Transdermal Iontophoresis of Fentanyl - Delivery and Mechanistic Analysis

Studies of electrical and physicochemical factors acting on the permeation kinetics of in vitro iontophoresis of fentanyl across hairless rat skin were performed. Iontophoresis increased the transdermal permeation flux of fentanyl as compared to the diffusion. An increase in the current density applied induced an enhancement of the flux through the skin. Continuous current was more potent than pulsed current (positive square wave 2.5 kHz on/off 1:1) at promoting fentanyl transdermal permeation. At the same current density (0.33 mA/cm(2)), a decrease in the duration of iontophoresis application from 6 to 1 h reduced the cumulated quantity of drug detected in the receptor compartment but the flux remained higher than diffusion for at least 6 h. Iontophoresis and diffusion were compared when the drug was introduced into a donor solution pH 7 or 3.5. Diffusion was higher at pH 7 than at pH 3.5. Iontophoresis was more efficient at acidic pH. The enhancement of the drug concentration in the donor compartment increased the flux through the skin. The mechanism of transport of fentanyl through the skin by iontophoresis was investigated. Electro-osmosis was not involved in the differences of kinetics observed after direct and pulsed current application since both induced the same water flux across the membrane. A period of iontophoresis shorter than 1 h did not modify the skin permeability. In contrast, the drug accumulated in the skin reservoir and was slowly released when the current was cut.