壳聚糖微球制备及工艺处方优化的研究

发布时间：2018-03-02 12:11

本文选题：微球　切入点：壳聚糖　出处：《青岛科技大学》2014年硕士论文　论文类型：学位论文

【摘要】：微球制剂作为一种药物新剂型,是近年来药物制剂领域中的一个热点研究方向。微球制剂的研发历史短,技术上不够成熟,因而极具开发潜力。微球制剂相对于传统药物剂型具有许多优点,例如掩盖药物的不良气味及口味、提高药物稳定性、使药物具有靶向性等。壳聚糖作为一种天然的多糖类载体材料具有良好的生物相容性,而且壳聚糖毒性低,不溶血的特点使其广泛应用于医药食品领域。本文即以壳聚糖作为载体材料,恩诺沙星为模型药物,探讨壳聚糖微球的制备工艺,并对制备工艺和处方进行优化。针对处方分析阶段和含量测定阶段的不同需要建立了紫外分光光度法和高效液相色谱法两种分析方法。紫外分析方法主要应用于工艺处方的筛选阶段,具有使用方便、操作简单、快捷的优点；高效液相色谱法应用于载药微球的含量测定,具有精确度高的优点。针对壳聚糖微球外壳不易破坏,含量测定准确度不高的问题,通过对不同试验方法的对比和总结分析,设计了水浴溶剂提取法作为微球含量测定的处理方法。正交试验得到优化的试验条件：5%醋酸溶剂量为800ml、水浴温度80℃、水浴时间3h。经过验证,通过水浴溶剂提取法得到的微球中药物含量准确。采用乳化交联法制备壳聚糖微球,因为影响因素较多,首先采用单因素试验筛选和确定影响因素的大致范围：药材比5：1、壳聚糖浓度2%左右、油水相比4：1左右、搅拌速度1000r/min、乳化时间3h、交联时间3h左右、交联温度25℃。然后针对对于恩诺沙星壳聚糖微球制备影响较大的油水相比、壳聚糖浓度、交联时间三个因素,采用星点设计-效应面法优化条件：油水相比4.2：1；壳聚糖浓度2%；交联时间3.5h.。制得的微球粒径分布均匀,跨距较小,微球圆整、无粘连,平均粒径7.21μm、包封率61.34%、载药量70.12%,重现性好,体外释放试验证明乳化交联法制备的壳聚糖微球具有良好的缓释性。因为乳化交联法存在制备微球的过程耗时较长、交联剂戊二醛具有一定的毒性等问题,设计新的试验方法并采用新的交联剂。采用组织捣碎匀浆机高速剪切制乳、采用谷氨酰胺转胺酶做交联剂,首先采用单因素试验筛选和确定影响因素的大致范围：交联PH6、交联温度在20-40℃、交联时问在2-4h、酶用量4g、转速10000r/min左右、匀浆时间5-11mmin。然后对微球制备影响较大的交联温度、交联时间、乳化转速三个因素,采用星点设计-效应面法优化条件：交联温度28℃、交联时间3h、乳化转速10000r/min为最佳工艺处方。制得的微球平均粒径3.95μm、包封率73.69%,重现性好,体外释放试验证明乳化交联法制备的壳聚糖微球具有良好的缓释性。将制备好的载药微球制备成混悬型注射剂,采用5%浓度的1,2-丙二醇作为润湿剂、1%浓度的西黄蓍胶作为助悬剂,经过影响因素试验和长期试验验证,制备的混悬剂放置6个月含量和再分散性都无明显下降,说明具有良好的稳定性。
[Abstract]:Microspheres as a new dosage form of drugs is a hot research direction in the field of medicine in recent years. The short developing history of microsphere preparation, technology is not mature enough, so it has great development potential. Compared with the traditional drug microspheres have many advantages, such as cover drug bad smell and taste, improve the drug stability, make the targeted drug. Chitosan is a natural polysaccharide carrier material has good biocompatibility, low toxicity and chitosan, no hemolysis. It is widely used in medicine and food fields. This paper uses chitosan as carrier material, enrofloxacin as a model drug to investigate preparation the process of chitosan microspheres, and the preparation process and formulation optimization.
According to the different needs of the measurement period analysis stage and content of prescription of UV spectrophotometry was developed and HPLC analysis method. Two kinds of UV screening phase analysis method is mainly used in prescription, has the advantages of convenient use, simple operation, quick; content determination method is applied to the microspheres of high high performance liquid chromatography, has the advantage of high accuracy. The chitosan microsphere shell is not easy to be damaged, the problem of low accuracy of determination, through analysis and comparison of different test methods and summarized the design method for the determination of solvent treatment bath microspheres content extraction method. Orthogonal experimental conditions were optimized: 5% the amount of acetic acid solvent is 800ml, water bath temperature is 80 degrees centigrade, water bath time 3h. after verification, by water bath solvent extraction method to get the drug content of microspheres accurately.
Preparation of chitosan microspheres by emulsion crosslinking method, because of many factors, the single factor test was used to determine the impact of screening and the approximate range of factors: material ratio 5:1, chitosan concentration 2%, the ratio of oil to water 4:1, stirring speed 1000r/min, emulsifying time 3h, crosslinking time 3h, crosslinking temperature of 25 DEG C and then compared. For the preparation of chitosan microspheres of enrofloxacin influenced water, chitosan concentration, crosslinking time of three factors, the ccd-rsm optimization conditions: the ratio of oil to water 4.2:1; chitosan concentration 2%; crosslinking time 3.5h.. Prepared uniform particle size distribution, small span, microspheres were round, no the adhesion, the average particle size of 7.21 mu m, the encapsulation rate was 61.34%, loading 70.12%, good reproducibility, in vitro release experiments show that chitosan microspheres were prepared by emulsion crosslinking excellent sustained release properties.
Because the emulsion crosslinking process of microspheres is time-consuming, glutaraldehyde has certain toxicity and other issues, designed a new test method and the new crosslinking agent. The tissue homogenate machine of high speed shearing emulsion preparation, using transglutaminase as cross-linking agent, first by single factor test and screening to determine the influence of roughly the range of factors: cross-linking PH6, cross-linking temperature at 20-40 degrees, when asked in crosslinked 2-4h, enzyme dosage 4G, speed 10000r/min, time 5-11mmin. and homogenate of microspheres preparation effect of crosslinking temperature, higher crosslinking time, emulsifying speed of three factors, the ccd-rsm optimization conditions: crosslinking temperature of 28 DEG C 3H, crosslinking time, emulsification speed of 10000r/min is the best prescription. The prepared microspheres with average particle size of 3.95 mu m, the encapsulation rate was 73.69%, with good reproducibility, the in vitro release test proved that the emulsion prepared by crosslinking Chitosan microspheres with excellent sustained release properties. The prepared microspheres were prepared by suspension injection, with 5% concentration of 1,2- propylene glycol as wetting agent, concentration of 1% tragacantha as suspending agent, through the influence factors test and long-term test preparation of suspension placed 6 months and the content of re dispersible had no obvious decline that has good stability.

【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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