CFTs、CTFTs制备、减肥活性及作用机制研究
发布时间：2018-07-27 20:25
【摘要】：因遗传,懒于运动或饮食习惯等不合理的缘由,超重和肥胖的人数日渐增多,“减肥”也成为了医学领域的热门话题,同时肥胖症带来的危害也引起了人们的高度重视,减肥药物也因此层出不穷,但绝大多数的减肥药物因安全性问题都陆续被禁止销售,目前针对减肥的药物极为缺乏,急需研究新的减肥药物来满足市场需求。壳聚糖(chitosan,CTS)是一种含有自由活性氨基的天然糖类产物,由于氨基的碱性性质,故其具有一定的降血脂,降血糖等生物活性,将壳聚糖通过酸水解、酶水解等各种降解方法能得到生物活性、生物利用度更高的壳寡糖(chitosan oligosaccharides,COS),而且其溶解性、吸收性能也较壳聚糖好。前期研究确证CTS和COS具有良好的减肥活性,因此,本研究在课题组前期基础上将CTS、COS制成服用方便的片剂,对于研发天然糖类减肥新药意义重大。本文以壳寡糖(M≤1000Da)、壳聚糖为主药制成壳寡糖薄膜包衣片(Chitosan oligosaccharide film coated tablets,CFTs)和壳聚糖薄膜包衣片(Chitosan film coated tablets,CTFTs),确定了两种片剂的处方和制备工艺。接着根据保健食品《减肥功能评价方法》中动物试验要求建肥胖动物模型,对CFTs和CTFTs的减肥活性进行评价,并将两者的药效进行了比较。CTFTs的制备主要通过不同辅料筛选及正交试验设计方法探究影响壳聚糖片剂制备工艺的处方因素和成型因素,最终得出的最优处方方案为:74%壳聚糖、5%PPVP、9%CaHPO4、10%MCC、2%微粉硅胶、5%CMC-NA胶浆(水为润湿剂)3%包衣增重,按此处方所制成的CTFTs各项指标均符合《中国药典》要求;CFTs的制备过程主要通过辅料种类筛选及单因素水平分析方法确定辅料含量,确定壳寡糖片剂的最佳处方以及明确影响片剂成型因素。由于壳寡糖的引湿性性质,所以需严格控制制剂室的条件:湿度≤40%。确定最终处方为:87.5%壳寡糖、4%PPVP、4%CaHPO4、4%MCC、0.5%硬脂酸镁、5%PVP溶液(95%的乙醇溶液)、3%包衣增重,按此处方所制成的CFTs片剂各项指标均符合《中国药典》要求。CFTs、CTFTs均能有效减轻肥胖大鼠的体重增加,体脂比,并且对肥胖大鼠的摄食量无影响,能显著改善肥胖大鼠血脂四项,具有一定的降脂作用。CFTs高剂量组(CFTs-H)、CFTs中剂量(CFTs-M)组对肥胖大鼠体重增重影响与Orlistat无明显差异;CTFTs高剂量组(CTFTs-H)、CTFTs中剂量(CTFTs-M)组对肥胖大鼠体重增重的影响也与Orlistat无明显差异,即三者减肥效果相当。虽然CFTs和CTFTs对体重增重的抑制作用相当,但CTFTs在给药期间容易引起肥胖大鼠腹泻,腹胀等不良反应,而CFTs无此现象。故综合而言:减肥活性大小为:CFTsCTFTs。采用荧光定量PCR检测CFTs、CTFTs对大鼠附睾脂肪内的早期脂肪分化因子c/EBPβ和PPARγmRNA的影响,结果表明CFTs、CTFTs均可通过抑制附睾脂肪组织中c/EBPβ、PPARγmRNA的表达,抑制脂肪早期分化,减少脂肪堆积。同时,也检测了CFTs、CTFTs对大鼠棕色脂肪内的产热标志物UCP1 mRNA,产热调控因子PRDM16、DIO2 mRNA的影响,结果表明CFTs可促进棕色脂肪组织中UCP1、PRDM16、DIO2 mRNA的表达,增加产热,消耗能量,进而达到减肥目的、而CTFTs无此作用。
[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.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96
本文编号：2149042
[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.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96
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