【作者】 范江洋；

【导师】 何志敏；

【作者基本信息】 天津大学 ， 化学工程， 2007， 博士

【摘要】 本文以魔芋葡甘聚糖(KGM)-黄原胶(XG)共混多糖作为释药载体,以西咪替丁为模型药物,制备了共混多糖凝胶骨架片、包芯片与共混多糖膜,并进行了体外药物释放研究;利用粘度计、傅立叶红外光谱、圆二色谱、X射线衍射、X射线小角散射、原子力显微镜等对于共混多糖的结构与相互作用机制进行了分析;建立了共混膜酶解过程模式图与关联米氏方程的药物释放模型。实验结果如下:本文制备了以KGM与XG的共混多糖作为释药载体的亲水性凝胶骨架片,对片剂的制备条件与体外释药的研究表明,在共混多糖中KGM与XG的比例不同,在片剂的制备过程中对于混合及制粒效果的影响不同,并且在体外释药过程中亲水性凝胶骨架片的药物释放能力也不同。KGM与XG比例为3:7的共混多糖作为凝胶骨架片的药物释放载体,缓释效果相对较好,亲水性凝胶骨架片药物释放符合零级释放的要求。以KGM与XG的共混多糖作为包衣材料的结肠定位压制包芯片进行的体外释药考察表明,KGM可以被大鼠盲肠内的细菌产生的酶所降解,并且其降解能力与0.220U·ml-1的β-甘露聚糖酶溶液降解KGM的能力相近。对以KGM与XG的共混多糖作为包衣材料的结肠定位压制包芯片进行的体外释药考察表明,由于强烈的协同作用,共混多糖在一定程度上提高了凝胶的强度,抗水性等,并保持了KGM的酶响应性特点;其中使用0.40g包衣的KGM70体系,在体外释放实验的前5h内药物泄漏低于6%,药物溶出实验进行24h时药物释放可以达到50%以上,是一种比较理想的结肠定位剂型设计,可以达到结肠定位给药的要求。使用不同的药物释放方程对实验数据进行拟合,结果表明药物的释放主要是以溶蚀方式进行的。本文制备了多糖共混膜,考察了不同比例的多糖共混膜的溶胀行为;并且采用自制装置与药典标准的溶出仪配合,考察了在不同浓度酶降解条件下的药物通过多糖共混膜的扩散行为。实验结果表明,多糖共混膜在一定离子强度下的中性溶液中溶胀度较小,而在去离子水以及pH较低的溶液中溶胀度较高;不同组成的多糖共混膜,其对药物释放的影响不同,释放介质中酶的加入会对体系中药物释放起到加速的作用,并且酶的浓度越高,加速作用越大;在释放体系中,膜中KGM含量不同,膜对酶的响应性也不同,KGM含量较高的体系,其对于酶的响应性越好。利用粘度计、傅立叶红外光谱、圆二色谱、X射线衍射、X射线小角散射、原子力显微镜等对于共混多糖的结构与相互作用机制进行了考察与分析。利用粘度计对多糖之间协同作用进行了考察,粘度测试结果表明,在KGM:XG=3:7时,KGM与XG分子间的相互作用较强,两者分子间形成的物理交联点较多,从而此时共混多糖表现出较差的流动性和较高的粘度;此外,各种比例共混多糖溶液都显示出假塑性流体的性质;FT-IR实验结果表明,在共混多糖中,KGM分子与XG分子之间以氢键发生相互作用;圆二色谱图说明由于KGM与XG之间存在强烈的相互作用,共混多糖分子链呈现一种有序的结构状态;使用X射线衍射和小角X射线散射考察了KGM、XG与共混多糖的聚集态结构,结果表明,KGM为无定形结构,XG结构中有少量结晶结构存在,且这部分XG有序结构主要参与了与KGM的相互作用区域的形成;通过原子力显微镜对共混多糖的观察说明,共混多糖以一定的规律形成了三维网络结构;根据实验结果建立了两种多糖在分子间相互作用的模式图,即:相互作用网络主要通过XG进行联结,KGM与XG相互作用在网格点上,同时网格间有部分游离的KGM与XG。研究了在酶解条件下药物通过多糖共混膜的释放行为,建立了在酶解条件下多糖共混膜的释药模式图;结合生物酶解过程的米氏方程,建立了基于生物酶解KGM为零级过程的药物释放动力学模型;通过与分子链剪切为一级过程的动力学方程比较,本文建立的模型实验数据拟合相关系数相对较高,且模型中各参数的物理意义明确,与酶解过程特性参数的关联性很好,这对于酶解过程中药物释放行为的研究具有重要的指导意义。更多还原

【Abstract】 Konjac Glucomannan (KGM), a water-soluble and high-molecular weight polysaccharide that is the main content of Amorphophallus Konjac plant. Xanthan gum (XG) is known to have a greater drug release retarding property and synergistically enhances gel properties. As the strong synergistic interaction between KGM and XG, the mixture of KGM and XG was employed in extend-release matrix tablets and compression coated colon drug delivery tablets. Cimetidine was used as model drug in the studies. The drug release behavior of tablets was investigated in dissolution studies. Films of polysaccharides mixture were made and the swollen abilities of them were investigated. The diffusion behavior of drug release from the films was studied in the dissolution conditions of different enzyme concentration. The structures and performances of KGM, XG and the mixture of them were investigated by viscosity meter, static laser light scattering (SLS), fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), X-ray diffraction (XRD) and small-angle X-ray scatter (SAXS). The drug release kinetics model that related enzymatic degradation process and drug release profiles was founded. The preparation process and the drug release behavior of the matrix tablets were researched. It could be found that different ration of KGM and XG may lead different effect to tablet preparation and drug release profile. It was shown that the synergistic interaction between KGM and XG would take effect on the drug diffusion that could retard drug release from tablets effectively. The experimental results demonstrated that the polysaccharides mixture of KGM and XG had a good potential application for controlled drug delivery system.Colon-specific compression coated tablets were prepared with polysaccharides mixtures as coat. 0.220U·ml-1β-mannanase solution in mimic colon media was determined by comparing the hydrolytic ability of mimic colon solution with that of 4%w/v rat cecal content media. It was shown that the synergistic interaction between KGM and XG and the hydrolysis of coat material byβ-mannanase. The experimental results demonstrated that the polysaccharides mixture of KGM and XG as compression coat had a good potential application for colon drug delivery system.It was found that the different diffusion profiles of drug were inducted by different proportion of KGM and XG in the polysaccharides mixture films. The results shown that the enzyme in the dissolution media led accelerate action to drug release.The viscosity of the polysaccharides mixture solutions were measured under different shear rates. The molecular weights of the polysaccharides were measured by static laser light scattering. The synergistic interactions between polysaccharides were observed by fourier transform infrared spectroscopy (FT-IR) and circular dichroism (CD). X-ray diffraction (XRD) and small-angle X-ray scatter (SAXS) were utilized to characterize the structures of the polysaccharides and the mixtures. Morphologies of them were scanned by atomic force microscopy (AFM) and the image of the polysaccharides shown that three-dimension networks were formed in the mixtures with some certain rules.According the drug release behavior from films of polysaccharides mixtures in different enzymatic activity solutions, the drug release kinetics model was founded based on the Michaelis-Menten equation. The model shows a good correlation with the experimental results, which could justify considering it for other biodegradable release system.更多还原