快速膜乳化法制备载紫杉醇聚乳酸类微球的研究
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摘要
微球作为难溶药物的传输载体因其具有增加难溶药物溶解性、增强透膜吸收,靶向传输等优势而成为目前研究的热点之一。为了解决传统方法所制备的微球粒径不均一的问题,本论文采用快速膜乳化法制备了粒径均一、可控的载难溶药物紫杉醇的聚乳酸(Polylactic acid,PLA)、聚乳酸-羟基乙酸共聚物[Poly (lactic-co-glycolic acid), PLGA]和聚(乳酸-聚乙二醇)二嵌段共聚物[(Monomethoxypoly(ethylene glycol)-b-poly-DL-lactic acid), PELA]微球,并对三种载药微球的表面形貌、药物分布、药物载药率和包埋率及体外释药行为进行系统考察和比较。
本论文工作分为三部分。第一部分采用快速膜乳化法制备PLA空白微球,通过制备条件优化,制备得到了粒径为900-1000 nm的均一的微球,多分散系数为0.005,与传统均质、超声法制备的微球进行比较,结果表明,快速膜乳化法制备的微球均一性大大优于传统方法。在此基础上,还制备了同样粒径的均一PLGA和PELA微球,形貌表征结果表明,PLA和PLGA微球球形圆整、表面光滑,而PELA微球表面出现褶皱,有类似孔道的结构。第二部分在第一部分工作的基础上制备了均一的载紫杉醇PLA、PLGA和PELA微球,并对载药率、包埋率、药物在微球中的分布及体外释药行为进行表征和比较。结果表明PLA、PLGA和PELA微球对紫杉醇的装载率分别为3.89%、4.93%和3.18%,包埋率分别为63.2%、71.6%和51.3%,紫杉醇在PLA微球中以细小的的颗粒较均匀的分布,在PLGA微球中以较小的块状分布,而在PELA中则以较大的块状分布。在磷酸盐缓冲液中释放60天后,PLGA微球的药物释放率为83.87%,PLA微球的药物释放率为50.25%,PELA微球的药物释放率为41.27%。第三部分尝试对微球的结构进行调控,以NH4CO3为内水相添加剂制备多孔PLA微球,考察了内水相盐浓度、制备初乳时超声破碎功率、时间以及油相乳化剂对微球结构的影响。
通过本论文的比较研究表明,与均质乳化法和超声破碎法相比,在制备均一的微球方面,快速膜乳化法具有明显的优势。对PLA、PLGA和PELA载紫杉醇聚乳酸类微球,因材料亲疏水性不同导致的难溶药物在微球内的分布不同,最终导致不同材料微球对药物装载率、包埋率及体外释药行为有所不同,只有亲水性适中的PLGA材料对药物有较高的药物装载率和包埋率,同时,因亲水性适中导致其体外释放也较快,有望成为合适的难溶药物载体材料。
Recently, many researchs focus on preparing microspheres as insoluable drug carrier because microsoheres own some advantages of improving solubility and adsorption of insoluable drug and targetable delivery. In order to overcome the problem that the size distribution of microsphere is broad with conventional methods, uniform-sized paclitaxel-loaded PLA, PLGA, PELA microspheres were prepared by premix membrane emulsification technique. In this study, surface morphology, drug distribution, drug loading efficency, encapsulation efficiency and drug release profiles were studied.
The dissertation is divided into three parts. The first part focus on using premix membrane emulsification to prepare uniform-sized PLA microspheres with the index polydispersity of 0.005. The size distribution of PLA microspheres was from 900 to 1000 nm. It suggested that premix membrane emulsification has great potential on preparing uniform-sized microspheres compared with homogenization and ultrosonification emulsification. Based on this, uniform-sized PLGA and PELA microsperes were prepared. The mophology characterization suggested PLA and PLGA microsperes had smooth surface, while the surface of PELA microspheres was folded and jagged with some pore channels.
In the second part paclitaxel-loaded PLA, PLGA and PELA microspheres are prepared and compared by premix membrane emulsification. The loading efficency of paclitaxel-loaded PLA, PLGA and PELA microspheres were 3.89%,4.93% and 3.18, and corresponding encapsulation efficency were 63.2%,71.6% and 51.3%, respectively. Paclitaxel exsited in PLA microspheres as fine particles. While in PLGA microspheres, paclitaxel precipited in situ and aggreated as spot adjuncts and in PELA microspheres bigger spot adjuncts were obsevered. The profile release of paclitaxel-loaded PLA, PLGA and PELA microspheres in vitro for 60 days were 83.87%,50.25% and 41.27%.
The third part focused on structure regulation. Porous PLA microspheres were prepared with NH4CO3 as pore-forming agent in internal water phase. The effects of NH4CO3 concentation, ultrosonification power, time and emulsifier were studied in this part.
The results suggested that premix membrane emulsification has great potenial on preparing uniform-sized microspheres comparing with conventional homogenization and ultrosonification technique. For PLA, PLGA and PELA microspheres, insoluable drug distributions were different because of the hydrophilicity of materials, furthermore, drug loading efficency, encapsulation efficency and the release profile in vitro were different. Only PLGA with suitable hydrophilicity had relative higher drug encapsulation efficency and faster ralease rate. It supposed to be chosen as suitable insoluable drug carrier.
本论文工作分为三部分。第一部分采用快速膜乳化法制备PLA空白微球,通过制备条件优化,制备得到了粒径为900-1000 nm的均一的微球,多分散系数为0.005,与传统均质、超声法制备的微球进行比较,结果表明,快速膜乳化法制备的微球均一性大大优于传统方法。在此基础上,还制备了同样粒径的均一PLGA和PELA微球,形貌表征结果表明,PLA和PLGA微球球形圆整、表面光滑,而PELA微球表面出现褶皱,有类似孔道的结构。第二部分在第一部分工作的基础上制备了均一的载紫杉醇PLA、PLGA和PELA微球,并对载药率、包埋率、药物在微球中的分布及体外释药行为进行表征和比较。结果表明PLA、PLGA和PELA微球对紫杉醇的装载率分别为3.89%、4.93%和3.18%,包埋率分别为63.2%、71.6%和51.3%,紫杉醇在PLA微球中以细小的的颗粒较均匀的分布,在PLGA微球中以较小的块状分布,而在PELA中则以较大的块状分布。在磷酸盐缓冲液中释放60天后,PLGA微球的药物释放率为83.87%,PLA微球的药物释放率为50.25%,PELA微球的药物释放率为41.27%。第三部分尝试对微球的结构进行调控,以NH4CO3为内水相添加剂制备多孔PLA微球,考察了内水相盐浓度、制备初乳时超声破碎功率、时间以及油相乳化剂对微球结构的影响。
通过本论文的比较研究表明,与均质乳化法和超声破碎法相比,在制备均一的微球方面,快速膜乳化法具有明显的优势。对PLA、PLGA和PELA载紫杉醇聚乳酸类微球,因材料亲疏水性不同导致的难溶药物在微球内的分布不同,最终导致不同材料微球对药物装载率、包埋率及体外释药行为有所不同,只有亲水性适中的PLGA材料对药物有较高的药物装载率和包埋率,同时,因亲水性适中导致其体外释放也较快,有望成为合适的难溶药物载体材料。
Recently, many researchs focus on preparing microspheres as insoluable drug carrier because microsoheres own some advantages of improving solubility and adsorption of insoluable drug and targetable delivery. In order to overcome the problem that the size distribution of microsphere is broad with conventional methods, uniform-sized paclitaxel-loaded PLA, PLGA, PELA microspheres were prepared by premix membrane emulsification technique. In this study, surface morphology, drug distribution, drug loading efficency, encapsulation efficiency and drug release profiles were studied.
The dissertation is divided into three parts. The first part focus on using premix membrane emulsification to prepare uniform-sized PLA microspheres with the index polydispersity of 0.005. The size distribution of PLA microspheres was from 900 to 1000 nm. It suggested that premix membrane emulsification has great potential on preparing uniform-sized microspheres compared with homogenization and ultrosonification emulsification. Based on this, uniform-sized PLGA and PELA microsperes were prepared. The mophology characterization suggested PLA and PLGA microsperes had smooth surface, while the surface of PELA microspheres was folded and jagged with some pore channels.
In the second part paclitaxel-loaded PLA, PLGA and PELA microspheres are prepared and compared by premix membrane emulsification. The loading efficency of paclitaxel-loaded PLA, PLGA and PELA microspheres were 3.89%,4.93% and 3.18, and corresponding encapsulation efficency were 63.2%,71.6% and 51.3%, respectively. Paclitaxel exsited in PLA microspheres as fine particles. While in PLGA microspheres, paclitaxel precipited in situ and aggreated as spot adjuncts and in PELA microspheres bigger spot adjuncts were obsevered. The profile release of paclitaxel-loaded PLA, PLGA and PELA microspheres in vitro for 60 days were 83.87%,50.25% and 41.27%.
The third part focused on structure regulation. Porous PLA microspheres were prepared with NH4CO3 as pore-forming agent in internal water phase. The effects of NH4CO3 concentation, ultrosonification power, time and emulsifier were studied in this part.
The results suggested that premix membrane emulsification has great potenial on preparing uniform-sized microspheres comparing with conventional homogenization and ultrosonification technique. For PLA, PLGA and PELA microspheres, insoluable drug distributions were different because of the hydrophilicity of materials, furthermore, drug loading efficency, encapsulation efficency and the release profile in vitro were different. Only PLGA with suitable hydrophilicity had relative higher drug encapsulation efficency and faster ralease rate. It supposed to be chosen as suitable insoluable drug carrier.
引文
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