Iontophoretic delivery of piroxicam across the skin in vitro

Iontophoresis of the non-steroidal anti-inflammatory drug, piroxicam, across hairless mouse skin in vitro has been investigated. The following drug delivery issues have been examined: (a) to what extent is the percutaneous absorption of the drug enhanced by iontophoresis; (b) how do current density, current duration, and drug formulation variables affect the efficiency of delivery; and (c) does the combination of iontophoresis with a chemical penetration enhancer (oleic acid) elicit additive or synergistic transport-promoting effects? Cathodal iontophoresis of negatively-charged piroxicam was carried out using three pH 7.4 formulations (a solution, a gel, and a gel containing 0.3% w/w oleic acid). From the solution, following a 6-h application period, iontophoresis at constant current densities in the range 0.07-0.50 mA/cm² delivered 100-1000 times more drug than passive diffusion. Penetration of intact piroxicam was directly proportional to current density. At the highest current density, iontophoretic flow of other ions in the system (especially Na⁺ and Cl^-) caused the piroxicam flux to peak and then gradually fall off with time. Short-duration current application (30 min) also increased the 6-h delivery of drug significantly (more than 10 times the no-current control at 0.07 mA/cm²,150-fold at 0.50 mA/cm² ). Piroxicam transport from a simple gel was not as well correlated with current density as that from the solution. A lower drug concentration and altered ionic transport numbers are believed to be the reason for this behavior. Nevertheless, enhancement over passive diffusion (following iontophoresis for both 0.5 and 6 h) was substantial. When the gel containing oleic acid was used, drug delivery at the lowest current density was reduced relative to the gel with no enhancer. At higher current densities, on the other hand, piroxicam transport is augmented by oleic acid. This change in the relative delivery could be a consequence of oleate ion competition for transport dominating at low current density, with the enhancement effects taking over at higher current. This conclusion was consistent with pretreatment experiments in which the skin was exposed to oleic acid for 3 h prior to iontophoretic piroxicam delivery from the simple gel without oleic acid. The degree of drug delivery was significantly greater than the sum of those achieved by pretreatment alone and by iontophoresis alone.