胰岛素pH敏感性水凝胶微球的研究

发布时间：2018-04-06 02:12

本文选题：pH敏感性水凝胶微球　切入点：溶胀性能　出处：《河北科技大学》2014年硕士论文

【摘要】：pH敏感水凝胶作为一种新型的药物载体，在人体内可以自动感应pH值的变化而进行收缩或溶胀，实现定点释药和智能给药。本课题使用悬浮聚合法和反相悬浮聚合法分别制备了两种pH敏感性水凝胶微球，在制备研究中考察了单体、交联剂、引发剂、分散剂、分散介质等因素对pH敏感性水凝胶微球成球性、粒径分布及溶胀率的影响，确定了最佳制备配方。通过傅里叶变换红外光谱仪对其进行分析，验证了聚合反应的完成；通过光学显微镜和扫描电子显微镜对水凝胶微球进行外部形态和内部结构的观察，表明制得的水凝胶微球粒径为微米级，内部为具有空隙的三维网格结构。以牛血清白蛋白(BSA)为模型药物，对两种pH敏感性水凝胶微球进行载药及体外释放初步研究中，均表现了明显的pH敏感性，在酸性条件下(pH1.2)BSA释放量小于20%，而在弱酸性条件下(pH6.8)的条件下快速达到释放平衡，完成体外释放试验时释放达到90%以上。随后选择载药量较大的P(AA-g-PEGMA)水凝胶微球进行胰岛素的载药及体外释放研究，在酸性条件下(pH1.2)胰岛素的释放量小于20%，而在弱酸性条件下(pH6.8)的条件下胰岛素快速达到释放平衡，释放量达到90%以上。采用Caco-2细胞对水凝胶微球进行了细胞毒性试验，不同浓度的水凝胶微球与细胞共同培养，最终的细胞存活率均接近100%，表明水凝胶微球对Caco-2细胞没有毒性；培养在Transwell板上的Caco-2单层细胞用于模拟小肠上皮细胞，胰岛素在Caco-2单层细胞的渗透性试验表明水凝胶微球促进了胰岛素的吸收，结果表明水凝胶微球适于作为胰岛素的口服药物载体。在体内动物试验中选用Wistar雄性大鼠建立糖尿病模型，通过对比研究口服胰岛素水凝胶微球与皮下注射胰岛素、口服胰岛素溶液等，显示胰岛素水凝胶微球具有降血糖疗效，其释放出来的胰岛素被小肠吸收，，最终发挥了降血糖疗效。以上这些结果都表明水凝胶微球作为大分子蛋白类药物的口服给药载体，具有潜在的研究价值和应用前景。
[Abstract]:As a new drug carrier, pH sensitive hydrogel can automatically contract or dilate in human body with the change of pH value, so as to realize fixed-point drug release and intelligent drug delivery.In this paper, two kinds of pH sensitive hydrogel microspheres were prepared by suspension polymerization and inverse suspension polymerization respectively. The monomer, crosslinking agent, initiator and dispersant were investigated.The influence of dispersing medium on the spheroidization, particle size distribution and swelling rate of pH sensitive hydrogel microspheres was studied.The polymerization was verified by Fourier transform infrared spectroscopy (FTIR), and the external morphology and internal structure of hydrogel microspheres were observed by optical microscope and scanning electron microscope.The results show that the size of the hydrogel microspheres is in the order of micron and the interior is a three-dimensional mesh structure with voids.Using bovine serum albumin (BSA) as a model drug, two kinds of pH sensitive hydrogel microspheres were loaded and released in vitro.The release amount of BSA was less than 20 in acidic condition, but in weak acid condition, the release balance was reached rapidly, and the release reached 90% when the release test was completed in vitro.Subsequently, the drug loading and in vitro release of insulin were studied by using the hydrogel microspheres of PnAA-g-PEGMA-loaded, and the release amount of insulin was less than 20 at acidic condition, but at pH 6.8 under weak acid condition.The amount released was more than 90%.Caco-2 cells were used to test the cytotoxicity of hydrogel microspheres. The cell survival rate of hydrogel microspheres with different concentrations of hydrogel microspheres was close to 100, indicating that hydrogel microspheres were not toxic to Caco-2 cells.Caco-2 monolayers cultured on Transwell plates were used to mimic small intestinal epithelial cells. The permeability test of insulin in Caco-2 monolayer cells showed that hydrogel microspheres promoted insulin absorption.The results showed that hydrogel microspheres were suitable for oral drug delivery of insulin.In vivo animal experiment, Wistar male rats were selected to establish diabetic model. By comparing the oral insulin hydrogel microspheres with subcutaneous insulin injection, oral insulin solution and so on, the results showed that insulin hydrogel microspheres had hypoglycemic effect.Its release of insulin is absorbed by the small intestine, and ultimately played a hypoglycemic effect.These results suggest that hydrogel microspheres as oral delivery carriers of macromolecular protein drugs have potential research value and application prospect.
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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