CN114395144A - 一种透明质酸-聚乙二醇-层状二氧化硅复合水凝胶及其应用 - Google Patents
一种透明质酸-聚乙二醇-层状二氧化硅复合水凝胶及其应用 Download PDFInfo
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- CN114395144A CN114395144A CN202210108428.2A CN202210108428A CN114395144A CN 114395144 A CN114395144 A CN 114395144A CN 202210108428 A CN202210108428 A CN 202210108428A CN 114395144 A CN114395144 A CN 114395144A
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- Prior art keywords
- hyaluronic acid
- polyethylene glycol
- hydrogel
- composite hydrogel
- salt
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 46
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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Abstract
本发明公开了一种透明质酸‑聚乙二醇‑层状二氧化硅复合水凝胶，包括透明质酸、层状二氧化硅、聚乙二醇、无机盐和水。本发明克服了现有技术下透明质酸在人体内吸收迅速以及在组织内停留时间短等缺点，利用层状二氧化硅提高透明质酸水凝胶的稳定性，能维持较长的填充效果，并利用聚乙二醇显著降低凝胶体系粘度增大的问题。本发明所述的复合水凝胶可作为新型组织填充剂、组织防粘连剂、组织工程支架、封合剂或栓塞剂用于临床诊断或治疗。
Description
技术领域
本发明属于生物医用材料领域，特别涉及一种可注射用的透明质酸-聚乙二醇-层状二氧化硅复合水凝胶及其应用。
技术背景
透明质酸(Hyaluronic acid简称HA)又称为玻尿酸，玻璃糖醛酸，琉璃糖碳基酸，是一种由双糖(D-葡萄糖醛酸及N-乙酰葡糖胺)基本结构组成的酸性粘多糖。透明质酸广泛存在于结缔组织、上皮组织和神经组织中，以其独特的分子结构和理化性质在机体内显示出多种重要的生理功能，如润滑关节，调节血管壁的通透性，调节蛋白质、水电解质扩散及运转，促进创伤愈合等。透明质酸在医药方面广泛应用于各类眼科手术，如晶体植入、角膜移植和抗青光眼手术等，还可用于治疗关节炎和加速伤口愈合。将其用于化妆品中，能起到独特的保护皮肤作用，可保持皮肤滋润光滑、细腻柔嫩、富有弹性，具有防皱、抗皱、美容保健和恢复皮肤生理功能的作用。
然而，尽管透明质酸具有良好的生物相容性和生物降解性的优点，作为生物材料而具有极高的应用价值，但其在人体内吸收迅速以及在组织内停留时间短等缺点而限制了其应用，通常以化学修饰的方式，利用透明质酸的羟基、羧基和乙酰氨基与交联剂进行交联反应。目前用于透明质酸的交联剂主要有两种，即二乙烯基砜(DVS)和1,4-丁二醇而环氧甘油醚(BDDE)，其中BDDE的副作用小而被广泛使用。但是，交联透明质酸的性能受交联剂的用量、交联反应条件的影响，常难以得到交联均匀性好，反应效率高的产品。
公开号为CN101056891B的专利在酸性或碱性条件下将含有10％以上透明质酸和交联剂搅拌混合，制备得到交联剂含量少且粘弹性好的交联透明质酸凝胶。此方法主要靠增加透明质酸的浓度，没有综合考虑其他反应物质的影响。公开号为CN100582146C的专利提到一种可生物降解的透明质酸水凝胶，制备方法是将多种具有不同交联度的聚合物混合，然而这些聚合物之间只是简单的物理混合，无法形成致密的交联网络结构，降解时间较短。发明专利CN110279889A通过自组装方式将透明质酸、羧甲基纤维素钠、聚乙二醇-聚丙二醇-聚乙二醇(PEO-PPO-PEO)进行组合，在一定温度下形成凝胶(-30～40℃)，虽然避免了通过化学反应而带来的复杂工艺问题，但缺少稳定性研究。
水凝胶类产品的物理性质可以通过加入无机纳米材料进行调控，例如无机纳米材料的加入可以用于改善药物缓释效果、酸碱度响应的药物递送、光热治疗等生物医药应用。其中，二氧化硅层状材料由于具有独特的静电性质、均一的尺寸和生物活性而在药物、化妆品和食物中作为有效成分或者粘度调节剂有广泛应用。例如，在明胶中加入二氧化硅层状材料可以提高水凝胶的稳定性，在48小时内的降解率由50％提高至接近90％。(Biotechnol.J.2020,1900456)将Laponite二氧化硅层状材料加入至海藻酸水凝胶中，制得剪切变稀的非牛顿流体，可以通过针筒注射，在体内形成固体凝胶。(Adv.Sci.2019,6,1901041)
发明内容
本发明针对现有技术透明质酸水凝胶易降解的问题，向透明质酸水凝胶加入层状二氧化硅以提高凝胶的稳定性，又利用聚乙二醇解决层状二氧化硅加入后导致凝胶粘度的大幅增加的问题，得到一种可注射的、稳定的透明质酸钠复合水凝胶。
本发明具体技术方案如下：
一种改性透明质酸复合水凝胶，包括透明质酸和/或其盐、层状二氧化硅、聚乙二醇、无机盐和水。
本发明所述透明质酸和/或其盐的分子量为10000-2000000Da，优选分子量为400000-1500000Da。
本发明所述聚乙二醇分子量为300-4000000Da。优选4000-10000Da。
本发明所述层状二氧化硅材料为天然或人工合成，本发明一个具体的示例，层状二氧化硅购自于德国BYK公司的Laponite XLG产品。
本发明所述无机盐为碱金属盐和/或者碱土金属盐，优选的，无机盐为钙盐和/或钠盐。一个具体的示例为氯化钙和氯化钠。
优选的，本发明所述的复合水凝胶中透明质酸/透明质酸钠、层状二氧化硅、聚乙二醇的质量比为0.05-3：0.05-5：0.05-5。优选0.25-2：0.5-3：0.5-3。
优选的，本发明所述的复合水凝胶中透明质酸/透明质酸钠、层状二氧化硅、聚乙二醇的质量百分含量分别为0.05-3％，0.05-5％和0.05-5％。优选0.25-2％，0.5-3％和0.5-3％更优选的，本发明所述的复合水凝胶包括透明质酸/透明质酸钠、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，透明质酸/透明质酸钠的分子量为400000-1500000Da，聚乙二醇分子量为4000-10000Da，透明质酸/透明质酸钠、层状二氧化硅、聚乙二醇的质量比为0.25-2：0.5-3：0.5-3。
本发明一个具体的方案，所述复合水凝胶包括透明质酸钠、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，透明质酸钠的分子量为1400000Da，聚乙二醇分子量为6000Da，透明质酸钠、层状二氧化硅、聚乙二醇的质量百分含量为0.5％，2％，3％。
本发明另一目的在于提供本发明所述的复合水凝胶在制备组织填充剂、组织防粘连剂、组织工程支架、封合剂或栓塞剂中的应用。
本发明还提供了所述复合水凝胶的制备方法，将透明质酸加入水中搅拌均匀，继续加入层状二氧化硅，搅拌均匀，进一步加入无机盐和聚乙二醇混合粉末，搅拌均匀，得到复合水凝胶。
本发明优点：
本发明利用层状二氧化硅提高透明质酸水凝胶的稳定性的过程中，发现虽然层状二氧化硅能够提高透明质酸水凝胶的稳定性，但是会引起体系粘度的大幅增加，这给注射或者通过细导管介入透明质酸水凝胶带来极大的问题。在解决上述问题过程中，本发明研究意外发现向体系内加入聚乙二醇后，能够显著改善体系粘度大的问题，同时保证透明质酸水凝胶的稳定性。本发明技术方案相对于化学交联法具有不引入交联剂和使用简单的优点，具有广阔的应用前景。
具体实施方式
下面结合具体实施例并参照数据进一步详细描述本发明，应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在本发明中使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1透明质酸复合水凝胶的制备
以分子量为140万的透明质酸钠为例，考察加入层状二氧化硅和聚乙二醇对水凝胶粘度的影响。
HA水凝胶1号样品：将0.25g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，得到HA水凝胶1号样品。
HA水凝胶2号样品：将0.25g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，继续加入2g层状二氧化硅Laponite，搅拌均匀，得到HA水凝胶2号样品。
HA水凝胶3号样品：将0.25g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和2g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶3号样品。
HA水凝胶4号样品：将0.5g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，得到HA水凝胶4号样品。
HA水凝胶5号样品：将0.5g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，继续加入2g层状二氧化硅Laponite搅拌均匀，得到HA水凝胶5号样品。
HA水凝胶6号样品：将0.5g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和3g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶6号样品。
HA水凝胶7号样品：将2g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，得到HA水凝胶7号样品。
HA水凝胶8号样品：将2g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀，继续加入2g层状二氧化硅Laponite搅拌均匀，得到HA水凝胶8号样品。
HA水凝胶9号样品：将2g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和2g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶9号样品。
粘度测定：将得到的水凝胶样品以SNB型旋转粘度测量仪测定粘度。
结果如表1所示，当HA的质量百分数为0.25％，0.5％，2％时，在HA水凝胶体系中加入层状二氧化硅Laponite后，其粘度均有大幅上升，而进一步加入PEG则能够显著降低体系粘度。
特别的，HA的质量百分数为0.5％时，通过对比水凝胶4-6号样品的粘度发现，在HA水凝胶体系中加入层状二氧化硅Laponite后，其粘度上升幅度巨大(水凝胶5号)，增大了5.42倍，并且形成流动性差的粘稠状体系，而进一步加入PEG能够显著降低体系粘度(水凝胶6号)。
表1层状二氧化硅和聚乙二醇对透明质酸水凝胶粘度的影响
实施例2
以分子量为140万的HA为例，考察加入不同分子量的聚乙二醇对水凝胶粘度的影响。
HA水凝胶10号样品：将0.5g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和3g分子量为600Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶10号样品。
HA水凝胶11号样品：将0.5g分子量为140万的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和3g分子量为4000000Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶11号样品。
表2不同分子量的聚乙二醇对透明质酸水凝胶粘度的影响
结果如表2所示，结果表明分子量在600-4000000范围内的聚乙二醇能够明显降低加入层状二氧化硅的透明质酸凝胶的粘度。
实施例3聚乙二醇对不同分子量的透明质酸水凝胶粘度调节能力HA水凝胶12号样品：将0.5g分子量为40万Da的HA加入至100mL去离子水中，机械搅拌均匀，得到HA水凝胶12号样品。
HA水凝胶13号样品：将0.5g分子量为40万Da的HA加入至100mL去离子水中，机械搅拌均匀，继续加入2g层状二氧化硅Laponite搅拌均匀，得到HA水凝胶13号样品。
HA水凝胶14号样品：将0.5g分子量为40万Da的HA加入至100mL去离子水中，机械搅拌均匀。继续加入2g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和2g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到HA水凝胶14号样品。
结果如表3所示，结合表1和表2的结果可知，分子量在40万-140万Da范围内的HA能够与层状二氧化硅和聚乙二醇形成粘度理想的复合凝胶。
表3质量分数为0.5％的HA水凝胶样品的粘度
实施例4本发明所述透明质酸-聚乙二醇-层状二氧化硅复合水凝胶的稳定性称取1g水凝胶样品置于离心管中，加入10mL，pH值为7.4的磷酸盐缓冲盐溶液，于控制在37℃的恒温水浴摇床中进行稳定性实验。每隔一定时间将样品取出观察状态，当无法取出明显的凝胶时即为降解终点。水凝胶1-9号的稳定性考察结果如表4所示，与纯HA水凝胶相比，加入层状二氧化硅后可以增加稳定性，继续加入聚乙二醇后稳定性不受影响。例如水凝胶7号为2％HA，其降解周期为28小时，加入2％层状二氧化硅的水凝胶8号，降解周期延长至120小时，而进一步加入2％聚乙二醇的水凝胶9号，降解周期延长至168小时，表明本发明所述的透明质酸-聚乙二醇-层状二氧化硅复合水凝胶具有理想的粘度以及良好的稳定性。
表4 HA水凝胶样品的稳定性
Claims (7)
1.一种透明质酸复合水凝胶，其特征在于包括透明质酸或其盐、层状二氧化硅、聚乙二醇、无机盐和水，所述透明质酸或其盐、层状二氧化硅、聚乙二醇的质量比为0.05-3：0.05-5：0.05-5。
2.根据权利要求1所述的复合水凝胶，其特征在于所述透明质酸或其盐的分子量为10000-2000000Da。
3.根据权利要求1所述的复合水凝胶，其特征在于所述聚乙二醇分子量为300-4000000Da。
4.根据权利要求1所述的复合水凝胶，其特征在于所述无机盐为碱金属盐和/或者碱土金属盐。
5.根据权利要求1所述的复合水凝胶，其特征在于包括透明质酸或其盐、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，透明质酸或其盐的分子量为400000-1500000Da，聚乙二醇分子量为4000-10000Da，透明质酸或其盐、层状二氧化硅、聚乙二醇的质量比为0.25-2：0.5-3：0.5-3。
6.根据权利要求1-5任一项所述的复合水凝胶在制备组织填充剂、组织防粘连剂、组织工程支架、封合剂或栓塞剂中的应用。
7.根据权利要求1-5任一项所述的复合水凝胶的制备方法，其特征在于将透明质酸或其盐加入水中搅拌均匀，继续加入层状二氧化硅，搅拌均匀，进一步加入无机盐和聚乙二醇混合粉末，搅拌均匀，得到复合水凝胶。
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