Insights of the controlled release effect of functional group on permeation enhancers’ enhancement capacity: A study on interaction mechanism and skin barrier function

Abstract

The objective of this study was to investigate the controlled release effect of various polar functional groups in acrylate pressure-sensitive adhesives (PSA) on permeation enhancers (PE), as well as to elucidate the disparities in their enhancing effects under such circumstances. The synthesis of acrylate PSA with hydroxyl group (AAOH), amide group (AACONH₂), hydroxyphenyl group (AAPhOH), and carboxyl group (AACOOH) was achieved via a solution polymerization process initiated by free radical. Gel permeation chromatography, molecular dynamic simulation and thermal analysis were conducted to characterize the properties of PSA. In vitro release study, Raman imaging and correlation analysis were performed to research the controlled release effect on the permeation enhancer azone (AZ). These were evaluated using a novel parameter called the control release factor (F_cr). The more negative the F_cr value, the stronger the control release effect. In vitro skin permeation study and pharmacokinetic study reflected the enhancing effects of AZ on drug ketoprofen (KET). Fourier-transform infrared spectroscopy, ¹H nuclear magnetic resonance (¹H NMR), molecular docking, rheology study, Raman spectra and solid-state nuclear magnetic resonance (ssNMR) characterized mechanisms of functional groups’ controlled release effect and the changes in skin barrier function. The results demonstrated that among the four PSA, AACOOH exhibited the most pronounced controlled release effect (F_cr = -45.91). This can be attributed to the formation of a robust ionic bond between AACOOH and AZ, which effectively restricted the release of AZ into the skin, resulting in minimal impact on disordering functionality of the skin barrier and enhancing drug permeation. The order of controlled release for the other three PSA on AZ was as follows: AAPhOH (F_cr = -43.60) > AACONH₂ (F_cr = -40.26) > AAOH (F_cr = -38.15), resulting the best enhancing effect attributed to AZ that released from AAOH into the skin. Besides, the interaction between the above three PSA and AZ was hydrogen bond, only the interaction of AAPhOH-AZ was a special hydrogen bond: ionic hydrogen bond. In summary, the type and strength of the interaction between PSA and PE determined the amount of PE entering the skin, thereby determining the extent to which PE disorder skin barrier function.