绵茵陈药材的提取、精制工艺及其“谱效结合”评价研究
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摘要
茵陈为《中华人民共和国药典》(2005版)收载品种,是保肝利胆复方中常用中药。目前在中药制剂工艺中多采用传统水煎工艺,个别制剂采用“水提醇沉”或乙醇渗漉工艺,未见对上述提取工艺评价的系统文献研究。
现代科学技术不断发展的背景下,在中药制备工艺中适宜的引进新的制剂技术,并对其作出科学的评价,对提高中成药的技术含量和科学内涵具有重要意义。
以单一成分保留率为指标的常用工艺评价方式,应用于多成分多部位的中药具有局限性,笼统的有效部位的评价方式具有模糊性。中药指纹图谱技术的发展为跟踪评价中药制剂工艺中药效物质基础的保留提供了更为精细的指标。即使如此,严谨的研究者仍有理由质疑,保留指纹图谱相关成分的同时,新工艺的运用是否保留了药材的药效。因此以“谱效结合”的方法,从物质基础和药效学的角度跟踪评价中药制剂新工艺,具有更强的说服力。
本课题以绵茵陈药材为载体,探索大孔树脂吸附工艺的运用及其科学评价的途径。针对绵茵陈药材的研究基础,在建立绵茵陈药材指纹图谱和探讨药材提取液中绿原酸稳定性影响因素基础上,以绵茵陈药材指纹图谱主峰保留率和保肝的药效学评价为指标,研究了绵茵陈提取工艺、大孔吸附树脂精制工艺,主要研究内容和成果如下:
1.绵茵陈药材指纹图谱的建立
采用反相高效液相色谱法建立绵茵陈药材指纹图谱,并进行相应的方法学考察,对不同产地和批次绵茵陈药材进行质量评价。
2.绵茵陈药材提取液中绿原酸稳定性的影响因素研究
采用HPLC法测定绵茵陈药材水提液、醇提液在不同受热时间和温度,以及不同pH条件下绿原酸的含量变化。结果表明,受热温度和pH是影响其中绿原酸稳定性的重要因素。提示在该药材提取、浓缩、干燥工艺过程中应关注受热温度和pH对绿原酸保留率的影响。
3.绵茵陈药材的提取工艺研究
选择绵茵陈药材指纹图谱中代表不同极性的绿原酸峰、8号峰和13号峰为指标成分,以三种成分的提取率进行多指标综合评分,对提取次数进行考察的基础上;再采用四因素三水平正交实验设计法考察绵茵陈药材的提取工艺参数;进一步以抗急性肝损伤的药效学研究,对所选优化工艺与传统水提工艺进行比较。结果表明,绵茵陈药材提取的优化工艺参数为10倍量、8倍量、8倍量的80%乙醇各提取1次,每次1h;ALT和AST以及病理学指标的比较表明绵茵陈醇提工艺有优于水提工艺的趋势。
4.绵茵陈药材的大孔树脂精制工艺研究
本课题先以静态吸附法确定树脂种类及吸附工艺影响因素。以吸光度和绿原酸的
Herba Artemisiae Scopariae ,which is adducted by Chinese Pharmacopeia, can be ofen seen in liver-protecting and cholagogue complex prescription. Presently it is usually extracted by water as tradition, and sometimes processed by "water extracted—alcohol precipitated" technology or percolation technology in Chinese drugs pharmaceutics, but research works are seldom done to evaluate the above-mentioned process.With the development of science and technology, the innovation of pharmaceutics technology and its serious evaluation is very important to the elevation of technique level and elucidation science connotation of Chinese formulated products.The commonly used technology evaluating system, with reservation rate of single ingredient in the herb as the parameter, is limited in the evaluation of multi-components Chinese herbs and the evaluating method of general effective regional is indefinite. The development of finger printing technology provides a more exquisite index to the evaluation of reservation of pharmacodynamic action substance in Chinese drugs pharmaceutics technology. Even so, rigorous researchers still have reasons to doubt that if the application of new technology keeps the drug' s action while keeping the correlated components in finger printing. Therefore, the method of "finger print combined with pharmacodynamics" as index which accompanies and evaluates new pharmaceutics technologies is more persuasive.This article explores the application of macroporous resin in the
extrcacting of Herba artemisiae scopariae , and scientific evaluation of the purification is also be done in the research. It has established the finger print of Herba artemisiae scopariae and investigated the influencing factor of chlorogenic acid in the extract to aim directly at the research foundation of Herba artemisiae scopariae , and studied the extraction process and purification process by macroporous resin with the reservation rate of the main peak in finger print of Herba artemisiae scopariae and the pharmacodynamics evaluation as indexes. The main contents and results are as followings:1. The establishment of finger print of Herba artemisiae scopariaeThe finger print of Herba artemisiae scopariae is established with reversed phase high performance liquid chromatdgraphy and the corresponding methodological research is undertaken to evaluate the quality of Herba artemisiae scopariae from different habitats and batches.2. Influencing Factors of Caffeotannic Acid' s Stability in Extracts of Herba Artemisiae ScopariaeThe Herba Artemisiae Scopariae decoctions by water or alcohol is heated in different pH and for different period, and the content of chlorogenic acid is determined. The result shows that the heat temperature and pH of the decoctions are important factors which influence stability of chlorogenic acid, and alcohol system is in favor of its stability. We should pay attention to these factors in the extracting, recovering the solvent, concentrating and drying process of Chinese drugs pharmaceutics which have the content of chlorogenic acid.3. The extraction process of Herba Artemisiae ScopariaeWith chlorogenic acid, peak No. 8 and peak No. 13, which stand for different polars in the finger print of Herba Artemisiae Scopariae, as the indexes, the different methods are comprehensively scored based on the extraction rate of the three compositions. After the extraction times is determined, the parameters of the extraction process of Herba Artemisiae Scopariae are examined with LOO orthogonal design. Then the chosen optimized process is compared with the traditional water-extraction process with the pharmacodynamics research of resisting acute liver injury. The results show that the optimized process parameters are the extraction of Herba Artemisiae Scopariae with 10 times, 8 times and 8 times of 80%alcohol for 3 times, 1 hour
per time. The comparison of ALT, AST and pathological indexes show the trend that the alcohol-extraction process is better than water-extraction process. 4. The purification process of Herba Artemisiae Scopariae decoction with macroporous resinIn this study, the influencing factors of static adsorbting process of extract of Herba Artemisiae scopariae with macroporous resin are studied at first. With the absorbances and the adsorption quantity of caffeotannic acid as indexes, the adsorption effect of different macroporous resin and timetable of static adsorption are investigated. The influence tendency and extent of density and pH of the physic liquor in the static adsorption by use of factorial experiment are investigated. With the HPLC finger print of extract of Herba Artemisiae scopariae as an index, the adsorption effect is investigated. The result shows that the adsorption effect are different with different types of macroporous resin , and the adsorption equilibrium time is 6 h;Density and pH of the physic liquor are important factors of adsorb. The results may offer some information for the determination of refinement process of Herba Artemisiae scopariae decoction with macroporous resin.Based on the results above, with the HPLC finger print of extract of Herba Artemisiae scopariae as indexes, the kinesis adsorb and elution process with quantity of caffeotannic acid are investigated and the maximum quantity of physic liquor and the type and quantity of elution solvent are determined. The results show that the maximum quantity of caffeotannic acid that each gramma of dray resin can adsorb is 20. 9mg, and the elution solvent determined is five times column volume of 80% alcohol;The verification experiment indicats that this process decreased the yield of extract to 2. 5%, and meanwhile it retained the whole components of the HPLC finger print effectly. So the Refinement process can enrich the active components in Herba Artemisiae scopariae effectively.5. Evaluation to the refinement process of extract of Herba Artemisiae Scopariae with Macroporous resin by the method of "pharmacodynamics combinded with finger print"The refinement process of extract of Herba Artemisiae Scopariae with macroporous resin is evaluated with the reservation rate of main peak in the finger print as an index. The CCL, is injected to mouse to establish a model of acute hepatic injury, then the activity of ALT and AST in the serum is
determined and the pathological diversity of the histological section is observed to compared the hepatoprotective effect of the refinement product with extract of Herba Artemisiae Scopariae. The results show that before or after the refinement, the finger prints of the extract of Herba Artemisiae Scopariae are almost the same, the hepatoprotective effects have no significant deviation and no obvious acute toxic reactions are observed.The results above show that the rate of extract can be decreased and the drug contents of the preparation can be increased while the main peak of the finger print and the hepatoprotective effects can be reserved by optimizing the extraction process and the purification process with Macroporous resin. This research can provide proof for reference for the use of Herba Artemisiae Scopariae in complex prescription of Chinese drugs pharmaceutics.
现代科学技术不断发展的背景下,在中药制备工艺中适宜的引进新的制剂技术,并对其作出科学的评价,对提高中成药的技术含量和科学内涵具有重要意义。
以单一成分保留率为指标的常用工艺评价方式,应用于多成分多部位的中药具有局限性,笼统的有效部位的评价方式具有模糊性。中药指纹图谱技术的发展为跟踪评价中药制剂工艺中药效物质基础的保留提供了更为精细的指标。即使如此,严谨的研究者仍有理由质疑,保留指纹图谱相关成分的同时,新工艺的运用是否保留了药材的药效。因此以“谱效结合”的方法,从物质基础和药效学的角度跟踪评价中药制剂新工艺,具有更强的说服力。
本课题以绵茵陈药材为载体,探索大孔树脂吸附工艺的运用及其科学评价的途径。针对绵茵陈药材的研究基础,在建立绵茵陈药材指纹图谱和探讨药材提取液中绿原酸稳定性影响因素基础上,以绵茵陈药材指纹图谱主峰保留率和保肝的药效学评价为指标,研究了绵茵陈提取工艺、大孔吸附树脂精制工艺,主要研究内容和成果如下:
1.绵茵陈药材指纹图谱的建立
采用反相高效液相色谱法建立绵茵陈药材指纹图谱,并进行相应的方法学考察,对不同产地和批次绵茵陈药材进行质量评价。
2.绵茵陈药材提取液中绿原酸稳定性的影响因素研究
采用HPLC法测定绵茵陈药材水提液、醇提液在不同受热时间和温度,以及不同pH条件下绿原酸的含量变化。结果表明,受热温度和pH是影响其中绿原酸稳定性的重要因素。提示在该药材提取、浓缩、干燥工艺过程中应关注受热温度和pH对绿原酸保留率的影响。
3.绵茵陈药材的提取工艺研究
选择绵茵陈药材指纹图谱中代表不同极性的绿原酸峰、8号峰和13号峰为指标成分,以三种成分的提取率进行多指标综合评分,对提取次数进行考察的基础上;再采用四因素三水平正交实验设计法考察绵茵陈药材的提取工艺参数;进一步以抗急性肝损伤的药效学研究,对所选优化工艺与传统水提工艺进行比较。结果表明,绵茵陈药材提取的优化工艺参数为10倍量、8倍量、8倍量的80%乙醇各提取1次,每次1h;ALT和AST以及病理学指标的比较表明绵茵陈醇提工艺有优于水提工艺的趋势。
4.绵茵陈药材的大孔树脂精制工艺研究
本课题先以静态吸附法确定树脂种类及吸附工艺影响因素。以吸光度和绿原酸的
Herba Artemisiae Scopariae ,which is adducted by Chinese Pharmacopeia, can be ofen seen in liver-protecting and cholagogue complex prescription. Presently it is usually extracted by water as tradition, and sometimes processed by "water extracted—alcohol precipitated" technology or percolation technology in Chinese drugs pharmaceutics, but research works are seldom done to evaluate the above-mentioned process.With the development of science and technology, the innovation of pharmaceutics technology and its serious evaluation is very important to the elevation of technique level and elucidation science connotation of Chinese formulated products.The commonly used technology evaluating system, with reservation rate of single ingredient in the herb as the parameter, is limited in the evaluation of multi-components Chinese herbs and the evaluating method of general effective regional is indefinite. The development of finger printing technology provides a more exquisite index to the evaluation of reservation of pharmacodynamic action substance in Chinese drugs pharmaceutics technology. Even so, rigorous researchers still have reasons to doubt that if the application of new technology keeps the drug' s action while keeping the correlated components in finger printing. Therefore, the method of "finger print combined with pharmacodynamics" as index which accompanies and evaluates new pharmaceutics technologies is more persuasive.This article explores the application of macroporous resin in the
extrcacting of Herba artemisiae scopariae , and scientific evaluation of the purification is also be done in the research. It has established the finger print of Herba artemisiae scopariae and investigated the influencing factor of chlorogenic acid in the extract to aim directly at the research foundation of Herba artemisiae scopariae , and studied the extraction process and purification process by macroporous resin with the reservation rate of the main peak in finger print of Herba artemisiae scopariae and the pharmacodynamics evaluation as indexes. The main contents and results are as followings:1. The establishment of finger print of Herba artemisiae scopariaeThe finger print of Herba artemisiae scopariae is established with reversed phase high performance liquid chromatdgraphy and the corresponding methodological research is undertaken to evaluate the quality of Herba artemisiae scopariae from different habitats and batches.2. Influencing Factors of Caffeotannic Acid' s Stability in Extracts of Herba Artemisiae ScopariaeThe Herba Artemisiae Scopariae decoctions by water or alcohol is heated in different pH and for different period, and the content of chlorogenic acid is determined. The result shows that the heat temperature and pH of the decoctions are important factors which influence stability of chlorogenic acid, and alcohol system is in favor of its stability. We should pay attention to these factors in the extracting, recovering the solvent, concentrating and drying process of Chinese drugs pharmaceutics which have the content of chlorogenic acid.3. The extraction process of Herba Artemisiae ScopariaeWith chlorogenic acid, peak No. 8 and peak No. 13, which stand for different polars in the finger print of Herba Artemisiae Scopariae, as the indexes, the different methods are comprehensively scored based on the extraction rate of the three compositions. After the extraction times is determined, the parameters of the extraction process of Herba Artemisiae Scopariae are examined with LOO orthogonal design. Then the chosen optimized process is compared with the traditional water-extraction process with the pharmacodynamics research of resisting acute liver injury. The results show that the optimized process parameters are the extraction of Herba Artemisiae Scopariae with 10 times, 8 times and 8 times of 80%alcohol for 3 times, 1 hour
per time. The comparison of ALT, AST and pathological indexes show the trend that the alcohol-extraction process is better than water-extraction process. 4. The purification process of Herba Artemisiae Scopariae decoction with macroporous resinIn this study, the influencing factors of static adsorbting process of extract of Herba Artemisiae scopariae with macroporous resin are studied at first. With the absorbances and the adsorption quantity of caffeotannic acid as indexes, the adsorption effect of different macroporous resin and timetable of static adsorption are investigated. The influence tendency and extent of density and pH of the physic liquor in the static adsorption by use of factorial experiment are investigated. With the HPLC finger print of extract of Herba Artemisiae scopariae as an index, the adsorption effect is investigated. The result shows that the adsorption effect are different with different types of macroporous resin , and the adsorption equilibrium time is 6 h;Density and pH of the physic liquor are important factors of adsorb. The results may offer some information for the determination of refinement process of Herba Artemisiae scopariae decoction with macroporous resin.Based on the results above, with the HPLC finger print of extract of Herba Artemisiae scopariae as indexes, the kinesis adsorb and elution process with quantity of caffeotannic acid are investigated and the maximum quantity of physic liquor and the type and quantity of elution solvent are determined. The results show that the maximum quantity of caffeotannic acid that each gramma of dray resin can adsorb is 20. 9mg, and the elution solvent determined is five times column volume of 80% alcohol;The verification experiment indicats that this process decreased the yield of extract to 2. 5%, and meanwhile it retained the whole components of the HPLC finger print effectly. So the Refinement process can enrich the active components in Herba Artemisiae scopariae effectively.5. Evaluation to the refinement process of extract of Herba Artemisiae Scopariae with Macroporous resin by the method of "pharmacodynamics combinded with finger print"The refinement process of extract of Herba Artemisiae Scopariae with macroporous resin is evaluated with the reservation rate of main peak in the finger print as an index. The CCL, is injected to mouse to establish a model of acute hepatic injury, then the activity of ALT and AST in the serum is
determined and the pathological diversity of the histological section is observed to compared the hepatoprotective effect of the refinement product with extract of Herba Artemisiae Scopariae. The results show that before or after the refinement, the finger prints of the extract of Herba Artemisiae Scopariae are almost the same, the hepatoprotective effects have no significant deviation and no obvious acute toxic reactions are observed.The results above show that the rate of extract can be decreased and the drug contents of the preparation can be increased while the main peak of the finger print and the hepatoprotective effects can be reserved by optimizing the extraction process and the purification process with Macroporous resin. This research can provide proof for reference for the use of Herba Artemisiae Scopariae in complex prescription of Chinese drugs pharmaceutics.
引文
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