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维药毛菊苣保肝有效部位及制剂研究
杨伟俊
学位类型博士
导师阿吉艾克拜尔.艾萨
2012-12
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业有机化学
关键词毛菊苣 保肝有效部位 二维相关红外光谱 液质联用 滴丸
摘要目的:探讨毛菊苣对肝损伤保护作用有效部位的物质基础。方法:运用红外光谱三级宏观指纹鉴定对多来源药材毛菊苣和菊苣进行分析,建立毛菊苣与菊苣的红外光谱鉴定方法;采用大孔吸附树脂分离纯化富含倍半萜类成分的毛菊苣有效部位 (Squiterpene-Rich Fraction,SRF);运用液质联用 (HPLC-APCI-MS)技术研究SRF化学成分;利用液相色谱等分析方法研究建立SRF质量标准;采取正交试验设计优化SRF滴丸制剂工艺;采用CCl4腹腔注射造成小鼠急性化学性肝损伤模型、小鼠尾静脉注射卡介苗加脂多糖(BCG+LPS)造成急性免疫性肝损伤模型,评价SRF保肝活性。结果:二阶导数红外光谱中,毛菊苣的1593 cm-1峰来自芳香类化合物,菊苣的1660 cm-1邻近峰来自蛋白质酰胺I带;毛菊苣中的1062 cm-1和957 cm-1峰与菊苣有明显差异。二维相关红外光谱差异明显;从SRF中得到20个化合物,在一个分析周期内推测鉴定了19个,其中倍半萜类成分13个,主要倍半萜类成分为山莴苣素及其3个异构体、山莴苣苦素、8-deoxylactucin、11β,13-dihyhrolactucn、deoxylactucopicrin,此外还含有4个倍半萜类似物。SRF中山莴苣素含量为9.18 mg?g-1;SRF滴丸剂的最佳制剂工艺条件为:取SRF按1:2.333的比例加入到熔融的PEG4000中,75℃熔融混匀,滴距6~8 cm、滴口径3.8/4.9 (mm/mm)、滴速为35~45 d?min-1,冷却剂12.5℃二甲基硅油;制剂质量符合中国药典2010年版滴丸剂项下有关规定,体外溶出符合Weibull方程,Td为16.50±1.38 min,T80为27.40±2.70 min;SRF能明显减轻CCl4所致的肝损伤程度,高剂量 (0.20 g/kg)降低AST (P = 0.001)、ALT (P = 0.000)和TBIL (P = 0.009)的效果最为显著。SRF能明显修复BCG+LPS所致的肝脏损伤,且呈剂量依赖关系,高剂量 (0.20 g/kg)降低血清酶AST (P = 0.003)、ALT (P = 0.003)和TBIL (P = 0.007)作用最为显著。结论:本研究结果表明,SRF对化学性肝损伤和免疫性肝损伤小鼠均具有明显的保护作用,其效果与其中的倍半萜类成分密切相关。; Objective:Systematacially explore the material basis for hepatoprotection of Cichorium glandulosum Boiss. et Huet. Methods: Multi-steps infrared macro-fingerprint method was used to identify C. glandulosum and C. intybus. Macroreticular resin was adopted to prepare the squiterpene-rich fraction (SRF) from aerial part of C. glandulosum. HPLC-APCI-MS was applied to explore the chemical constituents of SRF;Established a quality control standard of SRF using HPLC and other analytical methods. Orthogonal experimental design was used to optimize the preparation technology of SRF′s dropping pill, and its quality standards was established, too. Hepatoprotective effects of SRF were investigated on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in mice, and on priming with Bacillus Calmette–Guerin (BCG) followed by lipopolysaccharide (LPS) -induced immunological liver injury in mice. The acute toxicity of SRF was tested too. Results: The strongest peak at 1593 cm-1 of C. glandulosum is corresponding to aromatic compounds, while the peak at 1660 cm-1 of C. intybus L. is corresponding to the protein amide I band. The peak at 1062 cm-1and 957 cm-1 between them are obviously different. Further, the distinction of 2D2IR correlation spectra between the two is especially recognizable; 20 compounds was found in SRF using HPLC-APCI-MS method, and 19 of which was identified in a single analytical period. The main sesquiterpenoids included lactucin and its three isomer, lactucopicrin, 8-deoxylactucin, 11β,13-dihyhrolactucn, deoxylactucopicrin, and other four sesquiterpenoids. The content of lactucin in SRF was 9.18 mg?g-1; The best preparation for the process conditions of SRF′s dropping pill is as follows: SRF was added to melting PEG4000 at the ratio of 1:2.333 (g/g), blending at 75℃. Dropping high is 6~8cm, with a drop-head-caliber 3.8/4.9 (mm/mm) . cooling liquid is dimethyl silicon oil with a 12.5℃ conditions. The quality of the preparation is satisfied according to China pharmacopoeia 2010 edition. Dissolution rate in vitro of SRF dropping pills conformed to the Weibull equation, with Td=16.50±1.38 min and T80=27.40±2.70 min. SRF significantly reduced the impact of CCl4 toxicity. The highest dose of SRF (0.20 g/kg) was the most effective, reflected by significant reductions in the levels of AST (P = 0.001), ALT (P = 0.000) and TBIL (P = 0.009). The serum enzymatic levels induced by BCG and subsequent LPS injection were significantly and dose-dependently restored by SRF, reflected by significant reductions in the levels of AST (P = 0.003), ALT (P = 0.003) and TBIL (P = 0.007) for the highest dose of SRF (0.20 g/kg). Conclusion: Present results suggested that SRF is hepatoprotective in animal models of chemical and immunological acute liver injury, and its effects are attributed to sesquiterpenes.
文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4361
专题资源化学研究室
作者单位中国科学院新疆理化技术研究所
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杨伟俊. 维药毛菊苣保肝有效部位及制剂研究[D]. 北京. 中国科学院研究生院,2012.
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