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 (LHR H) analog, Nafarelin, have been studied in vitro. Peptide electrotrans port, at fixed current density as a function of concentration, and at fixed concentration as a function of current density, has been measure d across hairless mouse skin. The results indicate that Nafarelin deli very does not increase linearly with applied concentration: while ther e 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 decrea sed transport. At constant concentration, Nafarelin flux does increase with increasing current density (up to 0.63 mA/cm(2)), but the depend ence is very weak. Further experiments utilizing radiolabeled mannitol as a neutral marker of electroosmosis revealed that Nafarelin electro transport is very sensitive to the extent and direction of convective flow. With increasing amounts of applied Nafarelin, reversal of electr oosmosis (from the anode-to-cathode to the cathode-to-anode direction) was apparent; it appeared that the cationic peptide associated strong ly with, and neutralized, the net negative charge on the skin, thereby resulting in depression and, ultimately, reversal of the convective f low. This, in turn, inhibits Nafarelin transport by the electroosmotic mechanism and explains, we believe, both the inverse dependence of fl ux upon concentration and the only weakly dependent behavior upon curr ent density (where, although more current delivers more ions, more cur rent also drives more peptide into the skin and thereby diminishes ele ctroosmosis). Overall, then, this research emphasizes the complicated interplay between peptide structure, skin electrical properties and fo rmulation variables which must be carefully considered in the developm ent and optimization of an iontophoretic drug delivery device.