【作者】 郭雪红；

【导师】 葛志强； 陶遵威；

【作者基本信息】 天津大学 ， 制药工程， 2012， 硕士

【摘要】 齐墩果酸（oleanolic acid，OA）是天然五环三萜类化合物，在中国已作为常用保肝OTC药物治疗急性化学性肝损伤、慢性肝硬化和肝纤维化。本文利用超微粉碎和滴丸制剂工艺技术相结合，以PEG4000为基质材料，采用熔融法将齐墩果酸制备成滴丸剂，并对其处方、制备工艺、质量标准和稳定性进行了研究。拟解决齐墩果酸药物剂型单一，临床应用不足，进一步完善齐墩果酸滴丸制剂给药系统的研究和开发平台，为其它中药开发滴丸制剂提供方向。本文完成的主要工作和结论如下：主要工作：采用超微粉碎技术处理齐墩果酸药材，以溶散时间、圆整度等为主要评价指标，优化并确定了齐墩果酸滴丸的最佳处方；以主药比例、冷凝液温度、滴距为考察因素，以正交试验L₉（3）⁴和方差分析进行滴丸成型工艺优选；采用HPLC法测定齐墩果酸滴丸中的药物含量，考察滴丸的溶出度，并制定齐墩果酸滴丸产品的质量控制草案；初步考察了滴丸的稳定性。结果：本实验通过考察比较得出，采用超微粉碎处理后的齐墩果酸制成滴丸剂的各项指标均优于未处理过的；确定齐墩果酸滴丸的处方工艺条件：在PEG4000熔融的状态下加入齐墩果酸并搅拌混合均匀（齐墩果酸与PEG4000比例为1:5），选择内径3mm，外径4mm的滴头，滴距为7cm，滴入至装有二甲基硅油的冷凝管中（调控冷凝温度为15±5℃），制备成丸，清洗去除表面的冷凝剂，筛选包装即得，且制备的滴丸符合质量要求；齐墩果酸浓度在0.020740.07259mg/mL内呈良好线性关系（r=0.9997，n=6），加样回收率为98.58％103.03％（n=6），RSD=0.06％。45min时齐墩果酸滴丸的溶出度达到95.33％，远高于普通片剂（5.2％）和分散片（52.17％）；稳定性影响因素试验显示，高温（60±2）℃，高湿（25℃，RH92.5％±5％）对齐墩果酸滴丸影响很大；在高温（40±2）℃，光照（4500lx±500lx）条件下稳定性良好；高湿（25℃，RH75％±5％）使齐墩果酸滴丸有吸湿现象，丸重增加。在包装条件下，加速试验和室温留样试验均表明各项稳定性指标均无明显变化。结论：所筛选的工艺处方及制备方法能符合滴丸的质量要求；建立了齐墩果酸滴丸含量测定及溶出度的试验方法，在已有的齐墩果酸质量标准基础上，首次完整的提出了齐墩果酸滴丸剂型的质量标准；滴丸应在密封、防潮、阴凉、干燥处储存，有效期可暂定为1年。更多还原

【Abstract】 This paper study superfine crushing and dripping pill preparation technology,which is used PEG4000 as matrix material, by melting method to prepare oleanolicacid dropping pills. At the same time, the prescription, preparation process, qualitystandard and stability were studied. To solve the oleanolic acid pharmaceutical dosageforms a single, clinical application, further improvement of oleanolic acid droppingpill preparation delivery systems research and development platform for thedevelopment of Chinese medicine pill preparation.In the paper, the main work and conclusions are as follows:The best prescription of oleanolic acid dropping pills is optimized anddetermined through using the technology of superfine grinding process of oleanolicacid medicine, with the dissolving time and roundness as the main evaluation index.With the main drug proportion, temperature of condensate, dropping distance for theinvestigation of factors, the orthogonal experiment L₉（3）⁴ and variance analysis pillmolding process optimization. HPLC method measures the content of oleanolic aciddropping pills drug, tests dropping pills dissolution of oleanolic acid, and develop theproduct quality control protocol, preliminarily inspected pills stability.Results: The indicators of oleanolic acid dropping pills using superfine powderprocessing are better than the untreated. Oleanolic acid dropping pills prescriptionconditions: the oleanolic acid is joined in PEG4000 molten state and mixing together（the ratio of the oleanolic acid and PEG4000 is 1: 5）. Then it is drop into thecondenser pipe filled dimethyl silicone with dripping of diameter 3mm, diameter4mm, dripping distance 7cm （Condensation temperature: 15±5℃）. Finallypreparation pills by cleaning to remove surface condensing agent can be packaged andmeets quality requirements. The good linear relationship （r=0.9997, n = 6 ）, samplerecovery rate was 98.58%103.03% （n = 6） and RSD=0.06% shows with the oleanolicacid concentration 0.020740.07259mg/mL. Dissolution rate of oleanonlic acidreached 95.33% at 45min, which is much higher than ordinary tablet （5.2%） anddispersible tablet （52.17%）. The factors greatly affect the stability of test with hightemperature （60±2）℃, high humidity （25℃, RH92.5%±5%）. However, thestability are good at high temperature （40±2）℃, light（4500lx±500lx）. Thehygroscopic behavior of oleanolic acid dropping pills has a presence at high humidity（25℃，R H75％±5％）. At the same time the pills weight increase. With the packagingcondition, the stability index did not change significantly by accelerated test and roomtemperature test.Conclusion: the process of prescription and preparing method can meet qualityrequirements. On the basis of quality standards of oleanolic acid existing, the qualitystandards for oleanolic acid dropping pills is forwarded at the first. Pills should besealed, moistureproof,cooled and dry stored.更多还原