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Dhea composition and methodRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, Oxygen Double Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring SystemDhea composition and method description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060234992, Dhea composition and method. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. provisional application Ser. No. 60/125,201, filed Mar. 18, 1999, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention provides pharmaceutical formulations of DHEA enriched for polymorph form I or form II, which are useful for various therapeutic applications. In particular, the invention is directed to formulations of DHEA having more consistent bioavailability than previously used formulations. REFERENCES [0003] Arlt, W. et al., J. Clin. Endocrinol. Metab. 83(6):1928-1934 (1998). [0004] Barker, E. V. et al., Endocrinology 134:982-989 (1994). [0005] Barrett-Connor et al., New Engl. J. Med. 315:1519 (1986). [0006] Caira, M. R. et al., J. Chem. Crystallogr. 25:393 (1995). [0007] Chang, L. C. et al., J. Pharmaceut. Sci. 84:1169-1179 (1995). [0008] Comer, K. A. and Falany, C. N., Mol. Pharmacol. 41:645-651 (1992). [0009] Cox, P. J. et al., Acta Crystallogr. C46, 334-336 (1990). [0010] Falany, C. N. et al., Ann. NY Acad. Sci. 774:59-72 (1995). [0011] Frye and Maciel, J. Mag. Res. 48:125 (1982). [0012] Grodin, J. M. et al., J. Clin. Endo. Metab. 36:207-214 (1973). [0013] GUIDANCE FOR INDUSTRY: O2B VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY, HFD-210, CDER, Rockville, Md. [0014] Kuhnert-Brandstatter, M., THERMOMICROSCOPY IN THE ANALYSIS OF PHARMACEUTICALS, Pergamon Press, Oxford, U.K. (1971). [0015] Lacheline, G. C. et al., J. Clin. Endocrinol. Metab. 49(6):892-898 (1979). [0016] Longcope, C., Ann. NY Acad. Sci. 774:143-148 (1995). [0017] MacDonald, J. C., J. Mag. Res. 38:381 (1980). [0018] Meikle, A. W. et al., J. Steroid Biochem. Molec. Biol. 293-304 (1992). [0019] Orentreich, N. et al., J. Clin. Endocrinol. Metab. 59:551-555 (1984). [0020] van Cauter, E., Horm. Res. 32(2):45-53 (1990). [0021] Yen, S. S. et al., Ann. NY Acad. Sci. 774:128-142 (1995). BACKGROUND OF THE INVENTION [0022] Dehydroepiandrosterone (DHEA), also known as 3-beta-hydroxyandrost-5-en-17-one, dehydroisoandrosterone, trans-dehydroandrosterone, .DELTA..sup.5-androsten-3-.beta.-ol-17-one, and prasterone, is a naturally occurring intermediate formed in the course of synthesis of various steroids from cholesterol. DHEA is the most abundant steroid hormone in humans and is produced mainly by the adrenal cortex as an inactive sulfate ester (DHEA-S). DHEA production also occurs in the testes, ovaries, and brain. After achieving a plateau level during early adulthood (ages 16 to 24), total serum DHEA (DHEA+DHEA-S) declines steadily to about 5 to 10% of peak values by age 60 to 70 (Orentreich et al., 1984). [0023] DHEA has been proposed for use in treating many medical conditions, such as systemic lupus erythematosus (U.S. Pat. No. 5,817,650), primary adrenal insufficiency (U.S. Pat. No. 5,861,391), Addison's disease (ibid.), reduced libido (U.S. Pat. No. 5,855,548), obesity (U.S. Pat. No. 5,846,962), osteoporosis (U.S. Pat. Nos. 5,846,960 and 5,855,548), and fibromyalgia (U.S. Pat. No. 5,935,949). DHEA can be administered by various routes and is orally active. [0024] The pharmacokinetics of exogenously administered DHEA are complicated by endogenous production of DHEA and by the reversible interconversion between DHEA and DHEA-S, the major metabolite of DHEA, which acts as a reservoir for DHEA. DHEA exhibits wide diurnal variations in endogenous production, while DHEA-S levels show little variation during the day. Changes in plasma DHEA occur in parallel to those of ACTH and cortisol, with an early morning maximum, declining levels through the daytime, and minimal secretory activity in the early part of the night (van Cauter, 1990; Lacheline et al., 1979; Yen et al., 1995). [0025] Both DHEA and DHEA-S are bound by serum albumin, globulins, and steroidal sex hormone binding globulin (Meikle et al., 1992; Longcope, 1995). Only a small fraction of orally administered DHEA appears in the blood at any given time as DHEA; most undergoes conversion to DHEA-S by sulfotransferases in the liver and extrahepatic tissues (Barker, 1994; Corner, 1992; Falany, 1995; Arlt, 1998). DHEA-S is converted back to DHEA by peripheral tissues containing DHEA sulfatases, including lymphocytes and macrophages. DHEA is subsequently metabolized to androstenedione as well as the potent androgens, testosterone and dihydrotestosterone, and the estrogens, estrone and estradiol. Adipose tissue may serve as a substantial reservoir for adrenal androgens. The aromatization of DHEA in peripheral tissue is thought to account for the majority of estrogen biosynthesis in postmenopausal women (Grodin et al., 1973). [0026] The bioavailability of a drug can play an important role in its efficacy. It has been reported that DHEA occurs in at least three and as many as five anhydrous polymorphic forms and at least three hydrated forms, depending on environmental conditions and the manner of preparation (Chang et al., 1995). The known forms have been reported to be distinguishable on the basis of infrared spectroscopy and powder diffraction analysis, except that forms S3 and S4 are indistinguishable using the latter method (ibid.). Work conducted in support of the present invention indicates the existence of a sixth anhydrate form designated herein as form VI, which is detectable by solid state NMR but not by infrared spectroscopy or x-ray powder diffraction analysis. [0027] Although DHEA is available from a variety of commercial sources, these materials show significant variation in their polymorphic compositions, which can cause variations in bioavailability due to differences of absorption during uptake in vivo. [0028] Accordingly, it is an object of the present invention to provide DHEA formulations enriched in the form I polymorph or the form II polymorph, to achieve more consistent bioavailability and reliable efficacy. Formulations enriched in the form VI polymorph are also contemplated. SUMMARY OF THE INVENTION [0029] The present invention includes, in one aspect, a pharmaceutical formulation comprising dehydroepiandrosterone (DHEA), at least 85% of which is present as the form I polymorph, and at least one pharmaceutical excipient. Preferably, at least 90% of the DHEA is present as the form I polymorph, more preferably 95%, and most preferably greater than 99%. The invention also includes a composition of matter consisting essentially of the form I polymorph of DHEA. [0030] The invention also includes, in a second general embodiment, a pharmaceutical formulation comprising DHEA, at least 85% of which is present as the form II polymorph, and at least one pharmaceutical excipient. Preferably, at least 90% of the DHEA is present as the form II polymorph, more preferably 95%, and most preferably greater than 99%. [0031] Also included are pharmaceutical formulations comprising DHEA, at least 85% of which is present as the form VI polymorph, and at least one pharmaceutical excipient. Preferably, at least 90% of the DHEA is present as the form VI polymorph, more preferably 95%, and most preferably greater than 99%. The invention also includes a composition of matter consisting essentially of the form VI polymorph of DHEA. [0032] The invention also includes a method for preparing a capsular or tablet formulation of DHEA. In the method, at least one solid pharmaceutical excipient is mixed with DHEA, at least 85% of which is present as a single polymorph selected from form I and form II, and the solid formulation is either placed in a capsular container suitable for oral delivery or compressed to form a tablet. [0033] In another aspect, the invention includes a method of administering DHEA to a subject to obtain an ameliorative result, wherein a pharmaceutically acceptable amount of DHEA is administered such that at least 85% of the DHEA is present as a single polymorph selected from form I, form II, and form VI, and preferably selected from forms I and II. These methods are useful for treating a variety of medical conditions, such as systemic lupus erythematosus, loss of bone density, osteoporosis, chronic fatigue syndrome, or fibromyalgia, or in DHEA replacement therapy. [0034] The invention also includes a method for controlling the bioavailability of a DHEA formulation. In the method, a therapeutically effective amount of a DHEA formulation is administered to a subject, where the DHEA in the formulation consists of a preselected, known ratio of DHEA polymorphs. [0035] The compositions and methods are useful for achieving more uniform bioavailabilities in DHEA formulations than have previously been achieved, in light of the applicants' discovery that bioavailability of DHEA in vivo is dependent upon the polymorphic composition of the DHEA. [0036] These and other objects and features of the invention will be better understood in light of the following description. BRIEF DESCRIPTION OF THE DRAWINGS [0037] FIGS. 1 and 2 show mean baseline adjusted serum concentrations of DHEA and DHEA-S, respectively, in human subjects up to 72 hours after receiving a single dose of DHEA (formulation 1, 2 or 3, as described below) containing different proportions of DHEA forms I, II and VI; and Continue reading about Dhea composition and method... 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