroxyprogesterone esters, 17a-ethinyltestosterone, 17a-ethinyl-19-nor-testosterone and derivatives thereof. , norethindrone, norethindrone acetate, ethynodiol diacetate, didrogesterone, medroxy-progesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogeston, norgestrienone, dimethide rum, ethisterone nestrone nestrone nitrate 17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-ene-3-one oxime, cyproterone acetate, gestoden, norgestimate and desogestrel. 10 Pharmaceutical composition according to claim 1, characterized in that the progestin is norethindrone, norgestimate or progesterone. Pharmaceutical composition according to claim 1, characterized in that the estrogen is as defined in any of claims 2-5, and the progestin is selected from progesterone, 17-hydroxyprogesterone esters, 19-nor-17-hydroxyprogesterone esters, 17a -ethinyltestosterone, 17α-ethinyl-19-nor-testosterone and its derivatives, norethindrone, norethindrone acetate, ethynodiol diacetate, dihydro-gestester, medroxyprogesterone acetate, norethynodrel, allyl estrenone, lyno estreone ethanol, quingestanol acetate , levo-norgestrel, d-norgestrel, dl-norgestrel, d-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-ene-3-one oxime, gestoden, norgestimate and desogestrel, especially norethindrone, norgestimate or progesterone. Pharmaceutical composition according to claim 1, characterized in that the estrogen is piperazine estrone sulfate and the progestin is norethindrone, d-norgestrel or norgestimate. Pharmaceutical composition according to claim 1, characterized in that the number of dominant dosage units is 3. DK 174181 B1 Pharmaceutical composition according to claim 1, characterized in that 3 dosage units with relatively dominant estrogenic activity are alternated with 3 dosage units with relatively dominant progestin activity, etc. Pharmaceutical composition according to claim 1, characterized in that the amount of estrogen per dosage unit is approx. 0.3 mg to approx. 2.5 mg of pipe raisin estrosulfate or the corresponding amount of another synthetic or naturally occurring estrogen, and the amount of progestin per unit dose 10 is in the range of approx. 0.1 mg to approx. 5.0 mg of norethindrone or an equivalent amount of synthetic or naturally occurring progestin. Pharmaceutical composition according to claim 1, characterized in that 3 dosage units with 0.75 mg piperazine estrone sulfate are alternated with 3 dosage units with 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone, and the preparation is intended for oral administration. Pharmaceutical composition according to claim 1. characterized in that 3 dosage units with 0.75 mg of piperazine estrone sulfate and 0.15 mg of norethindrone are alternated with 3 dosage units with 0.75 mg of piperazine estrone sulfate and 0.35 mg of norethindrone and the preparation is intended for oral use. administration. Pharmaceutical composition according to claim 1, characterized in that 3 dosage units of transdermal 17β-estradiol (0.1 mg / day) are alternated with 3 dosage units of transdermal 17β-estradiol (0.1 mg / day) and transdermal norethindrone (0 , 35 mg / day). Pharmaceutical composition according to claim 1, characterized in that 3 days of transdermal 17β-estradiol (0.1 mg / day) and norethindrone (0.15 mg / day) are alternated with transdermal 17β-estradiol (0.1 mg / day). day) and transdermal norethindrone (0.35 mg / day).