肾合颗粒制备工艺及质量控制研究

【作者】 常增荣；

【导师】 石任兵；

【作者基本信息】 北京中医药大学 ， 中药化学， 2007， 硕士

【摘要】 肾合方是中医治疗阳痿的经验方,由淫羊藿、山茱萸、五味子、枸杞子、人参、菟丝子、肉桂、川牛膝八味中药组成,功效为温肾壮阳。用于阳痿肾阳亏虚证,症见阳痿、或举而不坚,肢冷畏寒,精神疲惫,腰膝酸软,少气懒言,小便频数。舌淡苔白、脉沉弱。功能性勃起功能障碍见上述症候者。本论文对该方的提取工艺、颗粒制剂工艺、质量标准与控制方法、制剂稳定性进行了研究。论文共分为三部分:第一部分文献综述论文就祖国医学对阳痿的认识和治疗的现状进行了综述;对近10年来有关肾合方组成各单味药的化学成分、质量控制和药理学研究进展进行综述,共引文献222篇。第二部分实验研究1.建立了肾合颗粒制剂工艺。在文献研究的基础上对该制剂的制备工艺进行了实验研究。以淫羊藿苷含量为指标,通过正交试验法优选淫羊藿、菟丝子、川牛膝水提取条件;以五味子醇甲含量为指标,对山茱萸、五味子、枸杞子、人参合并乙醇提取的工艺条件进行了正交优选。优化得出提取工艺:淫羊藿、菟丝子、川牛膝水提取的最佳工艺条件为加水14倍量,提取3次,每次1小时;山茱萸、五味子、枸杞子、人参合并乙醇提取的最佳工艺条件为:加4倍量70%乙醇,回流提取4次,每次1.5小时;肉桂挥发油的最佳工艺条件为:加8倍量水,不浸泡,水蒸气蒸馏提取8小时。通过实验优选肉桂挥发油环糊精包结工艺条件;浓缩干燥工艺以及颗粒剂成型的工艺条件。挥发油的最佳包结工艺为:将8gβ-环糊精加入100ml水中充分溶解,在40℃条件下,加入1ml挥发油包结,搅拌时间为1小时。颗粒剂成型的最佳辅料配比为提取物细粉1份,加1-1.5倍糊精调整制成量,加入制剂1.5%的阿斯巴坦调味。2.建立了制剂的质量标准与控制方法。为控制肾合颗粒的产品质量,进行了有关肾合颗粒质量标准的研究,运用高效液相色谱法测定了成品中淫羊藿苷、马钱苷、五味子醇甲的含量;采用薄层色谱法对方中淫羊藿中所含淫羊藿苷、山茱萸中熊果酸、五味子中五味子甲素、枸杞子、人参中人参皂苷Rg1进行了鉴别。实验表明,所建立的薄层色谱鉴别方法薄层斑点清晰,重现性好,空白无干扰。对所建立的高效液相色谱含量测定方法进行了系统的方法学考察,空白均无干扰;线性关系考察表明:淫羊藿苷在0.1514μg~0.7570μg范围内呈线性,回归方程为Y=2268425.4X-2023.4,相关系数(r)为0.9999;马钱苷在0.0771μg~1.1568μg范围内呈线性,回归方程为Y=1134748.9X+4539.2 ,相关系数(r)为0.9999;五味子醇甲在0.0868μg~0.8680μg范围内呈线性,回归方程为y = 2195662 x + 10039 ,相关系数(r)为0.9999,淫羊藿苷、马钱苷、五味子醇甲测定,重复性试验测定结果RSD依次为0.64%、0.54%、1.16%,平均回收率依次为99.50%、99.05%、99.33%,RSD分别为0.84%、0.84%、1.08%。3.考察了制剂的稳定性按照新药中药质量稳定性研究的技术要求,将模拟市售包装的肾合颗粒三批样品,置室温条件进行初步稳定性考察,时间为三个月,结果表明本制剂在3个月内质量稳定。第三部分结果与讨论论文所建立肾合颗粒的制剂工艺合理可行,所建立的质量标准与薄层及含量测定方法科学、合理,可多方位有效控制制剂质量。更多还原

【Abstract】 Shenhe Prescription is a Chinese prescription treats ED based on experiences. It composed of Herba Epimedii, Fructus Corni, Fructus Schisandrae Chinensis, Fructus Lycii, Radix Ginseng, Semen Cuscutae, Cortex Cinnamomi, and Radix Cyathulae, with the actions of warming the kidney to invigorate yang, and indicated for impotence due to deficiency of kidney yang, manifested by impotence, cold extremities and aversion to cold, neurolysis, Aching and weakness of the loins and knees, deficiency of qi and disinclination to talk, frequent urination, pale tongue with white fur, deep and weak pulse, and erection functional impairment with above symptoms. We have done the experiment study on extractive techniques and the shaping process, the quality standard and the method for quality control, the stability of the granule. This thesis consists of three parts:Part one: Literatures and summarizationsWe have reviewed the literature about the chemical composition and quality control and pharmacological of each herb of Shenhe Prescription in the past 10 years, by citing 222 articles totally, and having a good hand of the present study of erectile dysfunction in traditional Chinese medicine. Part two: Experiment studies1. To establish the preparation process of Shehe granule. Based on the literature review, we have done the experiment study on preparation process. Optimizing the water extractive techniques of Herba Epimedii, Semen Cuscutae, and Radix Cyathulae by the orthogonal experiment, with the content of icariin as the index; optimizing the alcohol extractive techniques of Fructus Corni, Fructus Schisandrae Chinensis, Fructus Lycii, and Radix Ginseng by the orthogonal experiment, and indexed by schisandrin. The experiment indicated: the best water extraction condition is that Herba Epimedii, Semen Cuscutae, and Radix Cyathulae added to 14 times amount water and extracted 3 times with each time for 1 hour; The best alcohol extraction condition is that Fructus Corni, Fructus Schisandrae Chinensis, Fructus Lycii, and Radix Ginseng added to 4 times amount 70% alcohol and extracted 4 times with each time for 1.5 hour; the best extraction condition of Cortex Cinnamomi is that added to 8 times amount water without soak, and extracted for 8 hoursOptimizing the cyclodextrin inclusion process of volatile oil from Cortex Cinnamomi; study on the concentration process and the shaping process. The best inclusion process is that added 8gβ-cyclodextrin to 100ml water and dissolved completely, then added 1ml volatile at 40℃, mixed for 1 hour. The optimal matching of accessories is that adds 1-1.5 times cyclodextrin to 1 times extraction powder, and added 1.5% Aspartame as flavoring.2. To establish the quality standard and the method for quality control of Shehe granule. For control the quality of Shehe granule, we studied the quality standard of it. Determined the contents of icariin, loganin, and schisandrin by high efficiency liquid chromatography (HPLC); identified the icariin of Herba Epimedii, prunol of Fructus Corni, schisandrin of Semen Cuscutae, panaxsaponin Rg1 of Fructus Lycii and Radix Ginseng by thin layer chromatography (TLC). The experiment indicated that the established TLC identification method has a good reproducibility, and the TCL stain is distinctly, with a non-interferential control stain. At the same time, we did a systemic methodology research on the assaying method, and the blank is no interferential too; it indicated that icariin has a good linear relationship at a range of 0.1514μg~0.7570μg, the regression equation is Y=2268425.4X-2023.4,the coefficient correlation (r) is 0.9999; loganin has a good linear relationship at a range of 0.0771μg~1.1568μg, the regression equation is Y=1134748.9X+4539.2,the coefficient correlation (r) is 0.9999; schisandrin has a good linear relationship at a range of 0.0868μg~0.8680μg, the regression equation is Y=2195662X+ 10039, the coefficient correlation (r) is 0.9999; loganin has a good linear relationship at a range of 0.0771μg~1.1568μg, the regression equation is Y=1134748.9X+4539.2, the coefficient correlation (r) is 0.9999. The RSD of repetitiveness test results of icariin, loganin, and schisandrin are 0.64%、0.54%、0.87% respectively, and the average recovery are 99.50%、99.05%、99.8%, and RSD are 0.84%、0.84%、1.08% respectively.3. To investigate the stability of the granule. According to technical requirements for registration of pharmaceuticals, we investigated the stability of 3 lots of granule that packaged as market by sample-keeping observation method for 3 months. The experiment indicated that this granule could maintain stable in room temperature for 3 months.Part three: Result and discussionThe established preparation process of Shehe granule is reasonable and feasible, and the established quality standard and TLC identification method and HPLC determination of it is scientific and reasonable, it can control the quality of it in many sides.更多还原