SKIN PERMEATION MODELS 41 The situation is quite different when a small amount (finite dose) of material is applied to the skin surface. Results are plotted in Figure 3 and summarized in Table II. Steady state is not established under finite dose conditions Table II lists the peak flux value in its place. An increase in the degree of binding causes a rise in the amount in the skin at 12 hours, although the incremental increase in skin amount is small (Table II). The most dramatic change is in penetration. Binding causes significant reductions in the amount that reaches the sink at 12 hours. Again, there is a 50-fold difference in the amounts penetrated between a situation in which 70% is bound and one in which 90% is bound. The peak flux value is also affected. An increase in the extent of binding causes a reduction in the maximum flux, particularly as the degree of binding approaches very large values. There is also a dramatic shift in the time at which the peak occurs. For example, in the absence of binding, the maximum flux is observed at about 12 hours with 50% bound, the peak time is 2 ! hours with 90% bound, peak time goes up to about 94 hours. The results indicate that binding makes skin penetration more difficult. This would probably have been predicted in a qualitative sense. However, the simulations show that at high fractions bound, the effect is much greater than might have been anticipated. When the fraction bound reaches 0.9, the rate of penetration and amount penetrated at FSC= 0 ---0'-- F SC = .3 • F SC =.5 ,& F SC = .7 '-, F SC = .9 0 0 20 40 60 80 100 TIME (h) Figure 3. Penetration flux as a function of extent of stratum corneum binding under finite dose conditions. (K = 0.4 h- •' PC = 15 donor concentration = 10 mg/ml donor volume = 2 IM).

42 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table II Results From Simulation Studies of Stratum Corneum Binding Under Finite Dose Conditions (K = 0.4 h- • PC -- 15 donor concentration -- 10 mg/ml donor volume -- 2 txl) Fraction bound Amount in skin Amount penetrated Peak flux in SC at 12 h (mg) at 12 h (mg) (mg/cm2/h) 0 0.013 0.0036 0.00051 0.3 0.015 0.0021 0.00038 0.5 0.017 0.0011 0.00029 0.7 0.018 0. 00029 0. 00018 0.9 0.019 0. 000006 0. 00006 early times are markedly reduced and the time for peak penetration shifts to a much larger value. SKIN WASH STUDIES A number of skin products are applied, allowed to remain on the skin for some period of time, and then washed off. The purpose of these simulations is to determine whether washing after a short period of time would limit skin uptake and penetration of product components. The model (Figure 4) was somewhat different from that shown in Figure 1, in that binding was not considered. In addition, the model contained a blood compartment in place of the "sink," and there was provision for elimination from the blood by a first-order kinetic process. Data from simulations were compiled to see the effect of wash time on blood concen- tration (Figure 5). The amount in the skin and blood concentration at 12 hours, as well MU LTICOMPARTMENTED MEMBRANE MODEL PC=K I/K. I K=INTER SC CONSTANT Kelim=ELIMINATION RATE CONSTANT Figure 4. Model for washing studies.