SKIN PERMEATION MODELS 39 between stratum corneum and aqueous compartment were 2 h-• in the binding sim- ulations and 0.03 min- • in all washing simulations. The transfer coefficient from aqueous compartment to the sink in the binding simulations was 5 h-l it was 0.08 min- 1 from aqueous compartment to the blood in the washing simulations. The cross-sectional area was 1 cm 2 in all cases, and the stratum corneum thickness was assumed to be 10 }xm. The values of the constants were arbitrary, as the simulations were intended to show trends rather than mimic a particular situation. The values were chosen so that transport control resided within the SC section of the model. RESULTS AND DISCUSSION BINDING STUDIES The model, shown in Figure 1, was modified from the original version (5) to include stratum corneum compartments (labeled B) that are not part of the transfer pathway. These compartments represent binding sites. Permeant molecules that leave the main channel and enter the B compartments cannot diffuse to other sections of the membrane until they redistribute from these blind sections of the model. This situation is analo- gous to binding to structural proteins within the stratum corneum, which would reversibly immobilize a bound molecule. Note that transport kinetics are unaffected by the portion which is bound only the "free" (unbound) permeant is available for diffu- sion. A series of penetration curves under infinite dose conditions is shown in Figure 2. Some data from the same study appears in Table I. The only variable in these simulation experiments was the extent of binding within the SC all other model parameters were kept fixed. Binding of the permeant results in an increase in its concentration within the skin. At early times the amount penetrated is reduced the higher the extent of binding, the smaller the amounts reaching the sink at any given time. Inspection of Table I shows that this effect is highly significant. With a change from 70% bound to 90% bound, • sc • PC=K I/K. I K=INTER SC CONSTANT Figure 1. Model for binding studies. The stratum corneum consists of five compartments connected in sequential fashion. Transfer is described by K, the intercompartmental transfer constant. Stratum corneum compartments labeled B contain bound permeant. The AQ compartment represents the viable skin tissues.

40 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS 0.3 I.- z o 0.2 0.1 0.0 FSC= 0 --'0-- FSC=.3 • F SC = .5 ,5, F SC = .7 "• FSC =.9 0 20 40 60 80 100 TIME (h) Figure 2. Amount reaching the sink with various degrees of stratum corneum binding, infinite dose conditions. F values shown in figure represent fraction bound. (K = 0.4 h-• PC = 15 donor concen- tration = 10 mg/ml donor volume -- ! ml). the amount reaching the sink in 12 hours is reduced 50-fold. However, Figure 2 shows that if the permeation process is permitted to continue long enough, the same steady- state flux will eventually be established regardless of the fraction bound (although the time required for this might be impractically long in the case of highly bound sub- stances). Thus an important effect of SC binding is delay in the establishment of a steady state. In terms of a simple diffusional model, we would say that the lag time has been increased. Table I Results From Simulation Studies of Stratum Corneum Binding Under Infinite Dose Conditions (K = 0.4 h- • PC = 15 donor concentration = 10 mg/ml donor volume = ! ml) Fraction bound Amount in skin Amount penetrated Steady-state in SC at 12 h (mg) at 12 h (mg) flux (mg/cm2/h) 0 0.065 0.011 0.00261 0.3 0.084 0.0067 0.00261 0.5 0.104 0.0036 0.00261 0.7 0.138 0.0010 0.00258 0.9 0.226 0.00002 * * Steady-state not reached in 100 hours.