【摘要】：高尿酸血癥是由基因遺傳或尿酸轉(zhuǎn)運(yùn)系統(tǒng)異常,引起嘌呤代謝紊亂,導(dǎo)致生成的尿酸在體內(nèi)蓄積、排泄受阻的一種疾病。高尿酸血癥不僅是痛風(fēng)病的發(fā)病基礎(chǔ),還與糖尿病、高血壓等心血管疾病密切相關(guān),嚴(yán)重威脅到人類的身體健康。近年來(lái),高尿酸血癥患者的數(shù)量越來(lái)越多,雖然降高尿酸西藥藥效快,但同時(shí)也帶來(lái)了一系列副反應(yīng)。因此,資源豐富,種類繁多的天然降尿酸藥物擁有巨大的開(kāi)發(fā)潛力,市場(chǎng)前景廣闊。但目前研究依然存在很多問(wèn)題,例如,藥物體內(nèi)篩選模型不穩(wěn)定、藥物降尿酸活性成分不明確等。本文建立了一種穩(wěn)定可靠的降尿酸藥物篩選模型,通過(guò)均勻設(shè)計(jì)法,結(jié)合藥效分析法,篩選出能夠確切治療高尿酸血癥的中藥組合物,并對(duì)其藥理機(jī)制和制劑工藝展開(kāi)研究與討論,有效地解決了天然降尿酸藥物研發(fā)中存在的一些問(wèn)題,為天然抗痛風(fēng)新制劑的研發(fā)提供參考。課題內(nèi)容包括以下六個(gè)章節(jié):第一章綜述本章節(jié)介紹了降尿酸天然產(chǎn)物的研究概況,并從降尿酸天然產(chǎn)物活性成分的分類及其作用機(jī)制、制劑和微丸制劑幾個(gè)方面進(jìn)行概述,為實(shí)驗(yàn)部分的研究奠定理論基礎(chǔ)。第二章尿酸分析方法及高尿酸血癥模型的建立本章節(jié)建立了RP-HPLC法分析小鼠體內(nèi)尿酸含量,方法學(xué)驗(yàn)證結(jié)果表明,該方法能夠準(zhǔn)確地檢測(cè)出小鼠血尿酸值;以次黃嘌呤(100 mg/mL)和氧嗪酸鉀乳劑(25 mg/mL)為造模劑,以別嘌醇為陽(yáng)性對(duì)照藥,建立小鼠急性高尿酸血癥模型,結(jié)果證明了該模型非常穩(wěn)定、重現(xiàn)性好、易于調(diào)控。第三章降尿酸中藥活性部位篩選本章節(jié)采用水提法和醇提法從8味中藥材中提取分離出16種中藥提取液;通過(guò)小鼠急性高尿酸血癥模型,對(duì)16種提取液進(jìn)行藥效學(xué)研究,以小鼠體內(nèi)的尿酸值為評(píng)價(jià)指標(biāo),初步篩出具有降尿酸作用的中藥活性部位。結(jié)果發(fā)現(xiàn),高良姜醇提物、車前草醇提物、蒲公英醇提物、甘草醇提物、菊苣水提物可明顯降低急性高尿酸血癥小鼠體內(nèi)的尿酸濃度(P0.05,P0.05,P0.05,P0.05,P0.05),為進(jìn)一步深入研究天然活性藥物抗痛風(fēng)作用奠定藥效基礎(chǔ)。第四章基于均勻設(shè)計(jì)的降尿酸中藥組方篩選在前期實(shí)驗(yàn)研究的基礎(chǔ)上,本章節(jié)將數(shù)學(xué)模型應(yīng)用于中醫(yī)藥研究,遵循中藥復(fù)方配伍理念,發(fā)揮中藥復(fù)方多途徑藥理作用優(yōu)勢(shì),采用均勻設(shè)計(jì)法設(shè)計(jì)實(shí)驗(yàn),建立小鼠高尿酸模型,以藥效為評(píng)價(jià)指標(biāo),尋找最佳藥物組合和最佳處方比例。結(jié)果發(fā)現(xiàn),中藥組合物的最優(yōu)組合為甘草醇提物、高良姜醇提物、蒲公英醇提物、菊苣水提物、車前草醇提物,最佳配比為10:8:7:6:10。此外,對(duì)最優(yōu)處方的作用機(jī)制進(jìn)行了考察,結(jié)果發(fā)現(xiàn),最優(yōu)處方通過(guò)抑制高尿酸血癥小鼠體內(nèi)的XOD活性和促進(jìn)尿酸排泄這兩種途徑有效降低小鼠血尿酸值。第五章降尿酸中藥組合物制劑工藝研究本章以五種藥材有效部位提取物為原料藥,參照中藥劑型選擇的基本原則,選用緩和、持久的微丸劑型,采用擠出滾圓法制備微丸,對(duì)擠出滾圓的各個(gè)工藝參數(shù)進(jìn)行了優(yōu)化,確定了最佳的擠出轉(zhuǎn)速、滾圓轉(zhuǎn)速和滾圓時(shí)間分別為40 RPM、35 RPM和3 min。最后,從微丸圓整度、收率及穩(wěn)定性等方面對(duì)降尿酸微丸進(jìn)行了體外評(píng)價(jià)。實(shí)驗(yàn)結(jié)果顯示,制備的微丸圓整度為(16.78±0.57)°,收率為(71.55±1.08)%,收率良好,批間差異小,符合相關(guān)制劑學(xué)要求。第六章降尿酸微丸有效成分的含量測(cè)定及藥效學(xué)研究本章節(jié)首先對(duì)微丸中的黃酮和粗多糖成分進(jìn)行定性分析,接著,以蘆丁為對(duì)照品,建立了紫外分光光度法測(cè)定降尿酸微丸中總黃酮含量的分析方法,并同時(shí)建立了苯酚-硫酸法測(cè)定降尿酸微丸中粗多糖含量的分析方法,最后,評(píng)價(jià)微丸制劑的降尿酸效果。結(jié)果測(cè)得:微丸中總黃酮含量約為10%,粗多糖含量約為1.94%,為降尿酸微丸治療痛風(fēng)病建立了質(zhì)量標(biāo)準(zhǔn);降尿酸微丸具有顯著降尿酸作用(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) 擄, 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.
【學(xué)位授予單位】：江蘇大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R283.6

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