CN113350572B - 一种医用温敏型水凝胶及其制备方法和应用 - Google Patents

一种医用温敏型水凝胶及其制备方法和应用 Download PDF

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CN113350572B
CN113350572B CN202011415104.0A CN202011415104A CN113350572B CN 113350572 B CN113350572 B CN 113350572B CN 202011415104 A CN202011415104 A CN 202011415104A CN 113350572 B CN113350572 B CN 113350572B
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谭回
任力杰
胡诗雨
冯宏业
王洋
雷志浩
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Shenzhen Second Peoples Hospital
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Abstract

本发明涉及一种医用温敏型水凝胶及其制备方法和应用，涉及生物分子医药技术领域，该医用温敏型水凝胶，由原料A、原料B和成胶液构成；原料A和原料B的质量之和在水凝胶中的质量百分比为5％‑50％，其中原料A为巯基封端的聚乙二醇，原料B为四臂端炔基修饰的聚乙二醇；医用温敏型水凝胶在低温下为溶液，随着温度的升高变为凝胶，转变温度介于34‑45℃，破裂强度大于100mHg。本发明还公开了水凝胶的制备方法，工艺简单，原料易得，产率高。

Description

一种医用温敏型水凝胶及其制备方法和应用
技术领域
本发明涉及生物分子医药技术领域，具体涉及一种医用温敏型水凝胶及其制备方法和应用。
背景技术
水凝胶是由相互贯通的高分子三维网络与周围介质组成的多元体系，是一种通过吸收水分来调节聚合物网格宏观性能的材料。自然界中普遍都存在水凝胶，包括许多生物体的组织都是由高分子水凝胶构成的。溶胀性能是水凝胶最重要的性质，是水凝胶核心性能的体现，而所谓的智能水凝胶就是指那些能根据周围环境条件变化如溶液浓度、pH、磁场、温度等来调控自身的物理化学性质。
温敏性水凝胶是指溶胀度随环境温度变化而发生改变的一类智能水凝胶，当环境温度高于低临界溶解温度(LCST)时，这类水凝胶的体积会突然收缩。水凝胶具备温敏响应性的原因主要取决于温敏性材料的使用，目前广泛使用的温敏性材料主要包括N-异丙基丙烯酰胺(NIPAAm)、甲基丙烯酸(MAAC)等。
专利CN104031361A公开了一种聚乙丙交酯-聚乙二醇-聚乙丙交酯的温敏水凝胶，可应用于内镜粘膜的剥离术中。但由于使用的是亲水性的二臂聚乙二醇，其产物的水溶液形成的温敏凝胶由于氢键的交联点较少，凝胶的破裂强度较低，应用受到较大的限制。
专利CN105131264A报道了一种可生物降解医用温敏水凝胶，由3-arm-PEG-PLGA嵌段共聚物组成，其中PEG为三臂聚乙二醇，分子量为400～50000；PLGA为丙交酯和乙交酯的共聚物，丙交酯和乙交酯的质量比为2:1～20:1，丙交酯与乙交酯之和的质量与三臂聚乙二醇的质量比为1.2:1～4:1；温敏水凝胶在低温下为溶液，随着温度的升高转变为凝胶，由液态转化为凝胶状的温度T液-胶范围为15～35℃，且具有可逆性，温敏水凝胶的破裂强度大于40mmHg。
综上所述，虽然各种温敏型水凝胶处于不同研究阶段，但目前公开的温敏水凝胶尚存在种类较少、破裂强度低等缺陷。因此，开发和研究新的温敏型医用水凝胶具有重要的临床意义。
发明内容
本发明所要解决的技术问题是：
本发明的第一个方面，是提供一种医用温敏型水凝胶，其特征在于：所述医用温敏型水凝胶由原料A、原料B和成胶液构成；原料A和原料B的质量之和在水凝胶中的质量百分比为5％-50％，其中原料A为巯基封端的聚乙二醇，原料B为四臂端炔基修饰的聚乙二醇；具备温敏性主要原因是由分子链上疏水性基团(-C(CH3)2)和亲水性基团(-NHCO-)所主导的亲水/疏水平衡受温度影响。当环境温度低于低临界溶解温度时，水凝胶分子链中的亲水基团通过氢键与水分子结合，水合作用力将推动分子链舒展，分子链处于亲水状态。当环境温度逐渐升高时，原先亲水基团与水分子构成的氢键平衡被打破，水凝胶分子链中疏水基团间的相互作用开始增加，水凝胶分子链开始由无规则线状组件形成球状。当环境温度高于低临界溶解温度后，疏水作用力开始占主导，水凝胶由球形继续收缩成疏水的核，出现相分离。
所述巯基封端的聚乙二醇的结构式为HSCH2C(CH3)2CH2O(CH2CH2O)mCH2C(CH3)2CH2SH：其中m为10-16000的整数；所述四臂端炔基修饰的聚乙二醇的结构式如式Ⅰ所示：
Figure BDA0002815239680000021
式Ⅰ中n为500-8000的整数；
所述成胶液为去离子水或者pH值在7-8的缓冲溶液；
所述原料A和原料B的质量比为(0.5-25)：1。
本发明的另一方面提供一种医用温敏型水凝胶的制备方法，包括步骤：将原料A和原料B加成胶液混合均匀，通过点击反应构建起交联网络得到医用温敏型水凝胶。
优选地，成胶时的聚合温度为60-100℃。
本发明另一方面涉及一种医用温敏型水凝胶在作为药物载体、栓塞材料或者组织工程材料中的应用。
与现有技术相比，本发明的有益效果是：
(1)本发明水凝胶的原料采用具有良好水溶性的大分子，原料本身安全无毒可生物降解，凝胶的形成过程无需使用有机溶剂，克服了水凝胶体内使用时的安全隐患。原料A和原料B均为现有高分子化合物，其来源为化学合成，相较于目前水凝胶大量采用的来自于植物和动物体内的高分子化合物，化学合成的原料具有结构可控制，更容易调节水凝胶的强度、降解速度、药物释放速度等优势；
(2)本发明水凝胶主要是特定结构大分子上的巯基和另一特定结构大分子上的炔基发生点击反应来构建凝胶网络，在人体正常体温范围和正常生理pH值下比较稳定，分子链上疏水性基团(-C(CH3)2)和亲水性基团(-NHCO-)所主导的亲水/疏水平衡受温度影响，进而呈现出极为实用的温敏特性；
(3)本发明水凝胶有较高的强度和韧性，具有生物降解性能，能被人体代谢；具有温度响应性及可注射性，可用作药物载体、栓塞材料以及组织工程材料等。
具体实施方式
下面结合具体实施例对本发明进一步的描述。本具体实施方式并非对其保护范围的限制。
实施例1
将16g巯基封端的聚乙二醇(m＝10000)和1.5g四臂端炔基修饰的聚乙二醇(n＝5700，Laysan)加85g磷酸氢二钠-磷酸二氢钠缓冲液(pH＝7.4)，先抽真空，再通入氮气，再抽真空，反复2次，最后在真空度为35Pa，聚合温度80℃条件下，反应2h。产物用3℃的纯水溶解，加热至60℃使共聚物沉淀弃去水层，反复操作3次以去除未反应的单体以及低分子水溶性物质。所得共聚物冷冻干燥，即得纯化的共聚物13g。
实施例2：性能测试
1、实验方法
温敏性能：采用倒置试管法确定相变，将实施里1中纯化的3-arm-PEG-PLGA共聚物配制成不同质量浓度的样品溶液，将5mL共聚物溶液放入内径为11mm的试管中，在4℃下静置24h达到平衡。把试管浸在水浴中，每3分钟使水浴升高1℃，待溶液胶凝后，将试管取出，若倒置试管凝胶不流动，且能保持10s以上，则发生了由液态到凝胶态的转变，判定对应的水浴温度为样品的转变温度T液-胶。每一样品平行测定4次，取其平均值为材料的转变温度T液-胶。
破裂强度测试：取新鲜的猪肠衣上打一个直径约0.15cm(±0.02cm)的洞，将实施例中制备的纯化3-arm-PEG-PLGA共聚物与在离子水中溶解，制备成质量分数不等的聚合物水溶液，将水溶液涂抹于此洞，然后升温至37℃形成规定厚度的水凝胶，在肠衣下方加压至凝胶破损，记录与传感器连接的数字读出器记录的最大压力数。
2、实验结果
表1：
浓度(wt％) T液-胶(℃) 破裂强度(mmHg)
15 40 100
20 38 104
25 34 107
注：所得可注射水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构，孔径在0.1mm-0.3mm。
试验结果表明：本申请所制备水凝胶的低临界溶解温度分布在34-40℃，是典型的温敏型水凝胶，且破裂强度较高。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。

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1.一种医用温敏型水凝胶，其特征在于：所述医用温敏型水凝胶由原料A、原料B和成胶液构成；原料A和原料B的质量之和在水凝胶中的质量百分比为5％-50％，其中原料A为巯基封端的聚乙二醇，原料B为四臂端炔基修饰的聚乙二醇；
所述巯基封端的聚乙二醇的结构式为HSCH2C(CH3)2CH2O(CH2CH2O)mCH2C(CH3)2CH2SH：其中m为10-16000的整数；所述四臂端炔基修饰的聚乙二醇的结构式如式Ⅰ所示：
Figure FDA0003983489490000011
式Ⅰ中n为500-8000的整数；
所述成胶液为去离子水或者pH值在7-8的缓冲溶液；
所述原料A和原料B的质量比为(0.5-25)：1。
2.根据权利要求1所述的医用温敏型水凝胶，其特征在于，所述原料A和原料B的质量之和在水凝胶中的质量百分比为5％-30％。
3.根据权利要求1所述的医用温敏型水凝胶，其特征在于，所述原料A和原料B的质量之和在水凝胶中的质量百分比为5％-20％。
4.根据权利要求1所述的医用温敏型水凝胶，其特征在于，所述原料A和原料B的质量之和在水凝胶中的质量百分比为5％-15％。
5.根据权利要求1所述的医用温敏型水凝胶，其特征在于，所述缓冲溶液采用磷酸氢二钠-柠檬酸缓冲液、磷酸二氢钾-氢氧化钠缓冲液、磷酸氢二钠-磷酸二氢钠缓冲液、巴比妥钠-盐酸缓冲液、三(羟甲基)氨基甲烷-盐酸缓冲液、硼酸-硼砂缓冲液、甘氨酸-氢氧化钠缓冲液、硼砂-氢氧化钠缓冲液、碳酸钠-碳酸氢钠缓冲液中的一种或者多种。
6.根据权利要求1-5任一项所述的医用温敏型水凝胶的制备方法，其特征在于，包括步骤：将原料A和原料B加成胶液混合均匀，通过点击反应构建起交联网络得到医用温敏型水凝胶。
7.根据权利要求1-5任一项所述的医用温敏型水凝胶用于制备药物载体、栓塞材料或者组织工程材料的用途。
8.根据权利要求7所述的用途，其特征在于，所述的药物载体为用于负载小分子药物的药物载体。
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