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).