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Hyperpigmentation on faces is a highly anxiety-producing symptom, especially for women from the aspect of beauty. We previously reported the skin whitening effect of linoleic acid (LA), 1,2) the mechanism of the whitening effect involving a decrease in tyrosinase level by LA, 3) and clinical trials of liposomal LA for skin hyperpigmentary disorders, such as melasma.4) Although these reports described the whitening effect of LA in transdermal application, and the stabilization of LA by liposomal formulation, it was not confirmed whether LA encapsulated in liposomes enhanced the skin whitening effect. There have been number of reports that describe transdermal application using liposomes on cutaneous absorption, 5-7) on the transdermal delivey of encapsulated drugs 8) and on effective interaction of dermal skin cells with liposomes containing drugs in liposomes.9-11) The synergistic effect of liposomes on active reagents for whitening via transdermal application was also reported.12) Compared to those reagents previously reported, LA is not only effective in whitening but also quite safe.13) Although there are many examples of the transdermal applications of liposomal formulations, little is known about the enhancement of drug efficacy by liposomalization. From this point of view, we were interested in the possible enhancement of LA's whitening activity by encapsulating it in liposomes. The present study clearly demonstrated that LA encapsulation in liposomes significantly enhanced it's whitening efficacy by transdermal application for UV-induced hyperpigmented dorsal skin of brownish guinea pigs. We also observed enhanced whitening efficacy by liposomalization of LA in UV-induced hyperpigmented human skin. MATERIALS AND METHODSWhitening Assay UVB-induced hyperpigmentation was elicited on the backs of brownish guinea pigs weighing about 600 g each (Saitama Experimental Animal Supply Co., Japan) using a modification of the method reported by Imokawa et al.14) Guinea pigs were gently tethered, and four separate areas (2.5 cmϫ2 cm) on the back of each animal were exposed to UVB radiation (ToRex FL20S-E-30/DMR, Toshiba, Japan) three times a week (every other day) for two consecutive weeks. The UVB intensity was 2 mW/cm 2 , and total energy dose was 1 J/cm 2 per exposure. Groups of six or more animals were used in each experiment. The animals were then left for an additional week to allow the UVBinduced hyperpigmentation to stabilize. Test samples were then topically applied daily to the hyperpigmented areas (0.01 ml/cm 2 ) five times per week for 3 successive weeks. The degree of pigmentation was assessed as the L-value measured with a chromameter (CR-200, Minolta, Japan) once every week from the beginning of sample application. The animals were cared for according to the guidelines for the Care and Use of Laboratory Animals of the University of Shizuoka.In the case of human skin assay, persons being tested were 6 healthy men in their 20 s or 30 s. After obtaining informed consents from the volunteers, UVB-induced hyp...

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Since the liposomal formulation of linoleic acid (LA) exhibited an enhanced skin-whitening effect, the influence of liposomalization on the cutaneous absorption of LA was examined using a three-dimensional (3D) reconstructed skin model. Liposome entrapped [ 14 C]-LA was applied on the skin model, and the permeation of LA through the skin was monitored. The permeation rate of LA in the liposomal formulation was found to be lower than that in the conventional formulation without liposomes, suggesting the increased retention time of LA in the skin by the liposomal formulation. Next, to investigate the dependence of the LA permeation on melanocyte conditions and intactness of the reconstructed skin model, the effect of UV irradiation on LA permeation was examined. Low-dose UVB irradiation (0.03 J/cm 2 for 3 times), which activated melanocytes in the skin, did not influence the extent of LA permeation, while high-dose irradiation (0.30 J/cm 2 for 3 times) enhanced the permeation of LA in both the conventional and liposomal formulation. The present results suggest the importance of skin intactness for LA permeation and that the 3D reconstructed skin model would be useful for evaluating the characteristics of skin-oriented cosmetics and drugs.

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