载多烯紫杉醇聚乳酸-羟基乙酸微球的制备、表征及其药物稳定性*

摘要 背景：目前临床使用的多烯紫杉醇注射液多采用吐温80作为增溶剂，容易导致过敏反应，且全身化疗不良反应大。采用聚乳酸-羟基乙酸包载多烯紫杉醇制备的缓释微球进行肿瘤间质化疗可提高肿瘤局部药物浓度，减轻全身不良反应。 目的：制备一种用于肿瘤间质化疗的载多烯紫杉醇聚乳酸-羟基乙酸缓释微球，并考察其理化性质、体外释放及药物稳定性。 方法：采用溶剂挥发法制备不同投料比载药微球，扫描电镜观察微球的表面形态、粒径，高效液相色谱法检测包封率、载药率及体外药物释放情况。将制备的微球于5，15，25 kGy 60Co 3种剂量辐照灭菌，体外细菌培养观察灭菌效果。 结果与结论：制备的载药微球呈圆球形，表面光滑，分散良好，平均粒径为23.1 µm。聚乳酸-羟基乙酸与多烯紫杉醇的投料比为100 mg/5 mg时可获得最佳的包封率(96.3%)和载药率(4.82%)；载药微球体外4周平稳释放药物达81.6%，无明显突释效应，包裹在微球内的多烯紫杉醇结构稳定性明显提高；3种剂量60Co辐照后均未见短小芽孢杆菌生长。说明采用溶剂挥发法可制备粒径及分布适宜、释放周期较理想、药物稳定性好的载多烯紫杉醇聚乳酸-羟基乙酸缓释微球。 关键词：多烯紫杉醇；聚乳酸-羟基乙酸；微球；缓释；生物材料与药物控释 doi:10.3969/j.issn.1673-8225.2010.21.013

Preparation, characterization and drug stability of poly (lactic-co-glycolic acid) microspheres containing docetaxel

Abstract BACKGROUND: Docetaxel injection and the solubilizer Tween 80 have a variety of side effects, while poly (lactic-co-glycolic acid) (PLGA) microspheres containing docetaxel used as interstitial chemotherapy can not only promote the drug concentration, but also reduce systemic toxicity. OBJECTIVE: To prepare sustained-release PLGA microspheres containing docetaxel for tumor interstitial chemotherapy, and investigate the physiochemical properties, in vitro release, and drug stability. MEHTODS: Sustained-release PLGA microspheres containing docetaxel were prepared by solvent evaporation method; thereafter, morphology and particle size were measured by scanning electron microscope, while drug loading, encapsulation efficiency, and in vitro release were examined by HPLC. The microspheres were performed with irradiation sterilization of 5, 15, 25 kGy 60Co. The effects of irradiation sterilization were examined. RESULTS AND CONCLUSION: Drug-loaded microspheres were round, smooth, and well scattered, with the mean diameter of 23.1 µm. The optimal drug loading rate (4.82%) and encapsulation efficiency (96.3%) were gained when the feed ratio of PLGA to docetaxel was 100 mg/5 mg. The cumulative release of docetaxel from microspheres was 81.6% within 4 weeks without occurrence of burst release, and docetaxel encapsulated in microspheres, detected by HPLC, kept stability of structure. No bacillus pumilus colony was cultured in microspheres after irradiation at three dosages of 60Co. Sustained-release PLGA microspheres containing docetaxel were successfully prepared by solvent evaporation method with optimal particle size and encapsulation efficiency, suitable release period, and high drug stability.