128 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS delivery have employed much larger dose volumes than those in Figures 1-3, we repeated the comparisons from Figure 3 under high-dose conditions. The results are shown in Figure 4 (large, occluded dose) and Figure 5 (large, non-occluded dose). Figure 4a demonstrates that 0.05% t-RA in the PC-liposome formulation and 0.05% t-RA in transcutol/water 68:32 have equal thermodynamic activity, since they both yielded the same diffusion rate for t-RA through an inert membrane. Additional diffusion experi- ments with 0.10% t-RA suspension in the transcutol/water vehicle (data not shown) showed that this activity was near maximal. However, on dermatomed skin (Fig. 4b) and isolated stratum corneum (Figure 4c), the transcutol/water formulation yielded 50-100% greater t-RA penetration than did PC liposomes. This is evidence for a mild permeability-enhancing effect oftranscutol on skin, as suggested by the work from other 40 30 20 10 0 40 30 20 10 0 40 30 20 10 0 (a) O 5 I O I 5 20 25 (b) T 0 5 I 0 I 5 20 25 (c) T 0 5 I 0 I 5 20 25 Time (hours) Figure 4. Penetration of high (200 mg/cm 2 of a 0.05% solution), occluded doses of t-RA through (a) silicone rubber membrane (b) dermatomed skin (3H20 flux = 3.94 mg/cm2) and (c) isolated stratum corneum (3H20 flux = 1.07 mg/cm2). The symbols and formulations are the same as in Figure 3 (geometric mean -+ SE, n = 7-8).

INFLUENCE OF LIPOSOMAL ENCAPSULATION 129 laboratories (31). Note, however, that dermatomed skin and isolated stratum corneum again yield nearly equivalent penetration rates for either control or liposomal t-RA, in agreement with the findings from the small-dose studies. A comparison of penetration ratios (Figure 4c/Figure 4b) gave no evidence for accumulation of liposomal t-RA in the skin. Figure 5 shows the results from a similar set of large-dose studies in which evaporation of the donor solution was allowed to occur. In this case, PC liposomes yielded higher t-RA penetration through the inert membrane than did transcutol/water (Figure 5a). This most likely reflects the decreased thermodynamic activity of t-RA in the transcutol/ water formulation, as the more volatile water component evaporated during the study. 40 I (a) T 30 10 0 • ' 0 5 I 0 I 5 20 25 m 12 ß _ 9 • 3 13= o E 12 3 0 (b) - 0 5 I 0 I 5 20 25 (c) __ 0 5 I 0 I 5 20 25 Time (hours) Figure 5. Penetration of high, non-occluded doses of t-RA through (a) silicone rubber membrane (b) dermatomed skin (3H20 flux = ].08 mg/cm2) and (c) isolated stratum corneum (3H20 flux = 0.98 mg/cm2). The symbols and formulations are the same as in Figures 3 and 4 (geometric mean --- SE, n =