Effect of polyolprepolymer on the disposition of retinoic acid in various strata of hamster ear following topical in vivo application of gel formulations: Correlation with disposition in human skin

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Abstract
The hamster ear has been shown to be an appropriate model for human pilosebaceous units. In this study, we report the deposition of retinoic acid (RA) into pilosebaceous units and other strata of the hamster ear 8 h after topical in vivo application of two hydroalcoholic gel formulations containing RA with and without polyolprepolymer-2 (PP-2). PP-2, a TopiCare Delivery Compound (Penederm, Inc.), consists of a mixture of high-molecular-weight oligomers, ranging in molecular mass from 1700 to 10,000 daltons (average of 4000), that can modify drug delivery by retaining drug on and in the upper layers of the skin. The formulations tested were (A) RA (0.025 wt%) in Penederm Gel with PP-2 and (B) RA (0.025 wt %) in Penederm Gel without PP-2. It was observed that the amount of RA found in the sebaceous glands was roughly fivefold greater from formulation B than from formulation A. Although total RA delivery was less from formulation A, the results suggest that formulation A containing PP-2 may target delivery into the pilosebaceous units, because the amount of retinoic acid found in the sebaceous glands relative to that found in the surrounding dermis was greater with formulation A than formulation B. The amounts of RA in the dennis, cartilage, and dorsal strata were negligibly small. This may be a very important finding because of the known toxicity and teratogenicity of this class of compounds. The amount of PP-2 in the pilosebaceous units was negligible. Furthermore, polyolprepolymer did not penetrate into the dermis, cartilage, and dorsal strata of the ear. Overall, formulation B was found to deliver larger amounts of retinoic acid into all strata of the hamster ear but formulation A containing PP-2 appeared to target delivery of RA specifically into the pilosebaceous units and not other strata, thus reducing undesirable side effects caused by the drug. The results are consistent with lowered extents of RA deposition with mouse skin in vivo as well as lowered amounts of RA permeating in in vitro human skin experiments from PP-2—containing formulations.