【作者】 李福全；

【导师】 郑玉斌；

【作者基本信息】 大连理工大学 ， 高分子化学与物理， 2010， 硕士

【摘要】 由于聚酸酐具有良好的生物相容性、表面溶蚀降解性、降解速度可调性及易加工性等优异性能,很快在医学前沿领域得到应用,是目前国内外药剂领域的一个重要研究课题。其中,聚[1,3-双(对羧基苯氧基)丙烷-癸二酸](CPP/SA摩尔比20：80),共聚物与卡氮芥组成的控释片于1996年获FDA批准的第一个治疗脑胶质瘤的新剂型。1,3-双(对羧基苯氧基)丙烷是合成聚[1,3-双(对羧基苯氧基)丙烷-癸二酸]的重要原料之一,它的工业化生产反应工艺收率较低,纯度不高,因此,探索1,3-双(对羧基苯氧基)丙烷合成新工艺和合成P(CPP-SA)的新方法是目前很重要的研究课题。本文主要针对这两点进行了研究工作。以对羟基苯甲酸甲酯和1,3-二溴丙烷为原料合成了中间体二甲酯,并进一步水解得到了高产率(83%)、高纯度(99%)的1,3-双(对羧基苯氧基)丙烷。比起目前工业化合成法(收率小于40%)收率提高到2倍多。另外,此方法反应时间短、工业流程简单等优点。在国内首次一步法合成了一系列P (CPP-SA)聚酸酐,其中CPP和SA比例为20：80的聚酸酐黏度达0.56dL／g。这些聚酸酐14天的降解率都76%以下,因此具有药物缓释释放短期应用价值。并从聚合物的降解谱图得出,聚合物初期降解速度快,后期缓慢,疏水性物质CPP含量的增加,也导致聚合物降解速度变缓。采用不同方法制备出CPP、SA, PEG预聚物的基础上,采用二步熔融缩聚法合成了一系列P (CPP-SA)和P (CPP-SA-PEG)不同黏度的聚酸酐,并体外降解试验得出P(CPP-SA-PEG)的降解比较快,因为PEG的引进增强了聚酸酐的亲水性,使降解速率加快,并且可以通过改变PEG的种类和比例来调节降解时间。本论文还利用固-液相转移催化法在不同催化剂和溶剂中,合成了一系列P(CPP-SA)活性端基聚酸酐。并考察了反应时间、催化剂用量、不同催化剂对聚酸酐黏度的影响。其中,CPP和SA比例为50：50的交替共聚物黏度达1.2dL／g,其体外降解曲线接近线性,呈现较为平稳的降解性能。另外,活性端基聚酸酐可以和其他聚酸酐能嵌段共聚,因此以后开发新型聚酸酐很有意义。更多还原

【Abstract】 Polyanhydrides have been investigated as an important biomaterial used for short-term release of drugs due to excellent biocompatibility, controlled release characteristics and good pocessability. In 1996, the Food and Drug Administration (FDA) was approved the use of the polyanhydride poly(1,3-bis(p-carboxyphenoxy) propane-co-sebacic acid) ([CPP]:[SA]=20:80, P(CPP-SA)) to deliver the chemotherapeutic agent BCNU for the treatment of brain cancer.1,3-bis(p-carboxyphenoxy)propane (CPP) is one of the most important raw materials for the synthesis of P(CPP-SA), but the yield and purity of products are lower in industrial field. In this paper, CPP with high purity was obtained via novel methods for the further synthesis of P(CPP-SA), and the polyanhydrides were prepared by improved techniques.The intermediate dimethyl esters were prepared using methyl p-hydroxybenzoate and 1,3-dibromopropane as raw materials, and then hydrolysis of esters were carried out to yield CPP. The purity of products arrived to 99%, and the product yield was up to 83% which was two times more than that obtained via traditional synthesis method (below 40%).Polyanhydrides were prepared using CPP and SA via one pot synthesis. The inherent viscosity of P(CPP-SA) (20:80) was up to 0.56 dL/g. It was degraded in phosphate buffer solution (PBS) for 14 days, and the weight loss was below 76%, which suggested that the polyanhydrides could be used for short-term release of drugs.A series of polyanhydrides, P(CPP-SA) and P(CPP-SA-PEG) were prepared using CPP, SA and PEG prepolymers via two-step method. P(CPP-SA-PEG) was degraded faster in PBS because PEG unites were introduced to improve the hydrophilicity of polymers. Furthermore, the amount of PEG could be used to control degradation period.P(CPP-SA) (50:50) were also synthesized via phase transfer catalysis using different catalysts in the various solvents. The effects of reaction time and the amount of phase transfer catalyst on the inherent viscosity of polyanhydrides were investigated. The polyanhydride with inherent viscosity up to 1.2 dL/g was obtained, and the contolled degradability was observed due to the curves of in vitro degradation. Furthermore, polyanhydrides with active end groups could be developed for other block copolymers.更多还原