【摘要】：因遺傳,懶于運(yùn)動(dòng)或飲食習(xí)慣等不合理的緣由,超重和肥胖的人數(shù)日漸增多,“減肥”也成為了醫(yī)學(xué)領(lǐng)域的熱門話題,同時(shí)肥胖癥帶來的危害也引起了人們的高度重視,減肥藥物也因此層出不窮,但絕大多數(shù)的減肥藥物因安全性問題都陸續(xù)被禁止銷售,目前針對(duì)減肥的藥物極為缺乏,急需研究新的減肥藥物來滿足市場(chǎng)需求。殼聚糖(chitosan,CTS)是一種含有自由活性氨基的天然糖類產(chǎn)物,由于氨基的堿性性質(zhì),故其具有一定的降血脂,降血糖等生物活性,將殼聚糖通過酸水解、酶水解等各種降解方法能得到生物活性、生物利用度更高的殼寡糖(chitosan oligosaccharides,COS),而且其溶解性、吸收性能也較殼聚糖好。前期研究確證CTS和COS具有良好的減肥活性,因此,本研究在課題組前期基礎(chǔ)上將CTS、COS制成服用方便的片劑,對(duì)于研發(fā)天然糖類減肥新藥意義重大。本文以殼寡糖(M≤1000Da)、殼聚糖為主藥制成殼寡糖薄膜包衣片(Chitosan oligosaccharide film coated tablets,CFTs)和殼聚糖薄膜包衣片(Chitosan film coated tablets,CTFTs),確定了兩種片劑的處方和制備工藝。接著根據(jù)保健食品《減肥功能評(píng)價(jià)方法》中動(dòng)物試驗(yàn)要求建肥胖動(dòng)物模型,對(duì)CFTs和CTFTs的減肥活性進(jìn)行評(píng)價(jià),并將兩者的藥效進(jìn)行了比較。CTFTs的制備主要通過不同輔料篩選及正交試驗(yàn)設(shè)計(jì)方法探究影響殼聚糖片劑制備工藝的處方因素和成型因素,最終得出的最優(yōu)處方方案為:74%殼聚糖、5%PPVP、9%CaHPO4、10%MCC、2%微粉硅膠、5%CMC-NA膠漿(水為潤濕劑)3%包衣增重,按此處方所制成的CTFTs各項(xiàng)指標(biāo)均符合《中國藥典》要求;CFTs的制備過程主要通過輔料種類篩選及單因素水平分析方法確定輔料含量,確定殼寡糖片劑的最佳處方以及明確影響片劑成型因素。由于殼寡糖的引濕性性質(zhì),所以需嚴(yán)格控制制劑室的條件:濕度≤40%。確定最終處方為:87.5%殼寡糖、4%PPVP、4%CaHPO4、4%MCC、0.5%硬脂酸鎂、5%PVP溶液(95%的乙醇溶液)、3%包衣增重,按此處方所制成的CFTs片劑各項(xiàng)指標(biāo)均符合《中國藥典》要求。CFTs、CTFTs均能有效減輕肥胖大鼠的體重增加,體脂比,并且對(duì)肥胖大鼠的攝食量無影響,能顯著改善肥胖大鼠血脂四項(xiàng),具有一定的降脂作用。CFTs高劑量組(CFTs-H)、CFTs中劑量(CFTs-M)組對(duì)肥胖大鼠體重增重影響與Orlistat無明顯差異;CTFTs高劑量組(CTFTs-H)、CTFTs中劑量(CTFTs-M)組對(duì)肥胖大鼠體重增重的影響也與Orlistat無明顯差異,即三者減肥效果相當(dāng)。雖然CFTs和CTFTs對(duì)體重增重的抑制作用相當(dāng),但CTFTs在給藥期間容易引起肥胖大鼠腹瀉,腹脹等不良反應(yīng),而CFTs無此現(xiàn)象。故綜合而言:減肥活性大小為:CFTsCTFTs。采用熒光定量PCR檢測(cè)CFTs、CTFTs對(duì)大鼠附睪脂肪內(nèi)的早期脂肪分化因子c/EBPβ和PPARγmRNA的影響,結(jié)果表明CFTs、CTFTs均可通過抑制附睪脂肪組織中c/EBPβ、PPARγmRNA的表達(dá),抑制脂肪早期分化,減少脂肪堆積。同時(shí),也檢測(cè)了CFTs、CTFTs對(duì)大鼠棕色脂肪內(nèi)的產(chǎn)熱標(biāo)志物UCP1 mRNA,產(chǎn)熱調(diào)控因子PRDM16、DIO2 mRNA的影響,結(jié)果表明CFTs可促進(jìn)棕色脂肪組織中UCP1、PRDM16、DIO2 mRNA的表達(dá),增加產(chǎn)熱,消耗能量,進(jìn)而達(dá)到減肥目的、而CTFTs無此作用。
[Abstract]:Because of the irrational cause of inheritance, lazy exercise or eating habits, the number of overweight and obese people is increasing, "weight loss" has also become a hot topic in the medical field. At the same time, the harm caused by obesity has also aroused people's attention, and the weight loss drugs are emerging in an endless stream, but the overwhelming majority of weight loss drugs are due to safety problems. The chitosan (CTS) is a natural sugar product containing the free active amino group. Because of the alkaline nature of the amino group, it has some biological activity, such as reducing blood lipid, reducing blood sugar, and passing chitosan through acid. Hydrolysis, enzyme hydrolysis and other degradation methods can be bioactive, the bioavailability of chitosan oligosaccharides, COS, and its solubility, absorption performance is better than the chitosan. Earlier studies confirmed that CTS and COS have good weight loss activity. Therefore, this study on the basis of the preliminary research group will be based on CTS, COS to take the prescription. The tablets of stool are of great significance for the development of new drugs for natural carbohydrates. In this paper, chitosan oligosaccharide film coating tablets (Chitosan oligosaccharide film coated tablets, CFTs) and chitosan film coated tablets (Chitosan film coated tablets) were made with chitosan oligosaccharides (M < < 1000Da) and chitosan as the main drug. The prescription and preparation of two kinds of tablets were determined. Then, according to the animal model of the weight loss evaluation method in the health food "weight loss evaluation method >" animal model, the weight loss activity of CFTs and CTFTs was evaluated, and the efficacy of both of them was compared and the preparation of.CTFTs was mainly prepared by different auxiliary materials screening and orthogonal test design method to investigate the prescription of the preparation process of chitosan tablet. The optimal formula is 74% chitosan, 5%PPVP, 9%CaHPO4,10%MCC, 2% micropowder silica gel and 3% coating of 5%CMC-NA glue (water wetting agent). All the CTFTs indexes made according to this prescription are in conformity with the requirements of China Pharmacopoeia. The preparation process of CFTs is mainly through the selection of the kind of excipients and the analysis of single factor level. Methods to determine the content of the excipient, determine the best prescription of the oligosaccharide tablets and clearly influence the forming factors of the tablets. Due to the wettability of the oligosaccharides, the condition of the preparation room should be strictly controlled. The final prescription of the humidity is less than 40%., and the final prescription is 87.5% chitosan oligosaccharides, 4%PPVP, 4%CaHPO4,4%MCC, 0.5% magnesium stearate, 5%PVP solution (95% ethanol solution), 3% packages. All the CFTs tablets made by this prescription were in accordance with the Chinese Pharmacopoeia (.CFTs). CTFTs could effectively reduce the weight gain and body fat ratio of obese rats, and had no effect on the intake of obese rats. It could significantly improve the fat four of the obese rats, with a certain lipid lowering effect,.CFTs high dose group (CFTs-H), CFTs medium. The effect of CFTs-M group on weight gain of obese rats was not significantly different from that of Orlistat; in CTFTs high dose group (CTFTs-H), the effect of CTFTs medium dose (CTFTs-M) on weight gain of obese rats was also not significantly different from that of Orlistat, that is, the three weight loss effect was equivalent. Although CFTs and CTFTs had the same inhibitory effect on weight gain, but CTFTs was given during the drug delivery period. It is easy to cause adverse reactions such as diarrhea and abdominal distention in obese rats, but CFTs has no such phenomenon. Therefore, the size of the weight loss activity is: CFTsCTFTs. uses fluorescence quantitative PCR to detect CFTs, CTFTs affects the early fat differentiation factor c/EBP beta and PPAR mRNA in the epididymal fat of rats, and the results indicate that CFTs, CTFTs can inhibit the epididymal adipose tissue. The expression of c/EBP beta, PPAR gamma mRNA inhibits the early differentiation of fat and reduces the accumulation of fat. At the same time, it also detects the effect of CFTs, CTFTs on the heat producing marker UCP1 mRNA in brown fat of rats, the influence of the heat producing regulator PRDM16, DIO2 mRNA. The results show that CFTs can promote the expression of UCP1, increasing heat and consumption in brown fat tissue. Quantity, and then to achieve weight loss, and CTFTs does not have this effect.
【學(xué)位授予單位】：廣東藥科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943;R96

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本文編號(hào)：2149042