CN106065048B - 一种可载药的温敏性水凝胶 - Google Patents

一种可载药的温敏性水凝胶 Download PDF

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CN106065048B
CN106065048B CN201610386948.4A CN201610386948A CN106065048B CN 106065048 B CN106065048 B CN 106065048B CN 201610386948 A CN201610386948 A CN 201610386948A CN 106065048 B CN106065048 B CN 106065048B
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曹渊
曲靖雯
胡贵林
陈金
徐彦芹
张瑞来
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Abstract

一种可载药的温敏性水凝胶,制备它的原料中有N‑异丙基丙烯酰胺、丙烯酰胺和羟乙基纤维素,相应步骤包括:将羟乙基纤维素于蒸馏水中溶解;将N‑异丙基丙烯酰胺和丙烯酰胺的均匀混合物加入羟乙基纤维素溶液内;再加入引发剂过硫酸钾、辅助剂四甲基乙二胺,然后通氮气保护以得枝接产物;将枝接产物干燥,用丙酮为提取剂,在索氏提取器内提取;将提纯后的枝接产物溶解于蒸馏水中,加入氢氧化钠、交联剂环氧氯丙烷,磁力搅拌后得到可载药的温敏性水凝胶的半成品;将所述半成品胶置于去离子水中浸泡得到最低临界溶解温度在37~41℃之间的可载药的温敏性水凝胶。本发明产品另有机械强度与现有技术相当,而制备操作更方便、节省工时成本的优点。

Description

一种可载药的温敏性水凝胶
技术领域
本发明涉及用纤维素改性的可载药的温敏性水凝胶。
背景技术
水凝胶是以水为分散介质的水溶性高分子物质,它具有三维网状的交联结构,形态介于液体和固体之间,既能显著溶胀又不溶于水。因此,人们就选用最低临界溶解温度(lower critical solution temperature,LCST)与人体生理温度很接近的水凝胶来作为某些靶向药物的载体材料之一,由单体N-异丙基丙烯酰胺(NIPAAm)制备得到的聚合物——聚N-异丙基丙烯酰胺(PNIPAAm)就是这类水凝胶的一种。只是,由于纯聚N-异丙基丙烯酰胺水凝胶存在机械强度差,难以加工成具有精细结构和固定形态的载体材料,另外还有温度响应速率较慢的问题,所以,还需对其进行改性。用棉纤维枝接(也称“接枝”)单体N-异丙基丙烯酰胺[刘今强,张芳等.棉纤维的N-异丙基丙烯酰胺接枝共聚及产物的温敏性研究[J].高分子学报,2009(12):1266-1273.]进而得到改性后的N-异丙基丙烯酰胺聚合物是改性方法之一。通过这样的改性,所得产物的机械强度和温度响应速率的确均优于未改性的聚N-异丙基丙烯酰胺。然而,其改性产物——棉纤维N-异丙基丙烯酰胺接枝共聚物的最低临界溶解温度却仍然只有32~33℃,也就是说,在温度达到32℃(最高为33℃)时,该棉纤维N-异丙基丙烯酰胺接枝共聚物就会快速响应剧烈收缩而失水。如果将其作为载体来制备靶向药物,这靶向药物至迟在温度升33℃时就要发生相分离(药剂和载体分离)。由于人体生理温度(正常情况下37℃左右,发烧时可达39℃上下)高于33℃,这就意味着若将棉纤维N-异丙基丙烯酰胺接枝共聚物作为载体来输送药剂,就基本无法将药剂输送到人们所希望达到的病变部位,更严重的是还可能对正常细胞造成伤害。
发明内容
本发明的目的是提供一种机械强度与现有技术相当,而其最低临界溶解温度却与人体的生理温度相近的可载药的温敏性水凝胶。
实现所述发明目的是这样一种可载药的温敏性水凝胶,它与现有技术相同的方面是,制备它的原料中包括N-异丙基丙烯酰胺和纤维素,其改进之处是,所述原料中还有丙烯酰胺,所述纤维素是羟乙基纤维素;该可载药的温敏性水凝胶由如下方法及相应步骤制备而成:
(1)将羟乙基纤维素溶解于蒸馏水中,在常温下搅拌均匀,通过超声震荡充分溶解;其中,羟乙基纤维素∶蒸馏水=0.50~1.00g∶20.0ml;
(2)在步骤(1)制得的溶液中加入N-异丙基丙烯酰胺和丙烯酰胺的均匀混合物,在常温下搅拌至完全溶解;其中,N-异丙基丙烯酰胺∶羟乙基纤维素=0.20g∶0.50~1.00g,N-异丙基丙烯酰胺∶丙烯酰胺=9~15g∶1g;
(3)在步骤(2)制得的溶液中加入引发剂过硫酸钾、辅助剂四甲基乙二胺,然后通氮气保护,在常温下磁力搅拌12h,得到枝接产物;其中,N-异丙基丙烯酰胺∶过硫酸钾=0.20g∶0.03g,N-异丙基丙烯酰胺∶四甲基乙二胺=0.20g∶0.18ml;
(4)将步骤(3)的枝接产物干燥,用丙酮为提取剂,索氏提取器提取12h;丙酮的用量以除尽均聚物以及未反应的引发剂和辅助剂为度;
(5)将步骤(4)中提纯后的枝接产物溶解于蒸馏水中,加入氢氧化钠粉末,磁力搅拌至充分混匀,加入交联剂环氧氯丙烷,磁力搅拌5min,于30℃烘箱中静置12h,得到可载药的温敏性水凝胶的半成品;其中,枝接产物∶氢氧化钠∶环氧氯丙烷∶蒸馏水=0.8g∶1.0g∶2.0ml∶20ml。
(6)将步骤(5)所述半成品胶置于去离子水中浸泡36h,每间隔2h更换一次去离子水,得到最低临界溶解温度在37~41℃之间的可载药的温敏性水凝胶;所述去离子水的每一次用量均以能够得到尽量多的纯净而透明的可载药的温敏性水凝胶为度。
从方案中可以看出,本发明为保持机械强度与温度响应速率现有技术相当,在对可载药的水凝胶单体进行枝接改性时,仍然采用了纤维素,不同的方面是所采用的纤维素不是棉纤维的,而是羟乙基纤维素,并且用于枝接改性的单体也不是单一的N-异丙基丙烯酰胺,而是N-异丙基丙烯酰胺和丙烯酰胺这两种单体的均匀混合物。这样一来,羟乙基纤维素的生物相容性和可降解性就得到了充分的发挥,进而保证了成为共聚物的最终产物——可载药的温敏性水凝胶的机械强度与温度响应速率能够与现有技术相当。关键之处是,将N-异丙基丙烯酰胺和丙烯酰胺这两种单体按照本发明所述配比混合后,就克服了现有技术仅用单一的N-异丙基丙烯酰胺来枝接,不能提高产物最低临界溶解温度的不足,验证表明,本发明产物的最低临界溶解温度到了37~41℃,也就与人体生理温度(正常情况下37℃左右,发烧时可达39℃上下)几乎一样了。如此一来,将本发明产物作为载体来输送药剂(药物)时,就能够保证准确到达到人体的病灶处,再在其温度影响下释放出来。不仅准确地发挥出靶向用药的作用,而且对人体的健康细胞不会造成伤害。从方案中还可以看出,相对于现有技术,本发明还另外用了交联剂环氧氯丙烷,在由氢氧化钠所造就的碱性环境中,该交联剂能够使羟乙基纤维素所构建的网状结构更好,也即使得本发明的可载药温敏性水凝胶成为形态很好的多孔网状聚合物,其载药量和最低临界溶解温度的释药功能又可得到提高。另外,若像现有技术那样用棉纤维在作为改性原料,那么在事前还需对其用热碱煮沸溶解,而本发明采用的羟乙基纤维素,因其自身就有很好的溶解性,就完全不需要在事前对其用热碱煮沸了,因此,与现有技术相比较,本发明还有操作更方便、且节省工时成本的优点。
下面将结合具体实施方式对本发明作进一步说明。
具体实施方式
一种可载药的温敏性水凝胶,制备它的原料中包括N-异丙基丙烯酰胺(NIPAAm)和纤维素,在本发明中,所述原料中还有丙烯酰胺(Am),所述纤维素是羟乙基纤维素(HEC);该可载药的温敏性水凝胶由如下方法及相应步骤制备而成:
(1)将羟乙基纤维素溶解于蒸馏水中,在常温下搅拌均匀,通过超声震荡充分溶解;其中,羟乙基纤维素∶蒸馏水=0.50~1.00g∶20.0ml;
(2)在步骤(1)制得的溶液中加入N-异丙基丙烯酰胺和丙烯酰胺的均匀混合物,在常温下搅拌至完全溶解;其中,N-异丙基丙烯酰胺∶羟乙基纤维素=0.20g∶0.50~1.00g,N-异丙基丙烯酰胺∶丙烯酰胺=9~15g∶1g;
(3)在步骤(2)制得的溶液中加入引发剂过硫酸钾(K2S2O8)、辅助剂四甲基乙二胺[(CH3)2NCH2CH2N(CH3)2],然后通氮气(N2)保护,在常温下磁力搅拌12h,得到枝接产物;其中,N-异丙基丙烯酰胺∶过硫酸钾=0.20g∶0.03g,N-异丙基丙烯酰胺∶四甲基乙二胺=0.20g∶0.18ml(本领域的技术人员清楚,在化学反应中,有时为了确保得到尽量多的产物,是会过量使用部分反应物的。在本步骤中,就是为了得到尽量多的枝接产物,而约为过量地使用了引发剂和辅助剂);
(4)将步骤(3)的枝接产物干燥,用丙酮(CH3COCH3)为提取剂,索氏提取器提取12h;丙酮的用量以除去均聚物[单体N-异丙基丙烯酰胺在纤维素枝接过程中发生副反应(自聚)产生的杂质]以及未反应的引发剂和辅助剂为度[通常,在按照步骤(3)的配比,以及用量的情况下,丙酮可取200ml];
(5)将步骤(4)中提纯后的枝接产物溶解于蒸馏水中,加入氢氧化钠粉末,磁力搅拌至充分混匀,加入交联剂环氧氯丙烷,磁力搅拌5min,置于30℃烘箱中静置12h,得到可载药的温敏性水凝胶的半成品;其中,枝接产物∶氢氧化钠∶环氧氯丙烷∶蒸馏水=0.8g∶1.0g∶2.0ml∶20ml。
(6)将步骤(5)所述半成品胶置于去离子水中浸泡36h,每间隔2h更换一次去离子水,得到最低临界溶解温度在37~41℃之间的可载药的温敏性水凝胶;所述去离子水的每一次用量均以能够得到尽量多的纯净而透明的可载药的温敏性水凝胶为度。
本发明通过了在实验室所做试验的验证。验证步骤与上面记载的步骤相同,得到产物——可载药的温敏性水凝胶之后,用岛津AGS-X万能材料试验机测试可承受最大强度值;然后将本发明制得的水凝胶破碎成细末配成凝胶溶液,用722型分光光度计测试最低临界溶解温度。验证结果见验证表1、2。
注:因步骤(5)中溶解液的配比没有变化范围,故在验证表中不再记载该溶解液的配比。步骤(4)和(6)也没有在验证表中记载的必要。即,验证表仅记载涉及到了数值范围的步骤(1)至(3)以及测试、检验所得到的技术参数。另,验证表中的“NIPAAm∶Am”代表N-异丙基丙烯酰胺与丙烯酰胺的质量比。
验证表1:
验证表2:
从验证表中可以看出,用本发明制备的可载药的温敏性水凝胶的机械强度的确与现有技术相当,而其最低临界溶解温度也的确与人体的生理温度相近。
特别说明,采用纤维素对水凝胶单体进行枝接改性,能够提高最终产物的机械强度,是本领域的技术人员所熟知的。从验证例1~6也可以看出来,本发明制备的可载药的温敏性水凝胶的可承受最大强度值的确是由羟乙基纤维素确定的。由于只要羟乙基纤维素的配比在本发明所限定的范围内,本发明制备的可载药的温敏性水凝胶就能够满足实际要求,所以,与用棉纤维改性后的机械强度相当的对比试验,就没有记载在本说明书中。
从验证例7~10可以看出,最低临界溶解温度是由N-异丙基丙烯酰胺与丙烯酰胺共同确定的,在实际应用中,应通过调节N-异丙基丙烯酰胺与丙烯酰胺的配比来确定具体载药体的最低临界溶解温度。

Claims (1)

1.一种可载药的温敏性水凝胶,制备它的原料中包括N-异丙基丙烯酰胺和纤维素,其特征在于,所述原料中还有丙烯酰胺,所述纤维素是羟乙基纤维素;该可载药的温敏性水凝胶由如下方法及相应步骤制备而成:
(1)将羟乙基纤维素溶解于蒸馏水中,在常温下搅拌均匀,通过超声震荡充分溶解;其中,羟乙基纤维素∶蒸馏水=0.50~1.00g∶20.0mL;
(2)在步骤(1)制得的溶液中加入N-异丙基丙烯酰胺和丙烯酰胺的均匀混合物,在常温下搅拌至完全溶解;其中,N-异丙基丙烯酰胺∶羟乙基纤维素=0.20g∶0.50~1.00g,N-异丙基丙烯酰胺∶丙烯酰胺=9~15g∶1g;
(3)在步骤(2)制得的溶液中加入引发剂过硫酸钾、辅助剂四甲基乙二胺,然后通氮气保护,在常温下磁力搅拌12h,得到接枝产物;其中,N-异丙基丙烯酰胺∶过硫酸钾=0.20g∶0.03g,N-异丙基丙烯酰胺∶四甲基乙二胺=0.20g∶0.18mL;
(4)将步骤(3)的接枝产物干燥,用丙酮为提取剂,索氏提取器提取12h;丙酮的用量以除尽均聚物以及未反应的引发剂和辅助剂为度;
(5)将步骤(4)中提纯后的接枝产物溶解于蒸馏水中,加入氢氧化钠粉末,磁力搅拌至充分混匀,加入交联剂环氧氯丙烷,磁力搅拌5min,于30℃烘箱中静置12h,得到可载药的温敏性水凝胶的半成品;其中,接枝产物∶氢氧化钠∶环氧氯丙烷∶蒸馏水=0.8g∶1.0g∶2.0mL∶20mL;
(6)将步骤(5)所述半成品胶置于去离子水中浸泡36h,每间隔2h更换一次去离子水,得到最低临界溶解温度在37~41℃之间的可载药的温敏性水凝胶;所述去离子水的每一次用量均以能够得到尽量多的纯净而透明的可载药的温敏性水凝胶为度。
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