IONTOPHORESIS OF MONOMERIC INSULIN ANALOGS IN-VITRO - EFFECTS OF INSULIN CHARGE AND SKIN PRETREATMENT

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontoph oretic transport across hairless mouse skin, and the effect of differe nt skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl an ode. The flux during cathodal iontophoresis through intact skin was in significant for human hexameric insulin, and only low and variable flu xes were observed for monomeric insulins. Using stripped skin on the o ther hand, the fluxes of monomeric insulins with two extra negative ch arges were 50-100 times higher than that of hexameric human insulin. I ntroducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontop horesis resulted in a 1000-fold increase in transdermal transport of i nsulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the ele ctrical resistance of the skin, presumably by lipid extraction. In con clusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave sub stantially, improved transdermal transport of monomeric insulins resul ting in clinically relevant delivery rates for basal treatment. (C) 19 98 Elsevier Science B.V.