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WO 2016/201286 Al 15 December 2016 (15.12.2016) P O P C T

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WO 2016/201286 Al 15 December 2016 (15.12.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/201286 Al 15 December 2016 (15.12.2016) P O P C T (51) International Patent Classification: (74) Agent: HANSEN, Christine M.; Buchanan Ingersoll & A61K 31/74 (2006.01) Rooney PC, P.O. Box 1404, Alexandria, Virginia 223 13- 1404 (US). (21) International Application Number: PCT/US20 16/036970 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) Date: International Filing AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 10 June 2016 (10.06.2016) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/174,262 11 June 2015 ( 11.06.2015) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/175,806 15 June 2015 (15.06.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/188,233 2 July 2015 (02.07.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/203,728 11 August 2015 ( 11.08.2015) US (84) Designated States (unless otherwise indicated, for every 62/21 1,470 28 August 2015 (28.08.2015) US kind of regional protection available): ARIPO (BW, GH, 62/213,927 3 September 2015 (03.09.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/222,494 23 September 2015 (23.09.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/297,598 19 February 2016 (19.02.2016) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 62/3 17,698 4 April 2016 (04.04.2016) US DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant: APPLIED BIOLOGY, INC. [US/US]; Suite LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 192, 17780 Fitch, Irvine, California 92614 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: GOREN, Ofer A.; c/o Applied Biology, INC., 17780 Fitch, Suite 192, Irvine, California 92614 (US). Published: MCCOY, John; c/o APPLIED BIOLOGY, INC., 17780 — with international search report (Art. 21(3)) Fitch, Suite 192, Irvine, California 92614 (US). 00 o v o (54) Title: TREATMENT OF SEXUAL DYSFUNCTION (57) Abstract: Compositions and methods for treating sexual dysfunction and enhancing sexual satisfaction using topical application of a therapeutic agent such as an alpha- 1 adrenergic receptor agonist to the nipple-areola complex are disclosed. [0001] This application claims the benefit of U.S. Provisional Application No. 62/317,898 filed on April 4 , 2018, 62/297,598 filed on February 19, 2016, U.S. Provisional Application No. 82/222,494 filed on September 23, 2015, U.S. Provisional Application No. 62/21 3,927 filed on September , 201 5 , U.S. Provisional Application No. 62/21 1,470 filed on August 28, 2015, U.S. Provisional Application No. 62/203,728 filed on August 11, 2015, U.S. Provisional Application No. 82/188,233 filed on July 2 , 201 5 , U.S. Provisional Application No. 82/175,806 filed on June 15 , 201 5 , and U.S. Provisional Application No. 62/174,262 filed on June 11, 201 5 , the entire content of each is incorporated herein by reference. TECHNICAL FjELD [0002] The present disclosure relates to methods to treat sexual dysfunction, particularly female sexual dysfunction, and related disorders pertaining to sexual activity and sexual satisfaction, and methods to enhance sexual satisfaction, particularly female sexual satisfaction. BACKGROUND DISCUSSION [0003] Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women. There are few treatment options. See Kyan J . Aliahdadi et aL, "Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges," Cardiovasc Hematol Agents Med Chern. 2009 Oct; 7(4): 260 269 FSD can be classified under many subtypes. For example, female sexual arousal disorder (FSAD) is a disorder characterized by a persistent inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity. Female Sexual Interest/Arousal Disorder (FSIAD) is a diagnosis found when a subject experiences a lack of or significantly reduced sexual interest or arousal. Female hypoactive sexual desire disorder (FHSDD) is a general loss of interest in sexual activity. Other subtypes exist, for example, anorgasmia, a difficulty achieving orgasm. Currently, off-label use of testosterone has been prescribed. A therapy approved by the FDA in August 2015 is the Sprout Pharmaceuticals, inc. product Addyi™ (flibanserin 100 mg), a once-daily, non- hormonal pill for the treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women n addition, there are several drugs that were the subject of clinical trials that affect signaling in the brain. See Wright, J.J., O'Connor, K.M. (201 5), "Female sexual dysfunction," Medical Clinics of North America, 99(3), 607-828. Because both hormonal and psycho-affective drugs can be associated with serious negative side effects, alternative treatment options would be desired for treating this prevalent condition. [0004] The arousal phase of the female sexual response cycle involves genital mechanisms, such as ciitorai, labial, and vaginal engorgement, as well as non- genital peripheral mechanisms, such as increases in body secretions, cutaneous vasodilation, and nipple erection. Nipple erection occurs via activation of adrenergic nerves. Smooth muscles in the nipple areola complex are contracted, thereby erecting the nipple. The role of nipple stimulation in influencing sexual desire and arousal in women prior to and during intercourse has been reported in the literature. Eighty-two percent of surveyed women report that stimulation of their nippies caused or enhanced their sexual arousal. See Levin, R., Meston, C . (2006), "Nipple/Breast stimulation and sexual arousal in young men and women," Journal of Sexual Medicine, 3(3), 450-454; Levin, R . (2006), "The breasf/nipple/areola complex and human sexuality," Sexual and Relationship Therapy, 2 1(2), 237-249. In addition, stimulation of a women's nipple has been shown to correlate with increased oxytocin levels in blood serum. See Stein, J.L., Bardeguez, A.D., Verma, U.L., Tegani, N . (1990), "Nipple stimulation for labor augmentation," Journal of Reproductive Medicine, 35(7), 7 10-714. Oxytocin is a peptide hormone shown to play a role in sexual satisfaction and desire. [0005] US Patent 4,853,216 (Koslo et al.) reports topical application of alpha- 1 adrenergic receptor agonists ("A1 AR agonists") to a hair-bearing skin area to facilitate the physical or chemical handling of the hair. The purpose is to activate the pilomotor effect and erect the hair on the skin. This may be applied as a pretreatment prior to shaving or incorporated into a shaving composition, such as shaving cream. US Patent 4,853,216 discloses that suitable A1AR agonists include phenylephrine and methoxamine. See US Patent 4,853,216 at col. 2 lines 46-48. WO2004041259 (Thurlow et a .) describes the use of alpha 1 adrenergic receptor antagonists for the treatment of FSD. The reference does not describe application of the antagonist to at least a portion of the nipple-areoia complex, and focuses rather on inhibitors of receptors in the vaginal tissue. It is unexpected from this teaching that an A1AR agonist would be useful for treatment of FSD when applied to at least a portion of the nipple-areoia complex. [0006] A 1 R agonists bind to a 1-receptors on vascular smooth muscle and induce smooth muscle cell contraction, thus mimicking the effects of sympathetic neurons activation of smooth muscles via adrenergic receptors. Phenylephrine is a selective A1AR agonist. Phenylephrine is used as a decongestant, for which it is sold as an oral medicine or a nasal spray. Phenylephrine is also sold as a topical ointment to prevent or reduce symptoms of hemorrhoids. Phenylephrine is used as an eye drop to dilate the pupil to faciiifafe visualization of the retina. US Patent Application Pub. 2004/0198706 (Carrara et ai.) discloses formulations for providing transdermal o transmucosai delivery of active agents. The formulations treat symptoms of hormonal disorders including female sexual desire disorder. The active agents may be selected from a large group of therapeutic agents, one of which is phenylephrine. The reference does not describe application of the transdermal or transmucal dosage forms to the nipple-areoia complex. It is unexpected from this teaching that an A 1AR agonist such a phenylephrine would be useful for treatment of FSD when applied to the nipple-areoia complex. S [0007] The present disclosure concerns a method of treating sexual dysfunction, in some embodiments treating female sexual dysfunction, the method comprising applying a therapeutically effective amount of a composition comprising an alpha- 1 adrenergic receptor agonist topically to a nipple- areola complex of a subject in need of such treatment in another embodiment, the disclosure concerns a method of reducing or alleviating a symptom of sexual dysfunction, in some embodiments a symptom of female sexual dysfunction, the method comprising applying a therapeutically effective amount of a composition comprising an aipha- 1 adrenergic receptor agonist topically to a nipple- areola complex of a subject in need of such treatment yet another embodiment, the disclosure concerns a method for enhancing sexual satisfaction in a subject, in some embodiments a female subject, comprising applying an effective amount of a composition comprising an alpha-1 adrenergic receptor agonist topically to a nipple- areola complex of the subject.
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