In vitro transdermal iontophoretic delivery of leuprolide under constant current application.

Transdermal delivery of Leuprolide, a nonapeptide LHRH agonist, was studied using constant current iontophoresis to explore methods for improving iontophoretic efficiency and determine the feasibility of delivery of therapeutic doses of the drug. Universal buffer consisting of citrate, phosphate and borate was used to carry out in vitro permeation experiments with heat separated human epidermis at pH 4.5 and 7.2. In addition, the effect of substituting this buffer with a macromolecular electrolyte, polymaleic acid, on the drug flux and the transference number was studied. Current densities from 0.5 to 2.3 microA/cm2 were used requiring moderate potential differences between 60 and 420 mV to be applied thus limiting irreversible epidermal membrane alterations. The rather high electrical resistance of the epidermis of the order of 200 kohms cm2 was related to the sub-physiological electrolyte concentration. Resistance was continuously monitored to guarantee barrier integrity of the membrane. The permeation rate increased linearly with the current density for the universal buffer and was at pH 7.2 almost double that at pH 4.5 despite the greater ionic valence of the drug at pH 4.5 compared to pH 7.2; this being because of the opposite direction of the electroosmotic flow at the two pH values. Drug transference number at both pH values was approximately 0.5%. Replacement of the universal buffer with polymaleic acid yielded higher drug permeation rates and increased its transference number at comparable pH. Transference number, however, was still approximately 1% at the highest current density, showing that concomitant ions from added electrolyte or extracted from the skin and the electrodes accounted for 99% of the total current. Further, transference number of the drug with polymaleic acid appeared to increase with current density. The fluxes obtained for both electrolyte systems with the present experimental arrangement could be extrapolated to deliver therapeutically relevant doses of the drug.