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WO 2008/089405 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 July 2008 (24.07.2008) WO 2008/089405 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/56 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (21) International Application Number: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, PCT/US2008/051431 EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (22) International Filing Date: 18 January 2008 (18.01.2008) LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, (25) Filing Language: English PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 60/881,528 19 January 2007 (19.01.2007) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): NEU- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ROSCI, INC. [US/US]; 1458 Clear Brook Drive, Dayton, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), OH 45440 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, (72) Inventor; and NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (75) Inventor/Applicant (for US only): GLASER, Rebecca, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). L. [US/US]; 7740 Washington Village Drive, Suite 110, Dayton, OH 45459 (US). Published: — with international search report (74) Agents: SERIO, John, C. et al.; Seyfarth Shaw LLP, — before the expiration of the time limit for amending the World Trade Center East, Two Seaport Boulevard, Suite claims and to be republished in the event of receipt of 300, Boston, MA 02210-2028 (US). amendments (54) Title: COMPOSITION OF MULTIPLE HORMONES DELIVERED VAGINALLY IN A SINGLE CREAM (57) Abstract: Pharmaceutical vaginal cream compositions comprising combinations of the hormones; estriol, estradiol, proges- terone, testosterone, and optionally DHEA delivered in a single cream to treat both local and systemic symptoms. The present invention is also directed to a method of treating a menopausal condition in a female in need thereof, the method comprising vagi- nally administering a pharmaceutical vaginal cream. COMPOSITION OF MULTIPLE HORMONES DELIVERED VAGINALLY IN A SINGLE CREAM CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 60/881,528 filed on January 19, 2007. FIELD OF THE INVENTION This invention relates to vaginal cream compositions containing hormones. More particularly, this invention relates to hormonal vaginal cream compositions having combinations and ratios of hormones that are beneficial to menopausal women. BACKGROUND OF INVENTION The vaginal delivery of hormones, including various estrogens, progesterone and testosterone, has been well established in the literature. It has been shown in multiple studies that hormones administered vaginally are absorbed systemically, bypass hepatic metabolism and are biologically active. Vaginally administered hormones are absorbed rapidly, with serum levels peaking between about 1 and 6 hours and gradually returning to baseline levels within 24 hours. It has also been shown that hormones applied to the mucous membranes are more readily absorbed than hormones applied to the skin. Hormones applied vaginally achieve higher plasma levels than if taken orally and the vaginal route appears to be more adequate than the oral one for hormone replacement therapy. Unfortunately, commercially available vaginal creams tend to be comprised of synthetic hormones. Symptomatic relief of genital urinary symptoms as well as climacteric symptoms with vaginally administered hormones has also been described and is dose dependent. Natural Hormone Replacement Therapy has been around for more than twenty years. The term "natural" comes from the fact that the hormones (estrogens such as estradiol, estrone, and estriol, testosterone, DHEA, pregnenolone and progesterone) come from natural sources. The reference to natural means that the hormones have substantially similar molecular structure as those produced by the body itself, thus the body recognizes the hormones as being "natural", because they are substantially and therapy utilizing these compounds is commonly referred to as Bio-identical Hormone Replacement Therapy (BHRT). It is thought that some of the benefits of BHRT include: fewer side effects compared with traditional Hormone Replacement Therapy (HRT) such as protection against heart disease, reduced risk of breast cancer, and improved lipid profile. A problem with available forms and sources of BHRT pharmaceutical compositions is the variability of compositions and the ratios of the components of those compositions has led to formulations have little or no therapeutic effect. The ratio of the component hormones, both natural and synthetic has not necessarily been well understood and therefore the variability of the concentrations of such compositions has been such that the efficacy of the topical hormone compositions has been varied. BRIEF SUMMARY OF THE INVENTION The present invention is directed to pharmaceutical vaginal cream compositions comprising combinations of various members of the Androgen, Estrogen, and Progestagen groups of sex hormones including, but not limited to, estriol, estradiol, progesterone, testosterone, and optionally Dehydroepiandrosterone (DHEA) delivered in a single cream to treat both local and systemic symptoms. The present invention is also directed to a method of treating a menopausal condition in a female in need thereof, the method comprising vaginally administering a pharmaceutical vaginal cream. It is a further aspect of the present disclosure that hormones, delivered through the mucous membranes of the labia and vagina are absorbed and have been shown to relieve climacteric symptoms. It is yet a further aspect of the present disclosure that vaginal application of hormones is a convenient method to deliver a combination of hormones which has a high rate of patient compliance and adherence. In another aspect of the invention vaginal cream compositions containing the following hormones in the formulation including, but not limited to, estriol (E3), estradiol (E2), progesterone (P) and testosterone (T). In a further aspect of the invention, the vaginal cream compositions contain about the following levels of hormones (per cc of vaginal cream base): estriol (1-2 mg), estradiol (0-1 mg), progesterone (100-400 mg), and testosterone (0.5-2 mg). In one illustrative embodiment according to the invention the hormones are found in about the following concentrations (per cc of vaginal cream base): estriol 2 mg, estradiol 0.5 mg, progesterone 100 mg and testosterone 2 mg. In yet another aspect of the invention, about 0.25 cc (1/4 ml) of hormone cream according to the invention is dispensed from a pre-filled 3 cc syringe delivering a measured dose of hormones providing about: estriol 0.5 mg, estradiol 0.125 mg, progesterone 25 mg and testosterone 0.5 mg per application. In one aspect of the invention the hormone composition relieves the following conditions in menopausal women: vaginal dryness, urinary complaints, repeated urinary tract infection, urgency, hesitancy, frequency, stress incontinence, relief of dyspareunia and sexual function. In a further aspect of the invention, the hormone composition according to the invention allows for the relief of systemic menopausal symptoms such as hot flashes, night sweats, foggy thinking, insomnia and fatigue. In yet a further aspect of the invention the vaginally applied hormone composition allows for the delivery of HRT with consistent absorption that is unaffected by food intake and does not result in accumulation of hormones. In a further aspect of the invention, the vaginally applied hormone composition is thought to mitigate the systemic toxicity associated with oral hormones because it bypasses first pass hepatic metabolism, resulting in the beneficial delivery of hormones with no evidence of liver toxicity, no affect on clotting factors, no evidence of increased blood clots, and decreased formation of metabolites, which are responsible for many of the side effects of hormone therapy, including a possible increased risk of breast cancer. In another aspect of the invention, vaginal delivery of estriol and estradiol has been shown not to increase the risk of breast cancer, thereby permitting the use of these two hormones in patients with breast cancer. In a further aspect of the invention, the vaginal delivery of estriol has been shown to be bone protective. In another aspect of the invention, the vaginal delivery of bio-identical estriol has been shown to be more effective than oral delivery, which results in rapid metabolism of the hormone. Without being bound to any particular theory, it is thought that methyl-testosterone is toxic to the liver and increases the risk of breast cancer if given orally. Methyl testosterone is toxic to the liver and methyl testosterone has been shown to increase the risk of breast cancer. Bio-identical testosterone has been shown to be breast protective. In yet another aspect of the invention, it is thought that vaginal testosterone is effective locally and provides therapeutic levels in serum and vaginal hormone therapy is superior to oral and topical hormone therapy for relief of vaginal and urinary symptoms. A further aspect of the invention is that vaginal progesterone therapy provides higher and more consistent levels of progesterone to the uterus than oral progesterone therapy and that vaginal progesterone has been shown to be heart protective with fewer side effects than oral progesterone therapy.
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