USOO6284263B1 (12) United States Patent (10) Patent No.: US 6,284,263 B1 Place (45) Date of Patent: Sep. 4, 2001 (54) BUCCAL DRUG ADMINISTRATION IN THE 4,755,386 7/1988 Hsiao et al. TREATMENT OF FEMALE SEXUAL 4,764,378 8/1988 Keith et al.. DYSFUNCTION 4,877,774 10/1989 Pitha et al.. 5,135,752 8/1992 Snipes. 5,190,967 3/1993 Riley. (76) Inventor: Virgil A. Place, P.O. Box 44555-10 5,346,701 9/1994 Heiber et al. Ala Kahua, Kawaihae, HI (US) 96743 5,516,523 5/1996 Heiber et al. 5,543,154 8/1996 Rork et al. ........................ 424/133.1 (*) Notice: Subject to any disclaimer, the term of this 5,639,743 6/1997 Kaswan et al. patent is extended or adjusted under 35 6,180,682 1/2001 Place. U.S.C. 154(b) by 0 days. * cited by examiner (21) Appl. No.: 09/626,772 Primary Examiner Thurman K. Page ASSistant Examiner-Rachel M. Bennett (22) Filed: Jul. 27, 2000 (74) Attorney, Agent, or Firm-Dianne E. Reed; Reed & Related U.S. Application Data ASSciates (62) Division of application No. 09/237,713, filed on Jan. 26, (57) ABSTRACT 1999, now Pat. No. 6,117,446. A buccal dosage unit is provided for administering a com (51) Int. Cl. ............................. A61F 13/02; A61 K9/20; bination of Steroidal active agents to a female individual. A61K 47/30 The novel buccal drug delivery Systems may be used in (52) U.S. Cl. .......................... 424/435; 424/434; 424/464; female hormone replacement therapy, in female 514/772.3 contraception, to treat female Sexual dysfunction, and to treat or prevent a variety of conditions and disorders which (58) Field of Search ..................................... 424/430, 434, are responsive to the active agents discussed herein. The 424/435, 464; 514/772.3 buccal dosage unit comprises a progestin, an estrogen and (56) References Cited optionally an androgenic agent, as well as a polymeric carrier that bioerodes and provides for delivery of the active U.S. PATENT DOCUMENTS agents throughout a predetermined drug delivery period. 4,507,323 3/1985 Stern. 4,521,421 6/1985 Foreman. 40 Claims, 2 Drawing Sheets O U.S. Patent Sep. 4, 2001 Sheet 1 of 2 US 6,284,263 B1 U.S. Patent Sep. 4, 2001 Sheet 2 of 2 US 6,284,263 B1 US 6,284,263 B1 1 2 BUCCAL DRUGADMINISTRATION IN THE (New York: Plenum Press, 1983). In such treatments, estro TREATMENT OF FEMALE SEXUAL gen is administered orally, parenterally (e.g., by injection), DYSFUNCTION or topically. With oral administration, as is true with the oral administration of many Steroid hormones, estrogens tend to CROSS-REFERENCE TO RELATED be inactivated; estradiol, for example, is converted to estriol APPLICATIONS and estrone and then conjugated to glucuronic acid or Sulfate. Additionally, estrogens also impair hepatic Secretory This application is a divisional of U.S. patent application activity. This “first pass” effect may lead to an undesirable Ser. No. 09/237,713, filed Jan. 26, 1999, now U.S. Pat. No. increase in the production of certain coagulation factors and 6,117,446. other biologically important compounds by the liver. Parenterally administered estrogen avoids the aforemen TECHNICAL FIELD tioned problems associated with oral administration. However, all estrogen-based therapies are known to increase This invention relates generally to pharmaceutical com the risk of endometrial hyperplasia and cancer, as well as the positions and methods for administering pharmacologically risk of breast cancer, in treated individuals. active agents. More particularly, the invention relates to 15 Because of the increased risk of endometrial hyperplasia buccal drug delivery, and to a buccal dosage unit and method and endometrial cancer encountered with unopposed estro for administering a combination of Steroidal active agents, gen therapies, estrogen/progestin combinations have been e.g., for female hormone replacement therapy, female employed. However, Such therapies, as is well known, result contraception, treatment of female Sexual dysfunction, and in a number of Side effects, including uterine bleeding and the like. the continuation of menstrual periods. Accordingly, there remains a need in the art to provide Safer and more effective BACKGROUND treatments for administering active agents Suitable for female hormone replacement therapy. Androgens are the hormones that cause most of the The present invention is directed in part to the aforemen masculinizing changes that occur in males during puberty. 25 tioned need in the art, and provides highly effective hormone Harrison's Principles of Internal Medicine, 12th Edition replacement therapy for women in need of Such treatment. (New York, N.Y.: McGrawHill, Inc., 1991). However, low The invention involves the use of a pharmaceutical compo levels of androgens are also present in normal females. Sition in the form of a drug dosage unit to be applied to the Testosterone and other androgens are Secreted by the ovary buccal mucosa. In contrast to prior methods for effecting and the adrenal cortex. See, e.g., Goodman & Gilman's The hormone replacement, the present invention avoids both Pharmacological Basis of Therapeutics, 9th Edition (New gastrointestinal degradation of the drug and the “first pass” York, N.Y.: McGraw Hill, Inc., 1996). Dehydroepiandros effect in the liver encountered with oral formulations, and terone (DHEA) and androstenedione are also synthesized by enables the use of Smaller doses of active agents (and thus both the adrenal gland and the Ovary and can be converted avoids the Side effects associated with conventional to testosterone or estrogen in peripheral tissues. The daily 35 formulations). In addition, when an androgenic agent is rate of production of testosterone in Women is on the order included, as in the preferred embodiment herein, essentially of 0.25 mg, about half of which is derived from the meta complete hormone replacement is provided. That is, with bolic conversion of androstenedione to testosterone at respect to the latter point, estrogen/progestin therapies do extraglandular sites. The plasma concentration of testoster not in fact provide “replacement of the complete hormone one in women alters with the menstrual cycle and ranges 40 profile of the premenopausal woman, because, as discussed from 15 to 65 nanogam/deciliter (ng/dl). AS with estrogen, above, androgens are also present in premenopausal women. testosterone levels peak at the preovulatory and luteal phases In a preferred embodiment, then, the present invention calls of the cycle. At menopause, plasma androgen and estrogen for one or more androgenic agents to be administered along levels are reduced but not completely absent in Women. with a progestin and an estrogen. Alteration in the hormone profile is believed to be an 45 The method and compositions of the invention may also underlying cause of menopausal Symptoms in Women, be used to treat other conditions for which the disclosed including vasomotor instability (“hot flash”), atrophy of the hormone combination is useful. For example, the novel drug urogenital epithelium and skin, decreased size of the breasts dosage units can be used to treat female Sexual dysfunction, and osteoporosis. See, e.g., Harrison's Principles of Internal to effect female contraception, to improve Vaginal muscle Medicine, Supra. 50 tone and tissue health, and to enhance vaginal lubrication. Alteration in normal hormonal levels can also cause Drug therapy for treating female Sexual dysfunction has Sexual dysfunction. For example, estrogen deficiency, caus been described. For example, U.S. Pat. No. 4,507.323 to ing vaginal atrophy and dySpareunia, is a common cause of Stem describes the use of the anxiolytic m-chloro-O-t- Sexual dysfunction. Dyspareunia is thought to affect butylamino-propiophenone in the treatment of Sexual dyS approximately 40% of women; it has been estimated that 55 function in male and female individuals. Pharmaceutical over 40 million female individuals will suffer dyspareunia at compositions containing the agent are described, which are Some time in their lives. On the order of twenty-five million presented in discrete units, e.g., cachets, tablets, capsules, Women will experience dySpareunia in the peri- and post ampules and Suppositories for oral or anal delivery of the menopausal periods (Kelly (1992) Clinical Practice and agent. Additionally, U.S. Pat. No. 4,521,421 to Foreman Sexuality 8(8):2; and Sato et al. (1992) Clinical Practices in 60 describes the treatment of Sexual dysfunction in male and Sexuality 8(5):1. female individuals using the Stereoisomers of octahydro EStrogen therapy is commonly used in the pharmacologi pyrimidoquinoline agents, centrally acting dopamine ago cal treatment of altered hormone profiles or Sexual dysfunc nists. U.S. Pat. No. 5,190,967 to Riley describes the treat tion in Women. Estrogen-based therapies are generally used ment of Sexual disorders in male and female individuals to increase mucous production, provide vasodilator effects, 65 using heterocyclic benzodioxinopyrrole compounds, which, and/or to increase the general health of the vagina. Nadelson like the drugs described in the aforementioned patents, are et al., eds., Treatment Interventions in Human Sexuality centrally acting agents. US 6,284,263 B1 3 4 Drug therapy involving buccal administration of Steroid and for enhancing vaginal lubrication, each of Such methods hormones has also been described. For example, U.S. Pat. involving buccal administration of a pharmaceutical com No. 4,755,386 to Hsiao et al. generally describes the buccal position as described herein to a woman in need of Such administration of various medicaments, including estrogens, treatment. proge Stins and androgens, combinations of the Additional objects, advantages and novel features of the medicaments, however, are not contemplated. Furthermore, invention will be set forth in part in the description which the buccal tablets of Hsiao et al., weighing on the order of follows, and in part will become apparent to those sldlled in 50 mg, contain adhesive, disintegrant and excipient in the art upon examination of the following, or may be learned addition to the active agent, with the inactive ingredients by practice of the invention.