Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: Roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair

Abstract

Though ion-pair strategy has been employed as an effective and promising method for controlling transdermal delivery of drugs, investigations into the underlying mechanisms involved in the controlled release process of ion-pairs are still limited. In the present study, a brand-new controlled release system combining acrylic pressure sensitive adhesive containing carboxyl group (carboxylic PSA) with ion-pair strategy was developed, and the molecular mechanism of ion-pair releasing from carboxylic PSA was systemically elucidated. Bisoprolol (BSP) and bisoprolol-lauric acid ion-pair (BSP-C₁₂) were chosen as model drugs. Carboxylic PSA was designed and synthesized. Effect of ion-pair on controlling BSP release from carboxylic PSA was evaluated by in vitro drug release study, in vitro skin permeation study and pharmacokinetic study. Molecular mobility of PSA, along with the strength of drug-PSA interaction was evaluated by thermal analysis and dielectric spectroscopy. Molecular details of drug-PSA interaction were identified by FTIR, XPS and Raman. Roles of drug-PSA interaction in the controlled release process were clarified by molecular modeling. Results showed that BSP-C₁₂ patch demonstrated a controlled release drug plasma profile, with lower C_max (193 ± 63 ng/mL) and longer MRT (19.9 ± 3.4 h) compared to BSP patch (C_max,BSP = 450 ± 28 ng/mL, MRT_BSP = 7.9 ± 0.9 h). Besides, there was no significant difference between the AUC of BSP-C₁₂ and BSP patch. It turned out that instead of PSA molecular mobility, molecular interaction between ion-pair and PSA played a dominant role in the controlled release process of BSP: as illustrated by FTIR, Raman and molecular docking, the ionic interaction between BSP-C₁₂ and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP-C₁₂ and PSA-COO^- controlled the release rate, which was the kinetic process. In conclusion, it was found that the doubly ionic hydrogen bond formed between carboxylic PSA and ion-pair controlled the release profile of BSP, which broadened our understanding about the molecular mechanisms involved in ion-pair controlled release transdermal patches and contributed to the design of controlled release TDDS.

Keywords: Controlled release; Doubly ionic hydrogen bond; Intermolecular interaction; Ion-pair; Pressure sensitive adhesive; Transdermal.