US 2005.0070488A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0070488A1 Coelingh Bennik et al. (43) Pub. Date: Mar. 31, 2005 (54) ESTROGENIC COMPOUNDS IN prises the oral administration of an estrogenic component COMBINATION WITH PROGESTOGENIC and a progestogenic component to a mammal in an effective COMPOUNDS IN amount to prevent or treat Symptoms of hypoestrogenism, HORMONE-REPLACEMENT THERAPY wherein the estrogenic component is Selected from the group (76) Inventors: Herman Jan Tijmen Coelingh Bennik, consisting of Substances represented by the above formula in Driebergen (NL); Evert Johannes which formula R, R2, R, R independently are a hydrogen Bunschoten, Heesch (NL); Christian atom, a hydroxyl group or an alkoxy group with 1-5 carbon Franz Holinka, New York, NY (US) atoms; each of Rs, R, R-7 is a hydroxyl group; and no more than 3 of R, R2, R, R are hydrogen atoms; precursors Correspondence Address: capable of liberating a Substance according to the aforemen William Logsdon tioned formula when used in the present method; and Webb Ziesenheim Logsdon Orkin & Hanson mixtures of one or more of the aforementioned Substances 700 Koppers Building and/or precursors. Another aspect of the invention concerns 436 Seventh Avenue a pharmaceutical kit comprising oral dosage units that Pittsburgh, PA 15219-1818 (US) contain the aforementioned estrogenic component and a (21) Appl. No.: 10/495,707 progestogenic component as well as an androgenic compo nent. (22) PCT Filed: May 23, 2002 (86) PCT No.: PCT/NL02/00332 (30) Foreign Application Priority Data Nov. 15, 2001 (EP)........................................ O1204377.4 Feb. 21, 2002 (EP)........................................ O2O75695.3 Publication Classification 51)1) Int. Cl.'C.7 ........................ A61K 31/5656; A61K 31/704 (52) U.S. Cl. .............................................. 514/26; 514/182 (57) ABSTRACT One aspect of the present invention relates to a method of hormone replacement in mammals, which method com US 2005/0070488 A1 Mar. 31, 2005 ESTROGENIC COMPOUNDS IN COMBINATION organism: normal estrogen levels make a decisive contribu WITH PROGESTOGENC COMPOUNDS IN tion to a woman's well-being. Notwithstanding the wide HORMONE-REPLACEMENT THERAPY Spread use of estrogens in HRT methods, there are still Some unsolved problems. Known estrogens, in particular the bio TECHNICAL FIELD OF THE INVENTION genic estrogens (i.e. estrogens naturally occurring in the human body), show serious pharmacokinetic deficits. Bio 0001. The present invention relates to a method of hor genic estrogens Such as estradiol, estrone, estrone Sulphate, mone replacement in mammals. More particularly the inven esters of estradiol and estriol become bioavailable only to a tion is concerned with a method of hormone replacement very low degree when taken orally. This degree may vary So that comprises the oral administration to a mammal of a much from perSon to person that general dosage recommen combination of an estrogenic component and a progestoge dations cannot be given. Fast elimination of these estrogens nic component in an effective amount to prevent or treat from the blood is another related problem. For instance, for Symptoms of hypoestrogenism. the main human biogenic estrogen 17B-estradiol the half-life is around 1 hour. As a result, between Separate (daily) BACKGROUND OF THE INVENTION administration events, blood Serum levels of Such biogenic estrogens tend to fluctuate considerably. Thus, Shortly after 0002 In hormone replacement therapy (HRT), some administration the Serum concentration is usually Several times also referred to as estrogen replacement therapy, times higher than the optimum concentration. In addition, if estrogens are administered to prevent or treat Symptoms the next administration event is delayed, Serum concentra resulting from estrogen deficiency or hypoestrogenism. tions will quickly decrease to a level where the estrogen is Hypoestrogenism can occur in both females and males, and no longer physiologically active. can lead to disorders and ailments Such as Osteoporosis (loss of bone mass), arteriosclerosis, climacteric Symptoms Such 0007. The most important synthetically altered estrogenic as hot flushes (flashes), Sweats, urogenital atrophy, mood steroid is 17O-ethinyl estradiol (EE). This estrogen is hardly disturbances, insomnia, palpitations. Estrogen deficiency used in HRT methods because prolonged administration of has also been associated with cognitive disturbances and EE has been associated with an increased risk of throm Alzheimer's disease. boembolism, which is deemed to be particularly detrimental in menopausal and post-menopausal females. Apart from 0.003 Hypoestrogenism, and in particular chronic EE, mestranol has been used in a few cases, mestranol is a hypoestrogenism, is frequently observed in (peri-)meno “prodrug” that is metabolised to EE in the organism. When pausal and post-menopausal women. However, it can also applied orally to humans, EE has a much better bioavail result from hypogonadism or castration, as well as from ability than the biogenic estrogens mentioned above, but its primary ovarian failure, treatment of e.g. breast cancer with aromatase inhibitor and gonadotropin-releasing hormone oral bioavailability varies to a large extent from individual analogue treatment of benign gynaecological diseaseS Such to individual. Several authors have pointed to this as well as as endometriosis, adenomyosis, uterine fibroids (leiomyo to the fact that concentrations in the blood proved to be mas), dysmenorrhoea, menorrhagia and metrorrhagia. highly fluctuating after oral application of this Substance. 0008. In addition to pharmacokinetic problems, the 0004 HRT employs continuous administration of effec known estrogens also show pharmacodynamic deficits. After tive amounts of an estrogen for prolonged periods of time. resorption from the intestinal lumen, orally applied active The administration of estrogens has been associated, how ingredients enter the organism via the liver. This fact is of ever, with endometrial proliferation in Women and it is now Specific importance for estrogenic agents as the liver is a widely accepted that “unopposed” estrogen therapy Substan target organ for estrogens, oral intake of estrogens results in tially increases the risk of endometrial cancer (Cushing et Strong estrogenic effects in the liver. The Secretion activity al., 1998. Obstet. Gynecol.91, 35-39; Tavani et al., 1999. that is controlled by estrogens in the human liver includes Drugs Aging, 14, 347-357). There is also evidence of a increased synthesis of transport proteins CBG, SHBG, TBG, Significant increase in breast cancer with long-term (10-15 Several factors that are important for the physiology of blood years) use of estrogen therapy (Tavani et al., 1999. Drugs clotting, and lipoproteins. If biogenic estrogens are intro Aging, 14, 347-357; Pike et al., 2000. Steroids, 65, 659 duced to the female organism while avoiding passage 664). through the liver (e.g. by transdermal application), the liver 0005. In order to counteract the negative effects of unop functions mentioned remain largely unchanged. Therapeu posed estrogen therapy, adjunctive progestogen treatment is tically equivalent doses of biogenic estrogens, when applied nowadays commonly applied. Regular progestogen admin orally, result in clear responses of hepatic parameters, Such istration is believed to inhibit the continual estrogen Stimu as increase of SHBG, CBG, angiotensinogen and HDL (high lation of the endometrium through an anti-proliferative density lipoprotein). These hepatic effects of estrogens are effect and appears to reduce the incidence of endometrial also observed when equine estrogen formulations (so-called carcinoma in post-menopausal women receiving estrogen conjugated estrogens) are used. Ethinyl estradiol and dieth replacement therapy (Beral et al., 1999. J. Epidemiol. Bio ylstilbestrol (DES) have an even greater hepatic estrogenic Stat., 4, 191-210). Such an adjunctive treatment, generally ity. Elger et al., J. Steroid Biochem. Molec. Biol. (1995), using Synthetic progestogens, is given either in continuous 55(3/4), 395-403, have reported that EE or DES have much combined regimens with estrogen, or added Sequentially, higher hepato-cellular than Systemic estrogenicity: in rela typically for about 14 days each month, to continuous tion to FSH-secretion inhibitory activity these estrogens are estrogen treatment. 4-18 times more active in the liver than estrone Sulfate. 0006 Endogenous and exogenous estrogens fulfil impor 0009. The aforementioned deficits are of considerable tant central nervous and metabolic functions in the female clinical significance when commonly known biogenic and US 2005/0070488 A1 Mar. 31, 2005 Synthetic estrogens are applied. Consequently, there is an as Endocrinologica, 98, 73-80: “Estetrol agonistic yet unmet need for estrogens that do not display these potency is 2% of the magnitude observed for 17B deficits and which can suitably be administered orally in estradiol in in vitro cell proliferation”. HRT methods to effectively replace endogenous ovarian Secretion of estradiol, i.e. to treat or prevent Symptoms of 0017 Holinka et al., 1980. Comparison of effects of hypoestrogenism. estetrol and tamoxifen with those of estriol and estra diol on the immature rat uterus. Biol. Reprod. 22, 913-926: “Subcutaneously administered estetrol has SUMMARY OF THE INVENTION Very weak uterotrophic activity and is considerable