Tang H, Mitragotri S, Blankschtein D, Langer R
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
J Pharm Sci. 2001 May;90(5):545-68. doi: 10.1002/1520-6017(200105)90:5<545::aid-jps1012>3.0.co;2-h.
Application of ultrasound enhances transdermal transport of drugs (sonophoresis). The enhancement may result from enhanced diffusion due to ultrasound-induced skin alteration and/or from forced convection. To understand the relative roles played by these two mechanisms in low-frequency sonophoresis (LFS, 20 kHz), a theory describing the transdermal transport of hydrophilic permeants in both the absence and the presence of ultrasound was developed using fundamental equations of membrane transport, hindered-transport theory, and electrochemistry principles. With mannitol as the model permeant, the role of convection in LFS was evaluated experimentally with two commonly used in vitro skin models- human cadaver heat-stripped skin (HSS) and pig full-thickness skin (FTS). Our results suggest that convection plays an important role during LFS of HSS, whereas its effect is negligible when FTS is utilized. The theory developed was utilized to characterize the transport pathways of hydrophilic permeants during both passive diffusion and LFS with mannitol and sucrose as two probe molecules. Our results show that the porous pathway theory can adequately describe the transdermal transport of hydrophilic permeants in both the presence and the absence of ultrasound. Ultrasound alters the skin porous pathways by two mechanisms: (1) enlarging the skin effective pore radii, or (2) creating more pores and/or making the pores less tortuous. During passive diffusion, both HSS and FTS exhibit the same skin effective pore radii (r = 28 +/- 13 A). In contrast, during LFS, r within HSS is greatly enlarged (r > 125 A), whereas r within FTS does not change significantly (23 +/- 10 A). The observed different roles of convection during LFS across HSS and FTS can be attributed to the different degrees of structural alteration that these two types of skin undergo during LFS.
超声的应用可增强药物的经皮转运（超声透皮给药）。这种增强作用可能源于超声引起的皮肤改变所导致的扩散增强和/或强制对流。为了理解这两种机制在低频超声透皮给药（LFS，20 kHz）中所起的相对作用，利用膜转运的基本方程、受阻转运理论和电化学原理，建立了一个描述亲水性渗透剂在有无超声情况下经皮转运的理论。以甘露醇作为模型渗透剂，使用两种常用的体外皮肤模型——人尸体热剥离皮肤（HSS）和猪全层皮肤（FTS），通过实验评估了对流在LFS中的作用。我们的结果表明，对流在HSS的LFS过程中起重要作用，而在使用FTS时其作用可忽略不计。所建立的理论用于表征以甘露醇和蔗糖作为两种探针分子时，亲水性渗透剂在被动扩散和LFS过程中的转运途径。我们的结果表明，多孔途径理论能够充分描述亲水性渗透剂在有无超声情况下的经皮转运。超声通过两种机制改变皮肤多孔途径：（1）增大皮肤有效孔径，或（2）产生更多孔隙和/或使孔隙的曲折度降低。在被动扩散过程中，HSS和FTS表现出相同的皮肤有效孔径（r = 28 +/- 13 Å）。相比之下，在LFS过程中，HSS内的r大幅增大（r > 125 Å），而FTS内的r变化不显著（23 +/- 10 Å）。在LFS过程中观察到的对流在HSS和FTS上的不同作用，可归因于这两种类型的皮肤在LFS过程中所经历的结构改变程度不同。
