摘要
目的：选择胰岛素作为蛋白质模型药物，以聚乳酸为载药聚合物，采用溶剂挥发法，对蛋白质的微球处方及制备条件进行优化。方法：以微球的成球情况、粒径、包封率、产率、含量为指标，首先应用正交设计分析筛选油相、乳化剂、乳化温度和溶剂挥发温度，然后应用均匀设计逐步回归法优化空白微球制备工艺；再根据空白微球的筛选结果，对聚乳酸相对分子质量和浓度两个重要因素进行正交试验，应用理想函数优选产率、包封率和载药量较高的胰岛素聚乳酸微球。应用电子显微镜扫描观察微球水解前后的表面形态。应用显微计数法测定微球粒径及分布。结果：空白微球筛选结果表明以液体石蜡为油相，山梨醇酯肪酸酯８０ 为乳化剂，在室温条件下进行乳化和溶剂挥发有利于微球的制备。均匀设计及逐步回归法筛选空白微球的制备工艺结果表明，聚乳酸的浓度和相对分子质量是决定粒径大小和微球产率的主要因素。载药微球筛选结果表明相对分子质量为１０ ｋＤ的聚乳酸当其浓度为２００ ～３００ ｍｇ·ｍｌ－ １ 时制备得到的微球包封率（ 达７５ ％ 以上） 、含量、产量都较高。胰岛素聚乳酸微球平均粒径为１９－３９ μｍ ，表面光滑，呈球状，在水解１５ ｄ 后表面出现孔隙，但球形骨架仍然完整。结论：采用一系列优选方?
OBJECTIVE: To investigate the preparation method and optimization technique of polylactic acid (PLA) microspheres containing polypeptides and proteins METHOD: Insulin was chosen as a model of protein drugs The trapping efficiency, drug loading and content of insulin were used to evaluate the formulations of microspheres Oil phases, emulsifiers, temperature of emulsification and temperature of solvent evaporation were chosen as variables for the optimization of PLA blank microspheres Ratio of aqueous phase/oil phase, PLA concentration, stirring speed and stirring time were optimized The concentration of emulsifier, PLA molecular weight and PLA concentration were optimized using uniform design and step regression PLA molecular weight and PLA concentration were evaluated by orthogonal design RESULTS: Light liquid paraffin and Span 80 was the optimum constitutents of PLA blank microspheres The orthogonal design demonstrated that PLA 10k at a concentration of 250 mg/ml would produce desirable trapping efficiency, yield and drug loading for insulin loaded microspheres Three batches of the optimum formulation were produced The result of SEM demonstrated that the microspheres had an intact outer surface with a smooth and non porous surface before hydrolysis After 15 days in release medium, small pores were seen while the matrices of the microspheres still remained The mean diameter of the microspheres was 20 μm CONCLUSION: An optimum formulation was obtained using several optimization steps The experimental values of the response variables of the fomulation were closen to the predicted values by mathematical models The methods of the optimization are useful for PLA microspheres containing insulin
出处
《中国药学杂志》
CAS
CSCD
北大核心
1999年第12期822-826,共5页
Chinese Pharmaceutical Journal
