Iontophoretic delivery across the skin: electroosmosis and its modulation by drug substances.

PURPOSE: The long-term objective of this research is to understand how the efficiency of iontophoresis depends upon the structural and physicochemical properties of the administered drug. Specifically, the ability of certain drug species to alter the permselective properties of the skin was examined.
METHODS: Using conventional in vitro methodology, the inhibition of electroosmotic flow induced by the iontophoresis of five different beta-blockers (of varying lipophilicity) was examined. The concomitant electrotransport of the most lipophilic species (propranolol) and the convective movement of solvent in the anode-to-cathode direction were measured. In addition, the possibility that electroosmosis might be augmented by the delivery of anionic drugs was also considered.
RESULTS: Iontophoresis of lipophilic, cationic beta-blockers caused a concentration-dependent inhibition of conventional electroosmosis. The most hydrophilic analogs elicited no effect. As a result of this charge neutralization phenomenon, the optimal concentration for propranolol iontophoresis was significantly less than the maximum achievable in aqueous solution. Only a very modest improvement in convective solvent flow was induced by the cathodal iontophoresis of anionic compounds.
CONCLUSIONS: The permselectivity of the skin can be altered by drugs which are positively charged and which possess a significant, adjacent hydrophobic surface. The latter seems able to "anchor" the molecule in the skin and the counter charge to the membrane's negative character ensures a tight association. Both lipophilicity and a positive charge are essential-without either, the phenomenon is not observed. The conformational flexibility of the drugs studied to-date, however, prevents unambiguous conclusions about the three-dimensional nature of the putative "binding site".