Mitragotri S, Edwards D A, Blankschtein D, Langer R
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139, USA.
J Pharm Sci. 1995 Jun;84(6):697-706. doi: 10.1002/jps.2600840607.
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.
尽管超声已被证明能增强多种药物的透皮转运，但这种现象背后的机制尚不清楚。在本文中，我们评估了各种与超声相关的现象，包括空化、热效应、对流速度的产生和机械效应，在超声增强透皮给药（超声导入法）中的作用。我们的实验结果表明，在所有评估的与超声相关的现象中，空化在使用治疗性超声（频率范围为1 - 3 MHz；强度范围为0 - 2 W/cm²）的超声导入法中起主导作用。此外，共聚焦显微镜结果表明，超声照射时角质层的角质形成细胞中会发生空化。据推测，空化气泡的振荡会导致角质层脂质双层结构紊乱，从而增强透皮转运。通过皮肤电阻测量提供了支持这一假设的证据。最后，建立了一个理论模型来预测超声对药物透皮转运的影响。该模型预测，超声导入增强作用最直接取决于被动渗透物的扩散系数，而不是通过皮肤的渗透系数。具体而言，预计以相对较慢速率被动扩散通过皮肤的渗透物会优先被超声增强。对包括雌二醇、睾酮、孕酮、皮质酮、苯、丁醇和咖啡因在内的七种渗透物的超声导入透皮转运增强的实验测量结果与模型预测在数量上相符。这些实验和理论发现为估计超声导入法增强透皮给药的疗效提供了定量指导。
