IONTOPHORESIS OF NAFARELIN - EFFECTS OF CURRENT-DENSITY AND CONCENTRATION ON ELECTROTRANSPORT IN-VITRO

The effects of administered concentration and applied current density on the iontophoresis of the leutinizing hormone releasing hormone (LHRH) analog, Nafarelin, have been studied in vitro. Peptide electrotransport, at fixed current density as a function of concentration, and at fixed concentration as a function of current density, has been measured across hairless mouse skin. The results indicate that Nafarelin delivery does not increase linearly with applied concentration: while there is an increase when the donor concentration is doubled from 0.5 to 1.0 mg/ml, further increments in applied peptide level result in decreased transport. At constant concentration, Nafarelin flux does increase with increasing current density (up to 0.63 mA/cm(2)), but the dependence is very weak. Further experiments utilizing radiolabeled mannitol as a neutral marker of electroosmosis revealed that Nafarelin electrotransport is very sensitive to the extent and direction of convective flow. With increasing amounts of applied Nafarelin, reversal of electroosmosis (from the anode-to-cathode to the cathode-to-anode direction) was apparent; it appeared that the cationic peptide associated strongly with, and neutralized, the net negative charge on the skin, thereby resulting in depression and, ultimately, reversal of the convective flow. This, in turn, inhibits Nafarelin transport by the electroosmotic mechanism and explains, we believe, both the inverse dependence of flux upon concentration and the only weakly dependent behavior upon current density (where, although more current delivers more ions, more current also drives more peptide into the skin and thereby diminishes electroosmosis). Overall, then, this research emphasizes the complicated interplay between peptide structure, skin electrical properties and formulation variables which must be carefully considered in the development and optimization of an iontophoretic drug delivery device.