Insight Into the Role of Release Kinetics of Chemical Penetration Enhancer on Drug Diffusion in Drug-in-adhesive Patch

Purpose As a key excipient in drug-in-adhesive patches, the diffusion behavior of chemical penetration enhancers (CPE) directly affects the diffusion behavior of drugs and thus determines whether the drug can achieve effective skin penetration. Therefore, the study of the release kinetics (RK) of CPE is pivotal. Methods RK of five CPEs (Span 80 (Span), Isopropyl palmitate (IPP); Dipropylene Glycol (DPG); Menthol (MEN) and N-methyl-2-pyrrolidone (NMP)) and its effect on drug diffusion were researched by in vitro release study, in vitro skin penetration study, molecular dynamic simulation and Raman imaging. And the molecular mechanisms were characterized using modulated-temperature differential scanning calorimetry, rheology study, Fourier transform infrared spectroscopy and 13 C nuclear magnetic resonance spectroscopy. Results The various RK behaviors of CPE enhanced the dynamic change in release rate ( k ) of drug at different degrees, and their RK parameters ( k a-CPEs and T lag-CPEs ) had a multilinear correlation (R 2  = 0.96) with the increment in k (Δ k ) over the whole diffusion process. Moreover, the physicochemical properties of CPE determined their k a-CPEs and T lag-CPEs , k a-CPEs were related to polarizability ( P ) and dielectric constant (ε’) and T lag-CPEs had linear relationship (R 2  = 0.98) with Log P o/w . Conclusions The miscibility between CPE and the matrix (assessed by Log P o/w and ε’) as well as the interaction strength between CPE and the matrix or drug (assessed by P ) determined the RK behaviors, thereby enhancing their overall effect on drug diffusion. The proposed mathematical model enabled prediction of CPE's regulatory effect on drug diffusion based on CPE’s inherent properties.