CA1332228C - Formulation and method for estrogen replacement therapy - Google Patents
Formulation and method for estrogen replacement therapyInfo
- Publication number
- CA1332228C CA1332228C CA 547744 CA547744A CA1332228C CA 1332228 C CA1332228 C CA 1332228C CA 547744 CA547744 CA 547744 CA 547744 A CA547744 A CA 547744A CA 1332228 C CA1332228 C CA 1332228C
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- unit doses
- progestin
- estrogen
- daily unit
- activity
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
This invention is concerned with a hormonal replacement formulation, a package and the use of the formulation in menopausal or castrate women wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity.
This invention is concerned with a hormonal replacement formulation, a package and the use of the formulation in menopausal or castrate women wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity.
Description
FORMULATIO~ AND METHOD FOR ESTROGEN
REPLAC~ME~T THERAPY
This invention is concerned with a hormonal replacement formulation and method for use in menopausal or castrate women which employs a combination of estrogen and progestin and wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity.
Estrogen replacement therapy is warranted in menopausal women for several reasons. Estrogen replacement will relieve hot flushes and this relief of flushes and night sweats improves sleep patterns and contributes to the patient's general feeling of well-being ~see Campbell S., Whitehead M.I. Estrogen therapy and the menopausal syndrome. In Clinics in Obstetric~ and Gynecology: Volume 4. The Menopause. Edited by R.B.
Greenblatt, J~W.W. Studd, London, W.B. Saunders, 1977, pages 31-47; Erlik Y., Tataryn I.V., Meldrum D.R. et al.
Association of waking episodes with menopausal hot flushes. JAMA 24:1741, 1981). Estrogen replacement protects against postmenopausal 1058 of calcium from the skeleton, especially from vertebral bodies, preventing crush fractures and 1055 of body height (see Lindsay R., Hart D.M., Forrest, C. et al. Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151, 1980). Several studies have now reported that long-term estrogen therapy is also associated with a reduction in the incidence of classical osteoporotic fractures of the forearm and hip (see Hutchinson, T.A., Polansky, S.M., Finestein, A. Postmenopausal estrogens protect again t fractures of hip and distal radius. Lancet 2:706, 1979;
Paganini-Hill, A., Ross, R.K., Gerkins, V.R., et al. A
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:~ I 33~228 case control study of menopausal estrogen therapy in hip fractures. Annals of Internal Medicine 95:28, 1981; Weiss N.S., Vre 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 beneficial effect of long-term estrogen use is the reduction of the risk of death from ischemic heart disease probably mediated by changes in blood lipoprotein concentrations (see ROSB R.K., Paganini-Hill A., Mack T.M. 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 of the vaginal mucosa and urinary tract. The only major risk factor associated with estrogen administration in the doses required to relieve menopausal symptoms, is hyperstimulation of the endometrium and an increased risk of endometrial cancer (see Cramer D.W., Knapp R.C. Review of epidemiologic studies of endometrial cancer and exogenous estrogen. Obstetrics and Gynecology 54:521, 1979 Shapiro S., Coughman D.W., Sloan D., et al. Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. New England Journal of Medicine 303:485, 1980).
Estrogens predispose to cancer of the endometrium by stimulating cell mitosis and proliferation and increasing the levels of DNA synthesis and nuclear estradiol receptors in the endometrium (see Whitehead M.I., Townsen P.T., 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; Whitehead M.I., ~-Townsen P.T., Pryce-Davies J., et al. Actions of ' ~ ' ~ ' '.
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~ 33~?'~8 progestins on t~e morphology and biochemistry o~ the endometrium of postmenopausal women receiving low dose estrogen therapy. American Journal of Obstetrics and Gynecology, 142:791, 1982).
The addition of a progestin for 13 days each mGnth has been demonstrated to protect the endometrium from these stimulatory effects of estrogen (see Gambrill R.D., Jr., Massey F.M., Castaneda et al. Use of the progestogen challenge test to reduce the risk of endometrial cancer.
Obstetrics and Gynecology 55:732, 1980; Studd J.W.W., Thom M.H., Patterson M.E.L., Wade-Evans T. The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens. In: Pasetto N., Paoletti R., Armbus J.L., Editors. 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 decrease nuclear estrogen bioavailability resulting in an antimitotic effect and lowering DNA synthesis. Progestins also increase the activity of endometrial estradiol-17beta-dehydrogenase, an enzyme which metabolize 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 postmenopau~al endometrium. ~ew England Journal of Medicine. 305:1599, 1981; King R.J.B., 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 :: : .- . ..
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Environmental Health, 4:249, 1978). The addition of progestin to estrogen replacement therapy may also result in an increase in bone mass when started within 3 years of the menopause (see ~achtigall L.E., ~achtigall R.H., Nachtigall R.D., et al. Estrogen replacement therapy: A
10 year prospective study in relationship to osteoporosis. Obstetrics and Gynecology 53:277, 1979;
Lindsay R., Hart D.M., Forrest C., et al. Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151, 1980~. However, concerns have been expressed about the potential adverse effects of progestin in suppressing high density lipoprotein cholesterol concentrations (see Hirvonen E., Malkonen M., Manninen 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 lowering of EDL
cholesterol by progestin could negate the long-term beneficial effects of estrogen in reducing the incidence of myocardial infraction. Other side effects of progestins include acne, breast tenderness, depression and irritability (see Barranco V.P. Effect of androgen dominant and estrogen dominant oral contraceptives on acne. Cutis 14:384, 1974; ~oyal College of General Practioners. Oral Contraceptives and Health: An Interim Report. ~ew York: Pitman, 1974). Since the side effects of progestins appear to be dose dependent, the dose of progestin used with postmenopausal estrogen replacement should be the minimum necessary to achieve endometrial protection. (see Padwick M.L., Pryce-Davies J., Whitehead M.I. A simple method for determining the optimal dosage of progestin in poqtmenopausal women receiving estrogens.
New England Journal of Medicine 315:930, 1986).
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~ 332~8 The biological effects of both estrogen and progestin in target tissues such as the endometrium are dependent on the levels of estrogen and progestin receptors. soth estrogen and progestins exert a modulating influence on the levels of their own receptors. For example, in the luteal phase of the menstrual cycle, serum progesterone levels increase and progesterone mediated secretory changes occur in the uterine endometrium. The presence of progesterone receptors has been shown to be a necessary prerequisite for progesterone action in the endometrium (see Walters M.R. 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 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 Clinical Endocrinology and Metabolism 46:635, 1978). O~
the other hand, progesterone exerts 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 acts to downregulate endometrial estrogen receptors possibly by induction of an estrogen receptor regulatory factor (see Leavitt W.W., Okulic~ 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 Steroid Biochemistry 22:686, 1985).
.'`, ' :' These physiologic changes can be reproduced pharmacologically as shown by the induction of estrogen and progestin receptors in postmenopausal women by the 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. (see Short-tgerm 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 demonstrated that administration of medroxyprogesterone acetate in estrogen-primed women decreases the concentration of endometrial progestin receptors while at the same time increasing the activity of 17beta-hydroxysteroid dehydrogenase, the enzyme which is responsible for metabolism of estradiol to the less potent estrone.
A complex interaction occurs between estrogen and progesterone or progestin in the human endometrium with the progestins acting as anti-estrogens. Estrogen and progestin interactions are also dynamic. For example, estrogen administration increased the concentration of both estrogen and progestin receptors to peak levels, 7 times above baseline, within 3 days (see Ekert R.L. and Katzenellenbogen B.S. Human endometrial cells 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 within one day. Normal physiologic levels of progesterone in the first 3 days of the luteal phase :, . .
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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).
Exogenous ad~inistration of progesterone to cynomolgous macaques significantly suppressed estrogen receptors within 1 to 2 days (see West N.B. and Brenner R.M.
Progesterone-mediated suppression of estradiol receptors in cynomolgous macaque cervix, endometrium and oviduct during sequential estradiol-progesterone treatment.
Journal Steroid Biochemistry 22:29, 1985) and medroxyprogesterone acetate was able to significantly suppress progestin receptor levels in premenopausal women within 4 hours (see Neumannova M., Kauppila A., Kivinen S.
and Vihko R. 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 withdrawal in the presence of constant estrogen levels has been shown to result in rapid (6 to 12 hours) recovery of nuclear estrogen receptors in sheep endometrium, associated with an estrogen induced biological response, i.e. 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 e~trogen receptor and oxytocin receptor in the ovine uterus following progesterone withdrawal. Journal Steroids and Biochemistry 22:686, 1985). A similar phenomenon occurs in pregnant guinea pigs when estrogen levels rise relative to progesterone levels prior to parturition in the guinea pig. Biology and Reproduction 22:1106, 1980).
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Therefore, it appears that estrogen acts to stimulate both estrogen and progestin receptor concentrations and to induce sensitivity of the endometrium to both estrogen and progestin. Progesterone or progestin exerts an anti-estrogen action by decreasing the concentration of estrogen receptors and by increasing 17beta-hydroxysteroid dehydrogenase activity in endometrial tissue. However, it appears that the stimulatory effects of progesterone on human endometrial function are of short duration probably because of a ~elf-provoked downregulation of progestin receptors (see Neumannova M., Kauppila A., Kivinen S. and Vihko R.
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; Whitehead M.I., Townsen P.T., Pryce-Davies J. et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. ~ew England Journal of Medicine. 305:1599, 1981). For example, the effect of progesterone on 17beta-hydroxysteroid dehydrogenase peaks at 3 days and is then followed in 2 to 3 weeks by suppression of the enzyme (see Whitehead M.I., Townsend P.T., Pryce-Davies J. et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. ~ew England Journal of Medicine 305:1599, 1981).
Current hormonal replacement consists of continuous (daily or cyclic) (example day 1-25 of each month) estrogen administration with the addition of a progestin for 10-13 days (example days 13-25) each month. This type of replacement regimen is effective in preventing menopausal symptoms and at the same time, protects the .
13~22~8 -9-endometrium against the development of hyperplasia or adenocarcinoma. However, the cyclic administration of a progestin leads to a scheduled withdrawal bleed or period in 65-75% of women (see Hellberg D., ~ilsson 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 cyclic estrogen/gestagen in postmenopausal women: Placebo controlled trial of its gynecologic and metabolic actions. American Journal of Obstetrics and Gynecology.
144:873, 1982). This withdrawal bleeding is usually not welcomed by the patient and can lead to problems with compliance. Also because the progestin administration is preceded by up to 13-16 days of unopposed estrogen therapy with endometrial proliferation and estrogen and progestin receptor induction, it is possible that a high dose of proge~tin is required to antagonize these effects resulting in a greater chance of side effects and adverse metabolic effects. Newer continuous low dose estrogen and - progestin regimens for hormonal replacement may avoid the problem of withdrawal bleeding (see Magos A.L., Brincatt M., O'Dowd T., et al. Amenorrhea and endometrial atrophy following continuous oral estrogen and progestogen therapy in postmenopausal women. Maturitas 6:145, 19~4).
However, daily administration of a progestin in these regimens induces depletion of both estrogen and progestin receptors resulting in endometrial atrophy which may be associated with breakthrough bleeding. Since abnormal bleeding in a postmenopausal woman is known to be associated with endometrial carcinoma, it must be ~
investigated by endometrial sampling for hypertrophy -usually by D~C. Daily administration of a progestin also raises the concern that the favourable effects of estrogen ~ -: ., -lo- - ~ 3 3 2 2 2 8 on HDL cholesterol metabolism will be adversely affected with a fall in HDL cholesterol (see Notelovitz M., Gudat J.C., Ware M.D., Dougherty M.C. British Journal of Obstetrics and Gynecology. 90:171, 1983).
Thus, in the present disclosure, a formulation is described that is better able to protect the endometrium against the estrogen related risk of endometrial hyperplasia and adenocarcinoma with a lower dose of progestin by administering progestin for a short period of time alternating with a short period of absent or reduced progestin. It has been demonstrated that a protective effect of progestin is related to the duration of administration with 12-13 days per month appearing to be the minimum required for greatest protection. The present formulation administers a low dose of progestin intermittently throughout the month for a minimum of 15 days exposure.
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The present invention provides a pharmaceutical preparation for administration to a woman comprising a series of consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses ` of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to ~, promote the development of progestin receptors in the I endometrium of a woman to whom said preparation is administered, and the daily unit doses of said progestin dominant phases contain said substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said preparation is ~ administered.
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In another aspect, the invention provides a pharmaceutical package containing a total dosage regimen of twenty to thirty-five consecutive daily unit doses in orally administrable tablet form arranged in said package in a fixed sequence corresponding to an intended order of administration in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of a woman to whom said doses are administered, and the daily unit doses of said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said doses are administered.
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In a final aspect, the invention provides the use of a pharmaceutical preparation for hormone replacement therapy for a female in need of such treatment comprising administering to said female repeating cycles of a pharmaceutical preparation, each cycle comprising a series of from 20 to 35 consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of said female, and the daily unit doses of :
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-lla-said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of said female.
More particularly the invention provides a pharmaceutical preparation for hormone replacement therapy comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amour.t of a substance exhibiting estrogen activity or an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulphate and the a~ount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone, and wherein each unit dose contains a pharmaceutically acceptable inert carrier when required. Other particular aspects include the package and use forms of this preparation.
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~ 3 3 ~ ~ J 8 - -llb-The inventlon also permits the daily unit doses of said estrogen dominant phases to contain an amount of substance exhibiting progestin activity ranging from O to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases to contain an amount of substance exhibiting progestin activity which activity is equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases. The formulation of the present 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 which limits growth by decreasing estrogen receptors and increasing 17beta-hydroxysteroid dehydrogenase.
Interaction of progestin with progestin receptors induces secretory changes in the endometrium which results in a denser stroma and endometrial stability. A return to relatively dominant estrogenic activity then again stimulates estrogen and progestin receptors and renews endometrial sensitivity to progestin. This push/pull activity keeps endometrial activity within a narrow range depending on the number of days of estrogenic and progestagenic activity and maintains a stable endometrium resulting in the absence of breakthrough or ~-~
withdrawal bleeding.
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~ 32228 -12-The current formulation allows better proges-tational effects with less progestin. With the current formulation the dose of progestin is significantly - decreased compared with a preparation containing constant ~` daily administration of a progestin. A total steroid - dosage is achieved which is similar to or even lower than ~ that of the present cyclic method of administering `- estrogen and progestin for hormonal replacement therapy of ~-- ovarian failure. A reduction in progestin dosage results ~i in less negative impact on HDL cholesterol levels. 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.
'' i - The estrogens which may be employed as a component in the hormonal replacement regimen of this invention may - be any of those conventionally available and may be in micronized form. Typically, the estrogen may be selected : from the group comprising synthetic and natural estrogens. The synthetic estrogens may be ~elected from, for example, ethinyl estradiol, mestranol and ;.~ ;
quinestranol. Particularly of interest are 17alpha-~`~ ethinylestradiol and esters and ethers thereof. The natural estrogens include, for example, conjugated equine estrogens, 17beta-estradiol, estradiol valerate, estrone, estrone sulphate, piperazine estrone sulphate, estriol, estriol succinate and polyestrol phosphate. The preferred estrogen is piperazine estrone sulphate.
~ The progestin component may be any progestationally ``` active compound and may be in micronized form. Thus, the progestin may be selected from, for example, progesterone and its derivatives such as 17-hydroxyprogesterone esters, ~, ,- ~, .
, ~': ~ ' ' ' : ' -~ -,.l9-nor-17-hydroxyprogesterone esters, 17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate~ medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone, d-norgestrel levo-norgestrel, dl-norgestrel, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime, cyproterone acetate, gestodene, norgestimate and desogestrel. Preferred progestins are norethindrone, norgestimate or progesterone.
In a preferred form of the invention, the plurality of dosages may comprise from one to five unit dosages, but preferably three unit dosages are employed. Thus, in a ~;
preferred form of the invention, three unit dosages of ~ -estrogen are alternated with three unit dosages of estrogen and progestin and so on continuously. It is also possible to employ combinations of two and three unit dosages, as well as combinations of three and four unit dosages.
Generally, the quantities of estrogen and protestin incorporated in the formulation of the invention are -dependent on the type of estrogen and progestin selected.
However, the quantities of progestin employed are generally less than those used in the currently marketed formulations for reasons mentioned earlier. In the present formulation, the estrogen level is kept constant while the progestin level is adjusted up or down to produce the required estrogen or progestin dominance.
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Typically, the amount of estrogen per unit dose may range from a minimum of about 0.3 mg of estrone sulphate or its equivalent to a maximum of about 2.5 mg of estrone sulphate or its equivalent. The amount of progestin per unit dosage may range from a minimum of O mg to a maximum of about 5 mg of norethindrone or its equivalent. (These amounts generally refer to oral dosages.) Some preferred combinations include the following:
1 . Three units dosages of 0.75 mg piperazine estrone sulphate alternating with three unit dosages of 0.75 mg of piperazine estrone sulphate with 0.35 mg of norethindrone.
2. Three unit dosages of 0.75 mg piperazine estrone sulphate and 0.15 mg of norethindrone alternating with three unit dosages of 0.75 mg of piperazine estrone sulphate and 0.35 mg of norethindrone.
The above combinations may also be grouped into three's and four~s, starting with either three or four day groups and ending with the other. For this invention, it may be ~dvantageous for the groups of dominant estrogen activity combination to comprise one more unit dosage than the dominant progestin activity combination unit dosages, or vice versa, for instance the numbers in the groups being 2 and 3 or 3 and 4.
The formulations of the invention may be administered orally, preferably in tablet form, parenterally, transdermally, intravaginally, sublingually or buccally. ~he method of administration determines the types of estrogens and progestins useful in the formulation, as well as the amounts per unit dosage.
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~r .t ~, ~ 33~J~28 - 14a -Methods for transdermal administration including the associated methods for manufacturing such systems are well known in the art. In this connection, reference may be had to U.S. Patents Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014.
Generally speaking, the formulations are prepared according to conventionally known procedures in accordance with the method of administration. Thus, the active ingredients are prepared according to known methods in a pharmaceutically acceptable form for administration. These ingredients, in their required quantities are combined with the appropriate pharmaceutical carriers such as additives, vehicles and/or flavour ameliorating substances. These substances may be referred to as diluents, binders and lubricants. Gums, starches and sugars are also common terms. Typical of these types of substances or excipients are pharmaceutical grades of mannitol, lactose starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. The active ingredient(s) may comprise from about 0.01% by weight to about 99.99% by weight of the to~al formulation and the remainder comprises the pharmaceutically acceptable carrier. The percentage of active ingredient(s) may vary according to the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.
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Thus, the active ingredients are compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet molding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.
In the oral form of the formulation, the contraceptives are preferably produced in the form of a :, .
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- 14b - I 332228 pharmaceutical kit or package, with the daily dosages arranged for proper sequential administration. Thus, in another aspect, the present invention also provides a pharmaceutical package which contains combination-type contraceptives in multiple dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration. This can be known as a multi-preparation pack.
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Preferably, such packages are in the form of a transparent package with twenty-eïght dosage units arranged sequentially and consisting of twenty-one or twenty-four tablets containing the combined estrogen/progestin formulation set up for the cyclical regimen of the invention and seven or four placebos thereafter.
Preferably the placebo tablets and tablets containing the hormones are different colours or shapes. Data indications may be provided on the packaging. The packaging may be a tube ; or box or a strip. The box may be circular, square, or ~i otherwise shaped with the tablets being accommodated separately therein for ease of administration. Date indications may -- appear adjacent each tablet corresponding with the days on ` which each tablet is to be taken. Some indication of the ` sequence in which the tablets are to be taken preferably appears on the packaging regardless of its form.
~; ~enerally, such packages are in the form of a transparent package with, for example, 21 or 30 dosage units, as required, arranged sequentially and consisting of 21 or 30 tablets containing the combined estrogen/progestin formulation set up for the cyclical regimen of the invention.
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~ 3322~8 -15-In the following examples, specific embodiments of the present invention are set forth. These are meant to be illustrative of the invention and are not meant to limit it in any way. All parts and percentages are by weight, unless indicated otherwise.
Three-day phases of daily unit dosages of 0.75 mg piperazine estrone sulphate alternating with three-day phases of daily unit dosages of estrone sulphate 0.75 mg and NET 0.35 mg given consecutively and orally.
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Three-day phases (daily unit dosages of estrone . sulphate 0.75 mg and norethindrone 0.15 mg) alternating with three-day phases of daily unit dosages of estrone sulphate 0.75 mg and norethindrone 0.35 mg given consecutively and orally.
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~ 3322~ EXAMPLE 3 - Three-day phases of daily unit dosages of oral micronized 17beta-estradiol 1 mg alternating with three-day phases of daily unit dosages of 17beta-estradiol 1 mg and norethindrone .35 mg given consecutively.
i Three-day phases of transdermal 17beta-estradiol i, (100 ~g/day) alternating with three-day phases of r, transdermal 17beta-estradiol (100~ug/day) and transdermal norethindrone (.35 mg/day) given continuously.
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Three-day phases of daily unit dosages of estrone sulphate 1.25 mg alternating with three-day phases of daily unit dosages of estrone sulphate 1.25 mg and norethindrone 0.35 mg given consecutively and orally.
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- Three-day phases of daily unit dosages of estrone sulphate 1.25 mg alternating with three-day phases of daily unit dosages of estrone sulphate 1.25 mg and ~ norethindrone 0.5 mg given consecutively and orally.
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One-day or two-day alternating phases using the daily unit dosages set forth in Exampl s 1 and 2 given consecutively and orally.
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Three-day and four-day phases of each of the combinations of daily unit dosages as set forth in Examples 1 and 2, starting with either a three- or four-day phase and given consecutively and orally.
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Two-day and three-day phases of each of the combinations of daily unit dosages as set forth in - Examples 1 and 2, starting with either a two- or three-day ~ phase and given consecutively and orally.
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REPLAC~ME~T THERAPY
This invention is concerned with a hormonal replacement formulation and method for use in menopausal or castrate women which employs a combination of estrogen and progestin and wherein a short period of relatively dominant estrogenic activity alternates with a short period of relatively dominant progestagenic activity.
Estrogen replacement therapy is warranted in menopausal women for several reasons. Estrogen replacement will relieve hot flushes and this relief of flushes and night sweats improves sleep patterns and contributes to the patient's general feeling of well-being ~see Campbell S., Whitehead M.I. Estrogen therapy and the menopausal syndrome. In Clinics in Obstetric~ and Gynecology: Volume 4. The Menopause. Edited by R.B.
Greenblatt, J~W.W. Studd, London, W.B. Saunders, 1977, pages 31-47; Erlik Y., Tataryn I.V., Meldrum D.R. et al.
Association of waking episodes with menopausal hot flushes. JAMA 24:1741, 1981). Estrogen replacement protects against postmenopausal 1058 of calcium from the skeleton, especially from vertebral bodies, preventing crush fractures and 1055 of body height (see Lindsay R., Hart D.M., Forrest, C. et al. Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151, 1980). Several studies have now reported that long-term estrogen therapy is also associated with a reduction in the incidence of classical osteoporotic fractures of the forearm and hip (see Hutchinson, T.A., Polansky, S.M., Finestein, A. Postmenopausal estrogens protect again t fractures of hip and distal radius. Lancet 2:706, 1979;
Paganini-Hill, A., Ross, R.K., Gerkins, V.R., et al. A
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:~ I 33~228 case control study of menopausal estrogen therapy in hip fractures. Annals of Internal Medicine 95:28, 1981; Weiss N.S., Vre 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 beneficial effect of long-term estrogen use is the reduction of the risk of death from ischemic heart disease probably mediated by changes in blood lipoprotein concentrations (see ROSB R.K., Paganini-Hill A., Mack T.M. 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 of the vaginal mucosa and urinary tract. The only major risk factor associated with estrogen administration in the doses required to relieve menopausal symptoms, is hyperstimulation of the endometrium and an increased risk of endometrial cancer (see Cramer D.W., Knapp R.C. Review of epidemiologic studies of endometrial cancer and exogenous estrogen. Obstetrics and Gynecology 54:521, 1979 Shapiro S., Coughman D.W., Sloan D., et al. Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. New England Journal of Medicine 303:485, 1980).
Estrogens predispose to cancer of the endometrium by stimulating cell mitosis and proliferation and increasing the levels of DNA synthesis and nuclear estradiol receptors in the endometrium (see Whitehead M.I., Townsen P.T., 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; Whitehead M.I., ~-Townsen P.T., Pryce-Davies J., et al. Actions of ' ~ ' ~ ' '.
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~ 33~?'~8 progestins on t~e morphology and biochemistry o~ the endometrium of postmenopausal women receiving low dose estrogen therapy. American Journal of Obstetrics and Gynecology, 142:791, 1982).
The addition of a progestin for 13 days each mGnth has been demonstrated to protect the endometrium from these stimulatory effects of estrogen (see Gambrill R.D., Jr., Massey F.M., Castaneda et al. Use of the progestogen challenge test to reduce the risk of endometrial cancer.
Obstetrics and Gynecology 55:732, 1980; Studd J.W.W., Thom M.H., Patterson M.E.L., Wade-Evans T. The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens. In: Pasetto N., Paoletti R., Armbus J.L., Editors. 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 decrease nuclear estrogen bioavailability resulting in an antimitotic effect and lowering DNA synthesis. Progestins also increase the activity of endometrial estradiol-17beta-dehydrogenase, an enzyme which metabolize 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 postmenopau~al endometrium. ~ew England Journal of Medicine. 305:1599, 1981; King R.J.B., 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 :: : .- . ..
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Environmental Health, 4:249, 1978). The addition of progestin to estrogen replacement therapy may also result in an increase in bone mass when started within 3 years of the menopause (see ~achtigall L.E., ~achtigall R.H., Nachtigall R.D., et al. Estrogen replacement therapy: A
10 year prospective study in relationship to osteoporosis. Obstetrics and Gynecology 53:277, 1979;
Lindsay R., Hart D.M., Forrest C., et al. Prevention of spinal osteoporosis in oophorectomized women. Lancet 2:1151, 1980~. However, concerns have been expressed about the potential adverse effects of progestin in suppressing high density lipoprotein cholesterol concentrations (see Hirvonen E., Malkonen M., Manninen 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 lowering of EDL
cholesterol by progestin could negate the long-term beneficial effects of estrogen in reducing the incidence of myocardial infraction. Other side effects of progestins include acne, breast tenderness, depression and irritability (see Barranco V.P. Effect of androgen dominant and estrogen dominant oral contraceptives on acne. Cutis 14:384, 1974; ~oyal College of General Practioners. Oral Contraceptives and Health: An Interim Report. ~ew York: Pitman, 1974). Since the side effects of progestins appear to be dose dependent, the dose of progestin used with postmenopausal estrogen replacement should be the minimum necessary to achieve endometrial protection. (see Padwick M.L., Pryce-Davies J., Whitehead M.I. A simple method for determining the optimal dosage of progestin in poqtmenopausal women receiving estrogens.
New England Journal of Medicine 315:930, 1986).
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~ 332~8 The biological effects of both estrogen and progestin in target tissues such as the endometrium are dependent on the levels of estrogen and progestin receptors. soth estrogen and progestins exert a modulating influence on the levels of their own receptors. For example, in the luteal phase of the menstrual cycle, serum progesterone levels increase and progesterone mediated secretory changes occur in the uterine endometrium. The presence of progesterone receptors has been shown to be a necessary prerequisite for progesterone action in the endometrium (see Walters M.R. 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 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 Clinical Endocrinology and Metabolism 46:635, 1978). O~
the other hand, progesterone exerts 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 acts to downregulate endometrial estrogen receptors possibly by induction of an estrogen receptor regulatory factor (see Leavitt W.W., Okulic~ 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 Steroid Biochemistry 22:686, 1985).
.'`, ' :' These physiologic changes can be reproduced pharmacologically as shown by the induction of estrogen and progestin receptors in postmenopausal women by the 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. (see Short-tgerm 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 demonstrated that administration of medroxyprogesterone acetate in estrogen-primed women decreases the concentration of endometrial progestin receptors while at the same time increasing the activity of 17beta-hydroxysteroid dehydrogenase, the enzyme which is responsible for metabolism of estradiol to the less potent estrone.
A complex interaction occurs between estrogen and progesterone or progestin in the human endometrium with the progestins acting as anti-estrogens. Estrogen and progestin interactions are also dynamic. For example, estrogen administration increased the concentration of both estrogen and progestin receptors to peak levels, 7 times above baseline, within 3 days (see Ekert R.L. and Katzenellenbogen B.S. Human endometrial cells 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 within one day. Normal physiologic levels of progesterone in the first 3 days of the luteal phase :, . .
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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).
Exogenous ad~inistration of progesterone to cynomolgous macaques significantly suppressed estrogen receptors within 1 to 2 days (see West N.B. and Brenner R.M.
Progesterone-mediated suppression of estradiol receptors in cynomolgous macaque cervix, endometrium and oviduct during sequential estradiol-progesterone treatment.
Journal Steroid Biochemistry 22:29, 1985) and medroxyprogesterone acetate was able to significantly suppress progestin receptor levels in premenopausal women within 4 hours (see Neumannova M., Kauppila A., Kivinen S.
and Vihko R. 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 withdrawal in the presence of constant estrogen levels has been shown to result in rapid (6 to 12 hours) recovery of nuclear estrogen receptors in sheep endometrium, associated with an estrogen induced biological response, i.e. 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 e~trogen receptor and oxytocin receptor in the ovine uterus following progesterone withdrawal. Journal Steroids and Biochemistry 22:686, 1985). A similar phenomenon occurs in pregnant guinea pigs when estrogen levels rise relative to progesterone levels prior to parturition in the guinea pig. Biology and Reproduction 22:1106, 1980).
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Therefore, it appears that estrogen acts to stimulate both estrogen and progestin receptor concentrations and to induce sensitivity of the endometrium to both estrogen and progestin. Progesterone or progestin exerts an anti-estrogen action by decreasing the concentration of estrogen receptors and by increasing 17beta-hydroxysteroid dehydrogenase activity in endometrial tissue. However, it appears that the stimulatory effects of progesterone on human endometrial function are of short duration probably because of a ~elf-provoked downregulation of progestin receptors (see Neumannova M., Kauppila A., Kivinen S. and Vihko R.
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; Whitehead M.I., Townsen P.T., Pryce-Davies J. et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. ~ew England Journal of Medicine. 305:1599, 1981). For example, the effect of progesterone on 17beta-hydroxysteroid dehydrogenase peaks at 3 days and is then followed in 2 to 3 weeks by suppression of the enzyme (see Whitehead M.I., Townsend P.T., Pryce-Davies J. et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. ~ew England Journal of Medicine 305:1599, 1981).
Current hormonal replacement consists of continuous (daily or cyclic) (example day 1-25 of each month) estrogen administration with the addition of a progestin for 10-13 days (example days 13-25) each month. This type of replacement regimen is effective in preventing menopausal symptoms and at the same time, protects the .
13~22~8 -9-endometrium against the development of hyperplasia or adenocarcinoma. However, the cyclic administration of a progestin leads to a scheduled withdrawal bleed or period in 65-75% of women (see Hellberg D., ~ilsson 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 cyclic estrogen/gestagen in postmenopausal women: Placebo controlled trial of its gynecologic and metabolic actions. American Journal of Obstetrics and Gynecology.
144:873, 1982). This withdrawal bleeding is usually not welcomed by the patient and can lead to problems with compliance. Also because the progestin administration is preceded by up to 13-16 days of unopposed estrogen therapy with endometrial proliferation and estrogen and progestin receptor induction, it is possible that a high dose of proge~tin is required to antagonize these effects resulting in a greater chance of side effects and adverse metabolic effects. Newer continuous low dose estrogen and - progestin regimens for hormonal replacement may avoid the problem of withdrawal bleeding (see Magos A.L., Brincatt M., O'Dowd T., et al. Amenorrhea and endometrial atrophy following continuous oral estrogen and progestogen therapy in postmenopausal women. Maturitas 6:145, 19~4).
However, daily administration of a progestin in these regimens induces depletion of both estrogen and progestin receptors resulting in endometrial atrophy which may be associated with breakthrough bleeding. Since abnormal bleeding in a postmenopausal woman is known to be associated with endometrial carcinoma, it must be ~
investigated by endometrial sampling for hypertrophy -usually by D~C. Daily administration of a progestin also raises the concern that the favourable effects of estrogen ~ -: ., -lo- - ~ 3 3 2 2 2 8 on HDL cholesterol metabolism will be adversely affected with a fall in HDL cholesterol (see Notelovitz M., Gudat J.C., Ware M.D., Dougherty M.C. British Journal of Obstetrics and Gynecology. 90:171, 1983).
Thus, in the present disclosure, a formulation is described that is better able to protect the endometrium against the estrogen related risk of endometrial hyperplasia and adenocarcinoma with a lower dose of progestin by administering progestin for a short period of time alternating with a short period of absent or reduced progestin. It has been demonstrated that a protective effect of progestin is related to the duration of administration with 12-13 days per month appearing to be the minimum required for greatest protection. The present formulation administers a low dose of progestin intermittently throughout the month for a minimum of 15 days exposure.
:
The present invention provides a pharmaceutical preparation for administration to a woman comprising a series of consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses ` of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to ~, promote the development of progestin receptors in the I endometrium of a woman to whom said preparation is administered, and the daily unit doses of said progestin dominant phases contain said substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said preparation is ~ administered.
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In another aspect, the invention provides a pharmaceutical package containing a total dosage regimen of twenty to thirty-five consecutive daily unit doses in orally administrable tablet form arranged in said package in a fixed sequence corresponding to an intended order of administration in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of a woman to whom said doses are administered, and the daily unit doses of said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said doses are administered.
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In a final aspect, the invention provides the use of a pharmaceutical preparation for hormone replacement therapy for a female in need of such treatment comprising administering to said female repeating cycles of a pharmaceutical preparation, each cycle comprising a series of from 20 to 35 consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of said female, and the daily unit doses of :
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-lla-said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of said female.
More particularly the invention provides a pharmaceutical preparation for hormone replacement therapy comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amour.t of a substance exhibiting estrogen activity or an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulphate and the a~ount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone, and wherein each unit dose contains a pharmaceutically acceptable inert carrier when required. Other particular aspects include the package and use forms of this preparation.
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~ 3 3 ~ ~ J 8 - -llb-The inventlon also permits the daily unit doses of said estrogen dominant phases to contain an amount of substance exhibiting progestin activity ranging from O to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases to contain an amount of substance exhibiting progestin activity which activity is equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases. The formulation of the present 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 which limits growth by decreasing estrogen receptors and increasing 17beta-hydroxysteroid dehydrogenase.
Interaction of progestin with progestin receptors induces secretory changes in the endometrium which results in a denser stroma and endometrial stability. A return to relatively dominant estrogenic activity then again stimulates estrogen and progestin receptors and renews endometrial sensitivity to progestin. This push/pull activity keeps endometrial activity within a narrow range depending on the number of days of estrogenic and progestagenic activity and maintains a stable endometrium resulting in the absence of breakthrough or ~-~
withdrawal bleeding.
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~ 32228 -12-The current formulation allows better proges-tational effects with less progestin. With the current formulation the dose of progestin is significantly - decreased compared with a preparation containing constant ~` daily administration of a progestin. A total steroid - dosage is achieved which is similar to or even lower than ~ that of the present cyclic method of administering `- estrogen and progestin for hormonal replacement therapy of ~-- ovarian failure. A reduction in progestin dosage results ~i in less negative impact on HDL cholesterol levels. 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.
'' i - The estrogens which may be employed as a component in the hormonal replacement regimen of this invention may - be any of those conventionally available and may be in micronized form. Typically, the estrogen may be selected : from the group comprising synthetic and natural estrogens. The synthetic estrogens may be ~elected from, for example, ethinyl estradiol, mestranol and ;.~ ;
quinestranol. Particularly of interest are 17alpha-~`~ ethinylestradiol and esters and ethers thereof. The natural estrogens include, for example, conjugated equine estrogens, 17beta-estradiol, estradiol valerate, estrone, estrone sulphate, piperazine estrone sulphate, estriol, estriol succinate and polyestrol phosphate. The preferred estrogen is piperazine estrone sulphate.
~ The progestin component may be any progestationally ``` active compound and may be in micronized form. Thus, the progestin may be selected from, for example, progesterone and its derivatives such as 17-hydroxyprogesterone esters, ~, ,- ~, .
, ~': ~ ' ' ' : ' -~ -,.l9-nor-17-hydroxyprogesterone esters, 17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate~ medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone, d-norgestrel levo-norgestrel, dl-norgestrel, d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime, cyproterone acetate, gestodene, norgestimate and desogestrel. Preferred progestins are norethindrone, norgestimate or progesterone.
In a preferred form of the invention, the plurality of dosages may comprise from one to five unit dosages, but preferably three unit dosages are employed. Thus, in a ~;
preferred form of the invention, three unit dosages of ~ -estrogen are alternated with three unit dosages of estrogen and progestin and so on continuously. It is also possible to employ combinations of two and three unit dosages, as well as combinations of three and four unit dosages.
Generally, the quantities of estrogen and protestin incorporated in the formulation of the invention are -dependent on the type of estrogen and progestin selected.
However, the quantities of progestin employed are generally less than those used in the currently marketed formulations for reasons mentioned earlier. In the present formulation, the estrogen level is kept constant while the progestin level is adjusted up or down to produce the required estrogen or progestin dominance.
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Typically, the amount of estrogen per unit dose may range from a minimum of about 0.3 mg of estrone sulphate or its equivalent to a maximum of about 2.5 mg of estrone sulphate or its equivalent. The amount of progestin per unit dosage may range from a minimum of O mg to a maximum of about 5 mg of norethindrone or its equivalent. (These amounts generally refer to oral dosages.) Some preferred combinations include the following:
1 . Three units dosages of 0.75 mg piperazine estrone sulphate alternating with three unit dosages of 0.75 mg of piperazine estrone sulphate with 0.35 mg of norethindrone.
2. Three unit dosages of 0.75 mg piperazine estrone sulphate and 0.15 mg of norethindrone alternating with three unit dosages of 0.75 mg of piperazine estrone sulphate and 0.35 mg of norethindrone.
The above combinations may also be grouped into three's and four~s, starting with either three or four day groups and ending with the other. For this invention, it may be ~dvantageous for the groups of dominant estrogen activity combination to comprise one more unit dosage than the dominant progestin activity combination unit dosages, or vice versa, for instance the numbers in the groups being 2 and 3 or 3 and 4.
The formulations of the invention may be administered orally, preferably in tablet form, parenterally, transdermally, intravaginally, sublingually or buccally. ~he method of administration determines the types of estrogens and progestins useful in the formulation, as well as the amounts per unit dosage.
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~r .t ~, ~ 33~J~28 - 14a -Methods for transdermal administration including the associated methods for manufacturing such systems are well known in the art. In this connection, reference may be had to U.S. Patents Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014.
Generally speaking, the formulations are prepared according to conventionally known procedures in accordance with the method of administration. Thus, the active ingredients are prepared according to known methods in a pharmaceutically acceptable form for administration. These ingredients, in their required quantities are combined with the appropriate pharmaceutical carriers such as additives, vehicles and/or flavour ameliorating substances. These substances may be referred to as diluents, binders and lubricants. Gums, starches and sugars are also common terms. Typical of these types of substances or excipients are pharmaceutical grades of mannitol, lactose starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. The active ingredient(s) may comprise from about 0.01% by weight to about 99.99% by weight of the to~al formulation and the remainder comprises the pharmaceutically acceptable carrier. The percentage of active ingredient(s) may vary according to the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.
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Thus, the active ingredients are compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet molding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.
In the oral form of the formulation, the contraceptives are preferably produced in the form of a :, .
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- 14b - I 332228 pharmaceutical kit or package, with the daily dosages arranged for proper sequential administration. Thus, in another aspect, the present invention also provides a pharmaceutical package which contains combination-type contraceptives in multiple dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration. This can be known as a multi-preparation pack.
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Preferably, such packages are in the form of a transparent package with twenty-eïght dosage units arranged sequentially and consisting of twenty-one or twenty-four tablets containing the combined estrogen/progestin formulation set up for the cyclical regimen of the invention and seven or four placebos thereafter.
Preferably the placebo tablets and tablets containing the hormones are different colours or shapes. Data indications may be provided on the packaging. The packaging may be a tube ; or box or a strip. The box may be circular, square, or ~i otherwise shaped with the tablets being accommodated separately therein for ease of administration. Date indications may -- appear adjacent each tablet corresponding with the days on ` which each tablet is to be taken. Some indication of the ` sequence in which the tablets are to be taken preferably appears on the packaging regardless of its form.
~; ~enerally, such packages are in the form of a transparent package with, for example, 21 or 30 dosage units, as required, arranged sequentially and consisting of 21 or 30 tablets containing the combined estrogen/progestin formulation set up for the cyclical regimen of the invention.
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~ 3322~8 -15-In the following examples, specific embodiments of the present invention are set forth. These are meant to be illustrative of the invention and are not meant to limit it in any way. All parts and percentages are by weight, unless indicated otherwise.
Three-day phases of daily unit dosages of 0.75 mg piperazine estrone sulphate alternating with three-day phases of daily unit dosages of estrone sulphate 0.75 mg and NET 0.35 mg given consecutively and orally.
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Three-day phases (daily unit dosages of estrone . sulphate 0.75 mg and norethindrone 0.15 mg) alternating with three-day phases of daily unit dosages of estrone sulphate 0.75 mg and norethindrone 0.35 mg given consecutively and orally.
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~ 3322~ EXAMPLE 3 - Three-day phases of daily unit dosages of oral micronized 17beta-estradiol 1 mg alternating with three-day phases of daily unit dosages of 17beta-estradiol 1 mg and norethindrone .35 mg given consecutively.
i Three-day phases of transdermal 17beta-estradiol i, (100 ~g/day) alternating with three-day phases of r, transdermal 17beta-estradiol (100~ug/day) and transdermal norethindrone (.35 mg/day) given continuously.
.~
Three-day phases of daily unit dosages of estrone sulphate 1.25 mg alternating with three-day phases of daily unit dosages of estrone sulphate 1.25 mg and norethindrone 0.35 mg given consecutively and orally.
l~ EXAMPLE 6 :~ .
- Three-day phases of daily unit dosages of estrone sulphate 1.25 mg alternating with three-day phases of daily unit dosages of estrone sulphate 1.25 mg and ~ norethindrone 0.5 mg given consecutively and orally.
:...
One-day or two-day alternating phases using the daily unit dosages set forth in Exampl s 1 and 2 given consecutively and orally.
.
:, ~.
'''' ~
~ 1 3 3 ~) ~ 2 ~3 EXAMPLE 8 Three-day phases of daily unit dosages of estrone sulphate 0.75 mg alternating with three-day phases of daily unit dosages of estrone sulphate 0.75 mg and norgestimate 0.050 mg given consecutively and orally.
., :3 EXAMPLE 9 ., ' '~
Three-day and four-day phases of each of the combinations of daily unit dosages as set forth in Examples 1 and 2, starting with either a three- or four-day phase and given consecutively and orally.
: `
. .~
, :
Two-day and three-day phases of each of the combinations of daily unit dosages as set forth in - Examples 1 and 2, starting with either a two- or three-day ~ phase and given consecutively and orally.
:, ~:
:
~`
b . ~
. ` ' , ~"' ., `' -',''' ~'~' .~' . ', ' ~Y`' ' ' .-,.. . , . , :
Claims (54)
1. A pharmaceutical preparation for hormone replacement therapy comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity or an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulphate and the amount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone, and wherein each unit dose contains a pharmaceutically acceptable inert carrier when required.
2. A pharmaceutical preparation according to Claim 1, wherein the daily unit doses of said estrogen dominant phases contain an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases contain an amount of substance exhibiting progestin activity which activity is equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases.
3. A pharmaceutical preparation according to Claim 1, wherein all of said daily unit doses contain a uniform amount of said substance exhibiting estrogen activity.
4. A pharmaceutical preparation according to Claim 1, wherein the daily unit doses of said estrogen dominant phases are free of substance exhibiting progestin activity.
5. A pharmaceutical preparation according to Claim 1, wherein said substance exhibiting estrogen activity is selected from the group consisting of 17.alpha.-ethinyl estradiol, 17.beta.-estradiol, 17.beta.-estradiol valerate, conjugated equine estrogens, and piperazine estrone sulfate and estropipate, and said substance exhibiting progestin activity is selected from the group consisting of norethindrone, desogestrel, levo-norgestrel, norgestimate, progesterone, medroxy-progesterone acetate, cyproterone acetate and gestodene.
6. A pharmaceutical preparation according to Claim 1, wherein said daily unit doses are in orally administrable form.
7. A pharmaceutical preparation according to Claim 1, wherein said daily unit doses are in transdermally administrable form.
8. A pharmaceutical preparation according to Claim 1, wherein said daily unit doses are in buccally administrable form.
9. A pharmaceutical preparation according to Claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of two daily unit doses each alternating with progestin dominant phases of two daily unit doses each.
10. A pharmaceutical preparation according to Claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
11. A pharmaceutical preparation according to Claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of four daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
12. A pharmaceutical preparation according to Claim 1, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of four daily unit doses each.
13. A pharmaceutical preparation according to Claim 1, wherein each estrogen dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate, and each progestin dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.
14. A pharmaceutical preparation according to Claim 1, wherein three unit dosages of 0.75 mg piperazine estrone sulphate and 0.5 mg of norethindrone are alternated with three unit dosages of 0.75 mg piperazine estrone sulphate and 0.35 mg of norethindrone and the preparation is in oral form.
15. A pharmaceutical preparation according to Claim 1, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
16. A pharmaceutical preparation according to Claim 1, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.15 mg norethindrone, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
17. A pharmaceutical preparation according to Claim 1, wherein three unit doses of 1.0 mg of 17.beta.-estradiol are alternated with three unit doses of 1.0 mg of 17.beta.-estradiol and 0.35 mg norethindrone.
18. A pharmaceutical package for hormone replacement therapy containing a total dosage regimen of from twenty to thirty-five consecutive daily unit doses arranged in said package in a fixed sequence corresponding to an intended order of administration in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity or an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulphate and the amount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone and wherein each unit dose contains a pharmaceutically acceptable inert carrier when required.
19. A pharmaceutical package according to Claim 18, wherein the daily unit doses of said estrogen dominant phases contain an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases contain an amount of substance exhibiting progestin activity which activity is equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases.
20. A pharmaceutical package according to Claim 18, wherein all of said daily unit doses contain a uniform amount of said substance exhibiting estrogen activity.
21. A pharmaceutical package according to Claim 18, wherein the daily unit doses of said estrogen dominant phases are free of substance exhibiting progestin activity.
22. A pharmaceutical package according to Claim 18, wherein said substance exhibiting estrogen activity is selected from the group consisting of 17.alpha.-ethinyl estradiol, 17.beta.-estradiol, 17.beta.-estradiol valerate, conjugated equine estrogens, and piperazine estrone sulfate and estropipate, and said substance exhibiting progestin activity is selected from the group consisting of norethindrone, desogestrel, levo-norgestrel, norgestimate, progesterone, medroxy-progesterone acetate, cyproterone acetate and gestodene.
23. A pharmaceutical package according to Claim 18, wherein said daily unit doses are in orally administrable form.
24. A pharmaceutical package according to Claim 18, wherein said daily unit doses are in transdermally administrable form.
25. A pharmaceutical package according to Claim 18, wherein said daily unit doses are in buccally administrable form.
26. A pharmaceutical package according to Claim 18, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of two daily unit doses each alternating with progestin dominant phases of two daily unit doses each.
27. A pharmaceutical package according to Claim 18, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
28. A pharmaceutical package according to Claim 18, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of four daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
29. A pharmaceutical package according to Claim 18, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of four daily unit doses each.
30. A pharmaceutical package according to Claim 18, wherein each estrogen dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate, and each progestin dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.
31. A pharmaceutical package according to Claim 18, wherein three unit dosages of 0.75 mg piperazine estrone sulphate and 0.5 mg of norethindrone are alternated with three unit dosages of 0.75 mg piperazine estrone sulphate and 0.35 mg of norethindrone and the package is in oral form.
32. A pharmaceutical package according to Claim 18, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
33. A pharmaceutical package according to Claim 18, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.15 mg norethindrone, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
34. A pharmaceutical package according to Claim 18, wherein three unit doses of 1.0 mg of 17.beta.-estradiol are alternated with three unit doses of 1.0 mg of 17.beta.-estradiol and 0.35 mg norethindrone.
35. The use of a pharmaceutical preparation for hormone replacement therapy comprising a series of from twenty to thirty-five consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of from one to four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity or an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, and the daily unit doses of said progestin dominant phases contain an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity, the amount of said substance exhibiting progestin activity being alternately increased in the progestin dominant phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the estrogen dominant phases to provide daily unit doses exhibiting estrogen dominant activity and wherein the amount of substance exhibiting estrogen activity per unit dose exhibits an estrogen activity equivalent to from about 0.3 to about 2.5 mg of piperazine estrone sulphate and the amount of substance exhibiting progestin activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to about 5 mg of norethindrone, and wherein each unit dose contains a pharmaceutically acceptable inert carrier when required.
36. The use of a pharmaceutical preparation according to Claim 35, wherein the daily unit doses of said estrogen dominant phases contain an amount of substance exhibiting progestin activity ranging from 0 to an amount which exhibits a progestin activity equivalent to 0.5 mg of norethindrone, and the daily unit doses of said progestin dominant phases contain an amount of substance exhibiting progestin activity which activity is equivalent to from 0.35 to 5 mg norethindrone, the amount of substance exhibiting progestin activity being greater in said progestin dominant phases than in said estrogen dominant phases.
37. The use of a pharmaceutical preparation according to Claim 35, wherein all of said daily unit doses contain a uniform amount of said substance exhibiting estrogen activity.
38. The use of a pharmaceutical preparation according to Claim 35, wherein the daily unit doses of said estrogen dominant phases are free of substance exhibiting progestin activity.
39. The use of a pharmaceutical preparation according to Claim 35, wherein said substance exhibiting estrogen activity is selected from the group consisting of 17.alpha.-ethinyl estradiol, 17.beta.-estradiol, 17.beta.-estradiol valerate, conjugated equine estrogens, and piperazine estrone sulfate and estropipate, and said substance exhibiting progestin activity is selected from the group consisting of norethindrone, desogestrel, levo-norgestrel, norgestimate, progesterone, medroxy-progesterone acetate, cyproterone acetate and gestodene.
40. The use of a pharmaceutical preparation according to Claim 35, wherein said daily unit doses are in orally administrable form.
41. The use of a pharmaceutical preparation according to Claim 35, wherein said daily unit doses are in transdermally administrable form.
42. The use of a pharmaceutical preparation according to Claim 35, wherein said daily unit doses are in buccally administrable form.
43. The use of a pharmaceutical preparation according to Claim 35, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of two daily unit doses each alternating with progestin dominant phases of two daily unit doses each.
44. The use of a pharmaceutical preparation according to Claim 35, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
45. The use of a pharmaceutical preparation according to Claim 35, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of four daily unit doses each alternating with progestin dominant phases of three daily unit doses each.
46. The use of a pharmaceutical preparation according to Claim 35, comprising a series of consecutive daily unit doses arranged in estrogen dominant phases of three daily unit doses each alternating with progestin dominant phases of four daily unit doses each.
47. The use of a pharmaceutical preparation according to Claim 35, wherein each estrogen dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate, and each progestin dominant phase consists of three orally administrable daily unit doses each containing 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.
48. The use of a pharmaceutical preparation according to Claim 35, wherein three unit dosages of 0.75 mg piperazine estrone sulphate and 0.5 mg of norethindrone are alternated with three unit dosages of 0.75 mg piperazine estrone sulphate and 0.35 mg of norethindrone and the preparation is in oral form.
49. The use of a pharmaceutical preparation according to Claim 35, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
50. The use of a pharmaceutical preparation according to Claim 35, wherein each estrogen dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.15 mg norethindrone, and each progestin dominant phase consists of three transdermally administrable daily unit doses each releasing 0.1 mg 17.beta.-estradiol and 0.35 mg norethindrone.
51. The use of a pharmaceutical preparation according to Claim 35, wherein three unit doses of 1.0 mg of 17.beta.-estradiol are alternated with three unit doses of 1.0 mg of 17.beta.-estradiol and 0.35 mg norethindrone.
52. A pharmaceutical preparation for hormone replacement therapy for administration to a woman comprising a series of consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of a woman to whom said preparation is administered, and the daily unit doses of said progestin dominant phases contain said substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said preparation is administered and wherein each daily unit dosage includes a pharmaceutically acceptable inert carrier when required.
53. A pharmaceutical package for hormone replacement therapy containing a total dosage regimen of twenty to thirty-five consecutive daily unit doses in orally administrable tablet form arranged in said package in a fixed sequence corresponding to an intended order of administration in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of a woman to whom said doses are administered, and the daily unit doses of said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of a woman to whom said doses are administered and wherein each daily unit dosage includes a pharmaceutically acceptable inert carrier when required.
54. The use of a pharmaceutical preparation for hormone replacement therapy for a female in need of such treatment comprising administering to said female repeating cycles of a pharmaceutical preparation, each cycle comprising a series of from 20 to 35 consecutive daily unit doses arranged in alternating estrogen dominant phases and progestin dominant phases, each phase consisting of at most four consecutive daily unit doses, wherein the daily unit doses of said estrogen dominant phases contain an amount of a substance exhibiting estrogen activity sufficient to promote the development of progestin receptors in the endometrium of said female, and the daily unit doses of said progestin dominant phases contain substance exhibiting estrogen activity and an amount of a substance exhibiting estrogen activity and an amount of a substance exhibiting progestin activity sufficient to antagonize the effect of estrogen on the endometrium of said female and wherein each daily unit dosage includes a pharmaceutically acceptable inert carrier when required.
Priority Applications (27)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 547744 CA1332228C (en) | 1987-09-24 | 1987-09-24 | Formulation and method for estrogen replacement therapy |
| IE2003/0160A IE84449B1 (en) | 1988-09-21 | Contraceptive packages containing oestrogen and progestin | |
| EP93107794A EP0559240B1 (en) | 1987-09-24 | 1988-09-23 | Contraceptive packages containing oestrogen and progestin |
| HU884989A HU214598B (en) | 1987-09-24 | 1988-09-23 | Process for producing contraceptive compositions containing estragen and progestin and applicable for hormonal therapy |
| AT88308840T ATE102484T1 (en) | 1987-09-24 | 1988-09-23 | HORMONAL COMPOSITION AND USE. |
| DE3856508T DE3856508T2 (en) | 1987-09-24 | 1988-09-23 | Contraceptive kits containing estrogen and progestin |
| AT93107794T ATE209919T1 (en) | 1987-09-24 | 1988-09-23 | CONTRACEPT PACKS CONTAINING ESTROGEN AND PROGESTIN |
| NZ226316A NZ226316A (en) | 1987-09-24 | 1988-09-23 | Pharmaceutical contraceptive preparations and packages containing from 20-35 unit dosages comprising an estrogen and a progestin; the unit dosages having alternating estrogen and progestin dominance |
| ES93107794T ES2169030T3 (en) | 1987-09-24 | 1988-09-23 | PACKAGING CONTAINERS CONTAINING STROGEN AND PROGESTINE. |
| DK198805296A DK174071B1 (en) | 1987-09-24 | 1988-09-23 | Contraceptive preparation in the form of a package comprising unit doses |
| EP88308840A EP0309263B1 (en) | 1987-09-24 | 1988-09-23 | Hormone composition and use |
| AU22760/88A AU630334B2 (en) | 1987-09-24 | 1988-09-23 | Hormone preparations for hormone replacement therapy and contraceptive method |
| NO884230A NO301689B1 (en) | 1987-09-24 | 1988-09-23 | Contraceptive preparation in the form of a package |
| DE3888269T DE3888269T2 (en) | 1987-09-24 | 1988-09-23 | Hormone composition and application. |
| FI884378A FI101601B (en) | 1987-09-24 | 1988-09-23 | The contraceptive and the use of estrogen and progestin in the method of making the contraceptive |
| ES88308840T ES2061672T3 (en) | 1987-09-24 | 1988-09-23 | HORMONAL PREPARATION AND ITS USE. |
| CN88107593A CN1042296C (en) | 1987-09-24 | 1988-09-24 | Hormone preparation and method |
| KR1019880012403A KR0170764B1 (en) | 1987-09-24 | 1988-09-24 | Pharmaceutical package for contraception |
| JP23956688A JP3314207B2 (en) | 1987-09-24 | 1988-09-24 | Hormone preparations and methods |
| US07/788,259 US5276022A (en) | 1987-09-24 | 1991-11-05 | Hormone preparation and method |
| US07/974,182 US5256421A (en) | 1987-09-24 | 1992-11-10 | Hormone preparation and method |
| AU30448/92A AU3044892A (en) | 1987-09-24 | 1992-12-24 | Hormone replacement therapy |
| US08/143,055 US5382573A (en) | 1987-09-24 | 1993-10-29 | Hormone preparation and method |
| US08/354,004 US5585370A (en) | 1987-09-24 | 1994-12-05 | Hormone preparation and method |
| FI972370A FI972370A (en) | 1987-09-24 | 1997-06-04 | Method for preparing a hormone preparation |
| JP34482398A JP3208482B2 (en) | 1987-09-24 | 1998-10-28 | Contraceptive preparation |
| DK200101066A DK174181B1 (en) | 1987-09-24 | 2001-07-06 | Compsn. for hormone replacement therapy and contraception - comprises alternating dominant oestrogen activity with dominant progestagenic activity combinations of oestrogen and progestin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 547744 CA1332228C (en) | 1987-09-24 | 1987-09-24 | Formulation and method for estrogen replacement therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1332228C true CA1332228C (en) | 1994-10-04 |
Family
ID=4136510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 547744 Expired - Lifetime CA1332228C (en) | 1987-09-24 | 1987-09-24 | Formulation and method for estrogen replacement therapy |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1332228C (en) |
-
1987
- 1987-09-24 CA CA 547744 patent/CA1332228C/en not_active Expired - Lifetime
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