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SMA 及其衍生物的合成、表征以及用作肠溶包衣材料的评价
Thesis Advisor高林
Degree Grantor中国科学院研究生院
Place of Conferral北京
Degree Name博士
Degree Discipline有机化学
Keyword苯乙烯马来酸酐共聚物 乙酯化 肠溶材料 Ph 敏感性能 包衣评价

本文从合成、表征、肠溶包衣性能评价到红霉素片剂包衣试验,以及材料的毒理、药理学试验对苯乙烯马来酸酐共聚物的乙酯化产物用作肠溶包衣材料进行了全面的评价。以苯乙烯和马来酸酐为原料,通过在不同条件下的聚合,制备了交替的苯乙烯-马来酸酐共聚物(SMA),对SMA 的合成条件和纯化条件进行了优化,并建立了该材料分子量及其分布、酸值等理化性能的检测方法体系,在此基础上进行SMA 合成的中试放大试验;通过考察苯乙烯马来酸酐交替共聚物(SMA)乙酯化过程中催化剂的选择及用量、反应时间和反应温度对酯化度的影响,得出三乙胺为该反应的最佳催化剂,以丁酮为溶剂,催化剂用量相当于酸酐基团15~20%(mol),80℃下反应8小时反应的酯化度最高,讨论了酯化度的计算方法、催化剂的活性以及三乙胺催化SMA 乙酯化反应的机理,通过红外及核磁表征了SMA 及其乙酯化产物的结构;考察了加入不同种类及用量的增塑剂制备的SMA 乙酯化产物薄膜的扫描电镜图、机械强度、抗透湿性能和吸湿性能,发现邻苯二甲酸二丁酯用量为20%制备的薄膜性能最佳;将水解后的SMA(HSMA)、SMA 的乙酯化产物用于红霉素肠溶片剂包衣试验,体外溶出试验发现HSMA 包衣的片剂在pH=1 的缓冲溶液中具有透湿性,这就有可能会破坏对pH 敏感的药物的稳定性,降低药效或产生毒副反应;而SMA 的乙酯化产物具有很强的抗透湿性能,当包衣增重为4-6%时该材料完全能够满足美国药典对肠溶包衣材料释放度的要求,在模拟胃液中2 小时的释放度小于0.2%,而在模拟肠液中45 分钟内的释放度超过了90%;毒理学试验结果表明该材料给小白鼠一次灌胃的最大耐受量大于8g/kg,相当于人临床拟用量的800 倍,没有急性毒性;药理学试验结果表明该材料对中枢神经系统、心血管系统、呼吸系统无明显影响。

Other Abstract
This article fully evaluated the SMA-ethanol as an enteric coating material from synthesis, characterization and film properties to tablet coating. Using styrene and maleic anhydride as the reactants, SMA copolymers were synthesized with different reacting condition. Both of the reacting and purification condition were optimized, and the characterization methods of the physicochemical properties such as molecular weight, molecular weight distribution and acid value were also established, based on which the pilot-plant-scale test of the synthesis of SMA was carried out. The effects of reacting condition to degree of esterification were evaluated, in which included the catalysts, the using amount of catalysts, the reacting time and the reacting temperature, the result indicated that the most fitting reacting conditions were as follow: MEK as the solvent, TEA as the catalyst, with the catalyst amount of 15-20%(mol percent), the reacting time was 8h with the reacting temperature of 80℃. SMA-ethanol with different degree of esterification had different pH-sensitive values; such polymers can be dissolved in different parts of the small intestine, which have a good perspective in the application of drug delivery system. This article also discussed the calculation of degree of esterification, the activity of catalysts and the mechanism of the esterification of SMA and ethanol catalysted by TEA. Free films were prepared by adding different kinds and amounts of plasticizers, the film surface topography was determined by a SEM, the tensile strength, water vapor transmission rate and moisture absorption were also tested to choose the most promising film. DBP was proved to be the most suitable plasticizer with a best using amount of 20%, such polymer films had low vapor transmission rate and low moisture absorption which were very important to an enteric coating material. The polymers was further characterized for film coating by evaluating the release of erythromycin tablets in vitro, hydrolyzed styrene maleic anhydride copolymer had lower water resistance in buffer solution of pH=1 which would result in destroy of the instable drug in acitic aqueous. Tablets coated with SMA-ethanol can satisfy the drug release requests of USP when the film weight gains were between 4-6%; tablets coated with both a subcoat and the polymer showed excellent gastro-resistance, less than 0.2% drug release occurred even with weight gains as less as 2% after 2h exposure to acid(pH=1), while over 90% drug release occurred in pH=6.8 sodium phosphate buffer within 45min, regardless of weight gains of coating material, moreover, we confirmed that the application of a subcoat could decrease the amount of required coating polymer. In conclusion, the potential use of SMA-ethanol as enteric coating material was demonstrated.
Document Type学位论文
Recommended Citation
GB/T 7714
赖小林. SMA 及其衍生物的合成、表征以及用作肠溶包衣材料的评价[D]. 北京. 中国科学院研究生院,2008.
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