An investigation on the effect of drug physicochemical properties on the enhancement strength of enhancer: The role of drug-skin-enhancer interactions

Abstract

The aim of present work was to investigate the influence of drug physicochemical properties on the enhancement effect of enhancers, which guided the application of enhancers in different drug transdermal prescriptions. Firstly, Polyglyceryl-3 dioleate (POCC) was selected as a model enhancer and its enhancement effect on ten drugs was assessed by in vitro skin permeation experiment. Secondly, the correlation analysis of physicochemical properties of drugs was carried out from the aspects of partition and permeation. The interactions of drug-skin-POCC were elucidated by FT-IR, molecular docking, solubility parameters calculation, ATR-FTIR, Raman study, molecular dynamics simulation and confocal laser scanning microscopy (CLSM). The results showed that the enhancement ratio (ER) of drugs was ranging from 2.23 to 7.45. On one hand, the miscibility between drugs with low polar surface area (P.S.A) and donor solution was decreased more pronounced by the addition of POCC because of the drug was difficult to form hydrogen-bond with POCC, facilitating the vehicle/SC partition of drugs. On the other hand, the permeation of drugs with low P.S.A and polarizability was enhanced more significantly by POCC because the drug was less likely to interact with skin lipids compared to others, causing that POCC had more chance to interact with skin lipids to improve permeation drugs across the SC more easily. In conclusion, the different strength of drug-skin-POCC interactions was the main reason for the discrepancy in the enhancement effect of the POCC on ten drugs, which laid a basis for the research on the drug-specific molecular mechanisms of enhancers.