A skin pharmacokinetics study of permeation enhancers: The root cause of dynamic enhancement effect on in vivo drug permeation

Skin pharmacokinetics (SPK) of permeation enhancers can answer the question of why enhancement effects different at the kinetic level. Herein, SPK of permeation enhancers were classified into two categories, namely, lateral elimination (elimination to surrounding stratum corneum (SC)) and longitudinal elimination (elimination to deep epidermal (EP)). They were evaluated with a specific parameter for permeation enhancers, diffusion ratio (DRSC-EP), according to results of tissue-distribution test, molecular dynamic (MD) simulation, and confocal laser scanning microscopy (CLSM). The linear relationship between ke-enahcer and Delta Cmax-drug (R2 = 0.92),MRTenhancer and Delta Tmax-drug (R2 = 0.97), AUCt-enhancer and Delta AUCt-drug (R2 = 0.90) suggesting that SPK of permeation en-hancers precisely controlled dynamic process of drug permeation in vivo. The molecular mechanisms of the dynamic effect of SPK process on drug transdermal behaviors were characterized by modulated-temperature differential scanning calorimetry (MTDSC), dielectric spectroscopy, small-angle X-ray scattering (SAXS), solid-state NMR. Permeation enhancers with high molecular weight (M.W.) and high polar surface area (P.S.A.) had good compatibility and strong interaction strength with SC, leading their lateral-elimination behavior, causing their low DRSC-EP and resulting in low ke-enhancer, long MRTenhancer, and large AUCt-enhancer. Consequently, skin barrier can be rapidly opened fast and to a great extent. In summary, compared with SPK of permeation enhancers with longitudinal elimination, SPK of permeation enhancers with lateral elimination can enable more sustainable and greater drug permeation. The information about SPK of permeation enhancers offered a criterion to estimate its permeation-enhancement effect on the drug and its subsequent application in transdermal formulations.

Automated summary

Skin pharmacokinetics (SPK) can explain the different effects of permeation enhancers on drug permeation at the kinetic level. SPK of permeation enhancers can be classified into lateral elimination and longitudinal elimination, and evaluated using the diffusion ratio (DRSC-EP). The linear relationship between parameters such as ke-enhancer and Delta Cmax-drug, MRTenhancer and Delta Tmax-drug, and AUCt-enhancer and Delta AUCt-drug suggests that SPK precisely controls drug permeation in vivo.