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j. Soc. Cosmet. Chem., 36, 237-249 (May/June 1985) Influence of depletion on percutaneous absorption characteristics JOEL L. ZATZ, Rutgers College of Pharmacy, P.O. Box 789, Piscataway, NJ 08854. Received October 12, 1984. Synopsis The effect of donor volume on percutaneous absorption has been studied by computer simulation. When relatively large volumes are applied to the skin surface (infinite dose conditions), the amount of permeant that leaves the donor is a small fraction of the original amount present and donor concentration does not change appreciably. Stratum corneum concentration rises gradually, as does the penetration rate, until a steady state is reached. With very small donor volumes, depletion of permeant leads to a decrease in donor concentration over time. As a result, stratum corneum concentrations and the rate of penetration rise to a peak and then fall, attaining much lower maximum values than with infinite dosing. The stratum corneum concentration gradient patterns are also influenced by depletion. If the transfer coefficient (K) is varied, donor concentration drops most rapidly and penetration rate is highest for the system with the largest value of K. However, the percentage reduction in penetration rate due to depletion is essentially independent of K. If the membrane/vehicle partition coefficient is varied, depletion affects the system with the highest partition coefficient to the greatest extent. With a donor volume of 0.0032 ml and K equal to 0.6 hr-2, an increase in partition coefficient of eight times resulted in only a doubling of penetration rate. INTRODUCTION Much of our current understanding of the quantitative aspects of percutaneous absorp- tion has been derived from in vitro experiments utilizing excised skin. It is common practice to mount whole skin or epidermis in a cell so that the dermal side is bathed with normal saline while a solution, gel, or some other system containing the permeant of interest is applied to the outer surface. If the volume of the applied preparation (donor) is relatively large, the small quantity of material that enters the skin during a typical experiment leaves the concentration within the donor essentially unchanged. Under these conditions, the amount of material permeating the skin rises until a steady state is reached (1). At steady state, a constant amount of permeant passes through the membrane while the amount within remains constant. These experimental conditions involving application of so-called infinite doses are useful because they permit calculation of a permeability constant, a measure of the influence of different membranes or of permeant chemical structure on skin penetration. Fur- thermore, from measurement of lag times or partitioning behavior and estimation of membrane (usually stratum corneum) thickness, it is possible to calculate an effective diffusion coefficient from the permeability constant. However, there are many instances where it would be more advantageous to study percutaneous absorption by applying small quantities to the skin. Such finite doses (2) 237