Research progress of penetration enhancers in transdermal drug delivery systems: Multidimensional exploration from mechanisms to clinical application

Transdermal drug delivery systems (TDDSs) have gained significant attention in pharmaceutical research due to their ability to bypass hepatic first-pass metabolism, maintain consistent plasma drug levels, and improve patient compliance. Despite these advantages, the highly organized "brick-and-mortar" architecture of the stratum corneum (SC) poses a substantial barrier, particularly to the permeation of hydrophilic drugs and macromolecules. Among the strategies developed to address this challenge, penetration enhancers (PEs) have emerged as a key approach, offering reversible modulation of the skin barrier to improve drug transport. This review provides an in-depth analysis of the diverse mechanisms by which PEs facilitate transdermal delivery, including disruption of lipid bilayers, alteration of keratin structure, enhancement of drug partitioning into the SC, and lipid extraction. The crucial contribution of advanced characterization techniques, such as Fourier-transform infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance, in revealing atomic-scale interactions between PEs and SC components is discussed.