Theoretical description of transdermal transport of hydrophilic permeants:Application to low-frequency sonophoresis

Application of ultrasound enhances transdermal transport of drugs (sonophor esis). The enhancement may result from enhanced diffusion due to ultrasound -induced skin alteration and/or from forced convection To understand the re lative 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 theo ry, and electrochemistry principles. With mannitol as tile model permeant, the role of convection in LFS was evaluated experimentally with two commonl y used in vitro skin models - human cadaver heat-stripped skin (HSS) and pi g full-thickness skin (FTS). Our results suggest that convection plays an i mportant role during LFS of HSS, whereas its effect is negligible when FTS is utilized. The theory developed was utilized to characterize the transpor t pathways of hydrophilic permeants during both passive diffusion and LFS w ith mannitol and sucrose as two probe molecules. Our results show that the porous pathway theory can adequately describe the transdermal transport of hydrophile permeants in both the presence and the absence of ultrasound. Ul trasound alters the skin porous pathways by two mechanisms: (1) enlarging t he 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 Angstrom), In contrast, duri ng LFS, r within HSS is greatly enlarged (r > 125 Angstrom), whereas r with in FTS does not change significantly (23 +/- 10 Angstrom). The observed dif ferent roles of convection during LFS across HSS and FTS can be attributed to the different degrees of structural alteration that these two types of s kin undergo during LFS. (C) 2001 Wiley-Liss, Inc, and the American Pharmace utical Association J Pharm Sci 90:545-568, 2001.