CN107011480B - 氨基酸作为配体的胆红素吸附剂制备方法 - Google Patents

氨基酸作为配体的胆红素吸附剂制备方法 Download PDF

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CN107011480B
CN107011480B CN201610056154.1A CN201610056154A CN107011480B CN 107011480 B CN107011480 B CN 107011480B CN 201610056154 A CN201610056154 A CN 201610056154A CN 107011480 B CN107011480 B CN 107011480B
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邹汉法
董靖
欧俊杰
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Abstract

本发明涉及一种应用于血液净化的胆红素吸附剂制备方法。本发明所述的胆红素吸附树脂基体是粒径在100μm－500μm的多孔环氧树脂，配体是赖氨酸或精氨酸。该制备方法操作简单，易于实现，制备成本低，特别是使用了生物相容性好的氨基酸作为配体。制备得到的胆红素剂对于溶液中的胆红素具有非常高效的去除作用。

Description

氨基酸作为配体的胆红素吸附剂制备方法
技术领域
本发明属于血液净化领域，涉及一种氨基酸作为配体的胆红素吸附剂的制备方法。
背景技术
胆红素是血红细胞中血红素的代谢产物，是人体肝脏功能是否正常的重要指标之一。血液中高含量胆红素的去除是医学界一直关注的焦点之一，用于去除血液中胆红素的医用吸附材料的制备是此焦点的关键技术。
高分子微球树脂材料由于具有良好的对血液中有害成分如胆红素的去除效果，已经被用于血液净化治疗。引自文献：S.R.Ash,T.A.Sullivan,D.J.Carr；TherapeuticApheresis and Dialysis；2006,.10,145:153Sorbent Suspensions vs.Sorbent Columnsfor Extracorporeal Detoxification in Hepatic Failure；P.Krisper,R.E.Stauber；Nature Clinical Practice Nephrology；2007,3,267:276Technology Insight:artificial extracorporeal liver support-how does Prometheus compare withMARS；
胆红素吸附树脂通常采用如下技术路线制备：用悬浮聚合法制备聚苯乙烯树脂，与氯甲醚反应得到氯甲基苯乙烯树脂，利用氯甲基上的活泼氯与胺进行胺基化反应，得到阴离子交换树脂用于吸附胆红素。该方法由于过程简单得到广泛应用，但其中会用到强烈致癌物质氯甲醚，并且反应过程需要消耗大量有机溶剂。本发明采用悬浮聚合方法以甲基丙烯酸缩水甘油酯为单体，双季戊四醇五丙烯酸酯为交联剂，制备得到易于衍生、交联度高、机械强度大及亲水性好的环氧树脂，碱性氨基酸在生理pH值下带正电荷，可以与负电荷的胆红素发生静电吸附作用，选择赖氨酸或精氨酸作为配体，固定在环氧树脂上得到胆红素吸附树脂。
发明内容
本发明采用悬浮聚合方法以甲基丙烯酸缩水甘油酯为单体，双季戊四醇五丙烯酸酯为交联剂，在致孔剂的存在下制备得到粒径在100μm－500μm范围的多孔微球树脂。用无水乙二胺与树脂上的环氧基团反应引入氨基。随后用戊二醛与带有氨基的树脂反应得到带有醛基的树脂。最后把赖氨酸或精氨酸水溶液与树脂混合进行反应得到胆红素吸附树脂。
具体包括如下内容：
(4)多孔环氧树脂的制备
配制含有分散剂的水溶液，将甲基丙烯酸缩水甘油酯、双季戊四醇五丙烯酸酯、引发剂和致孔剂的混合油相加入水溶液中，加热搅拌得到多孔微球树脂。
(5)醛基树脂制备
首先用无水乙二胺与环氧树脂混合，加热搅拌得到胺基树脂，随后把胺基树脂与戊二醛溶液进行混合，制备得到醛基树脂。
(6)胆红素吸附树脂的制备
用赖氨酸或精氨酸水溶液与醛基树脂反应得到胆红素吸附树脂。
上述反应中所述引发剂为过氧化苯甲酰，引发剂相对于单体的质量百分数为0.5－10％。
所述致孔剂可选用甲苯、乙苯、正己烷、正庚烷、正辛烷、正庚醇、邻苯二甲酸酯类或中的一种或二种以上致孔剂之间不同体积比的混合物，致孔剂相对于单体的质量百分比列在50-200％。
所述分散剂为聚乙烯醇和明胶，两者之间的质量比例1:1-6，分散剂与水的质量百分比例为0.4-8％。
步骤(1)所述加热搅拌通常在150-400r.p.m.，反应温度通常在70-80℃。
步骤(2)所述无水乙二胺与环氧树脂的反应在室温下进行，两者之间的质量数之比为1-5:1。
所述的胺基化反应的温度为60-90℃，反应时间为2-12小时，醛基化反应的温度为30-50℃，反应时间为8-12小时。
戊二醛与环氧树脂的质量数之比为1-5:1；戊二醛水溶液的质量浓度50％。
步骤(3)赖氨酸或精氨酸水溶液的质量浓度为0.5-10％，赖氨酸或精氨酸与醛基树脂的质量数之比为1-20:100，反应温度为40℃，反应时间为10-24小时。
本发明的优点为：所用配体生物相容性好，键和方法与传统的氯甲醚方法相比绿色环保。
附图说明
图1为胆红素吸附树脂制备示意图；
图2为胆红素吸附树脂扫描电镜图片。
具体实施方式
实施例1
(1)多孔环氧树脂的制备
配制含聚乙烯醇为10g/L和明胶为20g/L的水溶液1L作为悬浮聚合法制备环氧树脂反应体系的水相溶液。将120mg过氧化苯甲酰溶于含有12mL甲基丙烯酸缩水甘油酯、3mL双季戊四醇五丙烯酸酯和18mL正庚烷的混合溶液中，将该油性混合溶液加入到60mL水溶液中，得到的油水两相分层的混合体系在室温下以300r.p.m.的机械搅拌速度下搅拌1小时，然后将温度升高至80℃，聚合反应20小时，得到的产物环氧树脂依次用丙酮和乙醇洗涤三次后于60℃下真空干燥12小时后备用。
醛基树脂制备
把100mL乙二胺与30g环氧树脂混合，在80℃下反应5小时，得到胺基树脂，然后再与100mL的质量浓度50％戊二醛水溶液混合，在30℃搅拌反应10小时得到醛基树脂。
胆红素吸附树脂的制备
质量浓度为2％的赖氨酸水溶液100mL与30g醛基树脂混合，在40℃下反应8小时，得到的产物依次用水和乙醇洗涤三次后于60℃下真空干燥12小时后备用。
所制备的微球对15mL浓度为200mg/L的胆红素溶液中胆红素去除率为78.5％。
实施例2
(1)多孔环氧树脂的制备
配制含聚乙烯醇为8g/L和明胶为12g/L的水溶液1L作为悬浮聚合法制备环氧树脂反应体系的水相溶液。将120mg过氧化苯甲酰溶于含有12mL甲基丙烯酸缩水甘油酯、3mL双季戊四醇五丙烯酸酯和18mL正己烷的混合溶液中，将该油性混合溶液加入到60mL水溶液中，得到的油水两相分层的混合体系在室温下以300r.p.m.的速度机械搅拌1小时，然后将温度升高至80℃，聚合反应20小时，得到的产物环氧树脂依次用丙酮和乙醇洗涤三次后于60℃下真空干燥12小时后备用。
醛基树脂制备
把100mL乙二胺与30g环氧树脂混合，在80℃下反应5小时，得到胺基树脂，然后再与100mL的质量浓度50％戊二醛水溶液混合，在30℃搅拌反应10小时得到醛基树脂。
胆红素吸附树脂的制备
质量浓度为3％精氨酸水溶液100mL与30g醛基树脂混合，在45℃下反应8小时，得到的产物用依次用水和乙醇洗涤三次后于60℃下真空干燥12小时后备用。
所制备的微球对15mL浓度为200mg/L的胆红素溶液中胆红素去除率为82.8％。

Claims (6)

1.氨基酸作为配体的胆红素吸附剂制备方法，其特征在于：
采用悬浮聚合方法以甲基丙烯酸缩水甘油酯为单体，双季戊四醇五丙烯酸酯为交联剂，在致孔剂的存在下制备得到粒径在100μm－500μm范围的多孔微球树脂；用无水乙二胺与树脂上的环氧基团反应引入氨基；随后用戊二醛与带有氨基的树脂反应得到带有醛基的树脂；最后把赖氨酸或精氨酸水溶液与树脂混合进行反应得到胆红素吸附树脂。
2.按照权利要求1所述的制备方法，其特征在于：
具体步骤如下：
(1)多孔环氧树脂的制备
配制含有分散剂的水溶液，将甲基丙烯酸缩水甘油酯、双季戊四醇五丙烯酸酯、引发剂和致孔剂的混合油相加入水溶液中，加热搅拌得到多孔微球树脂；
(2)醛基树脂制备
首先用无水乙二胺与环氧树脂混合，加热搅拌得到胺基树脂，随后把胺基树脂与戊二醛溶液进行混合，制备得到醛基树脂；
(3)胆红素吸附树脂的制备
用赖氨酸或精氨酸水溶液与醛基树脂反应得到胆红素吸附树脂。
3.按照权利要求2所述的制备方法，其特征在于：
上述反应中所述引发剂为过氧化苯甲酰，引发剂相对于单体的质量百分数为0.5－10％；
所述致孔剂选用甲苯、乙苯、正己烷、正庚烷、正辛烷、正庚醇、邻苯二甲酸酯类中的一种或二种以上，致孔剂相对于单体的质量百分比例在50-200％；
所述分散剂为聚乙烯醇和明胶，两者之间的质量比例1:1-6，分散剂与水的质量百分比例为0.4-8％。
4.按照权利要求3所述的制备方法，其特征在于：
步骤(1)所述加热搅拌通常在150-400r.p.m.，反应温度通常在70-80℃。
5.按照权利要求2所述的制备方法，其特征在于：
步骤(2)所述无水乙二胺与环氧树脂的反应在室温下进行，两者之间的质量之比为1-5:1；
所述的胺基化反应的温度为60-90℃，反应时间为2-12小时，醛基化反应的温度为30-50℃，反应时间为2-12小时；
戊二醛与环氧树脂的质量之比为1-5:1；戊二醛水溶液的质量浓度50％。
6.按照权利要求2所述的制备方法，其特征在于：步骤(3)赖氨酸或精氨酸水溶液的质量浓度为0.5-10％，赖氨酸或精氨酸与醛基树脂的质量之比为1-20:100，反应温度为40℃，反应时间为10-24小时。
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