关节腔注射用甲氨蝶呤温敏性缓释凝胶的制备及性能考察

Injectable thermosensitive hydrogels for intra-articular delivery of methotrexate

目的利用聚己内酯-聚乙二醇-聚己内酯(PCL-PEG-PCL)两亲性聚合物温敏凝胶作为载体材料,构建抗类风湿性关节炎药物甲氨蝶呤关节腔注射用给药体系。方法采用开环聚合法,以辛酸亚锡为催化剂、PEG1500为引发剂,与己内酯单体开环聚合得到PCL-PEG-PCL两亲性嵌段共聚物;对得到的PCL-PEG-PCL嵌段共聚物的组成结构及相对分子质量进行表征;采用翻转试管法测定PCL-PEG-PCL聚合物的溶胶-凝胶相转变温度,绘制溶胶-凝胶相转变曲线;评价甲氨蝶呤PCL-PEG-PCL温敏凝胶载药体系的缓释性能;考察PCL-PEG-PCL温敏凝胶关节腔注射后在大鼠体内的生物相容性。结果 PCL-PEG-PCL两亲性嵌段共聚物水溶液具有温敏性溶胶-凝胶相转变能力,其溶胶-凝胶相转变温度介于室温与体温之间。甲氨蝶呤PCL-PEG-PCL温敏凝胶的体外释放研究表明PCL-PEG-PCL温敏凝胶对甲氨蝶呤具有较好的缓释能力,提高载药量和温敏凝胶浓度将减缓甲氨蝶呤从PCL-PEG-PCL温敏凝胶的释放。大鼠滑膜苏木精-伊红染色结果显示,关节腔注射PCL-PEG-PCL温敏凝胶未引起炎症反应发生。结论 PCL-PEG-PCL温敏凝胶作为关节腔局部注射用载药体系具有较好的药物缓释性能和生物相容性。

Objective To constract an injectable controlled delivery system of methotrexate（MTX） based on thermosensitive PCL-PEG-PCL hydrogels, and develop intra-articular drug delivery.Methods The thermosensitive PCL-PEG-PCL copolymers were prepared by the ring-opening polymerization of caprolactone in the presence of PEG as an initiator and stannous octoate as a catalyst.The synthesized PCL-PEG-PCL copolymers were characterized for their structure, composition and the sol-to-gel transition.The in vitro release of MTX from the PCL-PEG-PCL hydrogels was studied at 37 ℃ in PBS.Biocompatibility was evaluated by histological analysis following intra-articular injection of PCL-PEG-PCL hydrogels into healthy rats.Results The synthesized PCL-PEG-PCL copolymers aqueous solutions could form in situ gel rapidly after injection under physiological conditions.MTX loaded PCL-PEG-PCL hydrogels showed a biphasic release pattern.The cumulative release of MTX from PCL-PEG-PCL hydrogels slowed with the increase of the drug loading and the hydrogels concentration.Histopathology studies of the joints after intra-articular injection of MTX loaded PCL-PEG-PCL hydrogels demonstrated the biocompatibility of the PCL-PEG-PCL hydrogels.Conclusion These results suggest that the intra-articular joint delivery of PCL-PEG-PCL hydrogels may be a viable strategy for the controlled release of drugs in the therapy of arthritis disease.