Combined hydroxyphenyl-modified adhesive with the ion-pair strategy for long-lasting delivery of clonidine in single-layer matrix-type patch

Abstract

Existing long-acting patches usually use controlled-release membranes to achieve constant rate delivery of the drug, which is complex and costly to prepare due to the 5-layer structure, so there is a necessity to develop a method to simplify the patch design and to control constant rate drug delivery. This study prepared a 7-day long-acting clonidine (CLO) patch using the ion-pair strategy based on hydroxyphenyl-modified pressure-sensitive adhesive (HP-PSA) and clarified the molecular mechanism of controlled delivery. Single factorial and central composite design (CCD) experiments were used to optimize the patch formulation, which was evaluated by a pharmacokinetic study. The controlled drug delivery mechanism was investigated by FTIR, 1H NMR, differential scanning calorimetry (DSC), confocal laser scanning microscopy (CLSM), molecular modeling, and rheology study. The optimized patch was formulated with 4.80% (w/w) CLO-AA (azelaic acid) as API and HP-PSA as PSA matrix and 95.00 μm thickness. The single-layer patch not only simplifies the preparation process but also has a zero-level skin penetration profile (r = 0.9592) in vitro. Compared with the commercial patch (AUC0-t = 7748.51 ± 662.76 h ng/ml, MRT0-t = 71.04 ± 9.30h), the pharmacokinetic behavior of the optimization group was semblable (AUC0-t = 8160.28 ± 694.04 h ng/ml, MRT0-t = 63.19 ± 12.38h). Mechanistic studies showed that ion-pair improved drug interaction with HP-PSA, leading to controlled drug release. Changes in drug physicochemical properties decreased skin permeability and increased drug-skin interaction, resulting in a constant delivery rate. In conclusion, the 7-day long-acting drug delivery of the CLO patch was achieved by the ion-pair strategy, which simplified the preparation process, and inspired a long-acting transdermal drug delivery system.