【作者】 李金明；

【导师】 李延团；

【作者基本信息】 中国海洋大学 ， 药物化学， 2010， 硕士

【摘要】 本文以人参皂苷Rh2静脉注射亚微乳为研究对象,进行了处方前研究、质量控制方法的拟定及稳定性研究,旨在为人参皂苷Rh2静脉注射亚微乳研究开发奠定基础。采用高效液相色谱法测定原料药中人参皂苷Rh2含量,用十八烷基硅烷键合硅胶为填充剂；乙腈-水-磷酸(550：450：1.25)为流动相；检测波长：203nm；柱温：40℃；流速：1.0 mg·ml-1；在0.0542～1.084 mg·ml-1范围内,峰面积与人参皂苷Rh2浓度呈良好的线性关系,平均回收率为99.70%,RSD为0.92%,采用上述方法对3批样品进行了含量测定,原料药人参皂苷Rh2含量均大于80%。考察了人参皂苷Rh2在油中的稳定性,在水中和油中的溶解度,蛋黄卵磷脂对人参皂苷Rh2在注射用大豆油中的增溶行为,甘油对人参皂苷Rh2在水中溶解行为的影响,以及人参皂苷Rh2与各种辅料的相容性,结果表明：在油相中115℃、90分钟,人参皂苷Rh2的含量基本没有变化,没检测到新的降解成分,化学稳定性良好；人参皂苷Rh2在水中几乎不溶或不溶,人参皂苷Rh2在精制大豆油中极微溶解；蛋黄卵磷脂对人参皂苷Rh2在精制大豆油中有增溶作用,可使每克注射用大豆油溶解人参皂苷Rh2达0.03 g；注射用甘油对人参皂苷Rh2在水中的溶解度几乎没有影响；人参皂苷Rh：与精制大豆油,蛋黄卵磷脂等辅料制备成乳剂,光照和高温条件下,无絮凝、分层及乳析等现象,主药化学稳定性良好,表明人参皂苷Rh：与乳剂制备常用辅料相容性较好,为人参皂苷Rh2静脉乳剂的进一步开发奠定了较好的基础。采用高效液相色谱法测定静脉注射亚微乳中药物含量；采用精密pH计测定亚微乳pH值；采用Nicomp 380 ZLS电位／粒径测定仪运用动态光散射原理测定亚微乳粒径；采用间接碘量法测定亚微乳过氧化值；采用酸碱滴定法测定亚微乳游离脂肪酸；采用中国药典2005年版一部附录ⅩⅢB所示无菌检查法进行亚微乳无菌检查；采用中国药典2005年版一部附录ⅩⅢA所示热原检查法进行亚微乳热原检查；采用高效液相色谱法测定10批原料药及制剂进行了指纹图谱测定,建立了原料药及制剂指纹图谱共有模式,原料药及制剂与共有模式的相似度大于0.90。上述方法能有效控制人参皂苷Rh2静脉注射亚微乳质量。以性状、pH值、粒度、过氧化值、游离脂肪酸、无菌检查、热原检查、指纹图谱和主药含量为考察指标,进行了人参皂苷Rh2静脉注射亚微乳稳定性影响因素实验和室温长期实验,采用威布尔分布拟合法预测人参皂苷Rh2静脉注射亚微乳化学稳定性。结果表明在40℃条件下制剂pH值随放置时间的延长逐渐降低,游离脂肪酸值随放置时间的延长逐渐升高,本品应避免高温贮存；本品对光不稳定,应避光贮存；本品低温冻结不稳定,贮存时应避免冻结；威布尔分布拟合法较为准确地预测人参皂苷Rh2静脉注射亚微乳化学稳定性；室温18个月长期试验表明人参皂苷Rh2乳剂具有良好的稳定性。更多还原

【Abstract】 In this article, The properties of ginsenoside Rh2 and the quality control methodes and the stabilities about intravenous ginsenoside Rh2 submicro-emulsion are studied.Ginsenoside Rh2 is assayed by HPLC.The HPLC system consisted of a pump and a UV detector.A C18 reverse-phase column(5μm,4.6×250mm) is used at 40℃.The mobile phase consisted of methyl cyanide(55%), water(45%) and phosphoric acid(0.125%).The flowrate is 1.0ml·min-1.The injection volume is 20μl, and the signal is monitored at 203nm.As a result, a good linearity is obtained over the range of 0.0542～1.084 mg·ml-1 with r=0.9999 for ginsenoside Rh2, the average recovery is 99.70%, RSD is 0.92%.With this method three batches crude drug of ginsenoside Rh2 are detected.The content of ginsenoside Rh2 in the crude drug are all much more than 80%.Its stabilty in the oil, its solubilities in soybean oil and water, the influence of egg lecithine on its solubility in the soybean oil, the influence of glycerol on its solubility in the soybean oil, and the compatibilities of ginsenoside Rh2 and the adjuvants are investigated.Results suggest that it is stable in the soybean oil, it is insoluble in water and slightly soluble in soybean oil, egg lecithine can add its solubility to 0.03 mg-g-1 in soybean oil, glycerol can hardly influent its solubility in water, and the compatibilities of ginsenoside Rh2 and the adjuvants are fine.These investigation are helpful to the development of intravenous ginsenoside Rh2 submicro-emulsionIntravenous ginsenoside Rh2 submicro-emulsion is assayed for drug concentration by HPLC.Its pH is detected by precise pH meter.Its globule size distribution is evaluated by Nicomp 380 ZLC Zeta/particle detector.Indirect iodimetry is used to detect its peroxide value.Its free fatty acids are detected by acid-base titration.Its sterility and bacterial endotoxins are detected according to Chinese Pharmacopoeia 2005.The fingerprints of the crude drug and the preparation are investigated by HPLC, the results are analyzed by computer Similarity Evaluation System of Chinese Herbal Medicine on Chromatographic Fingerprint and similarities were more than 0.90.These studies are useful for quality control of the crude drug and intravenous ginsenoside Rh2 submicro-emulsionIn stability test, its physico-chemical properties for example appearance, pH, globule size distribution, peroxide value, free fatty acids, sterility, bacterial endotoxins, fingerprints, and drug content in intravenous ginsenoside Rh2 submicro-emulsion,et al are analyzed. Isothermal test-weibull distribution method, class isothermal method and long-term storage test are used to estimate the chemical stability of intravenous ginsenoside Rh2 submicro-emulsion, respectively. Compared with class isothermal method, weibull distribution method is more suitable for the chemical stability prediction of intravenous ginsenoside Rh2 submicro-emulsion. Intravenous ginsenoside Rh2 submicro-emulsion has steady physico-chemical properties after storing at 25℃for 18 months. Intravenous ginsenoside Rh2 submicro-emulsion will have a good development future.更多还原