SKIN PERMEATION MODELS 43 z z o z o o o o lOO 5O 10 min 20 min 40 min 90 min 180 min none 0 10 20 30 40 TIME (h) Figure 5. Effect of wash time (shown in figure) on blood concentration. (K = 0.01 min-• PC = 15' donor concentration = 10 mg/ml donor volume = 1 ml elimination rate constant = 0.00165 min- • volume of distribution = 5000 ml). as the total amount excreted at 48 hours, are compiled in Table III. In one case the donor was not washed this situation corresponds to the infinite dose type of application, which serves as a reference for the other results. As expected, shortening the contact time reduced the amount absorbed into and through the skin. The blood concentrations from all of the treatments are quite low, as would be expected for most substances that are absorbed through the skin. However, it should Table III Results From Simulation Studies in Which the Donor Was Washed From the Skin at Various Times After Application (K = 0.01 min-• PC = 15' donor concentration = 10 mg/ml donor volume = 1 ml elimination rate constant = 0.00165 min- •' volume of distribution = 5000 ml) Blood concentration Wash time Amount in skin at 12 h Amount in urine (min) at 12 h (mg) (mg/ml X 107) at 48 h (rag) 10 0.0032 2.8 0.0047 20 0.0061 5.2 0.0086 40 0.0106 8.8 0.0147 90 0.0184 14.8 0.0250 No wash 0.0694 36.8 0.0826

44 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS be noted that even when the application is washed off, significant penetration into the circulation does occur. At very short contact times, the amounts getting into the skin and then the circulation are approximately proportional to the exposure time (Figure 6). As the contact time is lengthened, this is no longer true. With an exposure time of one hour, the total amount absorbed is approximately 10% of that following extended contact. It should also be noted that blood concentrations continue to climb after washoff (Figure 5), with a peak blood level at about 15-20 hours. These data illustrate the storage function of the stratum corneum. Even after the skin is washed, the substances that have gotten into the stratum corneum continue to diffuse, and a significant proportion may eventually reach the viable skin layers and then the circulation. A series of simulations were run to determine the effect of changes in partitioning and transport parameters on skin uptake and penetration at 12 hours following a short (15-minute) exposure to the donor. The effect of changes in partition coefficient is simply stated: an increase in partition coefficient results in a proportional increase in both skin and blood levels (Figure 7). Alteration in transfer coefficient (K) is more complex, as shown in Figure 8. Blood concentrations increase as the value of K is made larger however, skin levels decrease because the rate of loss from the stratum corneum to the compartments downstream occurs at a faster rate. 40 30 20 10 0 60 120 180 WASH TIME (min) Figure 6. Relationship between wash time and relative amount in various locations. Parameter values are given in Figure 5. [], amount in skin at 12 hours /x,, blood concentration at 12 hours C), amount in urine at 48 hours.