The Enhancing Effect of Ion-pairing on the Skin Permeation of Glipizide

The purpose of the present study was to investigate the permeation of glipizide (GP) and observe the effect of an interaction with amines as counter ions, including diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, N-(2-hydroxylethyl) piperidine. Permeation experiments were performed in vitro, using rat abdominal skin as a barrier. The lipophilic donor system consisting of isopropyl myristate (IPM) and ethanol (EtOH; EI system, 8:2) produced a marked enhancement of GP flux through rat skin. All the amines investigated in this study had performed an enhancing effect on GP flux, and triethylamine had the most potent enhancing effect on GP in the vehicle IPM:EtOH = 8:2(w/w). In the presence of counter ions, the solubility of GP in the donor solution (IPM:EtOH = 8:2) was increased and the log K_o/w of GP was decreased, which may due to higher solubility of the GP in the IPM:EtOH = 8:2(w/w). ¹³C NMR spectroscopy was used to identify the ion-pairing formation between GP and the respective counter ion. It was surprising that all the four enhancers examined, such as isopropyl myristate, propylene glycol, N-methyl-2-pyrrolidone, azone, and oleic acid, had no enhancing effect on the percutaneous permeation of GP. This study showed that the formation of ion-pairs between GP and counter ions is a useful method to promote the skin permeation of GP.Key words: amine, counter ion, glipizide, ion-pair, percutaneous absorption