A molecular mechanism investigation of the transdermal/topical absorption classification system on the basis of drug skin permeation and skin retention

A transdermal/topical absorption classification system for the characterization of the systemic or local delivery of drugs is the theoretical basis for the design and evaluation of transdermal/topical formulations. A classification system was established on the basis of the in vitro and in vivo skin permeation/retention behaviors of 12 model drugs. Drug skin penetration/retention exhibited a significant correlation with physicochemical parameters (log KO/W, molecular weight, polar surface area, and polarizability). Four representative model drugs were selected to clarify the molecular mechanisms of drug skin permeation/retention behaviors. The excellent lipid-disrupting effect and enhanced partitioning exhibited by propranolol (high permeation–high retention) and zolmitriptan (high permeation-low retention) via the formation of moderate H-bonds with skin lipids were proven by ATR–FTIR (ΔνasCH2 > 2 cm−1), Raman spectra (ΔLPP, SPP > 0.2 nm), and X-ray scattering (lipid crystallization) and were supported by 13C NMR results. The low lipid miscibility of zolmitriptan (ΔHzolmitriptan-lipid = 126.92 J/g) caused the low skin retention of this drug. High polarizabiltiy (α = 38.5 × 10−24 cm3) and low H-bond forming capability (EH-bond = 0 kcal/mol) restricted terbinafine (low permeation–high retention) in terms of partitioning (kD-SC = 0.09). Diclofenac (low permeation–low retention) stabilized skin lipids through the formation of strong H-bonds and exhibited excessive drug–lipid miscibility (ΔHdiclofenac-skin = −128.73 J/g), thus restricting its skin absorption. This classification system reflects the most essential drug skin absorption characteristics and provides a theoretical basis for the design of transdermal/topical formulations.