均一尺寸聚乳酸和聚(乳酸／乙醇酸)纳微球的制备及应用
文献类型：学位论文
| 作者 | 田瑞 |
| 学位类别 | 硕士 |
| 答辩日期 | 2006-06-02 |
| 授予单位 | 中国科学院过程工程研究所 |
| 授予地点 | 过程工程研究所 |
| 导师 | 马光辉 |
| 关键词 | 快速膜乳化 控释微球 聚乳酸 聚乳酸/乙醇酸共聚物 治疗性疫苗 胰高血糖素样肽-1 |
| 其他题名 | Preparation and application of uniform-sized PLA and PLGA micro/nanospheres |
| 学位专业 | 生物化工 |
| 中文摘要 | 纳微球作为疫苗佐剂和药物载体是研究热点之一。本论文发展了新型膜乳化技术与溶剂挥发/萃取法相结合的工艺，制备了粒径均一、可控的聚乳酸(Polylactic, PLA)和聚乳酸/乙醇酸共聚物[Poly(lactic-co-glycolic acid), PLGA]微球，并将其用于两个方面研究，一是作为乙肝表面抗原佐剂，研究佐剂粒径对免疫效果的影响；二是对降糖药物胰岛素和GLP-1进行包埋，研究制备条件对药物包埋率、活性、体外释放行为的影响。 本论文工作分为三个部分。第一部分采用新型膜乳化技术结合单乳-溶剂去除法制备粒径均一的空白微球。在优化制备条件基础上，采用快速膜乳化技术制备得到了0.3~3µm，不同粒径的PLA及PLGA微球和纳微球，微球多分散系数低于0.050。第二部分采用第一部分工作中制备得到的PLA微球作为抗原佐剂制备新型治疗性乙肝疫苗制剂及冻干粉剂。以PLA微球为佐剂能同时显著增强HBsAg诱导的IFN-γ分泌水平和特异性CTL杀伤作用，呈现出较强的佐剂作用；在体液免疫方面，以PLA为佐剂的抗原制剂也能达到铝佐剂疫苗的效果；对冻干条件进行优化，得到便于运输保存的粉剂。第三部分采用快速膜乳化技术结合复乳-溶剂去除法制备粒径均一、包埋率高和活性保持好的载药微囊，采用的模型药物为胰高血糖素样肽-1(Glucagon-like peptide-1)。乳液的固化速率影响内外水相的融合时间，因而也影响微囊的包埋率。在优化条件下，GLP-1的包埋率可达80.1%以上，活性保留在75%以上，且能在20天内持续释放。微囊的粒径多分散性系数值都低于0.050，平均粒径为0.3~3µm。 研究表明，用粒径均一、可控的PLA微球作为乙肝疫苗佐剂，通过研究不同粒径纳微球作为佐剂的免疫效果，可以筛选出最佳粒径，这是传统制备方法无法实现的。由于本论文所采用的膜乳化法制备条件温和，可以很好地保持所包埋的多肽药物活性，同时，包埋率也较传统方法有所提高。因此，均一、可控的PLA/PLGA纳微球是一种有潜力的疫苗佐剂和多肽类药物载体。 |
| 英文摘要 | Nanospheres as vaccine adjuvants and drug carrier is one of research focuses. The objectiv of this dissertation is to develop a novel membrane emulsification technique for preparation of uniform-sized polylactide (PLA) and Poly(lactic-co-glycolic acid) (PLGA) micro/nanospheres, which can be used for two areas of interests: one is to investigate the application of PLA nanospheres in novel hepatitis B therapeutic vaccine and study the relationship between the particle sizes and immune effects; the other is to encapsulate Glucagon-like peptide-1 and study the relationship between particle sizes and drug encapsulation rate, bioactivity preservation and release in vivo. The dissertation is divided into three parts. The first part focuses on using membrane emulsification techniques to prepare uniform-sized micro/nanospheres. PLA and PLGA micro/nanospheres with the index of polydispersity less than 0.050 could be effectively prepared by premix membrane emulsification technique, and the particle diameters are from 0.3 to 3µm. The second part focused on preparation of novel hepatitis B therapeutic vaccine using PLA microspheres as adjvant. The microspheres vaccine could effectively stimulate the mice splenocytes and CD8+ T lymphocytes to secret HBsAg-specific IFN-γ, and the levels of IFN-γ secretion were higher compared with commercial alum vaccine. The cytolytic assays also demonstrated that microspheres vaccine could enhance the cytotoxic activity induced by HBsAg. In addition, the level of anti-HBsAg titer obtained from microspheres vaccine reached to those of alum-vaccine. The third part focused on preparation of drug containing microspheres with high encapsulation efficiency and bioactivity preservation. Insulin was encapsulated into PLA micro/nanospheres to develop single-shot injection. The size of microspheres was about 0.3~3µm, and the index of polydispersity was less than 0.050. And Glucagon-like peptide-1(GLP-1) was encapsulated into PLGA micro/nanospheres to develop single-shot injection. Under the optimized conditions the encapsulation rate of GLP-1 could be 80.1%, and the bioactivity preservation could be more than 75%, and GLP-1 could be released in 20 days. Study shows that PLA microspheres could be used as vaccine adjvant. And the optimized particle size could be got by comparing the immune effect of microspheres with different particle sizes. The conditions of membrane emulsification, which used in thia paper are moderate for encapsulating peptide drugs with bioactivity. In conclusion, the uniform-sized PLA and PLGA micro/nanospheres prepared by membrane emulsification technique have great potentials as carrier of protein drugs and adjuvant for therapeutic vaccine. |
| 语种 | 中文 |
| 公开日期 | 2013-09-16 |
| 页码 | 114 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/1294]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 推荐引用方式 GB/T 7714 | 田瑞. 均一尺寸聚乳酸和聚(乳酸／乙醇酸)纳微球的制备及应用[D]. 过程工程研究所. 中国科学院过程工程研究所. 2006. |
入库方式： OAI收割
来源：过程工程研究所
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