【作者】 李静；

【导师】 郭圣荣； 郭柏松；

【作者基本信息】 上海交通大学 ， 药学， 2016， 硕士

【摘要】 非血管腔道肿瘤会造成管腔狭窄,严重影响着人类的身体健康。支架植入技术提供了比较简捷、安全、有效的治疗方法,而单纯的裸金属支架不具有根本上治疗肿瘤的作用,分析研究载药支架给药系统在非血管领域的应用意义深远。乙烯-醋酸乙烯共聚物(EVA)具备较好的生物相容性和一定的粘弹性,就以EVA为载体的抗肿瘤药膜支架进行的研究取得较好的效果,但相关研究中所用的EVA型号较单一,药物从膜层中释放较慢,并不能有效的调节和控制药物的释放。根据上述研究背景及存在的问题,本课题设计不同的方式来改善载紫杉醇的覆膜支架。首先,基于具有不同VA含量的EVA为载体设计药膜,分别将EVA42/60、EVA32/43、EVA30/10同紫杉醇热熔混合、热压成型制膜,对药膜进行拉伸取向。对系列处方药膜的厚度、载药量及均匀度、力学性能和膜表面形貌进行研究,同时考察了支架药膜的体外释放行为。结果表明,各组药膜平整光滑,药膜厚度、药物含量均匀,制膜方法简便可行。力学性能测试结果显示VA含量较高的EVA药膜,弹性较好,但是抗击外力较差;取向药膜相比于直接压制膜,弹性较差,但抗击外力较强。实验中选择EVA30/10,厚度100μm的空白膜作为释放实验的背衬层,使得载药支架系统具有单向释药的特征。在开始的十天,各支架覆膜释放药物的速度都较快,接下来的阶段,释放速度逐渐变慢,维持近于恒速释放。药膜中EVA材料的选用及药膜是否取向对紫杉醇的累积释放量有所影响。VA含量高的药膜中累积释放的药量较大,压制药膜中累积释放的量略大于取向膜。同时,本课题选用EVA30/10为膜材制备背衬层,紫杉醇为模型药物、PLGA75/25为膜材制备药膜层,用浸入法制备覆双层药膜的PLGA支架。通过成膜因素、覆膜支架输送难易程度、膜厚度、载药剂量的测定等相关实验,确定支架制备的合适处方。并对空白覆PLGA支架溶胀与失重性能、PLGA支架中紫杉醇的释放性能进行初步研究。结果显示,不同处方所得支架覆膜的厚度、支架输送的难易程度各不相同。所制备的药膜支架性能与浸润液种类,浸润次数,浸润时间,浸润液中PLGA、PTX的浓度都有关系。同样规格的支架,浸润时间越长或是浸润次数越多,支架的载药量较大。浸润液中紫杉醇的相对浓度越高,载药量越大。载药量增大,药膜变得较脆。空白覆PLGA膜支架相比于单纯覆EVA膜的支架表现出更好的溶胀性能。空白覆PLGA支架的质量随着时间的变化有明显的减少。相比于EVA药膜支架,PLGA药膜支架实现了药物持续的快速释放,紫杉醇的释放率明显增大。通过调节支架的载药量,可以改变PLGA支架的释药行为。覆PLGA药膜支架是一种比较有潜力的控释给药系统。更多还原

【Abstract】 The non-vascular malignant tumors cause serious occlusion or stenosis of physiological tubular structures.Stent implantation technique provides relatively simple,safe and effective treatment.Since simple bare metal stent does not have a fundamental role in the treatment of tumors,it’s important to investigate drug controlled delivery systems of non-vascular stent.Ethylene-vinyl acetate copolymer(EVA)has good biocompatibility and a certain degree of viscoelasticity.Research on EVA as coating materials has achieved better results,however,the EVA style used was single and drug released slowly from the films.In this study,we designed different ways to improve drug controlled delivery systems of non-vascular stents.Firstly,we employed EVA with different VA content(EVA42/60,EVA32/43,EVA 30/10)as coating materials.EVA42/60、EVA32/43、EVA30/10 respectively,PTX were mixed and pressed into films by melting method.Simultaneously,we made the films by stretching orientation.The thickness,drug doses,mechanical properties,diffusion,drug release behavior and surface morphologies of the films were studied.We found that the preparation method was relatively simple and feasible.The mechanical tests showed that the higher content of VA led to the decrease of the modulus of elasticity and maximum tensile strength,and the increase of the maximum elongation.Orientation led to the decrease of the maximum elongation and modulus of elasticity,and the increase of the maximum tensile strength.In the experiment,we selected the EVA30/10 film(100μ m)as the backing layer.At the beginning of the ten days,the drug released fast.In the next stage,the drug release rate slowed down gradually,maintaining nearly constant release.The release profiles of coatings could be affected by the EVA materials and orientation.With higher VA content of EVA as coating materials,the drug release quantity was higher.The drug release quantity of orientation film was a little lower than that not.Also,we fabricated numerous PTX/PLGA stents with PLGA75/25 as the drug carrier and EVA30/10 as the drug-free backing layer using a dipping process.In this work,we explored the effects of preparation formulations of the PLGA stents on the mechanical performance and deliverability.Thisdemonstrated that the mechanical performance and deliverability could be modified by altering infiltration solvent,invasion times,invasion time and the concentration of liquid infiltration.We assessed the quality and drug release behaviors of the PTX/PLGA stents in vitro.With the increase of invasion times,invasion time and the ratio of PTX in the coating solution,drug loading could be increased.Compared to the PTX/EVA stents,the PTX/PLGA stents achieved sustained and rapid release of PTX.The drug release behaviors of the PTX/PLGA stents could be affected by the total drug loading.The PLGA stent coverd with drug-loaded films could be an potential drug delivery system.更多还原