黄连解毒汤提取过程及大孔树脂精制机理的初步研究
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摘要
中药复方是中医药理论体系的精髓，中药复方多以煎服汤剂的形式广泛地用于多种疾病的治疗，是临床应用的主要形式，是中成药生产的基础。因而从中药及其复方的水提液中获取药效物质，最能体现其安全性与有效性，是现代中药开发的主要研究思路。如何既保持其现有传统优势，又能更好、更方便地发挥中药复方治病的稳定疗效?如何充分体现数千年来中医药防病治病的安全性和有效性，使“继承”与“创新”得到有效结合、高度统一?对这些问题的回答迫使我们必须对中药复方水提液及其提取精制工艺进行深入的基础性研究，而这也正是中药复方现代化研究必须面临的问题。
本论文是工业化分离手段用于中药复方复杂体系分离研究的方向之一，探索将复杂系统科学原理引入诠释中药复方提取及精制过程中所面临的共性关键技术，旨在从有效部位群分离筛选与物理化学表征参数的角度，建立可与信息科学接轨的中药复杂系统表征技术体系。
本论文选用物质基础研究较多、作用机理较明确的经典方——黄连解毒汤作为研究起点，首先，针对其复方提取过程中产生沉淀的现象进行深入的探讨，对其提取过程进行动态考察，从研究提取过程中多种指标性成分的溶出变化及中药复方水提液中特征物理化学表征参数的变化入手，采用数学统计的方法，探讨不同指标性成分及理化参数与汤剂溶出过程中所产生沉淀之间的关系，从而为提高该复方临床使用的有效性提供了理论依据；建立了各相关指标性成分的溶出数学模型，用于初步模拟复方提取中各指标性成分的动态变化过程，同时对提取过程中体系物理化学表征参数的变化进行相关分析，提示一定范围内可以通过各阶段提取液体系的物理化学特征参数对整个提取的动态过程进行在线控制。
其次，在上述研究的基础上，对复方黄连解毒汤精制过程进行探讨，选用已广泛用于工业生产的现代精制技术——大孔树脂吸附分离技术，精制中药复方水提液，针对目前制约大孔树脂吸附技术精制中药复方领域的共性关键问题，探索在现代分离科学原理的指导下，通过监控我们可检测到的指标性成分在大孔树脂上实现吸附—分离的动力学过程、精制过程中复方体系的物理化学特性参数的动态变化过程以及相关药效学指征，运用数据挖掘软件进行分析和知识发现，揭示大孔吸附树脂的特性与复方中不同指标性成分的含量及其吸附动力学过程之间、大孔吸附树脂的特性与复方精制过程中体系特征物理化学参数之间以及它们与相关药效指标之间的相关性的规律。同时结合对大孔吸附树脂精制复方前后其本身的微观变化进行综合分析，旨在为大孔树脂吸附分离技术用于精制中药复方建立可科学表达的参照模型，保证工业化生产中中药复方精制后的安全性、稳定性和等效性。
本论文的主要研究工作：
1、采用HPLC法对组方药材进行了质量控制研究，本复方由黄连、黄柏、黄芩、栀子组成，分别采集不同产地的各种药材进行基源及含量测定研究，确保合格可控的原药材用于本论文研究。
2、对复方提取过程进行动态研究，考察复方各项指标及参数在10min～120min的提取时间内的变化。分别运用UV、HPLC法研究复方提取过程中指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的溶出变化，同时分别采用不同理化测定仪器对提取过程中各药液的物理化学表征参数——溶液pH值、电导率、盐度、粘度、浊度的变化进行研究，并与复方提取过程中的沉淀率、固含率进行比较分析，采用直观分析与数理统计分析结合，探讨各物理化学表征参数与各指标性成分之间的相关性；各指标性成分与沉淀率、固含率之间的相关性；各物理化学表征参数与沉淀率、固含率之间的相关性，建立相关模拟数学方程和模型，探讨复方提取过程中沉淀产生变化的过程，为建立能以体系物理化学表征参数的变化来对复方提取进行在线控制，以及探讨建立中药复方提取动力学模型提供研究基础。
3、采用大孔树脂静态吸附法，对组方中各单味药材分别进行了九种不同大孔吸附树脂的吸附动力学研究，分别采用UV、HPLC法测定相关指标性成分的量，计算不同树脂的吸附速率常数、比吸附量、比洗脱量，以及不同成分的吸附率、洗脱率，绘制了不同树脂的吸附动力学曲线，对其吸附过程中的动力学变化进行了比较研究。
4、采用静态吸附法，对复方分别进行了九种不同大孔吸附树脂的吸附动力学研究，分别采用UV、HPLC法测定相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量，计算不同树脂分别相对于总生物碱、总黄酮的吸附速率常数、比吸附量、比洗脱量，以及吸附率、洗脱率，分别绘制了不同树脂的吸附动力学曲线，同时以其中单个成分小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量分别进行比洗脱量和洗脱率的比较，对其复方吸附分离中的动力学过程进行了比较研究。
5、从中药水提液复杂体系的客观本质入手，运用物理化学的研究方法，对复方吸附分离过程中溶液体系的物理化学表征参数进行了研究，分别测定了上样前药液、吸附后药液及洗脱后药液的pH值、电导率、盐度、粘度、浊度的变化，并对其变化进行比较分析。
6、采用动态上柱法，对组方单味药材及复方分别进行了九种不同大孔吸附树脂的动态吸附分离研究，分别采用UV、HPLC法测定相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量，计算其转移率。同时考察了精制过程中各体系的物理化学表征参数——溶液pH值、电导率、盐度、粘度、浊度的变化。
7、采用体外血小板抑制聚集试验对比了九种不同大孔树脂的分离精制产物与精制前的药效学变化。
8、运用数据挖掘软件，对有关“大孔吸附树脂特征参数量——中药复方提取液精制前后物理化学特征参数量——中药复方提取液精制前后指标性成分特性量——大孔树脂吸附动力学特征参数量——药效学指标之间相关性进行数据挖掘研究，拟合不同的曲线，建立相关的数学方程，探讨大孔吸附树脂分离中药复方水提液的相关规律及机理。
9、基于知识发现，设计五种不同的树脂组合，分别进行静态及动态吸附实验，对其吸附动力学过程以及各相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量进行比较研究。
10、借鉴微观粒子的研究手段，采用电镜扫描法，对不同大孔树脂分离复方的吸附前、吸附后及洗脱后，其本身的微观形态的变化进行比较研究。
本论文的创新点：
在中医药理论的指导下，从精密微观的角度探讨中药复方提取精制过程的作用机理，通过采集大量中药化学、物理化学、吸附动力学参数，开展多变量数据挖掘实验研究：
1、首次对中药复方提取过程进行动态研究：多指标同时考察、引入物理化学表征参数量，用数学统计的方法探讨其复方煎煮中成分溶出的规律，为创建一种可较全面评价药效物质溶出状况的工艺考察模式提供了新的思路，并为进一步建立能以提取液的物理化学表征参数对提取过程进行在线控制创造了条件。
2、在现代分离科学理论的指导下，系统深入地探讨了大孔树脂精制中药复方的动力学过程，引入复杂体系中数据挖掘的方法对分离过程中多变量的相关性进行考察及知识发现，首次提出“基于知识发现的树脂组合”新概念，为创建面向中药复方复杂体系精制过程的新型大孔树脂技术，从而获取中药复方中科学合理的药效物质，迈出了重要的一步。
3、引入电镜扫描法，比较了大孔树脂精制中药复方前后，各大孔树脂本身表面及内部微观形态的变化，对精制过程进行综合考察。
本论文的研究意义：
1、为中药药剂学中提取及精制过程的研究提供了一条可与现代信息科学接轨的新思路。
2、精制是中成药生产过程中最关键的环节，也是目前制约中药质量提高的关键问题。本论文将中药复方作为一组特殊的化学药物整体进行“集群筛选”，依据现代分离科学理论，从分离的本质入手，以可实现生产上的在线检测为目标，初步建立了可科学、客观地表征中药水提液分离性质的、以溶液体系的物理化学特性量与主要化学组成特性量为主体组成的技术体系，为建立大孔树脂应用于生产的技术规范提供了简便易行的方法。
3、本论文运用数据挖掘的方法研究复方精制过程中不同成分间的竞争性吸附，以及如何保留原有复方中指标成分间的配比，阐明了各指标性成分的动力学过程。根据数据挖掘建立的数学模型和由此而衍生的知识发现，将实验中得到的大量纷繁复杂的数据进行了系统提练，即特征性地表征大孔树脂精制复方过程的动态变化，从而建立可与信息科学接轨的中药复杂系统表征技术体系，不仅可实现分离的靶向性，而且为初步探索现代分离科学理论在中药复方精制中的应用奠定了基础。
Chinese Medicine Compound, the quintessence of the theory of Traditional Chinese Medicine (TCM) and the main form of clinical application and foundation of proprietary Chinese Medicine production is extensively extracted with water and the decoction is applied to treat with many diseases. Thus, the substances that we separated form the decoction of TCM and Chinese Medicine Compound is helpful for our study up to now, and generally this substance is safe and effective to be used in clinic. How to maintain its advantage so as to Chinese Medicine Compound can play a better and more convenient role in modem society is important. In order to fully demonstrate the safety and effectiveness of Chinese medicine's preventing and have been treated diseases effectively for several thousand years, we must study on "inheritance" and "innovation" with Chinese Medicine Compound. Up to now, the basic research on the decoction of Chinese Medicine Compound and its refining process is essential, because Chinese Medicine Compound has more constituents than a single herbal medicine, and the study is so difficult that we use modem technology.
This dissertation is one of the studies on a complex system of Chinese Medicine Compound refined by the means of industrial isolation. Huanglianjiedu decoction is selected as experimental research system. Firstly, we took the study on the extraction process, and then, physical pharmacy were applied to investigate the active of the fractions that separated from the decoction, and statistical method was used to establish a forecast mathematical model so as to guide the extracting with Chinese herbal medicine. At last, we used macroporous resin technology that has been considered as modern separation and purification technology and widely applied in industrial production to separate and purify the Huanglianjiedu decoction. In this process, the data mining and knowledge discovery in database were applied to elucidate the separation and purification mechanism of macroporous resin. All of these studies are aimed to establish scientific expressional reference model when using this technology in modem medicine production, and ensure the safety and stability of Chinese Medicine Compound after being refined.
The premise study on separation and purification with Chinese Medicine Compound is the study on extraction with it. In this paper, firstly, we set our attention on precipitation that is obtained from decoction by extracted with water. Then, dynamic pseudomonas aeruginosa was used to study on the dissolution changes of multiple indexes substances from the extraction, and the changes of physical and chemical characterization parameters in this process were measured. In the end, mathematical and statistical methods were used to explore the mechanism of precipitation, and try to establish the relevant mathematical equations related guidance from Chinese herbal medicine.
In this dissertation, we developed a novel idea of applying modem information technology to study the process of extraction and refinement in the field of Chinese drugs pharmaceutics.
The process of separation and purification with TCM is the most crucial link in the production process of proprietary Chinese medicines, and the key issue which restrains the improvement of the Chinese herbal medicine quality. The technology of macroporous resin that play an role on adsorption_separation with TCM, as one of the high technologies that has been used in Chinese pharmaceutical industries must be promoted.
In this dissertation, Chinese Medicine Compound, considered as a special whole group of constituents was separated by "group selection". On the ground of modern separation scientific theory, we set about the common key issues which currently constraint macroporous resin technology, we combined advanced laboratory technology such as physical and chemical sciences to study on isolation and nature from the start, and then initially established a scientific, objective technical system which represents the separation characterization of Chinese Herbal Extract and recognized the physical and chemical properties of solution system (viscosity, turbidity, conductivity, pH, etc.) and the main chemical composition characteristics (pectin, starch, Tannins and key indicators components) as the main component.
In this dissertation, data mining methods were used to study and analysis competitive adsorption between different constituents groups in the refined process after the physics, chemistry, pharmacology and other data parameters were measured during the process of isolation with the decoction. This is the study on the characterization and kinetics of relevant components' solute transportion and proliferation. Through data mining and knowledge discovery, we systematically obtained a large number of data that changed from diverse and complex to simple, that is, through this study, we can mechanically indicate the component's movement in the macroporous resin, and then quantify the difference between multi component and the effective parts to achieve the target separation.
In this dissertation, the main studies are as following:
1. The method of HPLC was used to study the quality control of these four Chinese medicine herbs, which are Rhizoma Coptidis (Huanglian), Cortex Phellodendri (Huangbo), Radix Scutellariae (Huangqin) and Fructus Gardeniae (Zhizi) in this prescription. All kinds of herbs of different sources were collected for the study on the origin and content, so we could ensure the qualified and controlled original ingredients to be used in the experimental study.
2. The Change laws with Huanglianjiedu decoction in dynamic extracting process was detected by the method of indexes composition and physicochemical feature parameters through extracting with water from 10min to 120rain. The methods of UV and HPLC were used to study the dissolution laws of the different the indexes constituents including alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin, meanwhile, the changes on physical and chemical characterization including pH, conductivity, salinity, viscosity, turbidity of parameters system were detected. The quantity of solid was measured to estimate the rate of precipitation in dynamic process. Therefore, we can make a comparative analysis by combining the visual analysis and mathematical software analysis to detect the correlation between the the physical and chemical characterization parameters and components, and the correlation between characterization of the physical-chemical parameters and sedimentation rates, and the correlation between the composition and the rate of precipitation which we attempt to establish the relevant mathematical equations and models with, and explore the mechanism produced in this process. All of these provide basic evidence for the dynamic research in the process of Chinese Medicine Compound being boiled.
3. The comparative study on adsorption kinetics of single ingredients with nine different macroporous resins through static adsorption method. The methods of HPLC and UV were used to measure the quantity of relevant indicator constituents whose constant of adsorption rate, adsorption capacity and elution volume of different macroporous resins were detected closely. Different constituents have different rate of adsorption and elution, thus, the adsorption kinetics curve which the different constituents were drew with a different macroporous resin. Those data were related to the comparative study on adsorption kinetics in the process of adsorption.
4. According to study 1, those data, such as the constant of adsorption rate, the adsorption capacity and the elution volume of alkaloids, flavonoids were measured by the methods of HPLC and UV, and the different adsorption kinetics curves were drew, meanwhile, the single constituents, such as berberine, jatrorrhizine, palmatine, baicalin were studied with the same method. Then we studied on kinetics changes in the process of compound adsorption, and compared the changes with the related indicators of single ingredients. Meanwhile, one kind of resin AB-8 was chosen to observe the adsorption force under two different temperatures.
5. Beginning with the objective nature of the complex system deriving from Chinese medicine herbs' water extraction, the physical-chemical methods were used to study on the physical and chemical parameters of liquid system in the process of single ingredients and compound adsorption. In this study, static and dynamic adsorption methods were also chosen to determine pH, conductivity, salinity, viscosity, turbidity changes of those liquid samples in every steps, e. g., adsorption, water solution in the dynamic process, and elution. Thus, we detect deeply the change laws of these characteristic physical and chemical parameters to analysis the reasons for their changes.
6. The comparative study on adsorption kinetics of single ingredients with nine different macroporous resins through dynamic adsorption method. The methods of HPLC and UV were used to measure the quantity of relevant constituents including alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin and geniposide. Thus, we calculate the transfer rates and compare their quantities of solid between differentsamples.
7. We used inhibiting of platelet aggregation tests in vitro to compare the separation and purification products from nine different macroporous resins, and compared pharmacodynamics indicators between the products and samples before being refined.
8. Through data mining software, we set about study on data mining that be settled to detect the correlations among "characteristic parameters of macroporous resin adsorption-the amount of physical and chemical parameters before and after Chinese Medicine Compound being extracted and refined-the indicator components feature before and after Chinese medicine compound being extracted and refined-the characteristic parameters ofmacroporous resin adsorption kinietics-pharmacodynamica indicator characteristic parameters". Thus, we can fit different curves to build the relevant mathematical equations, and to detect mechanism of the separation and purification of the water extract of Chinese Medicine Compound by the means of macroporous resin. Then we look for the law to provide ideas and evidences which aim at designing a kind of special resins used in the complex system of Chinese Medicine Compound.
9. On the base of data mining and knowledge discovery, we designed five different resin compositions so as to begin with static and dynamic adsorption experiments. The amount of relevant indicator components, such as alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin and geniposide were measured, and these data were used to take a comparative study on the relevant adsorption parameters and curves which provide evidences for the data mining and the related knowledge discovery.
10. On the point of micro-perspective, we took in the research methods of microscopic particles so as to set about a comparative study on changes of nine different macroporous resins with their microstructures during the process from adsorption to elution by means of canning electron microscopy.
In this dissertation. The innovations are as following:
Under the guidance of Traditional Chinese Medicine theory, by the means of collecting amount of parameters of Chemistry of Chinese Materia Medica, Physical Chemistry and adsorption kinetics, the mechanism of extracting and refining of Chinese Medicine Compound was explored from the micro and precise point.
1. It's the first time that we apply dynamic study on extraction progress with Chinese Medicine Compound: multi-indicators detecting at the same time, combining the changes of the physical and chemical characterization parameters in the system, mathematical and statistical methods being used for exploring the dissolution law of constituents of Chinese medicine compound boiled with water, which providing a new method of inspecting craft model for overall evaluating dissolution situation of active constituents extracted by water, and further establishing characteristic physical and chemical parameters for quality control of extraction process on line.
2. Under the guidance of the theories of modern scientific isolation, On the base of data mining and knowledge discovery, we focus on the mechanisms of separation and purification with macroporous resin as using to refine Chinese herbal medicine. In this dissertation, it's the first time that we raise a novel concept of "based on new knowledge discovery of refining with assembly macroporous resin", which offered a new refining technique of macroporous resin to complex system of Chinese medicine compound, and it's an important step for obtaining effective substance from Chinese medicine compound.
3. We take a comparative study on the changes of its own external and internal micro-perspective shapes before and after different macroporous resins being used to refine Chinese Medicine Compound by the means of electron microscopy scanning for particulate research. Thus, we can analysis some relevant properties between Chinese Medicine Compound and the nature of macroporous resin during the refining process.
本论文是工业化分离手段用于中药复方复杂体系分离研究的方向之一，探索将复杂系统科学原理引入诠释中药复方提取及精制过程中所面临的共性关键技术，旨在从有效部位群分离筛选与物理化学表征参数的角度，建立可与信息科学接轨的中药复杂系统表征技术体系。
本论文选用物质基础研究较多、作用机理较明确的经典方——黄连解毒汤作为研究起点，首先，针对其复方提取过程中产生沉淀的现象进行深入的探讨，对其提取过程进行动态考察，从研究提取过程中多种指标性成分的溶出变化及中药复方水提液中特征物理化学表征参数的变化入手，采用数学统计的方法，探讨不同指标性成分及理化参数与汤剂溶出过程中所产生沉淀之间的关系，从而为提高该复方临床使用的有效性提供了理论依据；建立了各相关指标性成分的溶出数学模型，用于初步模拟复方提取中各指标性成分的动态变化过程，同时对提取过程中体系物理化学表征参数的变化进行相关分析，提示一定范围内可以通过各阶段提取液体系的物理化学特征参数对整个提取的动态过程进行在线控制。
其次，在上述研究的基础上，对复方黄连解毒汤精制过程进行探讨，选用已广泛用于工业生产的现代精制技术——大孔树脂吸附分离技术，精制中药复方水提液，针对目前制约大孔树脂吸附技术精制中药复方领域的共性关键问题，探索在现代分离科学原理的指导下，通过监控我们可检测到的指标性成分在大孔树脂上实现吸附—分离的动力学过程、精制过程中复方体系的物理化学特性参数的动态变化过程以及相关药效学指征，运用数据挖掘软件进行分析和知识发现，揭示大孔吸附树脂的特性与复方中不同指标性成分的含量及其吸附动力学过程之间、大孔吸附树脂的特性与复方精制过程中体系特征物理化学参数之间以及它们与相关药效指标之间的相关性的规律。同时结合对大孔吸附树脂精制复方前后其本身的微观变化进行综合分析，旨在为大孔树脂吸附分离技术用于精制中药复方建立可科学表达的参照模型，保证工业化生产中中药复方精制后的安全性、稳定性和等效性。
本论文的主要研究工作：
1、采用HPLC法对组方药材进行了质量控制研究，本复方由黄连、黄柏、黄芩、栀子组成，分别采集不同产地的各种药材进行基源及含量测定研究，确保合格可控的原药材用于本论文研究。
2、对复方提取过程进行动态研究，考察复方各项指标及参数在10min～120min的提取时间内的变化。分别运用UV、HPLC法研究复方提取过程中指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的溶出变化，同时分别采用不同理化测定仪器对提取过程中各药液的物理化学表征参数——溶液pH值、电导率、盐度、粘度、浊度的变化进行研究，并与复方提取过程中的沉淀率、固含率进行比较分析，采用直观分析与数理统计分析结合，探讨各物理化学表征参数与各指标性成分之间的相关性；各指标性成分与沉淀率、固含率之间的相关性；各物理化学表征参数与沉淀率、固含率之间的相关性，建立相关模拟数学方程和模型，探讨复方提取过程中沉淀产生变化的过程，为建立能以体系物理化学表征参数的变化来对复方提取进行在线控制，以及探讨建立中药复方提取动力学模型提供研究基础。
3、采用大孔树脂静态吸附法，对组方中各单味药材分别进行了九种不同大孔吸附树脂的吸附动力学研究，分别采用UV、HPLC法测定相关指标性成分的量，计算不同树脂的吸附速率常数、比吸附量、比洗脱量，以及不同成分的吸附率、洗脱率，绘制了不同树脂的吸附动力学曲线，对其吸附过程中的动力学变化进行了比较研究。
4、采用静态吸附法，对复方分别进行了九种不同大孔吸附树脂的吸附动力学研究，分别采用UV、HPLC法测定相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量，计算不同树脂分别相对于总生物碱、总黄酮的吸附速率常数、比吸附量、比洗脱量，以及吸附率、洗脱率，分别绘制了不同树脂的吸附动力学曲线，同时以其中单个成分小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量分别进行比洗脱量和洗脱率的比较，对其复方吸附分离中的动力学过程进行了比较研究。
5、从中药水提液复杂体系的客观本质入手，运用物理化学的研究方法，对复方吸附分离过程中溶液体系的物理化学表征参数进行了研究，分别测定了上样前药液、吸附后药液及洗脱后药液的pH值、电导率、盐度、粘度、浊度的变化，并对其变化进行比较分析。
6、采用动态上柱法，对组方单味药材及复方分别进行了九种不同大孔吸附树脂的动态吸附分离研究，分别采用UV、HPLC法测定相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量，计算其转移率。同时考察了精制过程中各体系的物理化学表征参数——溶液pH值、电导率、盐度、粘度、浊度的变化。
7、采用体外血小板抑制聚集试验对比了九种不同大孔树脂的分离精制产物与精制前的药效学变化。
8、运用数据挖掘软件，对有关“大孔吸附树脂特征参数量——中药复方提取液精制前后物理化学特征参数量——中药复方提取液精制前后指标性成分特性量——大孔树脂吸附动力学特征参数量——药效学指标之间相关性进行数据挖掘研究，拟合不同的曲线，建立相关的数学方程，探讨大孔吸附树脂分离中药复方水提液的相关规律及机理。
9、基于知识发现，设计五种不同的树脂组合，分别进行静态及动态吸附实验，对其吸附动力学过程以及各相关指标性成分——总生物碱、总黄酮、小檗碱、药根碱、巴马汀、黄芩苷、栀子苷的量进行比较研究。
10、借鉴微观粒子的研究手段，采用电镜扫描法，对不同大孔树脂分离复方的吸附前、吸附后及洗脱后，其本身的微观形态的变化进行比较研究。
本论文的创新点：
在中医药理论的指导下，从精密微观的角度探讨中药复方提取精制过程的作用机理，通过采集大量中药化学、物理化学、吸附动力学参数，开展多变量数据挖掘实验研究：
1、首次对中药复方提取过程进行动态研究：多指标同时考察、引入物理化学表征参数量，用数学统计的方法探讨其复方煎煮中成分溶出的规律，为创建一种可较全面评价药效物质溶出状况的工艺考察模式提供了新的思路，并为进一步建立能以提取液的物理化学表征参数对提取过程进行在线控制创造了条件。
2、在现代分离科学理论的指导下，系统深入地探讨了大孔树脂精制中药复方的动力学过程，引入复杂体系中数据挖掘的方法对分离过程中多变量的相关性进行考察及知识发现，首次提出“基于知识发现的树脂组合”新概念，为创建面向中药复方复杂体系精制过程的新型大孔树脂技术，从而获取中药复方中科学合理的药效物质，迈出了重要的一步。
3、引入电镜扫描法，比较了大孔树脂精制中药复方前后，各大孔树脂本身表面及内部微观形态的变化，对精制过程进行综合考察。
本论文的研究意义：
1、为中药药剂学中提取及精制过程的研究提供了一条可与现代信息科学接轨的新思路。
2、精制是中成药生产过程中最关键的环节，也是目前制约中药质量提高的关键问题。本论文将中药复方作为一组特殊的化学药物整体进行“集群筛选”，依据现代分离科学理论，从分离的本质入手，以可实现生产上的在线检测为目标，初步建立了可科学、客观地表征中药水提液分离性质的、以溶液体系的物理化学特性量与主要化学组成特性量为主体组成的技术体系，为建立大孔树脂应用于生产的技术规范提供了简便易行的方法。
3、本论文运用数据挖掘的方法研究复方精制过程中不同成分间的竞争性吸附，以及如何保留原有复方中指标成分间的配比，阐明了各指标性成分的动力学过程。根据数据挖掘建立的数学模型和由此而衍生的知识发现，将实验中得到的大量纷繁复杂的数据进行了系统提练，即特征性地表征大孔树脂精制复方过程的动态变化，从而建立可与信息科学接轨的中药复杂系统表征技术体系，不仅可实现分离的靶向性，而且为初步探索现代分离科学理论在中药复方精制中的应用奠定了基础。
Chinese Medicine Compound, the quintessence of the theory of Traditional Chinese Medicine (TCM) and the main form of clinical application and foundation of proprietary Chinese Medicine production is extensively extracted with water and the decoction is applied to treat with many diseases. Thus, the substances that we separated form the decoction of TCM and Chinese Medicine Compound is helpful for our study up to now, and generally this substance is safe and effective to be used in clinic. How to maintain its advantage so as to Chinese Medicine Compound can play a better and more convenient role in modem society is important. In order to fully demonstrate the safety and effectiveness of Chinese medicine's preventing and have been treated diseases effectively for several thousand years, we must study on "inheritance" and "innovation" with Chinese Medicine Compound. Up to now, the basic research on the decoction of Chinese Medicine Compound and its refining process is essential, because Chinese Medicine Compound has more constituents than a single herbal medicine, and the study is so difficult that we use modem technology.
This dissertation is one of the studies on a complex system of Chinese Medicine Compound refined by the means of industrial isolation. Huanglianjiedu decoction is selected as experimental research system. Firstly, we took the study on the extraction process, and then, physical pharmacy were applied to investigate the active of the fractions that separated from the decoction, and statistical method was used to establish a forecast mathematical model so as to guide the extracting with Chinese herbal medicine. At last, we used macroporous resin technology that has been considered as modern separation and purification technology and widely applied in industrial production to separate and purify the Huanglianjiedu decoction. In this process, the data mining and knowledge discovery in database were applied to elucidate the separation and purification mechanism of macroporous resin. All of these studies are aimed to establish scientific expressional reference model when using this technology in modem medicine production, and ensure the safety and stability of Chinese Medicine Compound after being refined.
The premise study on separation and purification with Chinese Medicine Compound is the study on extraction with it. In this paper, firstly, we set our attention on precipitation that is obtained from decoction by extracted with water. Then, dynamic pseudomonas aeruginosa was used to study on the dissolution changes of multiple indexes substances from the extraction, and the changes of physical and chemical characterization parameters in this process were measured. In the end, mathematical and statistical methods were used to explore the mechanism of precipitation, and try to establish the relevant mathematical equations related guidance from Chinese herbal medicine.
In this dissertation, we developed a novel idea of applying modem information technology to study the process of extraction and refinement in the field of Chinese drugs pharmaceutics.
The process of separation and purification with TCM is the most crucial link in the production process of proprietary Chinese medicines, and the key issue which restrains the improvement of the Chinese herbal medicine quality. The technology of macroporous resin that play an role on adsorption_separation with TCM, as one of the high technologies that has been used in Chinese pharmaceutical industries must be promoted.
In this dissertation, Chinese Medicine Compound, considered as a special whole group of constituents was separated by "group selection". On the ground of modern separation scientific theory, we set about the common key issues which currently constraint macroporous resin technology, we combined advanced laboratory technology such as physical and chemical sciences to study on isolation and nature from the start, and then initially established a scientific, objective technical system which represents the separation characterization of Chinese Herbal Extract and recognized the physical and chemical properties of solution system (viscosity, turbidity, conductivity, pH, etc.) and the main chemical composition characteristics (pectin, starch, Tannins and key indicators components) as the main component.
In this dissertation, data mining methods were used to study and analysis competitive adsorption between different constituents groups in the refined process after the physics, chemistry, pharmacology and other data parameters were measured during the process of isolation with the decoction. This is the study on the characterization and kinetics of relevant components' solute transportion and proliferation. Through data mining and knowledge discovery, we systematically obtained a large number of data that changed from diverse and complex to simple, that is, through this study, we can mechanically indicate the component's movement in the macroporous resin, and then quantify the difference between multi component and the effective parts to achieve the target separation.
In this dissertation, the main studies are as following:
1. The method of HPLC was used to study the quality control of these four Chinese medicine herbs, which are Rhizoma Coptidis (Huanglian), Cortex Phellodendri (Huangbo), Radix Scutellariae (Huangqin) and Fructus Gardeniae (Zhizi) in this prescription. All kinds of herbs of different sources were collected for the study on the origin and content, so we could ensure the qualified and controlled original ingredients to be used in the experimental study.
2. The Change laws with Huanglianjiedu decoction in dynamic extracting process was detected by the method of indexes composition and physicochemical feature parameters through extracting with water from 10min to 120rain. The methods of UV and HPLC were used to study the dissolution laws of the different the indexes constituents including alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin, meanwhile, the changes on physical and chemical characterization including pH, conductivity, salinity, viscosity, turbidity of parameters system were detected. The quantity of solid was measured to estimate the rate of precipitation in dynamic process. Therefore, we can make a comparative analysis by combining the visual analysis and mathematical software analysis to detect the correlation between the the physical and chemical characterization parameters and components, and the correlation between characterization of the physical-chemical parameters and sedimentation rates, and the correlation between the composition and the rate of precipitation which we attempt to establish the relevant mathematical equations and models with, and explore the mechanism produced in this process. All of these provide basic evidence for the dynamic research in the process of Chinese Medicine Compound being boiled.
3. The comparative study on adsorption kinetics of single ingredients with nine different macroporous resins through static adsorption method. The methods of HPLC and UV were used to measure the quantity of relevant indicator constituents whose constant of adsorption rate, adsorption capacity and elution volume of different macroporous resins were detected closely. Different constituents have different rate of adsorption and elution, thus, the adsorption kinetics curve which the different constituents were drew with a different macroporous resin. Those data were related to the comparative study on adsorption kinetics in the process of adsorption.
4. According to study 1, those data, such as the constant of adsorption rate, the adsorption capacity and the elution volume of alkaloids, flavonoids were measured by the methods of HPLC and UV, and the different adsorption kinetics curves were drew, meanwhile, the single constituents, such as berberine, jatrorrhizine, palmatine, baicalin were studied with the same method. Then we studied on kinetics changes in the process of compound adsorption, and compared the changes with the related indicators of single ingredients. Meanwhile, one kind of resin AB-8 was chosen to observe the adsorption force under two different temperatures.
5. Beginning with the objective nature of the complex system deriving from Chinese medicine herbs' water extraction, the physical-chemical methods were used to study on the physical and chemical parameters of liquid system in the process of single ingredients and compound adsorption. In this study, static and dynamic adsorption methods were also chosen to determine pH, conductivity, salinity, viscosity, turbidity changes of those liquid samples in every steps, e. g., adsorption, water solution in the dynamic process, and elution. Thus, we detect deeply the change laws of these characteristic physical and chemical parameters to analysis the reasons for their changes.
6. The comparative study on adsorption kinetics of single ingredients with nine different macroporous resins through dynamic adsorption method. The methods of HPLC and UV were used to measure the quantity of relevant constituents including alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin and geniposide. Thus, we calculate the transfer rates and compare their quantities of solid between differentsamples.
7. We used inhibiting of platelet aggregation tests in vitro to compare the separation and purification products from nine different macroporous resins, and compared pharmacodynamics indicators between the products and samples before being refined.
8. Through data mining software, we set about study on data mining that be settled to detect the correlations among "characteristic parameters of macroporous resin adsorption-the amount of physical and chemical parameters before and after Chinese Medicine Compound being extracted and refined-the indicator components feature before and after Chinese medicine compound being extracted and refined-the characteristic parameters ofmacroporous resin adsorption kinietics-pharmacodynamica indicator characteristic parameters". Thus, we can fit different curves to build the relevant mathematical equations, and to detect mechanism of the separation and purification of the water extract of Chinese Medicine Compound by the means of macroporous resin. Then we look for the law to provide ideas and evidences which aim at designing a kind of special resins used in the complex system of Chinese Medicine Compound.
9. On the base of data mining and knowledge discovery, we designed five different resin compositions so as to begin with static and dynamic adsorption experiments. The amount of relevant indicator components, such as alkaloids, flavonoids, berberine, jatrorrhizine, palmatine, baicalin and geniposide were measured, and these data were used to take a comparative study on the relevant adsorption parameters and curves which provide evidences for the data mining and the related knowledge discovery.
10. On the point of micro-perspective, we took in the research methods of microscopic particles so as to set about a comparative study on changes of nine different macroporous resins with their microstructures during the process from adsorption to elution by means of canning electron microscopy.
In this dissertation. The innovations are as following:
Under the guidance of Traditional Chinese Medicine theory, by the means of collecting amount of parameters of Chemistry of Chinese Materia Medica, Physical Chemistry and adsorption kinetics, the mechanism of extracting and refining of Chinese Medicine Compound was explored from the micro and precise point.
1. It's the first time that we apply dynamic study on extraction progress with Chinese Medicine Compound: multi-indicators detecting at the same time, combining the changes of the physical and chemical characterization parameters in the system, mathematical and statistical methods being used for exploring the dissolution law of constituents of Chinese medicine compound boiled with water, which providing a new method of inspecting craft model for overall evaluating dissolution situation of active constituents extracted by water, and further establishing characteristic physical and chemical parameters for quality control of extraction process on line.
2. Under the guidance of the theories of modern scientific isolation, On the base of data mining and knowledge discovery, we focus on the mechanisms of separation and purification with macroporous resin as using to refine Chinese herbal medicine. In this dissertation, it's the first time that we raise a novel concept of "based on new knowledge discovery of refining with assembly macroporous resin", which offered a new refining technique of macroporous resin to complex system of Chinese medicine compound, and it's an important step for obtaining effective substance from Chinese medicine compound.
3. We take a comparative study on the changes of its own external and internal micro-perspective shapes before and after different macroporous resins being used to refine Chinese Medicine Compound by the means of electron microscopy scanning for particulate research. Thus, we can analysis some relevant properties between Chinese Medicine Compound and the nature of macroporous resin during the refining process.
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