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.
Yamamoto
Akira
A
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. yamamoto@mb.kyoto-phu.ac.jp
Setoh
Kazunari
K
Murakami
Masahiro
M
Shironoshita
Masaru
M
Kobayashi
Takumi
T
Fujimoto
Kayoko
K
Okada
Naoki
N
Fujita
Takuya
T
Muranishi
Shozo
S
D000215:Acylation; D000279:Administration, Cutaneous; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D005227:Fatty Acids / Q000008:administration & dosage*; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism*; D012995:Solubility
D004151:Dipeptides; D005227:Fatty Acids; C040500:phenylalanylglycine