US 20090068255A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0068255 A1 Yu et al. (43) Pub. Date: Mar. 12, 2009 (54) USE OF MATRIX METALLOPROTEINASE Publication Classification INHIBITORS IN SKIN CARE (51) Int. Cl. A6IR 8/14 (2006.01) (76) Inventors: Betty Yu, Cambridge, MA (US); A6IR 8/49 (2006.01) Amir Nashat, Newton, MA (US); A63L/35 (2006.01) Daniel Griffith Anderson, A61O 19/08 (2006.01) Sudbury, MA (US); David Thomas A61O 1704 (2006.01) Puerta, Melrose, MA (US); A6IP 7/02 (2006.01) Benjamin Adams, Cambridge, MA A6IP35/00 (2006.01) (US); Scott Clark, Pittsfield, MA A6IP 700 (2006.01) (US); Yushan Kim, Cambridge, A61O 19/00 (2006.01) MA (US); Eric George Spengler, A6II 3/442 (2006.01) Ridgefield, CT (US); Ronald P. A 6LX 9/27 (2006.01) McLaughlin, Reading, MA (US); (52) U.S. Cl. ............ 424/450; 514/459:514/350: 424/59 Susan Eilidh Bedford, Carlisle, (57) ABSTRACT MA (US); Zhi Li, San Diego, CA (US) The application of matrix metalloproteinase (MMP) inhibi tors to the skin inhibits the degradation of proteins found in the skin including collagen, elastin, and other basement mem Correspondence Address: brane and extracellular matrix protein. MMP inhibitors may FITZPATRICK CELLAHARPER & SCINTO be used in both cosmetic compositions and pharmaceutical 30 ROCKEFELLER PLAZA compositions for application to skin. MMP inhibitors are NEW YORK, NY 10112 (US) formulated with a cosmetically suitable vehicle or pharma ceutically acceptable excipient for application to the skin as (21) Appl. No.: 12/112,374 creams, lotions, ointments, Solutions, face masks, etc. As cosmetics, the inventive MMP inhibitor compositions are (22) Filed: Apr. 30, 2008 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 pharmaceu Related U.S. Application Data ticals, the inventive MMP inhibitor compositions may also be (60) Provisional application No. 60/914,873, filed on Apr. applied to the skin to treat or prevent a skin disease (e.g., 30, 2007. proliferative disease, inflammatory disease). Patent Application Publication Mar. 12, 2009 Sheet 1 of 5 US 2009/0068255 A1 eule Seguoy effueuo ueeW esuOM -> 999 Patent Application Publication Mar. 12, 2009 Sheet 2 of 5 US 2009/0068255 A1 O CN r c) o v ‘Z?un61– euleSedG uOuJefueupGP CP ueewCP eSOM - - 1990 Patent Application Publication Mar. 12, 2009 Sheet 3 of 5 US 2009/0068255 A1 efueup ueeW eSOM --> JeeC Patent Application Publication US 2009/0068255 A1 Patent Application Publication Mar. 12, 2009 Sheet 5 of 5 US 2009/0068255 A1 %9 as IOM - - -one US 2009/0068255 A1 Mar. 12, 2009 USE OF MATRX METALLOPROTEINASE (oxytalan fibers) to the DEJ and are thinner than the elastic INHIBITORS IN SKN CARE fibers of the reticular dermis. Oxytalan fibers lack the elastin core while elaunin fibers contain a small amount of elastin. RELATED APPLICATIONS Mature elastin fibers are found primarily arranged in bundles in the reticular dermis and measure about 1-3 um in diameter. 0001. The present invention claims priority under 35 U.S. 0006 Aging and exposure to environmental insults affect C. S 119(e) to U.S. provisional patent application, U.S. Ser. the appearance and structure of the skin. Sun-protected, natu No. 60/914,873, filed Apr. 30, 2007, which is incorporated rally aged skin exhibits epidermal and dermal thinning, fra herein by reference. gility, and fine, shallow wrinkles. There is a loss of elastic fibers in the papillary dermis, and collagen fibers become BACKGROUND OF THE INVENTION increasingly dense and more randomly oriented. Exposure to 0002 The skin is the largest organ of the human body and ultraviolet radiation from the Sun accelerates and alters the extends over the entire body. The skin functions primarily to degenerative processes associated with aging, resulting in a protectus from the outside world. The skin also functions to constellation of changes collectively known as photodamage. regulate the temperature of the body, protects the body from As much as 80% of facial aging may well be attributable to harmful UV rays, provides a defense against pathogens, Sun exposure. Photodamaged skin is characterized by loss of stores fat, provides the sense the touch, excretes waste, Syn elasticity, deep wrinkles, increased roughness and dryness, thesizes vitamin D, and provides cushioning and attachment. and altered pigmentation (age spots). The skin may assume a In protecting us from the outside world, the skin is constantly leathery, thickened appearance characterized by deep fur exposed to harsh temperatures, Sunlight, dirt, dust, wind, OWS. chemicals, pathogens, and other insults. In addition, the skin 0007. Many individuals desire to preserve a youthful is routinely Subjected to washing and shaving. appearance. At the same time, tanned skin is considered 0003 Skin is composed of two major layers: the epidermis attractive and outdoor recreational activities are popular, and the underlying dermis, which are distinct interms of their resulting in significant Sun exposure and consequent photo architecture, physiology, and function. The epidermis is a damage to skin. Various approaches have been developed or stratified epithelium composed of four layers: the stratum are under investigation to reduce the visible signs of photo basale, stratum spinosum, Stratum granulosum, and the out damage (Stern, R., N. Engl. J. Med, 350:1526-1534, 2004). ermost stratum corneum. The stratum basale contains a single Use of sunscreens can help to prevent further damage. Topical layer of cuboidal keratinocytes attached to a basement mem retinoids (vitamin A derivatives) can reduce the severity of brane. Above this layer is the spinous layer, characterized by photoaging (U.S. Pat. No. 4,877,805; incorporated herein by presence of numerous desmosomes. The stratum granulosum reference). It has been proposed to treat the skin with com overlies the stratum spinosum and consists of keratinocytes positions containing inhibitors of collagenase or elastase that contain basophilic granules of keratohyalin as well as (U.S. Pat. Nos. 5.614,489; 6,884,425; each of which is incor lamellar granules in the intercellular compartment. The Stra porated herein by reference). Chemical peels, which involve tum corneum is the most Superficial layer and is composed of application of a variety of different chemical compounds to anucleated, flattened, fully keratinized cells (corneocytes) skin, result in temporary improvement in the appearance of fused together to form a plate-like structure. The intercellular photodamaged skin in some individuals. Microdermabrasion space is occupied by ordered lipid lamellae that contain spe and laser resurfacing are other alternatives. Injection of botu cialized proteins and lipids, such as ceramides, fatty acids, linum toxin (e.g., BotoxR) has gained popularity as a means and cholesterols, which are secreted from lamellar bodies in of reducing furrows caused by muscle hypertonicity. Skin the stratum granulosum. The resulting “bricks and mortar' fillers such as bovine collagen and hyaluronic acid are used structure provides the stratum corneum with the ability to for soft tissue augmentation to reduce the appearance of, or to perform its protective and moisture retaining functions. The treat deep wrinkles. thickness of the epidermis ranges from about 75 to 150 um 0008 Such factors as exposure to the sun contribute to the except on the soles and palms, where it is about 0.4 to 0.6 mm. premature aging of skin contributing to the formation of lines The dermoepidermal junction (DEJ) is an undulating base and wrinkles, skin dryness, skin fading, roughness, hyperpig ment membrane composed primarily of collagen that sepa mentation, age spots, and loss of elasticity. The physiological rates the epidermis from the dermis. and pathological degradation of the connective tissue com 0004. The dermis is a dense, fibroelastic connective tissue ponent of the skin by proteases from resident cells contributes that lies beneath the epidermis and provides a strong and to the loss of elasticity of the skin. A major class of enzymes flexible Supporting layer. It is composed of cells (e.g., fibro involved in this process is the matrix metalloproteinases blasts), ground Substance, and a fibrous network containing (MMPs). collagenous and elastic fibers and also contains blood vessels, 0009 MMPs are zinc.(II)-containing hydrolytic enzymes nerves, hair follicles, Smooth muscle, glands and lymphatic involved in the breakdown of components of the extracellular tissue. Collagen, primarily types I, III, V, and VI, forms the matrix (ECM) and basement membrane Such as aggrecan, majority of the fibrous component, making up about 75% of collagen, elastin, fibronectin, gelatin, and laminin. The ability the dry weight of the dermis and imparting firmness and of MMPs to degrade components of the ECM is essential to tensile strength. cell growth, cell division, bone growth, wound healing, 0005. The dermis can be divided into two regions. The embryogenesis, and angiogenesis. The MMPs are divided papillary dermis conforms to the shape of the overlying epi into several different classes. Over 10 different members have dermis. The reticular dermis lies below the papillary dermis been identified to date. They are referred to numerically as and forms the majority of the dermal layer, giving it most of MMP-1, MMP-2, etc. as well as by a common name. The its elasticity and strength. Elastic fibers of the papillary der MMPs share several structural and functional properties but mis are oriented parallel (elaunin fibers) or perpendicular differ in their substrate specificities. Examples of MMPs US 2009/0068255 A1 Mar. 12, 2009 include collagenase I (MMP-1, fibroblast collagenase; EC MMP inhibitor may be administered to the skin in the form of 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; a cream, lotion, ointment, powder, spray, Solution, gel, paste, EC 3.4.24.34); collagenase III (MMP-13); proteoglycanase, serum, stick, foam, patch, face masks, etc.