The effect of skin diffusion kinetics of isopropyl ester permeation enhancers on drug permeation: Role of lateral spread and penetration characteristics.

The purpose of present work was to study the effects of permeation enhancers' two kinetic behaviors of simultaneous lateral diffusion and vertical penetration in the skin on its enhancing effect. The skin diffusion kinetics of isopropyl ester permeation enhancers were characterized by the innovative concentric tape peeling study and Raman imaging, which were quantitatively assessed through innovative parameters, namely, lateral-to-vertical penetration amount (CL-V) and lateral-to-vertical penetration distance (DL-V). The enhancement effect of permeation enhancers on drug flurbiprofen (FLU) was assessed by in vitro skin permeation tests, which were confirmed by transdermal water loss and skin resistance study. The relationship between kinetic parameters of permeation enhancers and permeation parameters of FLU was carried out by correlation analysis. The molecular mechanisms of effect of skin diffusion kinetics of permeation enhancers on drug permeation were characterized by molecular docking, modulated-temperature differential scanning calorimetry (MTDSC), Raman spectra, solid-state NMR and molecular dynamic simulation. The results indicated skin diffusion kinetics of short-chain (C8-C12) isopropyl ester permeation enhancers were governed by vertical penetration, while long-chain (C14-C18) ones were characterized by lateral spread. Quadratic correlation between CL-V and enhancement ratio of permeation-retention ratio of FLU (ERQ/R) (R2 = 0.95), DL-V and enhancement ratio of permeation area (ERA) of FLU (R2 = 0.98) indicating that varied skin diffusion kinetics of permeation enhancers directly influenced the barrier function of stratum corneum (SC) and further enhancing drug permeation. In terms of molecular mechanism, long-chain isopropyl ester enhancers had good miscibility with SC, leading to their high CL-V and DL-V, and causing strong interaction strength with SC and resulting in weaker skin barrier function for drug permeation. In summary, in comparison to short-chain isopropyl ester enhancers that relied on penetration, long-chain ones that depended on lateral spread exhibited greater enhancement efficacy, which guided the application of enhancers in transdermal formulations.

Evaluation of Dose-Response Relationship of Permeation Enhancer Isopropyl Myristate Release on Drug Release: Release Enhancement Efficiency and Molecular Mechanism.

The objective of this study is to investigate the dose-response relationship between various concentrations of permeation enhancers (PEs) and their ability to enhance drug release from a polymer matrix, utilizing an innovative parameter known as release enhancement efficiency (K). Additionally, the molecular mechanism underlying dynamic enhancement was also examined. Isopropyl myristate (IPM) was used as model enhancer and zolmitriptan (ZOL) was used as model drug to investigate dose-effect relationship in pressure sensitive adhesives (PSA). The release behavior of the PEs was determined by LC-MS/MS and verified by confocal laser scanning microscopy (CLSM). The enhancing effect of the PE on ZOL release was evaluated through in vitro release experiments and further validated by pharmacokinetics study. And the molecular mechanism was characterized with thermal analysis (DSC), Fourier transform infrared spectroscopy (FT-IR) and molecular dynamics simulation. K was 0.156, 0.286 and 0.279 at 3%, 6% and 9% IPM concentrations, indicating that the enhancement efficiency reached the maximum when the 6% IPM was applied. According to the mechanism research results, the fluidity of PSA increased linearly with the increase of IPM concentrations, but the interaction between IPM and ZOL reached its strongest point at 6%. In summary, the increase of K value (from 0 to 6% IPM content) was caused by the synergy of increased mobility of PSA and interaction (dipole-dipole and hydrogen-bond) among three components, and when the above two actions were in antagonistic, K no longer increased (6-9% IPM content).