IONTOPHORETIC DELIVERY OF NAFARELIN ACROSS THE SKIN

The iontophoretic delivery of the luteinizing hormone releasing hormon e (LHRH) analogue, nafarelin ([D-Nal (2)(6)]LHRH) across hairless mous e skin in vitro has been investigated. The initial range-finding studi es showed that a pharmacologically significant amount of the decapepti de can be transported across the skin in a relevant period of time. Ho wever, metabolism of nafarelin was observed to take place during its t ransdermal delivery. It was further found that a reservoir of nafareli n could be established in the skin; for example, following current pas sage for a period of 12 h, the amount transported across the tissue wa s comparable to that which subsequently desorbed passively from the sk in over the next 12 h. Different current profiles were tested in an at tempt to improve drug delivery and minimize the apparent reservoir eff ect. In addition, the electro-osmotic transport (from both anode and c athode chambers of the in vitro diffusion cell) of an uncharged compou nd (namely, mannitol) with and without the anodal delivery of nafareli n was determined. It was found that iontophoresis of the peptide into the skin caused electro-osmotic flow to reverse in direction (from ano de-to-cathode to cathode-to-anode), relative to the control (no peptid e) situation. The anodal delivery of the cationic peptide into the cur rent-conducting pathways of the skin is believed to result in an assoc iation of the drug with the fixed negative charges on the membrane; th is neutralization and further concentration of the lipophilic peptide reverses the permselectivity of the skin and hence electro-osmotic flo w is also reversed. Overall, therefore, optimization of nafarelin deli very by iontophoresis is a complex challenge which warrants considerab le further study.