1999 ANNUAL SCIENTIFIC MEETING 65 SPECIAL PRESENTATION BARRIER FUNCTION AND AGING SKIN: CURRENT AND NEW THERAPEUTIC STRATEGIES Linda D. Rhein, Ph.D. SmithKline Beecham Consumer Healthcare, Parsippany, NJ 07054 Aging skin often has associated with it a variety of problems. Dryness, winter xerosis and even ichthyosis are common occurrences and are often associated with extreme itching. Photodamage resulting from chronic exposure to the sun leads to the appearance of wrinkles and fine lines. Other lesions that appear frequently are lentigens or age spots which are areas of hyperpigmentation. In the worst cases of photodamage patients often end up with skin cancers such as squamous or basal cell carcinomas and melanoma. The cosmetic industry is obligated to provide treatments for all these age-associated indications except skin cancer. Physical Chemical Strategies to Enhance Aging Skin Barrier Treatments for dry skin and winter xerosis involve a variety of therapeutic strategies based on the structure and function of stratum comeum. The cells of this horny layer are constantly being worn away and replaced by newly keratinised cells, in a continual cycle. This cycle of keratinisation, cell loss and replacement is important because a variety of skin problems, including ichthyosis, psoriasis, and eczema, involve disturbances of the normal sequence. The cycle may be disturbed by a variety of factors, including exposure to substances such as surfactants and emulsifiers often in cosmetics, low relative humidity, cold weather, vitamin A, alpha hydroxy acids, or drugs, as well as chemical messengers produced by the cells themselves such as in disease states, e.g. psoriasis which is characterised by accelerated cell formation. Stratum corneum is composed of lipids and proteins. Since treatments for dryness often are lipidoidal in nature and interact with the hydrophobic part of the membrane, a brief discussion of the lipids found in the stratum corneum is in order. Lipids in stratum corneum originate from the lameliar bodies. Lameliar bodies are formed on the Golgi. The lameliar body attaches to the cell membrane of the keratinocytes and their lipid contents are extruded into the intercellular spaces around the corneocytes. They are then modified by enzymes present in the intercellular spaces to produce the intercellular lipids found in the upper layers of the stratum comeum (see review by Abraham, W., in Surfactants in Cosmetics, Surfactant Science Series Vol. 68, Edited by Rhein and Reiger, 1997). Lipids in the upper layers contain predominantly cholesterol, ceramides and free fatty acids in a ratio of25:50:15 as weight percent. They are unique in that they do not contain phospholipids which are typically found in other biological membranes. During the process of modification to produce these lipids, phospholipids present in the lamellar body secretions are completely abolished converting them to free fatty acids glucosylceramides also present in the secretions are converted to ceramides.

66 JOURNAL OF COSMETIC SCIENCE The lipids are organized in a multilamellar structure and Friberg found that it typically exists as a liquid crystalline phase. However the phase behavior of this liquid crystal lipid structure can be effected by chemical treatment and relative humidity (Froebe et al, J. Soc. Cosmet. Chem. 41, 51-65, 1990 Mattai et al J. Soc. Cosmet. Chem. 44, 89-100, 1993). For example low relative humidity promotes dehydration of the lipid membrane with the formation of crystals in the structure. The lipid bilayers are attached hydrophobically to the comeocyte envelope on the surface of the comeocyte this envelope contains covalently attached co-hydroxyceramide, a lipid which serves as a template for the lipid bilayer attachment (Abraham, above). Moisturization of skin is the mainstay strategy to relieve dry skin. Moisturization can be defined in several ways from simply adding water back to the skin, retaining water inside the skin, elimination of the feeling of dryness of skin, reduction or elimination of dry skin scales, or enhancement of barrier lipid function / repair mechanisms. It can be achieved using a variety of strategies namely with masking emollients, occlusive agents, skin protectants, hygroscopic agents, lipid fluidizing agents, and biological enhancers of barrier repair. Current strategies are briefly summarized here. Simply placing a light emollient on the skin can appear to visibly remove the scales in a superficial way. The end result is apparent softening and smoothing of the skin but it is not a long term effect. Occlusive agents and skin protective agents such as petrolatum can be applied to the skin and these will hold water in the skin by providing a protective barrfer. OTifiemf½one, gfy'c•t-or •&,tr' petrolatum are known for their occlusive protective function and are considered drugs in the US Federal OTC Skin Protectant Monograph. Hydrophilic emollients are used to provide long term benefits on skin by hydrogen bonding to water keeping moisture in skin. Such agents are polymers of ethylene and propylene glycol, e.g .glycerine, propylene glycol, polyethylene glycol. Other hydrating agents affect hydrogen bonding to enhance barrier and such examples of these small molecules are urea and alpha hydroxy acids like lactic acid. These can alter the hydrogen bonding properties of the proteins in skin and result in changing the rheological properties and skin elasticity. Hydroxy acids can also alter cell turnover. The effects are generally longer term and the alpha hydroxy acids can even improve wrinkles and fine lines when used on a daily basis (Smith, Cosmetics and Toiletreis, 109, 41-48, 1994). Lactate and pyrrolidone carboxylic acid are part of the "natural moisturizing factor" identified in stratum corneum, both of which are known to be the most hygroscopic components of the water soluble fraction of the stratum comeurn (Rawlings, A. J. Invest. Derm. 731-740, 1994). They are thought to be derived from breakdown of stratum comeum proteins probably from filaggrin which degrades after the keratin fibers are stacked (Odland, G. in Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. Goldsmith, Oxford Univ. Press, 1991). Fluidization of the membrane lipid in the epidermis is the contemporary approach being studied to improve barrier. Lipid in skin as mentioned previously assumes a liquid