降尿酸中药组合物活性成分筛选及其制剂工艺研究

发布时间：2019-06-11 00:18

【摘要】：高尿酸血症是由基因遗传或尿酸转运系统异常,引起嘌呤代谢紊乱,导致生成的尿酸在体内蓄积、排泄受阻的一种疾病。高尿酸血症不仅是痛风病的发病基础,还与糖尿病、高血压等心血管疾病密切相关,严重威胁到人类的身体健康。近年来,高尿酸血症患者的数量越来越多,虽然降高尿酸西药药效快,但同时也带来了一系列副反应。因此,资源丰富,种类繁多的天然降尿酸药物拥有巨大的开发潜力,市场前景广阔。但目前研究依然存在很多问题,例如,药物体内筛选模型不稳定、药物降尿酸活性成分不明确等。本文建立了一种稳定可靠的降尿酸药物筛选模型,通过均匀设计法,结合药效分析法,筛选出能够确切治疗高尿酸血症的中药组合物,并对其药理机制和制剂工艺展开研究与讨论,有效地解决了天然降尿酸药物研发中存在的一些问题,为天然抗痛风新制剂的研发提供参考。课题内容包括以下六个章节:第一章综述本章节介绍了降尿酸天然产物的研究概况,并从降尿酸天然产物活性成分的分类及其作用机制、制剂和微丸制剂几个方面进行概述,为实验部分的研究奠定理论基础。第二章尿酸分析方法及高尿酸血症模型的建立本章节建立了RP-HPLC法分析小鼠体内尿酸含量,方法学验证结果表明,该方法能够准确地检测出小鼠血尿酸值;以次黄嘌呤(100 mg/mL)和氧嗪酸钾乳剂(25 mg/mL)为造模剂,以别嘌醇为阳性对照药,建立小鼠急性高尿酸血症模型,结果证明了该模型非常稳定、重现性好、易于调控。第三章降尿酸中药活性部位筛选本章节采用水提法和醇提法从8味中药材中提取分离出16种中药提取液;通过小鼠急性高尿酸血症模型,对16种提取液进行药效学研究,以小鼠体内的尿酸值为评价指标,初步筛出具有降尿酸作用的中药活性部位。结果发现,高良姜醇提物、车前草醇提物、蒲公英醇提物、甘草醇提物、菊苣水提物可明显降低急性高尿酸血症小鼠体内的尿酸浓度(P0.05,P0.05,P0.05,P0.05,P0.05),为进一步深入研究天然活性药物抗痛风作用奠定药效基础。第四章基于均匀设计的降尿酸中药组方筛选在前期实验研究的基础上,本章节将数学模型应用于中医药研究,遵循中药复方配伍理念,发挥中药复方多途径药理作用优势,采用均匀设计法设计实验,建立小鼠高尿酸模型,以药效为评价指标,寻找最佳药物组合和最佳处方比例。结果发现,中药组合物的最优组合为甘草醇提物、高良姜醇提物、蒲公英醇提物、菊苣水提物、车前草醇提物,最佳配比为10:8:7:6:10。此外,对最优处方的作用机制进行了考察,结果发现,最优处方通过抑制高尿酸血症小鼠体内的XOD活性和促进尿酸排泄这两种途径有效降低小鼠血尿酸值。第五章降尿酸中药组合物制剂工艺研究本章以五种药材有效部位提取物为原料药,参照中药剂型选择的基本原则,选用缓和、持久的微丸剂型,采用挤出滚圆法制备微丸,对挤出滚圆的各个工艺参数进行了优化,确定了最佳的挤出转速、滚圆转速和滚圆时间分别为40 RPM、35 RPM和3 min。最后,从微丸圆整度、收率及稳定性等方面对降尿酸微丸进行了体外评价。实验结果显示,制备的微丸圆整度为(16.78±0.57)°,收率为(71.55±1.08)%,收率良好,批间差异小,符合相关制剂学要求。第六章降尿酸微丸有效成分的含量测定及药效学研究本章节首先对微丸中的黄酮和粗多糖成分进行定性分析,接着,以芦丁为对照品,建立了紫外分光光度法测定降尿酸微丸中总黄酮含量的分析方法,并同时建立了苯酚-硫酸法测定降尿酸微丸中粗多糖含量的分析方法,最后,评价微丸制剂的降尿酸效果。结果测得:微丸中总黄酮含量约为10%,粗多糖含量约为1.94%,为降尿酸微丸治疗痛风病建立了质量标准;降尿酸微丸具有显著降尿酸作用(P0.01)。
[Abstract]:Hyperuricemia is a disease that is caused by an abnormality in the genetic or uric acid transport system of a gene, which causes a disorder in the metabolism of the methotrexate, which results in the accumulation of the generated uric acid in the body and the obstruction of excretion. Hyperuricemia is not only the basis of gout, but also is closely related to cardiovascular diseases such as diabetes and hypertension, which is a serious threat to human health. In recent years, the number of hyperuricemia patients is more and more, although the drug effect of reducing the hyperuricemia is fast, a series of side reactions are also brought. Therefore, the resource is rich, and a wide variety of natural uric acid drugs have great development potential, and the market prospect is wide. However, there are still many problems in the study, for example, the drug-in-vivo screening model is not stable, the drug-lowering uric acid active ingredient is not clear, and the like. A stable and reliable drug screening model for reducing uric acid is set up in this paper. By means of uniform design, the traditional Chinese medicine composition can be used for treating hyperuricemia, and its pharmacological mechanism and preparation process are studied and discussed. The invention effectively solves some problems existing in the research and development of the natural anti-gout medicine, and provides a reference for the research and development of the natural anti-gout new preparation. The contents of the subject include the following six chapters: Chapter 1: Overview of the study on the natural products of lowering uric acid, and the classification of the active components of the natural product of lowering uric acid and its mechanism of action, preparation and pellet preparation. And lays a theoretical foundation for the research of the experimental part. In the second chapter, the method of uric acid analysis and the establishment of hyperuricemia model were established. The content of uric acid in mice was analyzed by RP-HPLC. The results showed that the method can accurately detect the blood uric acid value of the mouse. The model of acute hyperuricemia in mice was established with the administration of subflavine (100 mg/ mL) and potassium oxymetaconic acid (25 mg/ mL) as the model, and the model of acute hyperuricemia in mice was established. The results showed that the model was very stable, good in reproducibility and easy to control. In the third chapter, the active part of the traditional Chinese medicine for lowering the uric acid is selected from 8 Chinese medicinal materials by using a water extraction method and an alcohol extraction method, and 16 Chinese medicinal extractive solutions are separated from the 8 Chinese medicinal materials, and the 16 kinds of extraction liquid are subjected to pharmacodynamic research through the mouse acute hyperuricemia model, and the uric acid value in the mouse body is the evaluation index, The active part of the traditional Chinese medicine with the action of lowering the uric acid is preliminarily screened out. The results showed that the extract of Alpinia officinarum, the alcohol extract of Herba Plantaginis, the ethanol extract of Herba Taraxaci, the extract of Radix Glycyrrhizae, and the aqueous extract of Herba Cichorii can obviously reduce the uric acid concentration in the mice with acute hyperuricemia (P0.05, P0.05, P0.05, P0.05, P0.05). In ord to further study that effect of the natural active drug for anti-gout. In the fourth chapter, based on the screening of the traditional Chinese medicine for lowering the uric acid based on the uniform design, the mathematical model is applied to the research of the traditional Chinese medicine, and the compound compatibility of the traditional Chinese medicine is followed, the advantages of the compound multi-way pharmacological action of the traditional Chinese medicine are taken into play, and the experiment is designed by adopting a uniform design method. A mouse hyperuricemia model was established to evaluate the drug effect as an evaluation index to find the optimal drug combination and the optimal formulation ratio. The results show that the optimal combination of the Chinese medicinal composition is the extract of the licorice, the extract of the high-galangal, the ethanol extract of the dandelion, the aqueous extract of the chicory, the alcohol extract of the plantain, the optimum ratio is 10:8:7:6:10. In addition, the mechanism of the optimal prescription was investigated, and the results showed that the optimal prescription can effectively reduce the blood uric acid value of the mouse by inhibiting the XOD activity in the hyperuricemia mice and promoting the excretion of uric acid. in that fifth chap, the preparation proces of the traditional Chinese medicine composition for lowering the uric acid is prepared by taking the effective part extract of the five medicinal materials as the raw material, referring to the basic principle of the selection of the traditional Chinese medicine dosage form, selecting a mild and durable micropill type, and adopting an extrusion rolling circle method to prepare the pellet, The optimum extrusion speed, the rolling speed and the rolling time were 40 RPM,35 RPM and 3 min, respectively. Finally, the in vitro evaluation of the reduction of uric acid pellets was carried out from the aspects of the roundness, the yield and the stability of the pellets. The results showed that the circularity of the pellets prepared was (16.78-0.57) 掳, the yield was (71.55-1.08)%, the yield was good, the inter-batch difference was small, and it was in accordance with the relevant preparation requirements. In chapter 6, the content and pharmacodynamics of the effective components of the lower uric acid pellets were determined. The contents of the total flavonoids and the crude polysaccharide in the pellets were analyzed by using the rutin as the control, and the determination of the total flavonoids in the lower uric acid pellets was established by UV-spectrophotometry. The method for determining the content of crude polysaccharide in the reduction of uric acid pellets by phenol-sulfuric acid method is also established, and the effect of reducing the uric acid of the pellet preparation is finally evaluated. The results showed that the total flavonoids in the pellets were about 10%, the content of crude polysaccharide was about 1.94%, and the quality standard was established for the treatment of gout.
【学位授予单位】：江苏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R283.6

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