TRANSDERMAL DELIVERY OF PEPTIDES BY IONTOPHORESIS

Transdermal administration by iontophoresis (enhanced transport via th e skin using the driving force of an applied electric field) has been successfully demonstrated but no formal relationship between peptide s equence/structure and efficiency of delivery has been established. The re are notable examples, such as the lipophilic leutinizing hormone re leasing hormone (LHRH) analogs, Nafarelin and Leuprolide, that exhibit down-regulation of their own transport across the skin under the infl uence of an iontophoretic current. The hypothesis that this phenomenon is due to neutralization of the skin's net negative charge by these c ationic peptides was examined with LHRH oligopeptides. The impact of t hese compounds on the electroosmotic flow of solvent into the skin, wh ich is induced by iontophoresis and which contributes significantly to the electrotransport of large, positively charged ions, was examined and quantified. Close juxtaposition of cationic and lipophilic residue s profoundly inhibited electroosmosis and, presumably, peptide flux. T he results indicate that the lipophilicity of the oligopeptides facili tates van der Waals interactions with hydrophobic patches along the tr ansport route, thereby permitting the positively charged oligopeptide to interact with carboxylate side chains that give the skin its net ne gative charge at neutral pH. The lipophilic, cationic oligopeptide, th erefore, becomes anchored in the transport path, neutralizing the orig inal charge of the membrane, and completely altering the permselective properties of the skin.