IONTOPHORETIC DELIVERY OF NAFARELIN ACROSS THE SKIN

The iontophoretic delivery of the luteinizing hormone releasing hormone (LHRH) analogue, nafarelin ([D-Nal (2)(6)]LHRH) across hairless mouse skin in vitro has been investigated. The initial range-finding studies showed that a pharmacologically significant amount of the decapeptide can be transported across the skin in a relevant period of time. However, metabolism of nafarelin was observed to take place during its transdermal delivery. It was further found that a reservoir of nafarelin could be established in the skin; for example, following current passage for a period of 12 h, the amount transported across the tissue was comparable to that which subsequently desorbed passively from the skin over the next 12 h. Different current profiles were tested in an attempt to improve drug delivery and minimize the apparent reservoir effect. In addition, the electro-osmotic transport (from both anode and cathode chambers of the in vitro diffusion cell) of an uncharged compound (namely, mannitol) with and without the anodal delivery of nafarelin was determined. It was found that iontophoresis of the peptide into the skin caused electro-osmotic flow to reverse in direction (from anode-to-cathode to cathode-to-anode), relative to the control (no peptide) situation. The anodal delivery of the cationic peptide into the current-conducting pathways of the skin is believed to result in an association of the drug with the fixed negative charges on the membrane; this neutralization and further concentration of the lipophilic peptide reverses the permselectivity of the skin and hence electro-osmotic flow is also reversed. Overall, therefore, optimization of nafarelin delivery by iontophoresis is a complex challenge which warrants considerable further study.