126 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS o 1.2 [ (a) O9 O6 O3 • DERMATOMED SKIN 00 ' ' ' ' 0 5 10 15 20 25 2.0 (b) I 5 lO 0 5 • , ETHAN?LIC SOL, UTION O0 ' 0 5 10 15 2o 25 Time (hours) Figure 2. In vitro penetration results for PC/PE/OA/CHEMS liposome system (geometric mean + SE). Dosing conditions were the same as in Figure 1. (a) Penetration of encapsulated t-RA through stratum corneum (n = 4, 3H20 flux = 0.35 mg/cm 2) and dermatomed skin (n = 7, 3H20 flux = 0.34 mg/cm2) (b) Penetration of encapsulated t-RA and ethanolic t-RA through dermatomed skin (n = 6-7, 3H20 flUX = 0.33 mg/cm2). was no significant difference in t-RA penetration between the two substrates at 24 h (Figure 2a). Furthermore, in a follow-up study, a 0.05% ethanolic solution of t-RA yielded equiv- alent penetration through dermatomed skin as the PC/PE/OA/CHEMS liposome system (Figure 2b). The 24 h t-RA penetration values were consistent with the results obtained by Lehman and Franz for solvent-deposited RA (25). We thus found no evidence of appreciable effects of liposomal encapsulation on t-RA delivery through or into the skin in these studies. Figure 3 shows the results of additional tests in which small doses of t-RA in either PC-liposomes or the transcutol/water control solution were applied to various mem-

INFLUENCE OF LIPOSOMAL ENCAPSULATION 127 4O 3O 2O 10 0 4 3 2 1 4 3 2 1 (a) T 3 2 1 0 0 5 1 0 1 5 2o 25 (b) T. ß 0.3 O2 0 I 0.0 0 5 1 0 15 20 25 (c) 0.0 0 5 I 0 I 5 2O 25 0.3 0.2 0 I Time (hours) Figure 3. Penetration of small (4.8 mg/cm 2 of a 0.05 % solution), non-occluded doses of t-RA through (a) silicone rubber membrane (b) dermatomed skin (3H20 flux = 1.29 mg/cm2) and (c) isolated stratum corneum (3H20 flux = 0.79 mg/cm2). &, PC-liposome vehicle O, transcutol/water vehicle (geometric mean - SE, n = 5-8). branes. Penetration of t-RA from the two formulations was essentially the same whether the testing was carried out on a synthetic membrane (Figure 3a), dermatomed skin (Figure 3b), or isolated stratum corneum (Figure 3c). Furthermore, t-RA penetration through the dermatomed skin samples was actually slightly higher than through the stratum corneum samples, reinforcing the findings from Figure 1 that the lower skin layers do not contribute appreciably to the diffusion barrier for t-RA. Again, there was no evidence for significant effects of liposomal encapsulation on t-RA delivery through or into the skin based either on a direct comparison of penetration values for liposomal and control formulations or on a comparison of the penetration ratios (Figure 3c/Figure 3b) as described in the Experimental section. Large-dose diffusion studies. Since a number of studies showing liposome effects on topical