QQ客服 官方微博 反馈留言

题名	蛋白质控释微球制备过程研究
作者	孟凡涛
学位类别	博士
答辩日期	2003
授予单位	中国科学院过程工程研究所
授予地点	中国科学院过程工程研究所
导师	苏志国
关键词	控释微球 W／O／W复乳化一分步固化法 单甲氧基聚乙二醇一聚-DL-乳酸共聚物 蛋白质活性 突释效应
其他题名	Studies on Preparative Process of Microspheres for Controlled Release of Proteins
中文摘要	与传统剂型相比较，多肚和蛋白质类药物控释微球具有较高的生物利用度，较小的副作用以及可减少患者痛苦和不便的优点，因此该类微球的制备成为近年的研究热点。本论文的目的在于开发一种新的以乙酸乙酷为有机溶剂的W／O／W复乳法，制备具有高蛋白质包埋率、高蛋白质生物活性保留、以及蛋白质释放速度稳定的控释微球，并对制备过程中各变量对微球特征的影响规律进行研究。本论文分为三个部分。第一部分合成及表征了一系列用来制备微球的膜材料，即单甲氧基聚乙二醇一聚-DL-乳酸共聚物（PELA）。第二部分为W／O／W复乳化一分步固化法的建立。其中一个重要发现是有机溶剂的去除速度决定被包埋血红蛋白（BHb，模型蛋白）的活性，由此初步确立了能保持BHb活性的微包埋方法，即以乙酸乙酷为有机溶剂的W／O／W复乳化一溶剂扩散法。为了进一步降低微球粒径同时提高微球的产率，首次尝试了分步扩散去除乙酸乙醋的方法，有效地抑制了由于乙酸乙酷扩散速度过快而导致PELA易形成沉淀的趋势，建立了以乙酸乙醋为有机溶剂的W／O／W复乳化一分步固化法。该法可分为五步：①初乳化（W1／O），②复乳化（W1／O／W2），③预固化，④固化，⑤纯化。第三部分为低蛋白质突释效应控释微球的制备及表征。以溶菌酶为模型蛋白，重点研究了分步固化法中各主要工艺变量对微球的粒径、表面形貌和蛋白质释放行为的影响。结果表明，以含MPEG2000嵌段，分子量为40000 dalton的共聚物PELA为膜材，采用该法制备微球，对溶菌酶的包埋率可保持在95％以上，在测试的100天内释放出的溶菌酶可保持天然活性。在分步固化法制备微球过程中，乙酸乙酷的去除速度决定微球的内部形态，从而决定微球的蛋白质释放行为。体积平均粒径为9.5μm的微球，突释效应为8％，随后的蛋白质释放速度稳定。当微球粒径降低至1μm时，突释效应为“％。 研究表明，这种新型的以乙酸乙醋为有机溶剂的W／O／W复乳化一分步固化法是一种有应用前景的包埋药用多肤或蛋白质制备控释微球的技术。
英文摘要	Preparation of biodegradable microspheres containing therapeutic peptides and proteins has received much attention in recent years, due to their numerous advantages compared to conventional dosage forms, which include improved efficacy, reduced toxicity, and improved patient compliance and convenience. The objectives of this research are to develop a novel W/O/W double emulsion method using ethyl acetate (EA) as organic solvent, which can prepare protein-loaded microspheres with high bioactivity preservation, high protein entrapment efficiency, and stable protein release behavior, as well as to investigate the effects of process parameters on the characteristics of microspheres. The dissertation is divided into three parts. The first part focused on the syntheses and characterization of a series of monomethoxypoly (ethylene glycol)-b-poly-DL-lactide (PELA) used as the matrix material of microsphere. The second part focused on the establishment of the method of W/O/W double emulsion-stepwise solidification. It was found for the first time that the removal rate of organic solvent during preparation decided the bioactivity of entrapped bovine hemoglobin (BHb, a model protein), the W/O/W double emulsion-solvent diffusion method using EA as organic solvent could maintain the bioactivity of the BHb. To further reduce the size of microsphere and improve microsphere yield, the removal of EA was carried out in a stepwise way for the first time, which efficiently limited the PELA precipitation caused by too rapid diffusing rate of EA. Based on this result, a novel W/O/W double emulsion-stepwise solidification method using ethyl acetate (EA) as organic solvent was established. The novel process was divided into five steps: primary emulsification (W,/O), re-emulsification (W,/O/W2)5 (D pre-solidification, ?solidification and (5) purification. The final part of the research focused on the preparation and characterization of protein-loading microsphere with low burst effect. Lysozyme was selected as a model protein. The effects of main variables in the stepwise solidification process on the size, morphology, and release behavior of the microspheres were emphasized. The results showed that, when PELA copolymer containing MPEG2000 block chain was used as wall material, the bioactivity of lysozyme released from the microspheres prepared by the novel method was close to that of native lysozyme within 100 days. During preparation, the removal rate of EA decided the internal morphology of microsphere, and thereby the protein release behavior of microsphere. The prepared microspheres with a volume-mean size of 9.5 (am showed a low burst effect (8%), followed with a constant lysozyme release. The microsphere size could be reduced to 1 (am, but the burst effect was as high as 66%. In conclusion, the novel W/O/W double emulsion-stepwise solidification method using ethyl acetate (EA) as organic solvent is a potential technique to prepare biodegradable microspheres containing therapeutic peptides and proteins.
语种	中文
公开日期	2013-09-16
页码	138
内容类型	学位论文
源URL	[http://ir.ipe.ac.cn/handle/122111/1401]
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	孟凡涛. 蛋白质控释微球制备过程研究[D]. 中国科学院过程工程研究所. 中国科学院过程工程研究所. 2003.

个性服务

查看访问统计

相关权益政策

暂无数据

收藏/分享

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。