抗结核病载药支架的制备及其药物释放行为和成骨性能评价
发布时间：2018-11-14 20:29
【摘要】：骨结核病是由结核杆菌引起的一种肺外结核病,严重威胁着人们的健康。在重症骨结核的治疗中,一般采用骨清除术清除病灶,并在术后进行骨修复治疗和长期多种药物治疗。病灶部位的药物浓度决定着治疗效果,然而全身高浓度的药物也难以保证病灶部位达到有效药物浓度,而长期全身多种药物治疗会对患者的肝肾造成严重损伤,同时术后的骨缺损修复也存在供体不足、修复效果不佳等问题。所以,亟需开发一种能够长期缓释多种药物的局部给药骨修复材料,不仅可以实现多种药物的持续释放,还可以促进骨再生修复。基于以上问题,本文旨在设计和制备可长期缓释多种药物的聚内酯载药支架,并研究和评价其药物释放行为和骨修复性能。首先,为了满足油溶性药物的负载与长效释放,本文通过开环聚合设计并制备了一种新型的聚内酯——聚(己内酯)-b-聚(丙交酯-co-乙交酯)(b-PLGC)三元嵌段共聚物,该聚合物与无规共聚物在热力学性能、亲疏水性、药物释放性能等方面有很大不同。本文将得到的b-PLGC与β-磷酸三钙(β-TCP)通过共混载药法复合,制备了负载油溶性利福平(RFP)的三维多孔支架,并通过扫描电镜、热重分析等测试分析了复合支架的形貌、孔结构、TCP含量及力学性能;通过紫外-可见分光光度计测试分析了复合支架的载药量、包封率及体外药物释放行为；通过体外细胞培养实验评价复合支架的细胞亲和性;通过兔桡骨缺损部位的动物实验评价支架的体内药物释放行为及成骨性能。结果表明：复合支架可以实现RFP的持续84天的缓慢释放,且体内的局部药物浓度高于全身血药浓度。同时,支架具有良好的细胞亲和性和成骨性能,在重症骨结核病的治疗中有良好的应用前景。其次,为了满足水溶性药物的负载与长效释放,本文通过水包油乳液法制备了负载水溶性异烟肼(INH)的TCP@明胶复合微球,并通过扫描电镜、热重分析等测试和分析了微球的形貌、TCP含量、药物释放行为,发现该微球可以实现INH的持续30天缓慢释放。本文将载INH的微球与b-PLGC复合,制备了负载INH的微球/b-PLGC复合支架,并通过扫描电镜、紫外-可见分光光度计等测试和分析微球／聚内酯支架的形貌、TCP含量及药物释放行为。结果表明：本文成功地将INH通过TCP@明胶复合微球负载于支架中,大大地降低了INH的初期爆发释放量,实现了INH从支架中长达84天的可持续缓慢释放。最后,本文将上述两种方法结合成功地制备了同时负载INH和RFP的缓释支架,该支架能够同时实现两种药物持续84天的缓慢平稳释放,为重症骨结核的长期多种药物治疗提供了新方法。该支架不仅能负载以INH和RFP为代表的水溶性/油溶性抗结核药物,也可以负载其他似溶解性的药物,从而满足其他需要多种药物同时治疗疾病的需求。
[Abstract]:Bone tuberculosis is a kind of extrapulmonary tuberculosis caused by Mycobacterium tuberculosis, which is a serious threat to people's health. In the treatment of severe bone tuberculosis, bone clearance is commonly used to clear the focus, and bone repair and long-term multi-drug therapy are performed after operation. The concentration of drugs in the lesion site determines the therapeutic effect. However, it is difficult to ensure the effective concentration of the drug in the focus area with high concentration of drugs throughout the body. However, long-term systemic drug therapy will cause serious damage to the liver and kidney of the patient. At the same time, the defect repair also has some problems, such as insufficient donor, poor repair effect and so on. Therefore, there is an urgent need to develop a local bone repair material that can release many drugs for a long time, which can not only realize the sustained release of many drugs, but also promote bone regeneration. In view of the above problems, the aim of this paper is to design and prepare poly (lactone) loaded stents that can release many kinds of drugs for a long time, and to study and evaluate their drug release behavior and bone repair performance. First, in order to satisfy the loading and long-term release of oil-soluble drugs, In this paper, a novel poly (caprolactone) -b (lactide co- glycolide) (b-PLGC) ternary block copolymer was designed and prepared by ring-opening polymerization. Hydrophobicity, drug release performance and other aspects are very different. In this paper, b-PLGC and 尾 -tricalcium phosphate (尾-TCP) were used to prepare the three-dimensional porous scaffolds loaded with oil-soluble rifampicin (RFP), and the scaffolds were prepared by scanning electron microscopy (SEM). The morphology, pore structure, TCP content and mechanical properties of the composite scaffold were analyzed by thermogravimetric analysis. The drug loading, encapsulation efficiency and drug release behavior of the composite scaffold were analyzed by UV-Vis spectrophotometer. The cell affinity of the composite scaffold was evaluated by cell culture in vitro and the drug release behavior and osteogenesis of the scaffold in vivo were evaluated by the animal experiment of rabbit radius defect. The results showed that the compound stent could release RFP slowly for 84 days, and the local drug concentration in vivo was higher than that in whole body. At the same time, the scaffold has good cell affinity and osteogenic properties, and has a good prospect in the treatment of severe bone tuberculosis. Secondly, in order to satisfy the loading and long-term release of water-soluble drugs, TCP@ gelatin composite microspheres loaded with water-soluble isoniazid (INH) were prepared by oil-in-water emulsion method. The morphology, TCP content and drug release behavior of the microspheres were measured and analyzed by thermogravimetric analysis. It was found that the microspheres could realize the slow release of INH for 30 days. In this paper, INH loaded microspheres and b-PLGC composite scaffolds were prepared, and the morphology of INH / b-PLGC composite scaffolds was measured and analyzed by scanning electron microscopy, UV-Vis spectrophotometer and so on. TCP content and drug release behavior. The results show that INH is successfully loaded into the scaffold through TCP@ gelatin composite microspheres, which greatly reduces the initial burst release of INH and realizes the sustained and slow release of INH from the scaffold for 84 days. Finally, the two methods were combined successfully to prepare the sustained release stents loaded with INH and RFP simultaneously. The stents could realize the slow and steady release of the two drugs for 84 days at the same time. It provides a new method for long-term multi-drug treatment of severe bone tuberculosis. The scaffold can not only load water-soluble / oil-soluble antituberculous drugs, such as INH and RFP, but also other dissolution-like drugs, so as to meet the need of other drugs to treat diseases simultaneously.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R318.08
本文编号：2332222
[Abstract]:Bone tuberculosis is a kind of extrapulmonary tuberculosis caused by Mycobacterium tuberculosis, which is a serious threat to people's health. In the treatment of severe bone tuberculosis, bone clearance is commonly used to clear the focus, and bone repair and long-term multi-drug therapy are performed after operation. The concentration of drugs in the lesion site determines the therapeutic effect. However, it is difficult to ensure the effective concentration of the drug in the focus area with high concentration of drugs throughout the body. However, long-term systemic drug therapy will cause serious damage to the liver and kidney of the patient. At the same time, the defect repair also has some problems, such as insufficient donor, poor repair effect and so on. Therefore, there is an urgent need to develop a local bone repair material that can release many drugs for a long time, which can not only realize the sustained release of many drugs, but also promote bone regeneration. In view of the above problems, the aim of this paper is to design and prepare poly (lactone) loaded stents that can release many kinds of drugs for a long time, and to study and evaluate their drug release behavior and bone repair performance. First, in order to satisfy the loading and long-term release of oil-soluble drugs, In this paper, a novel poly (caprolactone) -b (lactide co- glycolide) (b-PLGC) ternary block copolymer was designed and prepared by ring-opening polymerization. Hydrophobicity, drug release performance and other aspects are very different. In this paper, b-PLGC and 尾 -tricalcium phosphate (尾-TCP) were used to prepare the three-dimensional porous scaffolds loaded with oil-soluble rifampicin (RFP), and the scaffolds were prepared by scanning electron microscopy (SEM). The morphology, pore structure, TCP content and mechanical properties of the composite scaffold were analyzed by thermogravimetric analysis. The drug loading, encapsulation efficiency and drug release behavior of the composite scaffold were analyzed by UV-Vis spectrophotometer. The cell affinity of the composite scaffold was evaluated by cell culture in vitro and the drug release behavior and osteogenesis of the scaffold in vivo were evaluated by the animal experiment of rabbit radius defect. The results showed that the compound stent could release RFP slowly for 84 days, and the local drug concentration in vivo was higher than that in whole body. At the same time, the scaffold has good cell affinity and osteogenic properties, and has a good prospect in the treatment of severe bone tuberculosis. Secondly, in order to satisfy the loading and long-term release of water-soluble drugs, TCP@ gelatin composite microspheres loaded with water-soluble isoniazid (INH) were prepared by oil-in-water emulsion method. The morphology, TCP content and drug release behavior of the microspheres were measured and analyzed by thermogravimetric analysis. It was found that the microspheres could realize the slow release of INH for 30 days. In this paper, INH loaded microspheres and b-PLGC composite scaffolds were prepared, and the morphology of INH / b-PLGC composite scaffolds was measured and analyzed by scanning electron microscopy, UV-Vis spectrophotometer and so on. TCP content and drug release behavior. The results show that INH is successfully loaded into the scaffold through TCP@ gelatin composite microspheres, which greatly reduces the initial burst release of INH and realizes the sustained and slow release of INH from the scaffold for 84 days. Finally, the two methods were combined successfully to prepare the sustained release stents loaded with INH and RFP simultaneously. The stents could realize the slow and steady release of the two drugs for 84 days at the same time. It provides a new method for long-term multi-drug treatment of severe bone tuberculosis. The scaffold can not only load water-soluble / oil-soluble antituberculous drugs, such as INH and RFP, but also other dissolution-like drugs, so as to meet the need of other drugs to treat diseases simultaneously.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R318.08
【共引文献】
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