A mechanistic study of ultrasonically-enhanced transdermal drug delivery

Although ultrasound has been shown to enhance the transdermal transport of a variety of drugs, the mechanisms underlying this phenomenon are not clearly understood. In this paper, we evaluate the roles played by various ultrasound-related phenomena, including cavitation, thermal effects, generation of convective velocities, and mechanical effects, in the ultrasonic enhancement of transdermal drug delivery (sonophoresis). Our experimental findings suggest that among all the ultrasound-related phenomena evaluated, cavitation plays the dominant role in sonophoresis using therapeutic ultrasound (frequency range, 1-3 MHz; intensity range, 0-2 W/cm2). Furthermore, confocal microscopy results indicate that cavitation occurs in the keratinocytes of the stratum corneum upon ultrasound exposure. It is hypothesized that oscillations of the cavitation bubbles induce disorder in the stratum corneum lipid bilayers, thereby enhancing transdermal transport. Evidence supporting this hypothesis is presented using skin electrical resistance measurements. Finally, a theoretical model is developed to predict the effect of ultrasound on the transdermal transport of drugs. The model predicts that sonophoretic enhancement depends most directly on the passive permeant diffusion coefficient, rather than on the permeability coefficient through the skin. Specifically, permeants passively diffusing through the skin at a relatively slow rate are expected to be preferentially enhanced by ultrasound. The experimentally measured sonophoretic transdermal transport enhancement for seven permeants, including estradiol, testosterone, progesterone, corticosterone, benzene, butanol, and caffeine, agree quantitatively with the model predictions. These experimental and theoretical findings provide quantitative guidelines for estimating the efficacy of sonophoresis in enhancing transdermal drug delivery.