(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 PCT 6 November 2008 (06.11.2008) WO 2008/134712 A2 (51) International Patent Classification: Not classified [US/US]; 27 Armand Place, Ridgefield, CT 06877 (US). MCLAUGHLIN, Ronald, P. [US/US]; 115 Howard, (21) International Appbttrerlication Number: PCT/US2008/061992 Reading, MA 01867 (US). BEDFORD, Susan, Eilidh [GB/US]; 150 Aldershot Lane, Carlisle, MA 01741 (US). (22) International Filing Date: 30 April 2008 (30.04.2008) LI, Zhi [CN/US]; 17173 West Bernardo Drive Unit 203, (25) Filing Language: English San Diego, CA 92127 (US). (26) Publication Language: English (74) Agents: FITZPATRICK, Joseph, M. et al; Fitzpatrick, (30) Priority Data: Cella, Harper & Scinto, 30 Rockefeller Plaza, New York, 60/914,873 30 April 2007 (30.04.2007) US NY 10112-3801 (US). (71) Applicant (for all designated States except US): LIVING (81) Designated States (unless otherwise indicated, for every PROOF, INC. [US/US]; 6 1 Rogers Street, Cambridge, kind of national protection available): AE, AG, AL, AM, MA 02142 (US). AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (72) Inventors; and EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (75) Inventors/Applicants (for US only): YU, Betty [US/US]; IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, 57 Reservoir Street, Unit 2, Cambridge, MA 02138 LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, (US). NASHAT, Amir [US/US]; 100 Boulder Road, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, Newton, MA 02459 (US). ANDERSON, Daniel, Griffith PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, [US/US]; 28 Red Oak Drive, Sudbury, MA 01776 (US). SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, PUERTA, David, Thomas [US/US]; 29 Cleveland Street, ZA, ZM, ZW Melrose, MA 02176 (US). ADAMS, Benjamin [US/US]; 42 Pearl Street, Cambridge, MA 02139 (US). CLARK, (84) Designated States (unless otherwise indicated, for every Scott [US/US]; 107 Quirico Drive, Pittsfield, MA 01201 kind of regional protection available): ARIPO (BW, GH, (US). KIM, Yushan [US/US]; 324 Hurley Street Apt. 2, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Cambridge, MA 02141 (US). SPENGLER, Eric, George ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [Continued on next page] (54) Title: USE OF MATRIX METALLOPROTEINASE INHIBITORS IN SKIN CARE Figure 1. Appearance of Telangiectasia: Significant difference from placebo at 16 weeks * p-value < 0 1 Timepoint * p-value < 0 05 (57) Abstract: The application of matrix metalloproteinase (MMP) inhibitors to the skin inhibits the degradation of proteins found in the skin including collagen, elastin, and other basement membrane and extracellular matrix protein. MMP inhibitors may be used in both cosmetic compositions and pharmaceutical compositions for application to skin. MMP inhibitors are formulated with a cos metically suitable vehicle or pharmaceutically acceptable excipient for application to the skin as creams, lotions, ointments, solutions, face masks, etc. As cosmetics, the inventive MMP inhibitor compositions are applied to the skin to prevent or reduce the appearance of wrinkles, pigmentation changes, loss of elasticity, or other effects associated with aging or sun damage. As pharmaceuticals, the inventive MMP inhibitor compositions may also be applied to the skin to treat or prevent a skin disease (e.g., proliferative disease, inflammatory disease). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Published: FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, — without international search report and to be republished NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, upon receipt of that report CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). USE OF MATRIXMETALLOPROTEINASEINHIBITORS IN SKIN CARE Related Applications [0001] The present invention claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, USSN 60/914,873, filed April 30, 2007, which is incorporated herein by reference. Background of the Invention [0002] The skin is the largest organ of the human body and extends over the entire body. The skin functions primarily to protect us from the outside world. The skin also functions to regulate the temperature of the body, protects the body from harmful UV rays, provides a defense against pathogens, stores fat, provides the sense the touch, excretes waste, synthesizes vitamin D, and provides cushioning and attachment. In protecting us from the outside world, the skin is constantly exposed to harsh temperatures, sunlight, dirt, dust, wind, chemicals, pathogens, and other insults. In addition, the skin is routinely subjected to washing and shaving. [0003] Skin is composed of two major layers: the epidermis and the underlying dermis, which are distinct in terms of their architecture, physiology, and function. The epidermis is a stratified epithelium composed of four layers: the stratum basale, stratum spinosum, stratum granulosum, and the outermost stratum corneum. The stratum basale contains a single layer of cuboidal keratinocytes attached to a basement membrane. Above this layer is the spinous layer, characterized by presence of numerous desmosomes. The stratum granulosum overlies the stratum spinosum and consists of keratinocytes that contain basophilic granules of keratohyalin as well as lamellar granules in the intercellular compartment. The stratum corneum is the most superficial layer and is composed of anucleated, flattened, fully keratinized cells (corneocytes) fused together to form a plate-like structure. The intercellular space is occupied by ordered lipid lamellae that contain specialized proteins and lipids, such as ceramides, fatty acids, and cholesterols, which are secreted from lamellar bodies in the stratum granulosum. The resulting "bricks and mortar" structure provides the stratum corneum with the ability to perform its protective and moisture retaining functions. The thickness of the epidermis ranges from about 75 to 150 µm except on the soles and palms, where it is about 0.4 to 0.6 mm. The dermoepidermal junction (DEJ) is an undulating basement membrane composed primarily of collagen that separates the epidermis from the dermis. [0004] The dermis is a dense, fibroelastic connective tissue that lies beneath the epidermis and provides a strong and flexible supporting layer. It is composed of cells (e.g., fibroblasts), ground substance, and a fibrous network containing collagenous and elastic fibers and also contains blood vessels, nerves, hair follicles, smooth muscle, glands and lymphatic tissue. Collagen, primarily types I, III, V, and VI, forms the majority of the fibrous component, making up about 75% of the dry weight of the dermis and imparting firmness and tensile strength. [0005] The dermis can be divided into two regions. The papillary dermis conforms to the shape of the overlying epidermis. The reticular dermis lies below the papillary dermis and forms the majority of the dermal layer, giving it most of its elasticity and strength. Elastic fibers of the papillary dermis are oriented parallel (elaunin fibers) or perpendicular (oxytalan fibers) to the DEJ and are thinner than the elastic fibers of the reticular dermis. Oxytalan fibers lack the elastin core while elaunin fibers contain a small amount of elastin. Mature elastin fibers are found primarily arranged in bundles in the reticular dermis and measure about 1-3 µm in diameter. [0006] Aging and exposure to environmental insults affect the appearance and structure of the skin. Sun-protected, naturally aged skin exhibits epidermal and dermal thinning, fragility, and fine, shallow wrinkles. There is a loss of elastic fibers in the papillary dermis, and collagen fibers become increasingly dense and more randomly oriented. Exposure to ultraviolet radiation from the sun accelerates and alters the degenerative processes associated with aging, resulting in a constellation of changes collectively known as photodamage. As much as 80% of facial aging may well be attributable to sun exposure. Photodamaged skin is characterized by loss of elasticity, deep wrinkles, increased roughness and dryness, and altered pigmentation (age spots). The skin may assume a leathery, thickened appearance characterized by deep furrows. [0007] Many individuals desire to preserve a youthful appearance. At the same time, tanned skin is considered attractive and outdoor recreational activities are popular, resulting in significant sun exposure and consequent photodamage to skin. Various approaches have been developed or are under investigation to reduce the visible signs of photodamage (Stern, R., N. Engl. J. Med, 350:1526-1534, 2004). Use of sunscreens can help to prevent further damage. Topical retinoids (vitamin A derivatives) can reduce the severity of photoaging (U.S. Patent 4,877,805; incorporated herein by reference). It has been proposed to treat the skin with compositions containing inhibitors of collagenase or elastase (U.S. Patents 5,614,489; 6,884,425; each of which is incorporated herein by reference). Chemical peels, which involve application of a variety of different chemical compounds to skin, result in temporary improvement in the appearance of photodamaged skin in some individuals. Microdermabrasion and laser resurfacing are other alternatives. Injection of botulinum toxin (e.g., Botox®) has gained popularity as a means of reducing furrows caused by muscle hypertonicity. Skin fillers such as bovine collagen and hyaluronic acid are used for soft tissue augmentation to reduce the appearance of, or to treat deep wrinkles. [0008] Such factors as exposure to the sun contribute to the premature aging of skin contributing to the formation of lines and wrinkles, skin dryness, skin fading, roughness, hyperpigmentation, age spots, and loss of elasticity. The physiological and pathological degradation of the connective tissue component of the skin by proteases from resident cells contributes to the loss of elasticity of the skin.