The Use of an Artificial Skin Model to Study Transdermal Absorption of Drugs in Inflamed Skin

Abstract

Studies on drug disposition in inflamed skin are important for safe and effective application of topical drugs. Here, the absorption of flurbiprofen (FP) through inflamed skin was examined in vivo and in a skin-mimicking artificial model system. The model skin system consisted of a silicone membrane acting as a model stratum corneum, laminated dialysis membranes acting as a model of viable skin, and 2 microdialysis probes-one used for determination of FP concentration and one acting as a model vessel. This model system could be used for quantitative evaluation of complicated permeation processes. In the in vivo experiments, FP absorption was suppressed in rats with inflamed skin induced by an intracutaneous injection of a mixed solution of λ-carrageenan, zymosan, and casein. Bovine serum albumin solution was placed between the dialysis membranes in the model skin system to mimic protein leaching in skin; the results suggested that the delayed absorption of FP in inflamed skin was due to binding to serum proteins leaching in the tissue. Such a combination of in vivo experiments and a model skin system is useful for understanding complex phenomena in inflamed and damaged skin and reduces experimental animal use.Key words skin absorption; model skin system; inflamed skin; protein binding; flurbiprofen Although permeation through the stratum corneum is the rate-limiting step for transdermal absorption of drugs, the kinetics of drug transfer in the viable epidermis and dermis could influence the pharmacological effects of a drug systemically as well as locally. Prolonged retention of the drug in the epidermis could delay onset of the therapeutic effect and/or cause undesirable side effects in the local tissue. Binding of drugs to tissue components in the skin could relate to retention of the drugs. In the case of inflamed skin, the leaching of plasma proteins with drug-binding ability could also affect the disposition of the drugs in local tissue. 1,2) In the drug of low protein binding ratio, the effect of plasma proteins leached into the local tissue will be small, the drug of high protein binding ratio are conversely susceptible to leach of plasma proteins. Although most skin formulations are intended for sound skin without injury or inflammation, prolonged or repeated application can bring about skin inflammation; also, some topical preparations are applied specifically to treat skin with inflammation. Therefore, studies on drug disposition in inflamed skin are important for safe and effective application of topical drugs.Excised animal skin is usually used for in vitro permeation studies in the early stages of the formulation development of new products. However, in vitro experimental systems using such membranes are not suitable for evaluating the drug concentration profiles in skin because of the lack of local blood flow and physiological response.3-5) Various experimental designs, including in situ skin permeation experiments and in vitro isolated skin perfusion experiments, have been developed to study the d...

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