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(12) United States Patent (10) Patent No.: US 7,053,077 B1 Elger Et Al

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(12) United States Patent (10) Patent No.: US 7,053,077 B1 Elger Et Al US007053077B1 (12) United States Patent (10) Patent No.: US 7,053,077 B1 Elger et al. (45) Date of Patent: May 30, 2006 (54) USE OF BIOGENIC ESTROGEN (56) References Cited SULFAMATES FOR HORMONE REPLACEMENT THERAPY U.S. PATENT DOCUMENTS 5,314,694. A * 5/1994 Gale et al. (75) Inventors: Walter Elger, Berlin (DE); Pekka 5,633,242 A 5, 1997 Oettel Lähteenmäki, Turku (FI); Matti FOREIGN PATENT DOCUMENTS Lehtinen, Pispanristi (FI): Gudrun Reddersen, Jena (DE); Holger WO 95 O1161 1, 1995 Zimmermann, Ilmenau-Roda (DE); WO WO-96,05216- * 2/1996 Michael Oettel, Jena (DE); Sigfrid OTHER PUBLICATIONS Schwarz, Jena (DE) Elger, W. et al.: "Sulfamates of various estrogens are (73) Assignee: Schering AG, Berlin (DE) prodrugs with increased systemic and reduces hepatic estrogenicity at oral application.” Journal of Steroid (*) Notice: Subject to any disclaimer, the term of this Biochemisty and Molecular Biology, Vol. 55, No. 3-4 pp. patent is extended or adjusted under 35 395-403. U.S.C. 154(b) by 0 days. Elger, Wet al. “Novel oestrogen sulfamates: a new approach to oral hormone therapy” vol. 7, No. 4, 1998 pp. 575-658. (21) Appl. No.: 09/744,574 * cited by examiner (22) PCT Filed: May 13, 1999 Primary Examiner Sreeni Padmanabhan Assistant Examiner Abigail M. Cotton (86). PCT No.: PCT/DE99/O1496 (74) Attorney, Agent, or Firm Millen, White, Zelano & S 371 (c)(1), Branigan, P.C. (2), (4) Date: Apr. 5, 2001 (57) ABSTRACT (87) PCT Pub. No.: WO00/06175 The invention relates to the use of biogenic estrogen Sulfa mates for the oral discontinuous application for hormone PCT Pub. Date: Feb. 10, 2000 replacement therapy (HRT). The discontinuous administra tion takes place in intervals ranging from 2 to 40 days. The (30) Foreign Application Priority Data invention also provides the additional application of Jul. 28, 1998 (DE) ................................ 19834. 931 gestagens, preferably continuously in the form of an implant or in the form of an intrauterine releasing system (IUD). (51) Int. Cl. Estrone sulfamate, estradiol sulfamate or an N-acyl sulfa A6 IK3I/56 (2006.01) mate of estrone, estradiol or estriol having up to 7 C-atoms (52) U.S. Cl. ...................... 514/177, 514/178; 514/182: in the acyl chain, or a combination comprised of two or more 5147874 of said active ingredients are used as biogenic estrogen (58) Field of Classification Search ................ 514/310, Sulfamates. 514/177, 178, 182 See application file for complete search history. 15 Claims, 6 Drawing Sheets U.S. Patent May 30, 2006 Sheet 1 of 6 US 7,053,077 B1 anX 3a N. 5 O) D. 92 S. S C N U.S. Patent May 30, 2006 Sheet 2 of 6 US 7,053,077 B1 D CN gss N 8 S. s 3 U.S. Patent May 30, 2006 Sheet 3 of 6 US 7,053,077 B1 g8 s N a. N s O g S. g S o 9 O O U.S. Patent May 30, 2006 Sheet 4 of 6 US 7,053,077 B1 e?ouo?Ins–?E (G660) U.S. Patent May 30, 2006 Sheet S of 6 US 7,053,077 B1 OZ/009 (puusoldluu/6u)e?og?nseuou?se U.S. Patent May 30, 2006 Sheet 6 of 6 US 7,053,077 B1 OZ|| (luu/6d)SLE US 7,053,077 B1 1. 2 USE OF BIOGENCESTROGEN substances from the blood is also problematical in nature. SULFAMATES FOR HORMONE Even in cases where an oral preparation is given daily, the REPLACEMENT THERAPY active ingredient and its relevant metabolites are eliminated to a large extent between two intakes, so that it cannot be CROSS-REFERENCE TO RELATED assumed that the latter does not result in a disruption of the APPLICATIONS estrogenic action. In studies by Kuhnz et al. (Kuhnz, W.; Gansau, C.; Mahler, M.: "Pharmacokinetics of Estradiol, This application is a 371 of PCT/DE99/01496, filed May Free and Total Estrone, in Young Women. Following Single 13, 1999. Intravenous and Oral Administration of 17 BEstradiol.” Arz The invention relates to the use of biogenic estrogen 10 neim-Forsch/Drug Res. 43 (2), 9,966–973 (1993)), it was Sulfamates for oral, intermittent administration for hormone found that the estradiol and estrone values 24 hours after replacement therapy (HRT). administration of different doses of estradiol (2, 4 and 8 mg Estrogens are formed in the ovary predominantly by as a one-time administration) had dropped to less than 50% vesicular ovarian follicles and corpora lutea. In addition, of the maximum level. This observation shows that dose many organs and tissues are able to generate estrogens, for 15 increase is by no means able to eliminate the problem of example from androstenedione and dehydroepiandroster strong fluctuations of the hormone level in the 24-hour cycle one, which are secreted in Substantial amounts by the with daily intake. The relevance of this assumption can also adrenal glands of the human. Under certain circumstances, be supported by other observations. In postmenopausal several enzymes, and at the end of the chain, ultimately the women, estriol was not osteoporectively effective even at aromatase are involved in the corresponding conversion. very high oral dosages (Lindsay, R.; Hart, D. M.; Maclean, Another method for development of estrogens in the tissue A. Garwood, J.; Clark, A. C.; Kraszewski, A.: "Bone Loss is the hydrolytic cleavage of conjugates of the natural During Estriol Therapy in Postmenopausal Women’ Matu estrogens, primarily that of the estrone Sulfate. It has to be ritas Jun 1 (4), 279-285 (1979)). In women, it has an assumed that estrogens that are produced in the tissue locally especially short half-life of about 1.5–5.3 hours (Heithecker, play an important role in physiological and pathological 25 R.: Aedo, A. R.; Landgren, B. M.: Cekan, S. Z.: “Plasma processes. They are not able to prevent the estrogen defi Estriol Levels after Intramuscular Injection of Estriol and ciency in the overall organism, however, which occurs Two of its Esters' Horm. Res. 35, 234-238 (1991)). It was around age 50 upon the cessation of the ovarian function. demonstrated that this estrogen has a protective action in the Estrogens play an essential role in hormonal contracep bone after ovariectomy, if uniform active ingredient levels tion and in the menopausal hormone replacement therapy 30 are maintained in the blood (Elger, W.; Schneider, B.: Oettel, (HRT) as well as in the treatment of gynecological (e.g., M.: Ernst, M. Hübler, D.; Dittgen, M.: “Use of Estradiol for breast cancer) and andrological (e.g., prostate cancer) clini Treatment of Menopausal Osteoporosis' Patent DE-A 42 09 cal pictures. In the case of contraception, estrogens are 295). required one time to Suppress follicular maturation and In recent years, transdermal therapy processes were ovulation reliably; on the other hand they then substitute the 35 developed. The processes reduce the fluctuations of the largely Suppressed endogenic, ovarian secretion of estradiol. estrogen levels in the blood, but cannot quite avoid the latter. This Substitution is essential for preserving an artificial The essential drawback of this administration technology menstrual cycle and other functions of the sexual organs, presumably lies in the complicated use in comparison to which is not accomplished satisfactorily with a gestagen by simple oral administration. Oral preparations still predomi itself. In addition, endogenic and exogenic estrogens have 40 nate on the HRT market despite their discussed drawbacks. important central nervous and metabolic functions in the Transdermal forms of administration are abandoned by their female organism. Normal estrogen levels decisively contrib users, moreover, on average earlier than is the case for oral ute to well-being. Its presence counteracts the development preparations. of cardiovascular diseases by various mechanisms: produc The latter are rejected by medical science, citing their tion of “advantageous' lipoprotein patterns in the blood, 45 metabolic effects for the field of application of HRT. The inhibition of lipid retention in the vascular wall, lowering of most important synthetically modified estrogenic steroid is the blood pressure by advantageous influencing of Vasoto ethinylestradiol (EE). This estrogen is dominant in oral nia, reduction of perfusion resistance in important vascular hormonal contraception. In addition to EE, mestranol, which Zones, attenuation of contractile stimuli on vascular muscle. is a “prodrug, is used in a few products, and is metabolized Under the action of estrogens, the vascular inner walls 50 into EE in the organism. In the case of oral administration release factors that counteract the development of blood (human), EE is much more bio-available than the above clots. In women, estrogens are essential for preserving the mentioned natural estrogens, but the oral bio-availability bone structure. Its loss can produce the development of bone individually varies in an extraordinarily great manner. Dif destruction (osteoporosis). The last-mentioned “central ner ferent authors have pointed out this fact and the partially vous” and “metabolic effects of estrogens are essential 55 irregular behavior of the blood level plots after this sub considerations of HRT. stance is administered orally (Goldzieher, J. W.: Pharmacol In all positive aspects of estrogen therapy, there are ogy of Contraceptive Steroids: A Brief Review, “Am. f. unsolved problems that limit the therapeutic use of estrogens Obstet. Gynaecol. 160, 1260–1264 (1989); Goldzieher, J. or contain undesirable actions; the latter are discussed in the W.: “Selected Aspects of the Pharmacokinetics and Metabo following chapters with respect to the subject of the inven 60 lism of Ethinyl Estrogens and their Clinical Implications' tion. Am. J. Obstet. Gynaecol. 163, 318–322 (1990); Hümpel, Natural estrogens (estradiol, estrone, estrone sulfate, M.; Tauber, U. Kuhn, W. Pfeffer, M.; Brill, K.: Heithekker, esters of estradiol, estriol) are bio-available to only a very R.: Louton, T.; Steinberg, B.: “Comparison of Serum Ethinyl small extent when administered orally.
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