Maintaining a Near Zero-Order Drug Delivery from Minidose Reservoirs: Simultaneous Drug Diffusion and Binary Vehicle Evaporation

Abstract

The purpose of this study was to develop a new design for transdermal system that provides a nearly constant drug delivery rate for the desired period of time in the absence of a large excess of drug in the donor reservoir. Simultaneous drug diffusion and aqueous binary vehicle evaporation has been investigated as a means of maintaining constant drug delivery from minidose reservoirs. Benzocaine was used as the model drug and water–ethanol mixtures as the binary vehicles. Benzocaine is much more soluble in ethanol than in water. Simultaneous diffusion-evaporation experiments were conducted using the water-ethanol mixture saturated with benzocaine as the minidose reservoir. The reservoir vehicle was allowed to evaporate through a permselective membrane so as to maintain drug saturation in the vehicle even though the drug mass in the donor reservoir was constantly decreasing. Saturation activity of drug is maintained during donor depletion of drug by the selective loss of alcohol from the donor solvent, which concomitantly lowers the solubility. The superiority of the evaporable binary vehicle over a conventional sealed system was demonstrated by achieving near zero-order drug delivery with minimum drug remaining. A theoretical model was developed to predict drug flux, drug amount delivered, reservoir solvent volume and composition, and drug solubility during the two simultaneous processes of drug release and preferential solvent evaporation. Experimental data are in good agreement with theoretical calculations.