Recent advances in predicting skin permeability of hydrophilic solutes

Understanding the permeation of hydrophilic molecules is of relevance to many applications including transdermal drug delivery, skin care as well as risk assessment of occupational, environmental, or consumer exposure. This paper reviews recent advances in modeling skin permeability of hydrophilic solutes, including quantitative structure–permeability relationships (QSPR) and mechanistic models. A dataset of measured human skin permeability of hydrophilic and low hydrophobic solutes has been compiled. Generally statistically derived QSPR models under-estimate skin permeability of hydrophilic solutes. On the other hand, including additional aqueous pathway is necessary for mechanistic models to improve the prediction of skin permeability of hydrophilic solutes, especially for highly hydrophilic solutes. A consensus yet has to be reached as to how the aqueous pathway should be modeled. Nevertheless it is shown that the contribution of aqueous pathway can constitute to more than 95% of the overall skin permeability. Finally, future prospects and needs in improving the prediction of skin permeability of hydrophilic solutes are discussed.