Development of Tizanidine Drug-in-Adhesive Patch: Molecular Mechanism of Permeation Enhancer on Regulating Miscibility and Drug Release by Affecting the Status of Ion-Pair in Polymer Matrix

Abstract

The objective of this work was to develop a drug-in-adhesive (DIA) patch of TIZ by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release. Special attention was paid on the regulation effect of permeation enhancer on ion-pair status in pressure sensitive adhesives (PSA). Formulation factors including TIZ-fatty acids ion-pair, drug loading and permeation enhancer were investigated by ex-vivo transdermal experiments. Optimized patch was evaluated by pharmacokinetics study. The better polarity similarity and strong hydrogen bonding interactions between TIZ-caproic acid ion-pair (TIZ-C6) and PSA was confirmed by polarity determination, FT-IR, TOPEM of MDSC and theoretical calculation, which determined enhanced miscibility of ion-pair and PSA. The permeation enhancer affected status of ion-pair in PSA by regulating polarity similarity and interaction between ion-pair and PSA, resulting in increased drug-PSA miscibility and drug release, which was characterized by FT-IR, polarity determination, thermal analysis and molecular dynamics simulation. The optimized patch showed high drug-polymer miscibility and drug skin permeability with AUC0-t of 14641.12 ± 854.45 h ng/mL and Cmax of 834.55 ± 155.68 ng/mL, which was significantly higher than the control group. In conclusion, DIA patch of TIZ was prepared and it supplied a reference for design of DIA patches with TIZ.