Evaluation of in vitro and in situ transdermal absorption of drugs in pig and rat skin.

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Abstract
The permeability characteristics of newborn pig skin and adult rat skin, either fresh or stored, to model drugs were examined and compared. Special attention was paid to the design to a new experimental system suitable for evaluation of skin permeability to various substances. Two types of model substances were used; insulin, a poorly absorbable substance with high molecular weight as a representative of peptide drugs, and brilliant blue, a low- molecular, relatively well absorbable substance. In vitro experiments performed with both substances in pig and rat gave comparable values of skin permeability. Maximum insulin concentration in the receiver solution was very similar in all experiments (164.5- 180.5μU/ml/24h when Azone® was used and 136.5- 178.0 μU/ ml/24 h when N-methyl- 2- pyrrolidone (NMP) was used as a penetration enhancer). The donor side concentration of insulin was 2.5 mg/ml. The optimum concentrations of vehicle and penetration enhancer were 40.0% propylene glycol (PG) and 0.1% Azone® or 12.0% NMP, respectively. Brilliant blue experiments performed with the three skin preparations with 40.0% PG and 12.0% NMP gave similar values of the flux JT and permeability P of 1.38- 1.97 μg/cm 2/h and 1.56 × 10 -5- 2.22 × 10-5 cm/h, respectively. The concentration of brilliant blue in the donor compartment was 50 mg/ml. There were differences between the lag time in pig and rat skin experiments : about 3 h in the case of rat skin but 15 min in pig skin. In comparison to in vitro experiments, in situ studies gave much lower penetration of both test substances expressed as concentration in the receiver compartment. In the case of insulin with Azone® or NMP in the formulation, 30 times or 17 times lower concentration was found, and in brilliant blue experiments almost 5 times lower levels were observed. This new experimental system should be useful for examination of potential drug candidates as well as drug formulations for transdermal use.