支气管镜介入治疗用抗结核药物缓释剂的研究

发布时间：2018-06-23 13:09

本文选题：支气管镜 + 肺结核　；参考：《河北大学》2013年硕士论文

【摘要】：耐药结核病的产生给结核病的治疗带来了新的难题，使常规的治疗手段很难达到满意的治疗效果。支气管镜介入治疗是一种可直视病灶局部的靶向治疗方式，其投递药物多为口服或静脉真溶液药物或凝胶药物，虽然靶向性强、药物剂量控制准确,但是药物的缓释效果差，肺内的呼吸挤压还会阻碍凝胶药物向远端注入，影响治疗效果。因此本课题选择水溶性药物环丙沙星作为研究对象，开发其缓释微粒，作为支气管镜介入治疗用专属药物。本研究以壳聚糖作为药物载体，环丙沙星作为研究药物，应用乳化交联法制备环丙沙星壳聚糖微球，并对其粒径、粒径分布、载药量、包封率、通透性、降解度、肺部滞留性，缓释性，安全性等方面进行评价，进而评估其经支气管镜介入给药的可行性，以期达到抗结核药物环丙沙星肺部缓慢持续释放，减少给药次数，提高患者顺应性的目的。第一部分：环丙沙星壳聚糖微球的制备及体外释放初步研究制备支气管镜介入治疗用环丙沙星缓释微球，并通过考察环丙沙星壳聚糖微球多种影响因素，并对其表征及理化性质进行评价，筛选出适合支气管镜介入治疗用处方工艺。以戊二醛作为交联剂，采用乳化交联法制备环丙沙星壳聚糖缓释微球，，正交实验设计筛选处方工艺，并应用扫描电镜、激光粒度仪、UV等检测手段对其形态、粒径、载药量、包封率及恒温条件下体外释放度等指标进行测定。制备的环丙沙星壳聚糖微球球型完整，球体光滑，粒度分布均匀符合正态性分布，80%以上的微球粒径大小120-160μm，平均粒径（142.31±7.85）μm，平均载药量（14.20±0.61）%，平均包封率（56.43±1.31）%。该微球能顺利通过7号针头，可经支气管镜介入导管顺畅注射。在恒温条件下，壳聚糖微球缓释时间可达到48h，较明显的延缓了水溶性药物的释放时间。第二部分：环丙沙星壳聚糖多重交联微球的制备及体外评价为了更有效的延缓环丙沙星药物的释放时间，选取非离子型表面活性剂乙基纤维素作为辅料，制备环丙沙星壳聚糖-乙基纤维素多重交联微球。采用乳化交联法制备多重交联微球，以体外释放度作为主要参考指标，通过正交实验结果优化处方，综合考察该处方工艺制备的多重交联微球，对其体外释放度、体外降解度等情况进行评价。对处方条件下制备的壳聚糖缓释微球的形态、粒径分布、Zeta电位等指标进行检测，评定该多重交联微球的表征。制备3批壳聚糖载药微球，呈肉眼颗粒状，光镜观察球型圆整，黏连较少，电镜观察球体表面光滑，但存在少量褶皱；粒度分布均匀，平均粒径（142.31±7.85）μm，平均Zeta电位值为（51.68±2.3）mV；在恒温条件下，多重交联微球缓释时间可达到144h，较普通壳聚糖微球表现出更出色的缓释效果，更加明显的延缓了水溶性药物的释放时间，为接下来的体内实验提供了研究依据，更进一步的达到了支气管镜介入给药后靶向缓释的研究目的。第三部分：缓释系统体内生物相容性及安全性的初步研究综合考察该处方工艺制备的载药微球，需对其药效学、药动学及毒理学指标进行评价。通过兔肺内注入载药微球，考察2周内不同组别兔体温、进食、活动性等方面的变化，发现兔没有表现出明显的热源反应及表观生理性变化，较空白组无显著性差异；通过兔肺内注射自制的载药微球，考察其肺局部组织病理学变化及肺内滞留性，研究发现载药微球表现出很好的肺内滞留性，虽然体内降解实验中，28天载药微球未见完全降解，但兔呼吸正常，肺内支气管粘膜各层结构清晰可见，形态正常，肺泡结构完整，无间隙红细胞增多、肺泡间隔增厚等病理学改变。该方法制备的载药微球具有较出色的生物相容性及体内安全性，具有进一步开发支气管镜介入用专属缓释药物的可行性和必要性。
[Abstract]:The present invention relates to a targeting therapeutic method for treating tuberculosis , which has the advantages of strong targeting property and accurate drug dosage control , but the slow release effect of the drug is poor , and the slow release effect of the drug is affected .

Chitosan was used as the drug carrier , ciprofloxacin was used as the study drug , and its particle size , particle size distribution , drug loading , encapsulation efficiency , permeability , degradability , lung retention , sustained release and safety were evaluated .

The first part : preparation of ciprofloxacin chitosan microspheres and preliminary study on in vitro release

The microspheres were prepared by using glutaraldehyde as cross - linking agent . The microspheres were prepared by using glutaraldehyde as cross - linking agent . The microspheres were prepared by emulsion crosslinking method . The average particle size ( 14.20 卤 0.61 ) % , the average particle size ( 142.31 卤 7.85 ) 渭m , the average particle size ( 14.20 卤 0.61 ) % , the average entrapment efficiency ( 56.43 卤 1.31 ) % .

The second part : preparation and in vitro evaluation of ciprofloxacin chitosan multiple cross - linked microspheres

In order to delay the release time of ciprofloxacin drugs more effectively , the non - ionic surfactant ethyl cellulose was selected as the auxiliary material to prepare the ciprofloxacin chitosan - ethyl cellulose multiple cross - linked microspheres .
The average particle size distribution was ( 142.31 卤 7.85 ) 渭m and the average zeta potential was ( 51.68 卤 2.3 ) mV .
Under the constant temperature condition , the sustained - release time of the multiple cross - linked microspheres can reach 144h , the chitosan microspheres show better sustained - release effect , the release time of the water - soluble drug is obviously delayed , the research basis is provided for the following in vivo experiments , and further , the research purpose of targeting sustained release after the interventional administration of the bronchoscopic mirror is achieved .

The third part : preliminary study on biocompatibility and safety of sustained - release system

The pharmacodynamics , pharmacokinetics and toxicological indexes of the drug - loaded microspheres prepared by the prescription were evaluated . The changes of body temperature , feeding and activity of different groups in rabbits were investigated by injecting drug - loaded microspheres into the lung of rabbits .
The pathological changes of lung and the retention of lung were investigated by injection of self - made drug - loaded microspheres in rabbit lung . The results showed that the drug - carrying microspheres showed good intrapulmonary retention . Although the drug - loaded microspheres were not completely degraded in 28 - day drug - loaded microspheres , the structure of the lung was normal , the alveolar structure was intact , no gap erythrocytes were increased , and the thickening of alveolar septum was changed . The drug - loaded microspheres prepared by the method have excellent biocompatibility and in vivo safety , and have the feasibility and the necessity of further developing the sustained - release drug for the interventional therapy of the bronchoscopic mirror .
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R521;R96

【参考文献】