Forward 2003 ANNUAL SCIENTIFIC MEETING THE USE OF ANTI-INFLAMMATORY ACTIVES IN COSMEITC FORMULATIONS Nava Dayan, Ph.D. Lipo Chemicals, Inc., Paterson, NJ 213 It is known that various compounds in cosmetic formulations can provoke adverse effects, such as skin irritation, that may lead to inflammation. Among these ingredients are fragrances, preservatives, sunscreens, lanolin derivatives, and others. In most cases, the immune system of the skin is capable of eliminating these reactions without causing clinically apparent inflammation. A reaction will occur when a large amount of the irritating compound penetrates the outer layer of the skin, when the compound penetrates to an unusual (sensitive) location, or when the immune system has a difficulty metabolizing it ll_ The amount of irritant penetrating the stratum comeum (SC) is dependent on multiple parameters. These can be physicochemical properties of the compound, duration of skin contact, hydration state of the skin, area of application, the formulation composition, occlusion, and age. When designing a formula, one, therefore, must take the above into account. The safest formula will be one that does not contain any compounds with potential irritation, nor compounds that exhibit skin penetration/penetration enhancement properties. Nowadays in the cosmetic world, creation of such a formula is almost impossible. Moreover, in many cases the cosmetic formula will include active ingredients that claim to have properties such as anti-aging, rejuvenation and skin lightening. In these cases, the active ingredient's target of action is the living epidermis or even dermis. When opening the way to penetrate these layers, a potential skin irritation is almost inevitable 2 . Inflammatory Response An inflammatory response will occur when the body utilizes the immune system to fight invaders (or perceived invaders, such as allergens). This will result in inflammation, a reaction that will be manifested by four basic symptoms: redness (erythema), heat (elevation of local site temperature), swelling (edema) and pain. These symptoms of skin inflammation are the result of several cascades occurring simultaneously. Once the immune system identifies the invading molecule, a mobilization response to the site of contact occurs. This leads to an increased blood supply, increased vascular permeability and migration of granulocytes (at early stages) and mononuclear cells (at late stages). The removal of the invader is done in two stages: non-specific response, which is the immediate first line of defense, and specific response which takes four to five days to be established. The non-specific response is a relatively primitive recognition of the system between invader and self. It utilizes both the cellular and humeral arms. The later specific response is an acquired property and is done through a specific molecule recognition by either B or T cells. This response develops memory so when the antigen (invader) is re-introduced, the immune system already has a set of pre-determined cells that will respond. Among the cells that are responsible for the immune response in the skin are: langerhans, principle antigen presenting cells, keratinocyts and T-lymphocytes 1 . Anti-inflammatory Actives Over the past decade, with the growing concern of the consumer for both safe and effective products, the cosmetic industry looked into ways to prevent the inflammation cascade from occurring. This presentation will focus on three actives and will attempt to understand their mechanism of action in the prevention of skin inflammation. The actives are glycyrrhetinic acid, bisabolol and pseudopterosins. Glycyrrhitinic acid (GA) was found to inhibit the lytic pathway of the complement within the inflammation cascade. The complement is a group of mediators that are important in facilitating the immune system in defending against invaders. GA inhibits undesired cells lysis and prevents further tissue damage(J). It was also found to induce T-mature lymphocytes appoptosis 4 , enhance interleukin- I 2 production 5 and inhibit type 2 11-beta-hydroxysteroid dehydrogenase (I I-beta HSD), which inactivates cortiso1 5 _

214 JOURNAL OF COSMETIC SCIENCE Alpha-bisabolol is a sesquiterpene alcohol which was demonstrated to be able to block two of the three possible pathways of the formation of inflammatory-active leukotrienes and prostaglandins 6l . Pseudopterosins were found to inhibit prostaglandin E-2 and leukotriene C production showing that they mediate their anti-inflammatory effect via inhibition of eicosanoid release from inflammatory cells (7) . Pseudopterosins were also found to be involved in receptor mediated inflammatory events, suggesting involvement in the cellular arm of inflammation 8l Summary The Skin inflammation process is a protection mechanism where the body utilizes the immune system to fight off invaders. Although perceived symptoms may look the same, there are different types of inflammation that involve various mediators. While acute allergic inflammation is mediated by mast cells and immunoglobulin E, for example, cytotoxic inflammation is mediated by cytotoxic antibody and complement. Therefore, an anti­ .inflammatory compound should possess activity in major crossroads in the cascade to be able to prevent them from occurring. When designing a formula, thought should be put into its composition in terms of penetrability of its compounds, both in order to substantiate activity claims and prevent irritation. When irritation is expected, or when a product is designed for sensitive skin/skin areas, the addition of anti-inflammatory compounds can make the difference between a safe and unsafe f�rmula. References I) Gordon K.B. and Chan L.S., Inflammation and Immunity in: The Biology of the Skin, !'' Edition, 233-254, (2000). 2) Rougier A., In Vivo Percutaneous Absorption in: Percutaneous Absorption, 3rd Edition, 193- 211, (/999) 3) Fujisawa Y., Sakamoto M., Matsushita M., Fujita T., Nishioka K., Glycyrrhizin Inhibits The lytic Pathway q[Complement- Possible Mechanism of its Anti-!n.flammato,y Effect on liver Cells in Viral Hepatits, Microbial lmmunol. 44, 799-804, (2000). 4) Oh C., Kim Y., Eun J., Yokoyama T., Kato M., Nakashima I., Induction qf T lymphocyte Apoptosis by Treatment with Glycyrrhizin. Am J Chin Med 27, 217-26, (/999). 5) Van Uum S.H., Walken B.R., Hermus A.R., Sweep C.G., Smits P., de Leeuw P.W., Lenders J.W., E/fect of Glycyrrhetinic Acid on / I-Beta-Hydroxy Steroid Dehydrogenase Activity in Normatensive and Hypetensive Subjects. Clin. Sci 102, 203-11, (2002). 6) Stanzl K., Vollhardt J., Pickenhagen W., Nissen H.P., Protective and Curative in Vivo Efficacy qf Bisabo/ol against Sodium Hydroxide on SLS-induced Irritation on Human Skin - Indication for a Non-linear Dose Response Cure. I FSCC Congress 1998 Cannes France paper P004 I 06. 7) Mayer A.M.S., Jacobson P.B., Fenical W., Jacobs R.S., Glaser K.B., Pharmcological Characterization of Pseudopterosins. Novel Anti-Inflammatory Natural Products Isolated from the Caribbean Soft Coral, Pseudopterogorgia Elisabethae, Life Science 62(26) PL40 I­ PL407, (1998). 8) Dayan N., Ortega L., Riemer J., Moya C., Jacobs R. S., Pseudopterosins - Solubility Characteristics and Anti-Inflammatory Activity. 28th Inter. Symp. Control Rel. Bioact. Mater. Control Release Society, Inc. Proceed. USA, #5098, 2001.