Enhanced transdermal delivery of phenylalanyl-glycine by chemical modification with various fatty acids.

We synthesized three novel lipophilic derivatives of phenylalanyl-glycine (Phe-Gly), C4-Phe-Gly, C6-Phe-Gly and C8-Phe-Gly by chemical modification with butyric acid (C4), caproic acid (C6) and octanoic acid (C8). The effect of the acylation on the stability, permeability and accumulation of Phe-Gly in the skin was investigated by in vitro studies. The stability of Phe-Gly in skin homogenates was low, but was significantly improved by the acylation. In the transport studies, a Franz-type diffusion cell was used for the permeability experiments with Phe-Gly and its acyl derivatives. The permeability of acyl-Phe-Gly derivatives across the intact skin was higher than that of native Phe-Gly. Of all the acyl-Phe-Gly derivatives, C6-Phe-Gly was the most permeable compounds across the intact skin. On the other hand, the permeability of acyl-Phe-Gly derivatives across stripped skin was less than that of native Phe-Gly in the initial time period of transport studies, but their permeability was higher than that of native Phe-Gly at the end of the transport studies. When the skin was pretreated with ethanol, which could inactivate the peptidases responsible for the degradation of Phe-Gly, the permeability of native Phe-Gly was higher than that of acyl derivatives. These findings indicated the involvement of peptidases on the permeability of Phe-Gly across the skin. The relationship between the lipophilic indexes of Phe-Gly derivatives and the permeability coefficients indicated that there is an optimal carbon number of fatty acid for improving the transdermal permeability of Phe-Gly by the acylation. A good correlation was found between the accumulation of these acyl-Phe-Gly derivatives in the intact skin and their lipophilicity. These results suggest that the stability and permeability of Phe-Gly were improved by chemical modification with fatty acids and this enhanced permeability of Phe-Gly by the acylation may be attributed to the protection of Phe-Gly from the enzymatic degradation in the skin and the increase in the partition of Phe-Gly to the stratum corneum.