基于双重扩散机制的利培酮骨架微球/乙酸异丁酸蔗糖酯复合型原位贮库的制备与评价  

Preparation and evaluation of risperidone-loaded microsphere/sucrose acetate isobutyrate in situ forming complex depot with double diffusion barriers

作　　者：林霞[1,2] 唐星[3] 徐宇虹[1] 张宇[3] 张岩[3] 何海冰[3] 

机构地区：[1]上海交通大学药学院,上海200240 [2]江南大学药学院,江苏无锡214122 [3]沈阳药科大学药学院,辽宁沈阳110016

出　　处：《药学学报》2015年第6期775-782,共8页Acta Pharmaceutica Sinica

摘　　要：针对乙酸异丁酸蔗糖酯（sucrose acetate isobutyrate,SAIB）原位贮库前期药物突释问题,本文以利培酮为模型药物,将其预先包载于骨架微球中再分散至SAIB贮库系统中,制备利培酮骨架微球/SAIB复合型原位贮库。考察不同载体包括壳聚糖和聚乳酸-羟基乙酸共聚物[poly（lactide-coglycolide）,PLGA]、载体/药物比例及骨架微球形态对复合型贮库药物释放的影响。结果表明,与壳聚糖微球/SAIB贮库和单独SAIB贮库相比,PLGA骨架微球/SAIB复合型贮库（Ris-Pm-SAIB）可显著降低体外药物突释（0.64%）,体内药物突释也显著降低,0~4天药时曲线下面积（AUC0-4d）仅为（105.2±24.4）ng·m L-1·d;此外,通过调节微球形态控制贮库释药速度,多孔性PLGA微球/SAIB复合型贮库（Ris-PPm-SAIB）肌肉注射大鼠后AUC0-4d增至（194.6±15.8）ng·m L-1·d,突释略有增加,但78天时血药浓度仍为（9.0±2.5）ng·m L-1,4~78天AUC4–78d由（379.0±114.3）ng·m L-1·d增至（465.0±149.2）ng·m L-1·d,可保证药物充分释放。研究表明,多孔性PLGA骨架微球/SAIB复合型原位贮库在降低利培酮体内外药物突释的同时,可保证后期药物充分释放,实现体内持续释药78天。In the present study, a risperidone loaded microsphere/sucrose acetate isobutyrate （SAIB） in situ forming complex depot was designed to reduce the burst release of SAIB in situ forming depot and to continuously release risperidone for a long-term period without lag-time. The model drug risperidone （Ris） was first encapsulated into microspheres and then the Ris-microspheres were embedded into SAIB depot to reduce the amount of dissolved drug in the depot. The effects of different types of microsphere matrix, including chitosan and poly（lactide-coglycolide） （PLGA）, matrix/Ris ratios in microspheres and morphology of microspheres on the drug release behavior of complex depot were investigated. In comparison with the Ris- loaded SAIB depot （Ris-SAIB）, the complex depot containing chitosan microspheres （in which chitosan/Ris =1 ： 1, w/w） （Ris-Cm-SAIB） decreased the burst release from 12.16% to 5.80%. However, increased drug release rate after 4 days was observed in Ris-Cm-SAIB, which was caused by the high penetration of the medium to Ris-Cm-SAIB due to the hydrophilie of chitosan. By encapsulation of risperidone in PLGA microspheres, most drugs can be prevented from dissolving in the depot and meanwhile the hydrophobic PLGA can reduce the media penetration effect on the depot. The complex depot containing PLGA microspheres （in which PLGA/ drug=4 ： 2, w/w） （Ris-Pm-SAIB） showed a significant effectiveness on reducing the burst release both in vitro and in vivo whereby only 0.64% drug was released on the first day in vitro and a low AUC0-4d value [（105.2-v 24.4） ng·mL-l·d] was detected over the first 4 days in vivo. In addition, drug release from Ris-Pm-SAIB can be modified by varying the morphology of microspheres. The porous PLGA microspheres could be prepared by adding medium chain triglyceride （MCT） in the organic phase which served as pore agents during the preparation of PLGA microspheres. The complex depot containing porous PLGA microspheres （which were prepared

关 键 词：利培酮 乙酸异丁酸蔗糖酯 聚乳酸-羟基乙酸共聚物微球 原位贮库 控制释放 药动学 

分 类 号：R943[医药卫生—药剂学]