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DEVELOPMENT OF NEW BIORESORBABLE POLYMERS FOR THE HIGHLY EFFICIENT CONTROL OF DRUG-RELEASE

开发新型生物可吸收聚合物以高效控制药物释放

基本信息

批准号：
63550688
负责人：
KIMURA Yoshiharu
金额：
$ 1.28万
依托单位：
KYOTO INSTITUTE OF TECHNOLOGY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

This study deals with the synthesis, hydrolyis, and bioresorption of novel poly (alpha- hydroxy acids) comprising alpha-malic acid units, as well as with their use for the matrix materials on which a highly efficient release-control of drug isoestablished. The followings are principal findings.1. Preparation of Monomers: 3(S)-[(Benzyloxycarbonyl)methyll- (BMD) and 3(s)-[(ethoxy- carbonyl)methyl]-1.4-dioxane-2.5-diones (EMD) were prepared by lactonization of the coupling compounds of bromoacetyl chloride with beta-benzyl and beta-ethyl malates, respectively. NaHCO_3 was the only base for the successful de-hydobromination reaction.2. Polymerization and Copolymerization: Ring-opening polymerizations of both BMD and EMD were carried out in bulk with tin octylate as the catalyst to give poly(glycolic acid-co-alpha-malic acid esters). By the similar ring-opening copolymerizations of L-lactide with BMD and EMD, the terpolimers consisting of lactic acid (L), glycolic acid (G), and alpha-malic … More acid esters (M^*) were obtained. The copolymers comprising BMD units were subjected to hydrogenolytic deprotection in the presence of a Pd-C catalyst to obtain the alpha-malic acid (M)-containing copolyesters (L-G-M) having carboxy pendants.3. Hydrolyzability and Bioresorbability: The films of the L-G-M copolymers were immersed in a phosphate buffer, by which the hydrolyzability of alpha-malic acid-containing polyesters was found to be much higher than that of poly (lactic acid). The same films were implanted under the dorsal skin of rats to investigate their bioresorbability. The results indicated that the rate of degradation in vivo is comparable with that in vitro, that the resorption rate increases with increasing M ratio in the copolymers, and that the biocom- patibility of the copolymers are excellent without rejection symptoms observed in the sites of implantation. From the above results poly (alpha -hydroxy acids) comprising alpha-malic acid units were known to be used as the drug matrix, on which new drug delivery system is possibly to be developed. At present, the preparation of microspheres based on these copolymers is under way. Less

本研究涉及包含α-苹果酸单元的新型聚（α-羟基酸）的合成、水解和生物再吸收，以及它们作为基质材料的用途，在所述基质材料上建立了药物的高效释放控制。以下是主要的调查结果。单体的制备：溴乙酰氯与苹果酸β-苄酯和β-乙酯的偶联物分别经内酯化反应制得3（S）-[（苄氧羰基）甲基]（BMD）和3（S）-[（乙氧羰基）甲基]-1，4-二氧六环-2，5-二酮（EMD）。NaHCO_3是脱溴反应成功的唯一碱.聚合和共聚：以辛酸锡为催化剂，对BMD和EMD进行了本体开环聚合，得到了聚（乙醇酸-co-α-苹果酸酯）。通过L-丙交酯与BMD和EMD的类似开环共聚，得到了由乳酸（L）、乙醇酸（G）和α-苹果酸（α-maleic acid，α-maleic acid）组成的三元共聚物， ...更多信息得到酸酯（M^*）。将包含BMD单元的共聚物在Pd-C催化剂的存在下进行氢解脱保护，以获得具有羧基侧基的含α-苹果酸（M）的共聚酯（L-G-M）。水解性和生物吸附性：将L-G-M共聚物的膜浸入磷酸盐缓冲液中，发现含α-苹果酸的聚酯的水解性远高于聚乳酸的水解性。将相同的薄膜植入大鼠背部皮肤下，以研究其生物可吸收性。结果表明，共聚物的体内降解率与体外降解率相当，吸收率随共聚物中M比例的增加而增加，共聚物的生物相容性良好，植入部位无排斥反应。从上述结果可知，含有α-苹果酸单元的聚（α-羟基酸）可用作药物基质，在其上可能开发新的药物递送系统。目前，基于这些共聚物的微球的制备正在进行中。少