Influence of pH-responsive compounds synthesized from chitosan and hyaluronic acid on dual-responsive (pH/temperature) hydrogel drug delivery systems of Cortex Moutan

Abstract

The polysaccharide-based pH-responsive compounds, namely, N,N,N-trimethyl chitosan (TMC), polyethylene glycolated hyaluronic acid (PEG-HA), and polysaccharide-based nano-conjugate of hyaluronic acid, chitosan oligosaccharide and alanine [HA-Ala-Chito(oligo)] were chemically synthesized using biopolymers chitosan and hyaluronic acid, and applied here to observe the changes in morphology, pH-stability, mechanical and drug-release behavior, and cytotoxicity of thermo-responsive polymer: Poloxamer 407 (PF127)-based drug delivery systems for traditional Chinese medicine Cortex Moutan (CM). The thermo-responsive hydrogel of PF127 loaded with CM (Gel^C) was used as control. The dual-responsive (pH/temperature) hydrogels: PF127/TMC/PEG-HA (Gel¹) and PF127/HA-Ala-Chito(oligo) (Gel²) showed improved mechanical behavior as obtained by rheology and mechanical agitation study, and pH-stability under various external pH conditions, and those improvements occurred due to the addition of polysaccharide-based pH-responsive compounds in the systems. Both, Gel¹ and Gel² showed better morphology than Gel^C as obtained by SEM or TEM suggesting that interaction of polysaccharide-based pH-responsive compounds with PF127 in either gel or sol state gave better porous network structure in the hydrogels or more dispersed micellar arrangements in sol-state, respectively. Gel¹ showed the highest cumulative drug release (86.5%) after 5 days under mild acidic condition (pH 6.4) suggesting that release behavior of a hydrogel drug carrier was dependent on morphology, mechanical behavior, and pH-stability. The transdermal release (ex-vivo) results indicated that gallic acid, the active marker of CM passed through porcine ear skin and all the formulations showed more or less similar transdermal release properties. The hydrogels loaded with CM showed no cytotoxicity (cell viability >90.0%) on human HaCaT keratinocytes within concentration range of 0.0-20.0 μg/ml as obtained by MTT assay, and cell viability was more than 100% at a concentration of 20.0 μg/ml for Gel². The formulations without loaded drug namely, Gel¹-CM and Gel²-CM exhibited strong anti-bacterial action against gram positive bacteria Staphylococcus aureus.

Keywords: Chitosan; Cortex Moutan; Drug delivery; Dual-responsive hydrogel; Traditional Chinese medicine; Transdermal therapy.