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2012/051374 A2 (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 . _ 19 April 2012 (19.04.2012) 2012/051374 A2 (51) International Patent Classification: (74) Common Representative: THE PROCTER & GAM¬ A61K 8/41 (2006.01) A61P 17/14 (2006.01) BLE COMPANY; c/o Eileen L. Hughett, Global Patent Services, 299 East Sixth Street, Sycamore Building, 4th (21) International Application Number: Floor, Cincinnati, Ohio 45202 (US). PCT/US201 1/056076 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 13 October 201 1 (13.10.201 1) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Langi English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (30) Priority Data: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 61/393,489 15 October 2010 (15.10.2010) US ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (71) Applicant (for all designated States except US): THE RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PROCTER & GAMBLE COMPANY [US/US]; One TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, Procter & Gamble Plaza, Cincinnati, Ohio 45202 (US). ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/ Applicants (for US only): DICOLANDREA, kind of regional protection available): ARIPO (BW, GH, Teresa [US/US]; 67 Forest Ave., Cincinnati, Ohio 45215 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (US). YOUNGQUIST, Robert, Scott [US/US]; 85 11 UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, Charleston Knoll C , Mason, Ohio 45040 (US). XIE, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, Sancai [US/US]; 4325 Logsdon's Woods Dr., Liberty DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, Township, Ohio 4501 1 (US). BINDER, Robert, Lloyd LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, [US/US]; 10371 Birkemeyer Dr., Montgomery, Ohio SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, 45242 (US). FUENTES, Gary, Richard [US/US]; 45 16 GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). E. Pierson Rd., Batesville, Indiana 47006 (US). LADE, Published: Deborah [US/US]; 6077 Ramblingridge Dr., Cincinnati, Ohio 45247 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (54) Title: USE OF MONOAMINE OXIDASE INHIBITORS TO IMPROVE EPITHELIAL BIOLOGY 1%Pargy!ineHCL 3 - ♦ • l%SelegilineHCL 3 - - Vehicle - - 0.06%Triac 1%Rasagilinemesylate ø2 -»- 0.5%Pherielzine S ® 1%Lazabemide 0.5%Moclobemide → - 1%ClorgylineHCL < Day of Study (57) Abstract: The invention provides a method for improving hair biology, e.g., hair growth. The method comprises administer © ing to a subject a monoamine oxidase inhibitor and a vasodilator, a zinc salt of a carboxylic acid, a xanthine compound, pyrithione or a salt thereof, saponin, tritapene, crataegolic acid, celastrol, asiatic acid, an inhibitor of 5-alpha-reductase, l,4-methyl-4-azas- o teroid, an androgen receptor antagonist, azelaic acid or a derivate thereof, cyclosporin, triiodothyronine, diazoxide, retinoic acid, a prostaglandin analogue, aminexil, carnitine tartrate, apigenin, procapil, or adenosine, in an amount effective to achieve a desired effect. The invention further provides a method of reducing or delaying the appearance of an age-related skin imperfection. The method comprises administering to the subject a composition comprising an MAO inhibitor. A kit for improving hair growth also is provided. USE OF MONOAMINE OXIDASE INHIBITORS TO IMPROVE EPITHELIAL BIOLOGY FIELD OF THE INVENTION The invention generally relates to methods of using monoamine oxidase inhibitors to improve the quality of hair and skin. BACKGROUND OF THE INVENTION Hair loss and skin appearance can have a profound effect on individuals' psychological well-being and quality of life. Anti-aging products represent a high percentage of skin and hair care product sales in the U.S. and abroad, and sales are expected to rise in many Western markets having an aging demographic. (Lennard, "Hair Care Growth Thinning for Near Term," Global Cosmetics Industry Magazine, May 2009.) Consumers seek these products to counteract age- related changes to epithelial biology that lead to skin imperfections (e.g., loss of elasticity, discoloration, dryness, and rough surface texture) and hair loss and thinning. Thinning hair and significant hair loss, i.e., "baldness," is regarded in many cultures as less attractive. Hair growth is a cyclical process consisting of a growth stage (anagen), a regression stage (catagen), and a quiescent stage (telogen). During anagen, the hair bulb within the follicle penetrates the dermis and contacts the dermal papilla, triggering division of hair matrix keratinocytes. The new keratinocytes dehydrate and condense to form the hair shaft, which is pushed through the epidermis by newly dividing keratinocytes in the hair root. Hair growth ends in the catagen phase. The hair bulb separates from the dermal papilla, retracts from the dermis, and the follicle shrinks in size. In telogen, the hair remains attached to the follicle but, due to its shallow position in the epidermis, can easily be released from the skin. Normally, the follicle transitions back into anagen phase, during which the hair is pushed out of the follicle by hair newly formed by dividing keratinocytes. Disruption of the hair growth cycle leads to thinning and baldness. On the scalp, hair follicles shrink and shed terminal (long, pigmented) hair. The lost hair is either not replaced by new hair or is replaced by vellus (thin, short, non- pigmented) hair, resulting in the appearance of baldness. The most common pharmacotherapeutics currently used to treat hair loss is minoxidil and 5-alpha reductase inhibitors, such as finasteride. The precise mechanism by which minoxidil reduces hair loss is unknown, and there is a significant percentage of patients that do not respond to therapy. While finasteride has been shown to slow hair loss in men, the drug is associated with several side effects, including gynecomastia and sexual dysfunction. Both minoxidil and anti-androgens can require several weeks to increase hair count, and must be continued indefinitely on a daily basis to maintain effectiveness. Thus, there exists a need for materials and methods for reducing or delaying the effects of age on epithelial biology, particularly with respect to skin imperfections and hair loss. SUMMARY OF THE INVENTION The invention provides methods, compositions, and kits for improving epithelial biology and, in particular, reducing or delaying changes in hair and skin quality associated with age. In one aspect, the invention provides a method for improving hair growth in a subject. The method comprises administering to a subject a monoamine oxidase (MAO) inhibitor and a vasodilator in an amount effective to improve hair growth. In addition, the invention is directed to a method for improving hair biology, the method comprising administering to a subject (a) a MAO inhibitor and (b) one or more agents selected from the group consisting of a zinc salt of a carboxylic acid, a xanthine compound, pyrithione or a salt thereof, saponin, tritapene, crataegolic acid, celastrol, asiatic acid, an inhibitor of 5-alpha-reductase, l,4-methyl-4-azasteroid, an androgen receptor antagonist, azelaic acid or a derivate thereof, cyclosporin, triiodothyronine, diazoxide, retinoic acid, a prostaglandin analogue, aminexil, carnitine tartrate, apigenin, procapil and adenosine, in an amount effective to improve hair biology in the subject. Also provided is a method of reducing or delaying the appearance of an age-related skin imperfection in a subject. The method comprises topically administering to the subject a composition comprising an MAO inhibitor including, but not limited to, clorgiline, paragyline, lazabemide, selegiline, phenelzine, or rasagiline, in an amount effective to reduce or delay the appearance of an age-related skin imperfection. The composition does not comprise an iron chelator, an antiapoptotic agent, a neuroprotective agent, cholinesterase inhibitor, or an N- methyl-D-aspartic acid (NMDAR) receptor inhibitor. The invention further provides a kit comprising a composition comprising a monoamine oxidase (MAO) inhibitor and, in the same composition or in a different composition, a vasodilator, in an amount effective to improve hair growth. The kit also comprises instructions for applying the composition(s) to the skin of a subject. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a line graph tracking hair growth (as estimated by visual melanogenesis grades (y-axis)) induced in a telogen conversion assay (TCA) by Triac, selegiline, paragyline, rasagiline, phenelzine, moclobemide, and lazabemide over a treatment period of 19 days (x-axis). Figure 2 is a line graph tracking hair growth (as estimated by visual melanogenesis grades (y-axis)) induced by Triac (0.06%) and selegiline (1%) in C3H and C57BL/6 mice over a treatment period of 32 days (x-axis). With Triac, a strong driver of hair growth, hair growth was induced at the same time for both mouse strains. Selegiline induced hair regrowth significantly earlier compared to that observed in subjects administered only vehicle, but the timing of selegiline-mediated induction differed between the mouse strains in a manner consistent with natural differences in hair growth rhythm in each strain. Figure 3 is a line graph tracking hair growth (as estimated by visual melanogenesis grades (y-axis)) induced by minoxidil (5%), selegiline (1%), and a combination of minoxidil (5%) and selegiline (1%) in two independent studies of C57B1/6 mice over a treatment period of 2 1 days (x-axis).
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