Iontophoretic Transport of Donepezil Hydrochloride through Skin: Flux Enhancement by Chemical Enhancer and Iontophoresis

The objective of this work is to investigate the effect of chemical enhancer and current on the flux of donepezil hydrochloride (DH) through skin. Ethanol and N-methyl pyrrolidone (NMP) were used as chemical enhancers in combination with iontophoresis. We also have studied the effect of pH on flux and evaluated the role of electroosmosis. In vitro flux study was performed at $33^{\circ}C$, using side-by-side diffusion cell and full thickness hairless mouse skin. Passive flux of DH without enhancer was very small. As the concentration of enhancer increased, passive flux increased. After current application, flux increased markedly and the time to reach maximum decreased. Without enhancer, maximum flux was about 50 fold larger than that obtained without current. These results indicate that electromigration is playing a major role for the transport. As the enhancer concentration increased, flux also increased. NMP and ethanol increased not only the passive delivery, but also the iontophoretic delivery. Flux results indicate that ethanol has better ability than NMP in enhancing the transport of DH. The magnitudes of increase in flux by these enhancers indicate that there is a large synergistic effect in flux enhancement. Flux results from pH study showed that electroosmotic flow is reversed at low pH and the flux is hindered. These results provided some information on the flux enhancing ability of ethanol and NMP in combination with iontophoresis. The data also provided some mechanistic insights into the role of electromigration and electroosmosis on flux through skin.