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A Pharmaceutical Product for Hormone Replacement Therapy Comprising Tibolone Or a Derivative Thereof and Estradiol Or a Derivative Thereof

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A Pharmaceutical Product for Hormone Replacement Therapy Comprising Tibolone Or a Derivative Thereof and Estradiol Or a Derivative Thereof Europäisches Patentamt *EP001522306A1* (19) European Patent Office Office européen des brevets (11) EP 1 522 306 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: A61K 31/567, A61K 31/565, 13.04.2005 Bulletin 2005/15 A61P 15/12 (21) Application number: 03103726.0 (22) Date of filing: 08.10.2003 (84) Designated Contracting States: • Perez, Francisco AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08970 Sant Joan Despi (Barcelona) (ES) HU IE IT LI LU MC NL PT RO SE SI SK TR • Banado M., Carlos Designated Extension States: 28033 Madrid (ES) AL LT LV MK (74) Representative: Markvardsen, Peter et al (71) Applicant: Liconsa, Liberacion Controlada de Markvardsen Patents, Sustancias Activas, S.A. Patent Department, 08028 Barcelona (ES) P.O. Box 114, Favrholmvaenget 40 (72) Inventors: 3400 Hilleroed (DK) • Palacios, Santiago 28001 Madrid (ES) (54) A pharmaceutical product for hormone replacement therapy comprising tibolone or a derivative thereof and estradiol or a derivative thereof (57) A pharmaceutical product comprising an effec- arate or sequential use in a method for hormone re- tive amount of tibolone or derivative thereof, an effective placement therapy or prevention of hypoestrogenism amount of estradiol or derivative thereof and a pharma- associated clinical symptoms in a human person, in par- ceutically acceptable carrier, wherein the product is pro- ticular wherein the human is a postmenopausal woman. vided as a combined preparation for simultaneous, sep- EP 1 522 306 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 522 306 A1 2 Description [0008] The review article of Journal of Steroid Bio- chemistry and Molecular Biology (2001), 76(1-5), FIELD OF THE INVENTION: 231-238 provides a review of some of these compara- tive studies. It further concludes that tibolone works on [0001] The present invention relates to a pharmaceu- 5 the estradiol receptor. In other words, tibolone and es- tical product comprising an effective amount of tibolone tradiol are both working on the same receptor. or derivative thereof, an effective amount of estradiol or [0009] WO0074684A1 describes numerous different derivative thereof and a pharmaceutically acceptable possible combinations of different steroid hormones for carrier, wherein the product is provided as a combined treatment of postmenopausal women. Virtually all pos- preparation for simultaneous, separate or sequential 10 sible theoretical combinations are listed including differ- use in a method for hormone replacement therapy or ent combinations of estrogens, androgens, progestins, prevention of hypoestrogenism associated clinical selective estrogen receptor modulator (SERM), selec- symptoms in a human person, in particular wherein the tive androgen receptor modulator (SARM) and selective human is a postmenopausal woman. progestin receptor modulator (SPRM). No specific rele- 15 vant actual example results are provided. One list of the BACKGROUND OF THE INVENTION: description is a list of a number of different suitable SERM molecules. This list includes tibolone. Another list [0002] In hormone replacement therapy (HRT), includes a number of different suitable estrogens. This sometimes also referred to as estrogen replacement list includes estradiol. therapy, estrogens are administered to prevent or treat 20 [0010] The article of European Journal of Gynaeco- symptoms resulting from estrogen deficiency or hypoes- logical Oncology, (2002) 23 (2) 127-30 describes a trogenism. Hypoestrogenism can occur in both females study analyzing possible breast cancer risks of tibolone. and males, and can lead to disorders and ailments such The studies are performed in vitro on a human breast as osteoporosis (loss of bone mass), arteriosclerosis, cancer cell line. The aim of the study was to compare climacteric symptoms such as hot flushes (flashes), 25 tibolone to HRT using estradiol and norethisterone. Ti- sweats, urogenital atrophy, mood disturbances, insom- bolone was examined alone and in the presence of 0.1 nia, palpitations. Estrogen deficiency has also been as- nM estradiol. sociated with cognitive disturbances and Alzheimer's disease. SUMMARY OF THE INVENTION: [0003] Hypoestrogenism, and in particular chronic hy- 30 poestrogenism, is frequently observed in perimenopau- [0011] The problem to be solved by the present inven- sal and post-menopausal women. However, it can also tion is to provide a pharmaceutical composition with im- result from hypogonadism or castration, as well as from proved properties in relation to treatment or prevention primary ovarian failure, treatment of e.g. breast cancer of hypoestrogenism associated clinical symptoms, in with aromatase inhibitor and gonadotropin-releasing 35 particular of a postmenopausal woman. Improved prop- hormone analogue treatment of benign gynaecological erties include less unwanted negative side effects such diseases such as endometriosis, adenomyosis, uterine as less risk for breast cancer development. fibroids (leiomyomas), dysmenorrlioea, menorrhagia [0012] As explained above, the prior art describes that and metrorrhagia. tibolone and estradiol are both working on the same re- [0004] Hormone replacement therapy (HRT) has 40 ceptor. Among others, despite of this fact, the present been used for many years for alleviation of hypoestro- inventors investigated the effects of a pharmaceutical genism associated clinical symptoms such as postmen- product combining both tibolone and estradiol. Surpris- opausal symptoms as well as prophylaxis of osteoporo- ingly, they found that such a pharmaceutical product had sis in postmenopausal women. improved properties in relation to treatment or preven- [0005] Suitable estrogens, such as estradiol, have 45 tion of hypoestrogenism associated clinical symptoms, been used in HRT. Estradiol is many times used in com- in particular of a postmenopausal woman. bination with some progestins such as norethindrone (a [0013] Accordingly, a first aspect of the invention re- synthetic progestin also termed norethisterone), me- lates to a pharmaceutical product comprising an effec- droxiprogesterone and others. tive amount of tibolone or derivative thereof, an effective [0006] Tibolone is a synthetic steroid which elicits es- 50 amount of estradiol or derivative thereof and a pharma- trogenic, progestogenic and androgenic properties. Ti- ceutically acceptable carrier, wherein the product is pro- bolone is used as an alternative to estradiol in HRT. vided as a combined preparation for simultaneous, sep- [0007] Numerous studies have been carried out to arate or sequential use in a method for hormone re- compare the effectiveness of tibolone and estradiol on placement therapy or prevention of hypoestrogenism symptoms in postmenopausal women. Generally, all 55 associated clinical symptoms in a human person, in par- these studies are based on that a group of women gets ticular wherein the human is a postmenopausal woman. tibolone and another group gets estradiol or estradiol [0014] A second aspect of the invention relates to use plus a progestin such as norethindrone. of a pharmaceutical product, as described herein, for the 2 3 EP 1 522 306 A1 4 manufacture of a medicament for hormone replacement Derivatives: therapy or prevention of hypoestrogenism associated clinical symptoms in a human person, in particular [0022] This section is a general description of deriva- wherein the human is a postmenopausal woman. tives. Tibolone and estradiol are active components. [0015] This second aspect may alternatively be for- 5 [0023] The active components may be converted into mulated as a method for hormone replacement therapy derivatives thereof, like esters and ethers, which, within or prevention of hypoestrogenism associated clinical a pharmaceutical composition as described herein, are symptoms in a human, in particular wherein the human all covered by the present invention. The derivatives can is a postmenopausal woman, comprising administering be prepared by standard procedures known to one to a human in need thereof an effective amount of phar- 10 skilled in the art. maceutical product as described herein. [0024] Esters and ethers may e.g. be prepared by the [0016] A third aspect of the invention relates to a methods given in the literature, for example, in Ad- method for making a pharmaceutical product for use in vanced Organic Synthesis, 4th Edition, J. March, John a method for hormone replacement therapy or preven- Wiley & Sons., 1992. tion of hypoestrogenism associated clinical symptoms 15 [0025] Generally, a derivative of tibolone denotes in a human person, in particular wherein the human is herein a derivative that at least is capable of triggering a postmenopausal woman, comprising making a phar- a response in vivo that in essence corresponds to the maceutical product comprising an effective amount of response in vivo of tibolone. In order for tibolone to trig- tibolone or derivative thereof, an effective amount of es- ger such a response tibolone normally have to bind to tradiol or derivative thereof and a pharmaceutically ac- 20 tibolone receptors, which receptors are found in various ceptable carrier as described herein. tissues within the human body. A derivative of tibolone denotes herein a derivative that is capable of binding to Embodiment(s) of the present invention is described a tibolone receptor in a similar way as tibolone bind to below, by way of example(s) only the same tibolone receptor. Based on e.g. known 3-di- 25 mensional structure of tibolone and a tibolone receptor DETAILED DESCRIPTION
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