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(12) United States Patent (10) Patent No.: US 7,572,779 B2 Aloba Et Al

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(12) United States Patent (10) Patent No.: US 7,572,779 B2 Aloba Et Al US00757 2779B2 (12) United States Patent (10) Patent No.: US 7,572,779 B2 Aloba et al. (45) Date of Patent: Aug. 11, 2009 (54) ORAL PHARMACEUTICAL PRODUCTS 5,855,906 A 1/1999 McClay ...................... 424/433 5,928,668 A 7/1999 Greaves et al. .... ... 424/489 CONTAINING 17B-ESTRADIOL-3-LOWER ALKANOATE, METHOD OF 5,976,570 A 11/1999 Greaves et al. .... ... 424/470 ADMINISTERING THE SAME AND PROCESS 6,200,593 B1 3/2001 Place ..... ... 424/435 OF PREPARATION 6,221,379 B1 4/2001 Place ......................... 424/435 OTHER PUBLICATIONS (75) Inventors: Oluwole T. Aloba, Morristown, NJ (US); Tina M deVries, Long Valley, NJ (US) March, Advanced Organic Chemistry, 3rd ed., 1985, p. 334-338.* Lieveritz, R.W., Amer, J. of Obstetrics and Gynecology, vol. 156, pp. (73) Assignee: Warner Chilcott Company LLC, 1289-1293, 1987. Fajardo, PR (US) Stumpf, P.G., Obstetrics and Gynecology, vol. 75 (suppl)pp.9S-17S, 1990. Marsh, M.S., et al., British Medical Bulletin, vol. 48, pp. 426-457. (*) Notice: Subject to any disclaimer, the term of this 1992. patent is extended or adjusted under 35 Lobo, R.A., et al., J. of Reproductive Medicine, vol. 37, pp. 77-84, U.S.C. 154(b) by 802 days. 1992. Woolfson, D., et al., J. of Controlled Release, vol. 61, pp. 319-328, (21) Appl. No.: 10/833,997 1999. Kuhl, H., Maturitas, vol. 12, pp. 171-197, 1990. (22) Filed: Apr. 29, 2004 Powers, M., et al., Amer. J. of Obstetrics and Gynecology, vol. 152, pp. 1099-1 106, 1985. (65) Prior Publication Data Remington: The Science and Practice of Pharmacy, 19" ed., 1995, pp. 1413, 1623-1626. US 2004/0209856A1 Oct. 21, 2004 Wolfe et al., Journal of Lipid Research, 2000; 41:368-375. March, Advance Organic Chemistry, 3' ed., 1985, pp. 334-338. Related U.S. Application Data * cited by examiner (62) Division of application No. 10/023,748, filed on Dec. 21, 2001, now Pat. No. 6,962,908. Primary Examiner Sreeni Padmanabhan Assistant Examiner Sahar Javanmard (51) Int. Cl. (74) Attorney, Agent, or Firm Fitzpatrick, Cella, Harper & A6 IK3I/56 (2006.01) Scinto AOIN 25/08 (2006.01) (52) U.S. Cl. ....................... 514/170; 514/178; 514/171; (57) ABSTRACT 514/182: 424/409 (58) Field of Classification Search ................. 514/170, A pharmaceutical dosage unit for oral administration to a 514/171, 178, 182 human female comprising a therapeutically effective amount See application file for complete search history. of 17f8-estradiol-3-lower alkanoate, most preferably 17 B-es tradiol-3-acetate, and a pharmaceutically acceptable carrier is (56) References Cited disclosed. Also disclosed is a method for treating a human U.S. PATENT DOCUMENTS female in need of 17 B-estradiol and a contraceptive method by oral administration of the pharmaceutical dosage unit and 2,156,599 A 5/1939 Scholz ....................... 552,625 a method of preparing a pharmaceutical composition that 3,478,070 A 11, 1969 Stein ....... ... 260/.397.5 may be used to form the pharmaceutical dosage unit of the 3,568,828 A 3/1971 Lerner ......................... 206.42 invention. 4,544.554 A 10/1985 Pasquale ..................... 514,170 5,382,434 A 1/1995 de Haan et al. ............. 424/465 5,824,667 A 10/1998 Spona ........................ 514,170 5 Claims, No Drawings US 7,572,779 B2 1. 2 ORAL PHARMACEUTICAL PRODUCTS known in the art for the oral administration of estrogen for CONTAINING 17B-ESTRADIOL-3-LOWER HRT include estradiol-3,17-diacetate, estradiol-17-acetate, ALKANOATE, METHOD OF estradiol-3,17-valerate, estradiol-3-valerate, estradiol-17 ADMINISTERING THE SAME AND PROCESS Valerate, ethinyl estradiol, and equine estrogens. The latter are OF PREPARATION mixtures of estrogens purified from the urine of pregnant mares and containing Sulphate and glucouronide derivatives, This application is a divisional application of U.S. patent and equine-specific estrogens such as equilin not normally application Ser. No. 10/023.348, filed Dec. 21, 2001, the found in humans Stumpf, 1990. In addition, less potent disclosure of which is incorporated by reference herein in its metabolites of 17 B-estradiol have been administered by this entirety. 10 route, for example, estrone or its conjugates A number of difficulties arise concerning the oral admin BACKGROUND OF THE INVENTION istration of estrogens. Although micronized 173-estradiol is an efficient form of the natural hormone for its oral adminis 1. Field of the Invention tration, micronization represents an additional process for This invention relates to a pharmaceutical dosage unit for 15 pharmaceutical production, with associated increased costs oral administration containing 17 B-estradiol-3-lower and inconvenience. Micronized 17 B-estradiol has been alkanoate, most preferably 17 B-estradiol-3-acetate, that shown to be equivalent in pharmacokinetic terms to the oral unexpectedly provides improved bioavailability of estrogen administration of 17 B-estradiol valerate, which is metabo when orally administered to a human female in need of estro lised to the parent hormone in vivo. 17 B-estradiol Valerate is gen replacement therapy or receiving estrogen for contracep a highly lipophilic ester with no measurable aqueous solubil tive purposes. The invention also relates to a process for ity, as are other ester derivatives of 17 B-estradiol adminis producing the pharmaceutical dosage unit. tered by the oral route Woolfson, D., et al., J. of Controlled 2. Related Background Art Release, Vol. 61, pp. 319-328, 1999). Orally administered In the normal, healthy human female, 17 B-estradiol is the 17B-estradiol and its various ester and equine conjugates principal estrogen produced by the functioning premeno 25 undergo extensive first-pass hepatic metabolism, resulting in pausal ovary during each menstrual cycle Lieveritz, R. W., poor bioavailability by the oral route. In addition, hepatic Amer. J. of Obstetrics and Gynecology, Vol. 156, pp. 1289 metabolism causes undesirable non-physiological circulating 1293, 1987. Estrogen deficiency may occur due to disease, levels of the metabolite estrone and elevation of hepatic pro oophorectomy, traumatic injury or as a natural consequence teins. Conjugated equine estrogens, in particular, exert a pro of the aging process. As aging progresses, ovulation becomes 30 found hepatic effect Kuhl, H., Maturitas, Vol. 12, pp. 171 less frequent and predictable, resulting in diminished produc 197, 1990 and are thus clinically less desirable than tion of 17B-estradiol. Gradual loss of ovarian function occurs derivatives of the parent hormone. Oral administration of naturally around 45-55 years of age leading to the eventual 17B-estradiolor its conjugates requires a significantly higher cessation of the menstrual cycle, that is, the menopause. dose for clinical efficacy compared to non-oral routes Pow During normal ovulatory cycles ovarian production of 35 ers, M., et al., Amer. J. of Obstetrics and Gynecology, Vol. 17 B-estradiol ranges from 60-600 ug per day, resulting in 152, pp. 1099-1106, 1985). circulating levels of 173-estradiol in serum ranging from Much of the prior art literature for preparation of oral 40-400 pg/ml. Circulating 17 B-estradiol levels vary during pharmaceutical formulations of steroids Such as estradiol the monthly cycle in the premenopausal woman. At the meno comprises broad disclosures of Solution or Suspension wet pause, when irreversible ovarian failure occurs, 17f-estradiol 40 granulation methods (for example, Pasquale, U.S. Pat. No. production decreases dramatically to less than 20 ug per day, 4,544.554; Lerner, U.S. Pat. No. 3,568,828; Greaves, U.S. giving circulating levels of the hormone in serum of less than Pat. No. 5,976,570) or dry mixing using specialized excipi 30 pg/ml. Stumpf, P. G., Obstetrics and Gynecology, Vol. 75 ents (for example, DeHaan, U.S. Pat. No. 5,382,434; Greaves, (suppl.) pp. 95-135, 1990. This low level of estrogen produc U.S. Pat. No. 5,928,668). tion may result in typical postmenopausal symptoms Marsh, 45 Dry mixing of low dose drugs is especially prone to sig M. S., et al., British Medical Bulletin, Vol. 48, pp. 426457, nificant lack of uniformity in drug distribution, even with the 1992. The physiological consequences of the fall in estradiol use of specialized excipients. Wet granulation using organic levels typically include vasomotor instability (hot flushes), Solvents such as chloroform, as described by Lerner, is gen urogenital atrophy and a loss of bone mineral mass leading to erally unacceptable from an environmental, cost, and health osteoporosis. 50 and safety standpoint. On the other hand, aqueous wet granu The most active, naturally occurring human estrogen is lation (e.g. Greaves, U.S. Pat. No. 5,976,570) could readily unbound 17 B-estradiol. Hormone replacement therapy induce hydrolysis of ester derivatives of 17 B-Estradiol. A (HRT) seeks to counteract the detrimental effects associated method for producing uniform, stable orally administered with low circulating plasma estrogen levels by restoring estrogen products with improved bioavailability is therefore these, as far as possible, to a premenopausal physiological 55 highly desirable. status. It follows, therefore, that the preferential estrogen for This invention discloses a method for improving the bio HRT is 17 B-estradiol and that the aim of HRT is to deliver this availability of orally administered estrogen in the form of hormone at Such a rate as to maintain physiological plasma 17 B-estradiol-3-lower alkanoate. Parenteral administration levels of 17 B-estradiol. of estradiol esters such as estradiol Valerate, estradiol cypio 17 B-Estradiol is not absorbed efficiently from the gastric 60 rate and estradiol benzoate are well known. 17 B-Estradiol-3- mucosa following administration by the oral route and must, acetate has been shown to be an efficient form of estrogen for therefore, be formulated for administration in micronized intravaginal delivery of HRT (Woolfson et al., 1999, and form (to provide an increased surface area) or as a conjugate McClay U.S.
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