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雷公藤有效成分分离研究
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摘要
雷公藤是一种传统中药,广泛分布于中国南方地区,主要用于治疗炎症、癌症、慢性肾炎、麻风病、系统性红斑狼疮、器官移植等免疫抑制性疾病。雷公藤甲素、雷公藤乙素、雷公藤生物碱是雷公藤多甙药物中的主要活性成分。本文重点研究了雷公藤甲素、雷公藤乙素和四种雷公藤生物碱的分离纯化工艺。主要内容包括:
     (1)建立了LC/APCI-MS同时测定雷公藤提取物中雷公藤甲素、雷公藤乙素的分析方法。
     (2)建立了HPLC同时测定雷公藤提取物中雷公藤春碱、雷公藤吉碱、雷公藤定碱以及雷公藤次碱的分析方法。
     (3)以雷公藤叶浸膏为原料,建立了高速逆流色谱分离雷公藤甲素的工艺。优化了两相溶剂系统的比例,并考察了流动相流速和转速对固定相保留率的影响。
     (4)研究了雷公藤甲素的层析分离工艺,考察了柱层析精制雷公藤甲素的工艺操作参数,包括溶剂组成、洗脱剂流速、进样体积和进样浓度的影响,得到了优化条件。采用层析动力学模型对雷公藤甲素层析过程进行了模拟,较好地反映了雷公藤甲素层析分离过程。
     (5)以雷公藤多甙为原料,建立了液液萃取富集雷公藤乙素和高速逆流分离制备高纯度雷公藤乙素的工艺。优化筛选了液液萃取溶剂系统。同时对高速逆流色谱两相溶剂系统的比例进行了优化,考察了流动相流速和螺旋管柱的转速对固定相保留率的影响。
     (6)以雷公藤多甙生产废弃物为原料,建立了同时分离雷公藤春碱、雷公藤吉碱、雷公藤定碱以及雷公藤次碱的高速逆流色谱工艺,优化了两相溶剂系统的比例,并考察了流动相流速、螺旋管柱转速的影响。
Tripterygium wilfordii Hook. f. (TWHF) is a traditional Chinese herb grown in the south of China and used for various immune and inflammatory diseases for many years. The extracts of the roots of TWHF are used widely for the treatment of a number of autoimmune disorders such as rheumatoid arthritis, organ transplantation, systemic lupus erythematosus, and skin diseases. The main active constituents of the herb have been reported to be diterpenes, triterpenes and alkaloid's compounds. In this dissertation, a series of rapid, sensitive and accurate LC/MS analytical methods were established for the determination of triptolide, tripdiolide, wilfortrine, wilfordine, wilforgine and wilforine in extract of TWHF. The separation and isolation of triptolide, tripdiolide, wilfortrine, wilfordine, wilforgine and wilforine from TWHF is emphasized in this dissertation. The main contents of this work are as following:
    (1) A novel method using liquid chromatography (LC) coupled with an atmospheric pressure chemical ionization mass spectrometry (APCI-MS) in the negative mode has been developed and validated for the rapidly simultaneous determination of triptolide and tripdiolide.
    (2)The first analytical procedure determination of wilfortrine-1, wilfordine-2, wilforgine-3 and wilforine-4 is described. Identity of the analytes was confirmed in a LC-MS experiment, with all compounds being clearly assignable in an atmospheric pressure chemical ionization (APCI) positive mode.
    (3)The sample preparation of crude triptolide from leaves of TWHF was optimized. A single-step preparative high-speed counter-current chromatography (HSCCC) method was developed for the separation and purification of triptolide from the extract of leaves of TWHF. The ratio of compositions of the solvent system composed of petroleum ether-ethyl acetate-ethanol- water were optimized. The effects of rotation speed of the multilayer coil column and flow rate of mobile phase on the retention of the stationary phase were investigated.
    (4)In column chromatography, the technique of separation of triptolide was researched with silca as solid phase. The effect of solvent, flow-rate of mobile phase, loading amount and
    concentration on the resolution and theoretical plate height were investigated. A rate model was set up to simulate the experimental elution curve. The model fits the experimental elution curve well.
    (5)Separation of triptolide by solvent extraction coupled with HSCCC was developed for the enrichment and purification of tripdiolide from the multi-glycoside of Tripterygium wilfordii Hook F (GTW). The effects of the species and the volume ratio of extract solvents on the distribution coefficients of triptolide in several extraction system were studied. The purity of triptolide of the GTW was improved significantly after extraction. Then the triptolide enriched extract was subjected to HSCCC. The ratio of compositions of the solvent system for HSCCC separation were also optimized. The effects of rotation speed of the multilayer coil column and flow rate of mobile phase on the retention of the stationary phase were investigated.
    (6) A HSCCC method was developed for preparative isolation and purification of alkaloids from TWHF waste material. Preparative HSCCC with a two-phase solvent system composed of light petroleum-ethyl acetate-ethanol-water as the two-phase solvent system.. The ratio of compositions of the solvent system composed of light petroleum-ethyl acetate-ethanol-water were optimized. The effects of rotation speed of the multilayer coil column and flow rate of mobile phase on the retention of the stationary phase were investigated. In a single operation, four kinds of alkaloids were obtained.
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