| 题名 | 几丁降糖的制备及其在给药系统中的应用研究 |
| 作者 | 仰振球 |
| 学位类别 | 博士 |
| 答辩日期 | 2003 |
| 授予单位 | 中国科学院过程工程研究所 |
| 授予地点 | 中国科学院过程工程研究所 |
| 导师 | 欧阳藩 |
| 关键词 | 几丁质 几丁聚糖 微波 流态化 控制释放 微囊 微球 |
| 其他题名 | Studies on Preparation of Chitosan and Its Application in Drug Delivery Systems |
| 中文摘要 | 几丁聚糖是几丁质脱乙酚反应后的产物，具有良好的生物相容性和生物可降解性能，应用领域十分广泛。本文针对几丁聚糖传统生产工艺中存在的反应时间长、污染严重等问题，利用微波流态化技术，进行了几丁聚糖制备的相关基础研究，为产业化实施提供依据。在几丁聚糖的应用方面，制备了几丁聚糖微囊、微球给药系统载体，考察了模型药物的体外释放特性，对开发设计药物控释剂型以及几丁聚糖高价值开发方面具有指导意义。本文的主要研究内容为：（1）根据微波快速加热及非热效应的优点，以及流态化技术的优点，利用微波流态化床反应器进行了几丁质脱乙酞反应制备几丁聚糖的基础研究，考察了反应时一间和反应温度对脱乙酞反应的影响。该方法将传统的批式反应转变为连续反应，克服了传统制备方法中存在的批间质量不易控制的缺点；反应时间从8-16小时缩短到1-3小时，提高了生产效率，降低了生产成本。（2）以戊二醛作为交联剂，用化学交联法制备了几丁聚糖微囊。考察了乳化剂、几丁聚糖浓度、分子量、搅拌转速和酸溶剂类型对微囊制备的影响。选用Span型和Tween型混合乳化剂，由于氢键作用，乳化剂分子间形成了络合物，增强了液滴表面膜的强度，将微囊的平均粒径从626.5微米降低到31.8微米左右。微囊的粒径随转速的增大而下降，但是当转速上升到1500rpm左右，下降趋势变慢。对于一元酸，经共价交联所形成的膜（囊壁）强度较高。对于二元酸和三元酸，由于产生了“竞争交联”作用，影响了微囊壁的强度和微囊的形貌及其他相关性能的不同。（3）以硫酸作为交联剂，采用离子交联的方法制备了几丁聚糖生物粘附性微球。考察了离子强度、油相的粘度对微球制备的影响。所制得的微球与用硫酸盐作为交联剂相比，交联紧密，机械强度高，在模拟肠液条件下保存3个月未见变化。利用四因素二次回归统计方法，得到了几丁聚糖浓度、交联剂浓度、交联时间和搅拌转速对微球粒径影响的方程。随着粘度的增大，微球的粒径相应减小。加入硬脂酸作为分散剂，可减小微球的粒径，缩小粒径的分布范围，同时减少粒子间的粘结、聚并现象。（4）比较了离子交联的几丁聚糖微球和戊二醛交联的微囊的生物粘附性能。由于交联机理的不同，所得微囊、微球的性质不同，前者的粘附率高于后者。5）考察了几丁聚糖载药微囊的体外释放特性。表明药物可持续释放达30小时以上，同时几丁聚糖的分子参数和酸溶剂类型均影响模型药物的包封率和体外释放特性。分子量和脱乙酞度的增加，包封率上升，释放量下降。体外释放时一，有明显的“突释”现象。一元酸（醋酸、乳酸）作为酸溶剂时，包封率比二元酸、三元酸的情况时高而释放速率却相反。药物释放主要受扩散过程控制。（6）考察了几丁聚糖载药微球的体外释放特性。表明药物可持续释放达10小时以上，同时几丁聚糖的分子参数和酸溶剂类型同样也影响模型药物的包封率和体外释放特性。随着微球粒径的增大，药物释放速率相应减小，释放曲线呈现S型。酸溶剂类型同样影响着几丁聚糖微球内药物的释放速率。由于每种酸的解离常数的不同，导致了交联作用的差异。对于二元酸或三元酸来说，与硫酸根阴离子产生了“协同交联”的现象。（7）利用天然高分子聚合物制备了一种新型的多单元胃漂浮给药系统载体，考察了两种聚合物不同比例对载体形貌、漂浮性能的影响，进一步考察了模型药物的释放特性。微球载体内部具有微气球，使得载体具有良好的漂浮性能，适合于胃部定位给药系统的应用。 |
| 英文摘要 | Chitosan, derivative of chitin by deacetylation, biocompatible and biodegradable, is widely used in many fields. In order to overcome the problems, such as long reaction time, serious pollution, in the conventional process of chitosan production, microwave-fluidization technology was employed and fundamental studies were conducted in this study, and the results can be used as the principles for the coming industrialization of this technology. Chitosan microcapsules and microsphere were prepared to use as carrier for drug delivery systems, and in vitro drug release characteristics were also studied. It embodies instructive importance in achieving drug controlled release formulation based on chitosan and improving the value of chitosan. The main study contents of this thesis are as the following: (1) Combing the advantages of microwave heating and fluidization, microwave fluided-bed reactor was designed to prepare chitosan, and foundational research was conducted. The effects of reaction time and temperature on DD were investigated. By this technology, conventional batch process was converted to a continuous one, and reaction time was shortened significantly from 8~16 h to 1~3 h, and productivity shifted, the cost decreased. ( 2 ) Chitosan microcapsule was prepared by covalent cross-linking with glutaraldehyde. The effects of surfactant, concentration of chitosan, MW, rotation speed and acid type on the characteristics of microcapsule were investigated. The mixed surfactant of Span type and Tween type was introduced to the W/O system. Because of enhanced membrane was formed on the surface of the dispersed phase, the average diameter was reduced from 626.5 urn to 31.8 urn. The diameter decreased with the increase of rotation speed, but the decrease rate slowed down when the rotation speed increased to 1500 rpm. For monoacid, the intensity of the membrane was higher than that of the binary acid and ternary acid. For the latter, because competitive crosslinking resulted in lower cross-linking density, and thereby affected the strength of the microcapsule wall, morphology and other related characteristics. (3 ) With the sulfuric acid solution as the crosslinker, chitosan bioadhesive microspheres were prepared via ionically cross-linking. Effect of ionic strength and viscosity of oil phase on the preparation of microsphere were investigated. The microsphere could be kept in the artificial simulated intestinal juice for more than 3 months, and also had high mechanical strength and more compact surface, compared with the microspheres crosslinked by sulfate. The diameter of the microsphere is the principal factor of influencing the kinetic of drug delivery. With the experimental design, four factors second order orthogonal regression composite design, the influence of the factors of chitosan concentration, crosslinker concentration, cross-linking time and the agitation speed were investigated, and the regression equation with high reliability was obtained. Diameter decreased with the increase of the viscosity. By adding dispersant (Stearic acid), diameter was reduced, the size distribution narrowed, and the coherence reduced. (4) The bioadhesive ability of chitosan microcapsule and microsphere was investigated by the rat small intestine. Because of different properties caused by different mechanisms of cross-linking, the rate of bioadhension of microsphere is higher than that of microcapsule. (5 ) In vitro drug release characteristics of drug loaded microsphere was investigated, which shown that the model drug (theophylline) can be released for more than 30 hours, the molecular parameters and the acid type of chitosan solvent affected the encapsulation efficiency (EE) of model drug, also affected the drug release. With the increase MW and DD, the EE increased, but the release rate decreased. There was "burst" during the first. With monoacid (Acetic Acid, Lactic Acid) as the solvent, the EE was higher than that of binary and ternary acid, but counter to the release rate. The drug release from microcapsules was mainly controlled by diffusion. (6) In vitro drug release characteristics of drug loaded microsphere was investigated, which shown that that the model drug (theophylline) can be released for more than 10 hours, the molecular parameters and the acid type of chitosan solvent affected the encapsulation efficiency (EE) of model drug (theophylline), also affected the drug release. With the increase of the diameter, the release rate decreased, and the release profile appeared sigmoid. Acid type of the solvent also affected the drug release. Difference of pKa among acids results different attraction in physical cross-linking. For binary and ternary acid, acid radicals generated synergistic cross-linking with the acid group of sulfuric acid. (7)Based on natural polymers gelatin and xanthan gum, a novel multi-unit gastric floating drug delivery system was proposed. The effect of the ratio of two polymers on morphology, floating ability of earner and drug release were investigated. The result shows that the model drug can be sustainedly released for 10 hours. With microballoons inside, the carrier (microsphere) bears good floating ability, and suits for gastric site-specific drug delivery system. |
| 语种 | 中文 |
| 公开日期 | 2013-09-16 |
| 页码 | 155 |
| 内容类型 | 学位论文 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/1400]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 推荐引用方式 GB/T 7714 | 仰振球. 几丁降糖的制备及其在给药系统中的应用研究[D]. 中国科学院过程工程研究所. 中国科学院过程工程研究所. 2003. |
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