本文選題：天然藥物 + 鎮(zhèn)靜催眠　； 參考：《江蘇大學》2017年碩士論文

【摘要】：睡眠是人體重要的生理功能,高質(zhì)量而充足的睡眠可以有效恢復人體機能。睡眠由中樞神經(jīng)系統(tǒng)發(fā)生并受之調(diào)控,同時也受機體與外界多種因素影響。隨著現(xiàn)代社會壓力的不斷增加,失眠現(xiàn)象普遍發(fā)生,失眠發(fā)病率逐年提高,嚴重影響著人們的工作生活。西醫(yī)藥物治療主要為鎮(zhèn)靜催眠藥,存在較大的副作用,如安全性低、依賴性、成癮性和戒斷性等,因而其應用受到限制。近年來研究發(fā)現(xiàn),許多天然藥物(中藥組方、中藥提取物、中藥活性成分及天然活性單體)具有良好的鎮(zhèn)靜催眠作用,而且副作用小,具有良好的開發(fā)研究價值。因此,本課題從傳統(tǒng)中藥中探尋具有改善睡眠作用的活性物質(zhì),并對活性成分的納米制劑進行研究。第一章綜述本章對天然藥物治療失眠的研究現(xiàn)狀進行綜述,重點總結(jié)分析了近10年來天然來源的鎮(zhèn)靜催眠單體及其作用機制的研究進展,展望了鎮(zhèn)靜催眠中藥單體的研究新方向。隨著天然產(chǎn)物研究的不斷深入,從天然產(chǎn)物中尋找天然助眠活性成分將成為今后失眠研究的重要方向。第二章助眠天然藥物JD-XM1提取工藝及活性部位藥效研究本章以藥效跟蹤法,從天然藥物JD-XM1中篩選鎮(zhèn)靜催眠活性部位,并對活性部位藥效進行評價。單因素法篩選JD-XM1的提取工藝,優(yōu)選提取工藝為:乙醇濃度70%、提取溫度90 oC、提取時間2 h、液固比12:1。JD-XM1提取物依次用石油醚、二氯甲烷、乙酸乙酯及正丁醇萃取,以閾劑量戊巴比妥鈉誘導小鼠睡眠試驗評價各極性部位藥效,與空白組相比,正丁醇組部位能夠顯著縮短睡眠潛伏期(182.7±7.6 vs 227.7±29.7 s,P0.01),延長睡眠時間(5518.7±1558.3 vs 2265.8±606.0 s,P0.01)。小鼠自主活動試驗和PCPA致小鼠失眠模型評價JD-XM1正丁醇部位藥效,結(jié)果表明,正丁醇部位能夠顯著減少活動距離(P0.01)和活動時間(P0.05),且呈現(xiàn)劑量相關性。正丁醇部位可恢復PCPA導致的小鼠失眠行為,與模型組相比,正丁醇部位(300 mg/kg)可縮短戊巴比妥鈉誘導的睡眠潛伏期,延長睡眠時間(P0.01)。第三章JD-XM1助眠活性成分的篩選及其結(jié)構(gòu)分析研究本章采用活性跟蹤法,從JD-XM1的正丁醇活性部位中,系統(tǒng)分離純化具有鎮(zhèn)靜催眠作用的活性單體,并進行結(jié)構(gòu)解析。采用硅膠層析柱對JD-XM1正丁醇活性部位進行分離純化,得到多種流分。閾劑量戊巴比妥鈉誘導小鼠睡眠試驗篩選,發(fā)現(xiàn)Fr 6流分(二氯甲烷:甲醇=2:1)能夠縮短戊巴比妥鈉誘導的睡眠潛伏期,延長睡眠時間。C18柱對Fr 6繼續(xù)純化,得到白色粉末Compound A,通過NMR和MS進行結(jié)構(gòu)鑒定,為3,5-二甲氧基-4-羥基苯甲酸(丁香酸)。鎮(zhèn)靜催眠藥效實驗顯示,高劑量丁香酸(200 mg/kg)能夠顯著延長戊巴比妥鈉誘導的睡眠時間(P0.01),縮短睡眠潛伏期(P0.05),并呈現(xiàn)劑量相關性。第四章丁香酸脂質(zhì)體的制備及其體外評價針對本文篩選出來的JD-XM1活性成分丁香酸,本章建立了HPLC丁香酸的體外分析方法,并進行了方法學考察。結(jié)果表明,建立的體外分析方法,系統(tǒng)適用性好,制劑輔料對分析無干擾;在0.5-100μg/m L范圍內(nèi)線性關系良好;48 h內(nèi)穩(wěn)定性良好;方法日內(nèi)/日間精密度高(RSD2%);方法回收率高,可用于丁香酸的定量分析。平衡溶解度實驗表明,丁香酸在各種介質(zhì)中的溶解度均較低,在p H 7.4磷酸緩沖液中的溶解度最大,但僅為78.82±4.68μg/m L,而在水和p H 1.2鹽酸溶液中的溶解度接近,分別為66.05±2.65μg/m L和66.86±2.19μg/m L,表明丁香酸的溶解度較差。此外,油水分配系數(shù)測定表明,丁香酸log P為1.31,表明丁香酸口服后不易在胃腸道內(nèi)吸收。以薄膜分散法制備丁香酸脂質(zhì)體,單因素法篩選處方,優(yōu)選處方為丁香酸100 mg,大豆磷脂1200 mg,膽固醇200 mg,膽酸鈉800 mg,肉豆蔻酸異丙酯800 mg,水化介質(zhì)為20 m L的PBS(p H 7.4),制得的丁香酸脂質(zhì)體澄清,包封率高(82.20±2.30%)。體外表征表明,制備的丁香酸脂質(zhì)體呈類球形,分布均勻,平均粒徑為154.67±7.09nm,粒徑分布較窄,分散性系數(shù)(PDI)為0.14±0.04,Zeta電位為-27.61±3.65 m V。穩(wěn)定性試驗表明,丁香酸脂質(zhì)體15天穩(wěn)定性良好,未出現(xiàn)明顯的絮凝或渾濁現(xiàn)象,且包封率未有明顯變化。第五章丁香酸脂質(zhì)體大鼠體內(nèi)藥動學及小鼠組織分布研究本章以HPLC建立了測定大鼠血漿及小鼠組織中丁香酸含量的體內(nèi)分析方法,并進行了方法學考察。在不同生物樣品中,線性均良好(r20.99),日內(nèi)、日間精密度均小于5%,樣品回收率良好,符合體內(nèi)藥物檢測的方法學要求。丁香酸脂質(zhì)體的大鼠藥動學研究表明,丁香酸脂質(zhì)體可以提高口服生物利用度。與丁香酸原料藥相比,丁香酸脂質(zhì)體提高了Cmax,給藥95 min之后的血藥濃度均高于原料藥(1.81±0.94 vs 0.12±0.03μg/m L),表明脂質(zhì)體能夠增加藥物吸收,且延緩了丁香酸在體內(nèi)的消除;t1/2顯著延長(116.67±14.40 vs 25.36±1.99 min),平均滯留時間顯著延長(286.27±18.32 vs 37.98±1.02 min),說明脂質(zhì)體能夠延長丁香酸在體循環(huán)時間;丁香酸脂質(zhì)體顯著提高了口服生物利用度,藥時曲線下面積AUC0-360min顯著提高,為原料藥的237.30%。丁香酸脂質(zhì)體的小鼠組織分布研究表明,丁香酸原料藥在血漿中的濃度隨著時間的延長快速下降,而脂質(zhì)體在0.5 h和2 h的血藥濃度均顯著高于原料藥,說明脂質(zhì)體能夠減緩藥物消除過程,延長藥物在體時間;丁香酸及丁香酸脂質(zhì)體在各組織器官中藥物濃度大小依次為:腎肝肺脾心腦,均趨向于向腎、肝分布;腦部能夠檢測到丁香酸,說明丁香酸能夠透過血腦屏障(BBB),脂質(zhì)體可減緩藥物在腦部的消除,延長藥物在腦部的滯留時間,以發(fā)揮鎮(zhèn)靜催眠作用。
[Abstract]:Sleep is an important physiological function of the human body. High quality and sufficient sleep can effectively restore the function of the human body. Sleep is controlled by the central nervous system and is regulated by the body and a variety of external factors. With the increasing pressure of modern society, insomnia is widespread, the incidence of insomnia is increasing year by year, which seriously affects the incidence of insomnia. People's working life. Western medicine is mainly composed of sedative and hypnotic drugs, which have large side effects, such as low safety, dependence, addiction and abstinence, so their application is limited. In recent years, many natural drugs (traditional Chinese medicine, traditional Chinese medicine extract, active ingredients of Chinese medicine and natural active monomer) have good town. The static hypnotic effect, and the side effect is small, has the good development research value. Therefore, this topic seeks to improve the sleep activity from the traditional Chinese medicine, and studies the nanoscale preparation of the active ingredient. The first chapter summarizes the review of this chapter on the research status of insomnia in the treatment of natural drugs, focusing on the analysis of nearly 10 The research progress of the sedative hypnotic monomers and their mechanisms of action of natural sources in the past year, the new direction of the study of sedative hypnotic Chinese medicine monomers is prospected. With the development of natural products, the search for natural hypnotic active components from natural products will become an important direction for the study of insomnia in the future. The second part of the JD-XM1 extraction of natural drugs The study on the efficacy of the active site in this chapter is to screen the sedative hypnotic active parts from the natural drug JD-XM1 and evaluate the active sites. The single factor method is used to select the extraction process of JD-XM1. The optimum extraction process is as follows: the concentration of ethanol is 70%, the extraction temperature is 90 oC, the extraction time is 2 h, and the liquid and solid ratio 12:1.JD-XM1 extract is used in turn. Petroleum ether, dichloromethane, ethyl acetate and n-butanol were extracted with the threshold dose pentobarbital sodium induced mouse sleep test to evaluate the efficacy of each polar part. Compared with the blank group, the n-butanol group could significantly shorten the sleep latency (182.7 + 7.6 vs 227.7 + 29.7 s, P0.01), and prolong the sleep time (5518.7 + 1558.3 vs 2265.8 + 606 s, P0.01). The mouse autonomic activity test and PCPA induced insomnia model evaluated the efficacy of JD-XM1 butanol. The results showed that the location of n-butanol could significantly reduce the activity distance (P0.01) and activity time (P0.05), and showed a dose correlation. The location of n-butanol could restore the behavior of insomnia caused by PCPA, compared with the model group (300 mg/kg). It can shorten the sleep latency induced by pentobarbital sodium and prolong the sleep time (P0.01). Third chapter JD-XM1 the screening and structural analysis of the active components of the hypnotic activity. This chapter uses the active tracking method to separate and purify the active monomers with the sedative and hypnotic effect from the active part of n-butanol in JD-XM1, and analyze the structure. The active parts of JD-XM1 butanol were isolated and purified by the chromatography column. The threshold dose pentobarbital sodium induced a mouse sleep test. It was found that the Fr 6 fraction (dichloromethane: methanol =2:1) could shorten the sleep latency induced by pentobarbital sodium and prolong the sleep time.C18 column to purify Fr 6 and obtain white powder Compound A, Structural identification by NMR and MS for 3,5- two methoxy -4- hydroxybenzoic acid (Ding Xiangsuan). The sedative hypnotic efficacy experiments showed that high dose of syringic acid (200 mg/kg) could significantly prolong the sleep time (P0.01) induced by pentobarbital sodium (P0.01), shorten the sleep latency (P0.05), and present a dose correlation. The preparation of fourth chapter syringic acid liposomes and the preparation of fourth chapters of syringic acid liposome In vitro evaluation of the JD-XM1 active component syringic acid selected in this article, this chapter established an in vitro analysis method of HPLC syringic acid and conducted a methodological investigation. The results showed that the established method of in vitro analysis was good, the preparation excipients did not interfere with the analysis, and the linear relationship in the range of 0.5-100 mu g/m L was good; 48 h was stable. Good sex, high precision (RSD2%) in day / day, high recovery rate and can be used for quantitative analysis of syringic acid. The equilibrium solubility experiment shows that the solubility of syringic acid in various medium is lower and the solubility in P H 7.4 phosphate buffer is the most, but it is only 78.82 + 4.68 Mu g/m L, and the solution in water and P H 1.2 hydrochloric acid solution is dissolved. The degree approach is 66.05 + 2.65 g/m L and 66.86 + 2.19 mu g/m L respectively, indicating that the solubility of syringic acid is poor. In addition, the determination of oil and water distribution coefficient indicates that syringic acid log P is 1.31, indicating that syringic acid is not easily absorbed in the gastrointestinal tract after oral administration. The preparation of syringic acid liposomes by thin film dispersion method is selected by single factor method and the optimum prescription is syringic acid 10 0 mg, soybean phospholipid 1200 mg, cholesterol 200 mg, sodium cholate 800 mg, isopropyl myrisate 800 mg, the hydration medium is 20 m L PBS (P H 7.4), the prepared syringic acid liposomes are clarified and the encapsulation efficiency is high (82.20 + 2.30%). In vitro characterization shows that the prepared syringic acid liposomes are spherical and evenly distributed, the average particle size is 154.67 + 7.09nm, particle size distribution The dispersion coefficient (PDI) was 0.14 + 0.04 and the Zeta potential was -27.61 + 3.65 m V. stability test. The stability of the liposome of syringic acid was good for 15 days, no obvious flocculation or turbidity, and the encapsulation efficiency was not obviously changed. The study on the pharmacokinetics and the tissue distribution of mice in the fifth chapter of syringic acid liposomes was established by HPLC In vivo analysis of the content of syringic acid in rat plasma and mice tissues, and a methodological investigation. In different biological samples, the r20.99 was in good linearity. In the day, the precision of the day was less than 5%, the recovery rate of the sample was good, which accords with the prescription of the drug test in the body. The kinetic study of the rodenticide of syringic acid liposome The syringic acid liposome could improve the oral bioavailability. Compared with the eugenic acid, the syringic acid liposome increased Cmax. The concentration of the blood after 95 min was higher than that of the drug (1.81 + 0.94 vs 0.12 + 0.03 mu g/m L), indicating that the liposomes could increase the absorption of the drug and delayed the elimination of the syringic acid in the body, and the t1/2 was significantly prolonged (1 The average retention time of 16.67 + 14.40 vs 25.36 + 1.99 min) was significantly prolonged (286.27 + 18.32 vs 37.98 + 1.02 min), indicating that liposomes could prolong the body circulation time of Ding Xiangsuan, and the syringic acid liposomes significantly increased the oral bioavailability, and the area AUC0-360min under the curve of the drug was significantly increased, as the 237.30%. syringic acid liposome of the raw material. The study of tissue distribution in mice showed that the concentration of syringic acid in plasma decreased rapidly with time, and the plasma concentration of liposomes in 0.5 h and 2 h was significantly higher than that of the drug. It indicated that liposomes could slow down the process of drug elimination and prolong the time of drug in body; the drug of butylate and syringic acid liposomes were drugs in various tissues and organs. The concentration size is: kidney, liver, lung, spleen, heart and brain, all tend to kidney, liver distribution, the brain can detect Ding Xiangsuan, indicating that syringic acid can pass through the blood brain barrier (BBB), liposome can slow down the elimination of drugs in the brain, prolong the time of drug retention in the brain, and play a sedative and hypnotic effect.
【學位授予單位】：江蘇大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R283.6;R285

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