J. Cosmet. Sci., 54, 161-174 (March/April 2003) Effect of formulation on the topical delivery of o-tocopherol MEERA RANGARAJAN and JOEL L. ZATZ, Organon USA, 3 75 Mt. Pleasant Avenue, West Orange, NJ 07052 (M.R.), and Laboratory of Cancer Research, Rutgers University, 41-D Gordon Road, Piscataway, mJ 08854 (J.L.Z.). Accepted for publication August 19, 2002. Synopsis The objective of this research was to investigate the effect of concentration and delivery system on skin permeation of (x-tocopherol ((x-T). Also, the addition of sunscreens and oleic acid on (x-T permeation was studied using an in vitro micro-Yucatan pig skin model. Various delivery systems of (x-T (1%) were formulated, which included simple solution, gels, emulsions, and microemulsions. The experimental design chosen for this study was a statistical randomized complete block design. (x-T delivery was proportional to its concentration. The hydroalcoholic gel delivered significantly higher amounts of (x-T into the receptor than the other gels used. A microemulsion containing isopropyl myristate emerged as the best delivery system for (x-T among all the systems studied. Pig skin is a suitable in vitro model for studying the permeation of (x-T and possibly other antioxidants, though in vivo experiments in humans are required to further corroborate the data. INTRODUCTION Research has shown that UV radiation damages DNA and genetic material, oxidizes lipids and produces harmful free radicals, causes inflammation that also produces free radicals, disrupts cell communication, causes expression of stress response genes, and weakens the immune response of the skin. o•-Tocopherol (o•-T) is the major lipophilic antioxidant in many biological systems (1). Topical application of o•-T has been shown to protect against UV-induced cutaneous damage, carcinogenic and mutagenic activity of ionizing radiation, and chemical agents (2). o•-T has been found to reduce tumor incidence in mice (3) and decrease fine lines, wrinkles, and sagging induced by photo- aging (4,5). o•-T is now considered essential for the stabilization of biological mem- branes, particularly those containing large amounts of polyunsaturated fatty acids. The oxidation of unsaturated fats produces lipid peroxides, which interfere with the structure and function of biological membranes. When dl-o•-tocopherol was added to commercial Address all correspondence to Meera Rangarajan. 161

162 JOURNAL OF COSMETIC SCIENCE creams in concentrations of 0.1% or 1%, no marked increase in lipid peroxides was observed during a 96-hour exposure to sunlight (6). The antioxidant activity of c•-to- copherol has been summarized elsewhere (7). Varying concentrations of c•-T have been used in different studies. Beijersbergen van Henegouwen et •/. (8) have used 0.25% of c•-TAc to study its UV protecting activity in vivo in rat. c•-T in low concentrations of 0.05-2% was used as an antioxidant in topical preparations. In higher concentrations (2-10%) c•-T seemed to have benefit in stratum corneum hydration (9,10). Pure c•-T and concentrated c•-T preparations (10-20%) could irritate human skin, and cases of allergic contact dermatitis and other types of immu- nologic hypersensitivity reactions are reported (11). However, there is no systematic study in the literature on the effect of concentration of c•-T on skin permeation. Sunscreens are the second type of photoprotectants that are commonly used along with antioxidants. Very little information, however, is available on the augmentation of the activity of either the sunscreens in the presence of antioxidants or vice versa. Darr et•/. (12) studied the combination of the two antioxidant vitamins, C and E, with commercial UVA sunscreen (oxybenzone) and found greater than additive protection against pho- totoxic damage. These results emphasize the importance of combining antioxidants with common sunscreens to maximize photoprotection. Alberts eta/. (13) reported that in a survey about 62% of sunscreen formulations contained some form of c•-T. They caution, however, that further research has to be performed to study the potential harmful effects of"other ingredients" (like c•-T) that can be added to commercial sunscreens. Alteration of the skin transport of chemicals can be achieved by means of permeation-enhancing agents such as oleic acid and dodecylazacycloheptan-2-one (laurocapram, azone) (14). Bhatia et•/. (15) used a combination of ethanol and 10% oleic acid pretreatment to significantly increase the permeability coefficient of cholecystokinin-8. Kitagawa and Li (16) found that 1% 1-menthol plus 15% ethanol increased the permeability of benzoic acid but decreased that of its higher alkyl substituents. Morgan et•/. (17,18) studied a new class of penetration enhancers, octyl salicylate (OSal) and padimate O (Pad O), which have been used as effective sunscreens, along with oleic acid, to enhance the permeability of the sex hormones testosterone, estradiol, and progesterone. They found OSal to give the highest enhancement in permeability. The effects of padimate O and oleic acid were comparable to each other, albeit better than the control. Previous work done by the authors using the prodrug ester of c•-T, c•-tocopheryl acetate (c•-TAc), demonstrated the metabolism of c•-TAc to c•-T in pig skin (19). Permeation of c•-TAc and its metabolism were found to be a function of the delivery system (20). An emulsion system containing isopropyl myristate (IPM) emerged as the most desirable formulation in terms of skin delivery of c•-TAc. The objective of this work was to (i) formulate different delivery systems for c•-T, (ii) delineate the effect of both biphasic and uniphasic delivery systems on the permeation of c•-T, (iii) study the effect of concentration on c•-T permeation, (iv) characterize the effect of sunscreens on c•-T permeation, and (v) formulate and study c•-T permeation with oleic acid, which is believed to function as a penetration enhancer. MATERIALS AND METHODS CHEMICALS AND INSTRUMENTS D-o•-Tocopherol was obtained as a gift from Archer Daniels Midland Company (IL).