CN102895176B - 一种制备含重组人血管内皮抑制素的多孔凝胶的方法 - Google Patents
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Abstract
本发明涉及一种可用作注射用重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶的制备方法。该方法包括将重组人血管内皮抑制素、单体N-异丙基丙烯酰胺、海藻酸钠、交联剂及致孔剂溶于水中；加入引发剂及促进剂；密封，室温反应至形成凝胶；将凝胶用水反复漂洗，除去未反应单体；将凝胶置于水中，均匀收缩后，取出，真空干燥至恒重，即得含重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶。
Description
技术领域
本发明涉及一种制备含重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶的方法。
背景技术
随着国内生物技术和药学的发展，原位凝胶在一些难以用传统给药方式给药的不稳定药物以及长效控释制剂、靶向定位制剂方面展示了优势。原位凝胶能够以液体状态自由加载各种性质及分子量的药物。此外，多样化的胶凝机制为设计不同途径的药物传递系统提供了丰富的选择，特别是温度响应性水凝胶，通过调整水凝胶的体积相变温度或对水凝胶进行改性使其对某一生理现象敏感，从而实现靶向给药的目的。
温度响应性水凝胶结构中具有一定比例的亲水和疏水基团，温度的变化可以影响这些基团的疏水相互作用或大分子链间的氢键作用，从而改变水凝胶的网络结构，产生体积相变。聚N-异丙基丙烯酰胺(PNIPAM)水凝胶是最常用的温敏高分子，它在32℃左右有一个最低临界溶解温度(LCST)。在此温度附近PNIPAM水凝胶表现出不连续的可逆的相转变。当体系温度高于LCST时，水凝胶表面会发生收缩，导致水化层收缩，形成薄的致密皮层，阻止内部水分或溶质向外释放；当温度低于LCST时，表面皮层溶胀吸水。通过在凝胶的骨架中引入不同亲、疏水基团以改变凝胶网络的亲水/疏水比，而达到改变水凝胶的LCST的目的。
凝胶溶胀或收缩过程主要是高分子网络吸收或释放溶剂，这是一个慢的扩散过程，而且接近临界点时更慢。但对于一个具有相互连接的孔结构的网络来说，溶剂的吸收或释放通过孔由对流产生，这一过程比非孔凝胶中的扩散过程快。因此，合成具有孔结构的水凝胶可以提高其响应速率。
注射用重组人血管内皮抑制素（恩度，Endostar），是首个血管内皮抑制素肺癌新药。恩度目前的给药方式是病人需要每天静脉滴注一次，疗程为14天，休息一周后，再继续下一疗程，治疗费用高，患者依从性不佳。近期有研究发现动物体内小剂量持续给予Endostatin的药效要优于间歇性给药（Minoru Kuroiwa,et al.J.Pediatr.Surg.38:1499-1505,2003;Oliver Kisker,et al.Cancer Res.61:7669-7674,2001）。因此，将其开发成注射一次可以持续释药的长效制剂非常必要。
制备注射用重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶，药物在室温下被吸收进入溶胀的水凝胶内，当携带药物的凝胶制剂进入人体后，由于人体的温度高于其体积相变温度，导致凝胶收缩挤出药物和溶剂，使药物在体内缓慢平稳的释放，延长药物在体内的半衰期，减少肿瘤病人每个疗程的给药次数，从每天静脉滴注给药一次改为1-2周给药一次，提高了病人顺应性，降低了用药的成本，具有良好的临床疗效和市场前景。同时为目前临床恩度注射液的最佳给药方式的确定提供理论和实践的依据。
发明内容
本发明的目的是提供一种可用作注射用重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶的制备方法。
在智能水凝胶的实际应用中，对其机械强度、低临界溶解温度、溶胀比、溶胀/退溶胀速率等往往有特定要求；此外，对于一些特殊的应用，如大分子药物的控制释放，要求凝胶有较大的孔径，有利于大分子药物的负载和释放。以碳酸钙、聚乙二醇、硅胶为致孔剂也用于制备大孔PNIPAM凝胶。该凝胶制备过程在低温及生理温度条件下完成，不涉及高温处理，这对于稳定性差的大分子蛋白非常适合，有助于保持生物活性。
本发明提出的一种可用作注射用重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶的制备方法，包括以下各步骤：
将重组人血管内皮抑制素、单体N-异丙基丙烯酰胺、海藻酸钠、交联剂及致孔剂溶于水中；其中所述的重组人血管内皮抑制素为重组人血管内皮抑制素Endostar，占水重量的5%～15%；所述的单体N-异丙基丙烯酰胺占水重量的10%～25%；所述的海藻酸钠占水重量的0.5%～2.5%；所述的交联剂为丙烯酰胺、亚甲基二丙烯酰胺、N-羟甲基丙烯酰胺、丙烯酸、甲基丙烯酸、甲基丙烯酸酯、双丙烯酸聚乙二醇酯中的一种，占水重量的0.25%～1%；所述的致孔剂为L-精氨酸、氯化钠、中链脂肪酸甘油酯中的一种，占水重量的5%～15%。
在上述水溶液中加入引发剂及促进剂；其中所述的引发剂为过硫酸铵或过硫酸钾，占水重量的0.15%～0.65%；所述的促进剂为四甲基乙二胺或偏重亚硫酸钠，占水重量的0.15%～0.65%。
密封，室温反应至形成凝胶。室温优选地为16～26℃，进一步优选地为18～25℃。
将凝胶用水反复漂洗，除去未反应单体。
将凝胶置于35～40℃水中，优选地为37℃水中，均匀收缩后，取出，真空干燥至恒重，即得含注射用重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶。
本发明的优点有：
1、与微球等给药系统相比，本发明中多孔聚（N-异丙基丙烯酰胺）凝胶的工艺路线简单可行，成本低廉；制备条件温和，可以避免制备过程中高温的影响，对蛋白活性影响很小，载药能力大。
2、本发明得到的凝胶具有孔结构，可以提高其响应速率，可调控活性成分的释放时间，使在体内的释放时间在7天～28天，甚至更长。
附图说明
图1凝胶扫描电镜图。其中（a）实施例一凝胶，（b）实施例二样品1，（c）实施例二样品2，（d）实施例二样品3。
图2凝胶累积释放曲线图。
具体实施方式
本发明通过以下实施例作更详细的描述，但不能将其解释为限制本发明的保护范围。
实施例一
将1g重组人血管内皮抑制素、1.5g N-异丙基丙烯酰胺（NIPAM）单体、0.1g海藻酸钠和0.05g丙烯酸溶于10mL去离子水中，搅拌均匀，加入0.02g过硫酸铵和0.02g偏重亚硫酸钠，密封，室温下反应48h后，取出凝胶用去离子水浸泡一周，每天换水以洗去未反应的单体，将凝胶置于37℃去离子水中使其均匀收缩，真空干燥至恒重即得。
实施例二
将重组人血管内皮抑制素、NIPAM单体、海藻酸钠、交联剂和致孔剂溶于10mL去离子水中，搅拌均匀，加入引发剂和促进剂，密封，室温下反应48h后，取出凝胶用去离子水浸泡一周，每天换水以洗去未反应的单体，将凝胶置于37℃去离子水中使其均匀收缩，真空干燥至恒重即得。反应物组成及配比见表1。
实施例三
将实施例一中的凝胶样品及实施例二中的样品1，样品2和样品3用冷冻干燥机除去水分，切取干燥后的小块样品表面经喷金后，用扫描电子显微镜观察（参见图1）。未加入致孔剂的凝胶表面致密，而加入致孔剂的凝胶表面形成孔洞。
实施例四
取实施例二中的样品1，样品4，样品7形成的凝胶分别置于37℃恒温水浴震荡器中，加入100mL磷酸盐缓冲液PBS7.4。每个取样点取释放液2mL，同时补充同体积新鲜的磷酸缓冲液。释放样品中Endostar的含量用BCA法测定。用药物的累积释放百分率与释药时间作图（参见图2）。凝胶释放时间可以调节为7～28天。
表1制备凝胶的反应物组成及配比
Claims (7)
1.一种制备含重组人血管内皮抑制素的多孔聚（N-异丙基丙烯酰胺）凝胶的方法，其特征在于：
步骤(1)将重组人血管内皮抑制素、单体N-异丙基丙烯酰胺、海藻酸钠、交联剂及致孔剂溶于水中；
步骤(2)加入引发剂及促进剂；
步骤(3)密封，室温反应至形成凝胶；
其中所述的单体N-异丙基丙烯酰胺占步骤(1)水重量的10%～25%，所述海藻酸钠占步骤(1)水重量的0.5%～2.5%，所述的致孔剂选自L-精氨酸、中链脂肪酸甘油酯中的一种，占步骤(1)水重量的5%～15%。
2.根据权利要求1中所述的制备方法，其特征在于形成的凝胶用水反复漂洗，除去未反应单体；然后将凝胶置于温度为T的水中，均匀收缩后，取出，真空干燥至恒重；所述T为35～40℃。
3.根据权利要求2中所述的制备方法，其特征在于所述T为37℃。
4.根据权利要求1～3中任一项所述的制备方法，其特征在于所述的重组人血管内皮抑制素为重组人血管内皮抑制素Endostar，占步骤(1)水重量的5%～15%。
5.根据权利要求1～3中任一项所述的制备方法，其特征在于所述的交联剂选自丙烯酰胺、亚甲基二丙烯酰胺、N-羟甲基丙烯酰胺、丙烯酸、甲基丙烯酸、甲基丙烯酸酯、双丙烯酸聚乙二醇酯中的一种，占步骤(1)水重量的0.25%～1%。
6.根据权利要求1～3中任一项所述的制备方法，其特征在于所述的引发剂为过硫酸铵或过硫酸钾，占步骤(1)水重量的0.15%～0.65%。
7.根据权利要求1～3中任一项所述的制备方法，其特征在于所述的促进剂为四甲基乙二胺或偏重亚硫酸钠，占步骤(1)水重量的0.15%～0.65%。
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