CN108586775A - 可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法 - Google Patents
可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法，制备方法包括以下步骤：将含活泼氢的金属化合物与含羟基或氨基化合物混合，然后与环氧类化合物反应，制备超支化聚醚多元醇；将含活泼氢的金属化合物与超支化聚醚多元醇混合，然后与环氧乙烷反应，制备超支化聚醚‑多臂聚乙二醇；将超支化聚醚‑多臂聚乙二醇分别与含双键的分子和含巯基的分子进行反应，将这两种反应产物经原位交联反应制得超支化聚醚类水凝胶。本发明制得的超支化聚醚类水凝胶具有良好的稳定性、生物相容性、透光性，同时在较低浓度下就能快速成胶。
Description
技术领域
本发明属于眼内填充物技术领域，具体涉及一种可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法。
背景技术
玻璃体是眼球内不可再生的透明凝胶体，在治疗玻璃体视网膜疾病的玻璃体切除术中，切除玻璃体后需向眼内注入玻璃体替代物，以此支撑视网膜、修复眼损伤、重建视功能并防止眼球萎缩。目前临床上常用的主要为空气、惰性气体、重水、硅油等。以上除了硅油外，均为短期应用。然而，硅油虽为相对惰性材料，但长期填充硅油容易发生乳化，乳化后的硅油对眼内组织具有毒性，一定程度上增加了视网膜玻璃体手术的术后并发症，影响了手术效果，限制了视功能的恢复。然而传统的高分子水凝胶用于人工玻璃体长期填充时存在成胶时间长、成胶浓度大、易降解、有生物毒性等问题，不利于临床应用，因此，颇为亟待寻找一种理想的可用于眼内长期填充的人工玻璃体填充物。
发明内容
针对现有技术中存在的上述问题，本发明提供一种可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法，可有效解决目前的玻璃体替代物成胶时间长、成胶浓度大、易降解、有生物毒性等问题。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
可用于眼内填充的原位交联超支化聚醚水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将含活泼氢的金属化合物与含羟基或氨基化合物混合，然后与环氧类化合物反应，反应温度为0-150℃，反应时间为24-72h，制得超支化聚醚多元醇；其中，含活泼氢的金属化合物与含羟基或氨基化合物的摩尔比为1:1-20，含羟基或氨基化合物与环氧类化合物的摩尔比为1:30-1000；
(2)制备超支化聚醚-多臂聚乙二醇
将含活泼氢的金属化合物与超支化聚醚多元醇混合，然后与环氧乙烷反应，反应温度为0-150℃，反应时间为24-72h，制得超支化聚醚-多臂聚乙二醇；其中，含活泼氢的金属化合物与超支化聚醚多元醇的摩尔比为1:1-40，超支化聚醚多元醇与环氧乙烷的摩尔比为1:50-1000；
(3)将超支化聚醚-多臂聚乙二醇与含双键的分子进行反应，反应温度为0-100℃，反应时间为24-100h，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中超支化聚醚-多臂聚乙二醇与含双键的分子的摩尔比为1:2-100；
(4)将超支化聚醚-多臂聚乙二醇与含巯基的分子进行反应，反应温度为0-100℃，反应时间为24-100h，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中超支化聚醚-多臂聚乙二醇与含巯基的分子的摩尔比为1:2-100；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为15-37℃。
进一步地，步骤(1)中含活泼氢的金属化合物与含羟基或氨基化合物的摩尔比为1:1-8，含羟基或氨基化合物与环氧类化合物的摩尔比为1:30-80，反应温度为50-80℃，反应时间为24-56h。
进一步地，步骤(1)中含活泼氢的金属化合物为甲醇钾；含羟基或氨基化合物为三羟甲基丙烷、季戊四醇、双季戊四醇或乙二醇；环氧类化合物为环氧丙醇。
进一步地，步骤(2)中含活泼氢的金属化合物与超支化聚醚多元醇的摩尔比为1:2-40，超支化聚醚多元醇与环氧乙烷的摩尔比为1:150-800。
进一步地，步骤(2)中含活泼氢的金属化合物为甲醇钾或氢化钾；反应温度为50-80℃，反应时间为24-48h。
进一步地，步骤(3)中超支化聚醚-多臂聚乙二醇与含双键的分子的摩尔比为1:20-60，反应温度为25-100℃，反应时间为24-65h。
进一步地，步骤(3)中含双键的分子为甲基丙烯酸酐、2-(溴甲基)丙烯酸乙酯或2-(氯甲基)丙烯酸乙酯。
进一步地，步骤(4)中超支化聚醚-多臂聚乙二醇与含巯基的分子的摩尔比为1:15-40，反应温度为25-100℃，反应时间为24-48h。
进一步地，步骤(4)中含巯基的分子为巯基乙酸、巯基乙醇、2-巯基丙酸或L-高半胱氨酸。
进一步地，步骤(5)中原位交联反应的溶剂为水、质量百分浓度为0.9％的氯化钠水溶液或pH值为7.2-8.0的磷酸盐缓冲液。
本发明提供的可用于眼内长期填充的原位交联超支化聚醚类水凝胶及其制备方法，具有以下有益效果：
(1)本发明通过阴离子聚合合成超支化聚醚多元醇，再进一步引发环氧乙烷的聚合，得到以超支化聚醚为核，PEG为支化臂的超支化聚醚-多臂聚乙二醇，然后进一步对超支化聚醚-多臂聚乙二醇进行功能化改性，分别得到两种可在体温环境自发进行反应的功能化超支化聚醚-多臂聚乙二醇，再将这两种聚合物经原位交联反应制得水凝胶。
(2)超支化聚醚-多臂聚乙二醇的结构赋予了水凝胶高的稳定性，良好的亲水性和生物相容性；另外，超支化结构提供多位点，在可降低成胶浓度的同时加快成胶时间，在较低浓度下(6mg/mL)以较快速度成胶，成胶时间低于10min，同时透光性好，有效的满足了临床手术要求，解决了目前用于眼内长期填充的人工玻璃体成胶时间长、成胶浓度大、易降解、有生物毒性等问题。
附图说明
图1为超支化聚醚-多臂聚乙二醇的核磁共振氢谱图谱。
图2为原位交联超支化聚醚类水凝胶的储存模量(G')和损耗模量(G”)结果图。
图3为原位交联超支化聚醚类水凝胶的透光率结果图。
图4为原位交联超支化聚醚类水凝胶在0.9％的氯化钠水溶液中的表观图以及冻干后的SEM形貌图；其中，A为孵育0天，B为孵育60天。
具体实施方式
本发明将含活泼氢的金属化合物与含羟基或氨基化合物混合，然后与环氧类化合反应，制备超支化聚醚多元醇；将含活泼氢的金属化合物与超支化聚醚多元醇混合，然后与环氧乙烷反应，制备超支化聚醚-多臂聚乙二醇；将超支化聚醚-多臂聚乙二醇分别与含双键的分子和含巯基的分子进行反应制得功能化超支化聚醚-多臂聚乙二醇，其具体合成路线图如下：
实施例1
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与三羟甲基丙烷按摩尔比为1:1混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，三羟甲基丙烷和环氧丙醇的摩尔比为1:50，反应温度为60℃，反应时间为24h；
(2)制备超支化聚醚-多臂聚乙二醇
将甲醇钾与超支化聚醚多元醇按摩尔比为1:2混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚聚醚多元醇和环氧乙烷的摩尔比为1：150，反应温度为60℃，反应时间为24h；
(3)将超支化聚醚-多臂聚乙二醇与甲基丙烯酸酐进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与甲基丙烯酸酐的摩尔比为1：20，反应温度为25℃，反应时间为48h；
(4)将超支化聚醚-多臂聚乙二醇与巯基乙酸进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与巯基乙酸的摩尔比为1:20，反应温度为25℃，反应时间为48h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为水。
实施例2
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与三羟甲基丙烷按摩尔比为1:5混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，三羟甲基丙烷和环氧丙醇的摩尔比为1:50，反应温度为80℃，反应时间为24h；
(2)制备超支化聚醚-多臂聚乙二醇
将甲醇钾与超支化聚醚多元醇按摩尔比为1:5混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚醚多元醇和环氧乙烷的摩尔比为1：300，反应温度为80℃，反应时间为24h；
(3)将超支化聚醚-多臂聚乙二醇与2-巯基丙酸进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与2-巯基丙酸的摩尔比为1：30，反应温度为50℃，反应时间为24h；
(4)将超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯的摩尔比为1:30，反应温度为50℃，反应时间为24h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为水。
实施例3
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与季戊四醇按摩尔比为1:2混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，季戊四醇和环氧丙醇的摩尔比为1:30，反应温度为50℃，反应时间为48h；
(2)制备超支化聚醚-多臂聚乙二醇
将甲醇钾与超支化聚醚多元醇按摩尔比为1:3混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚醚多元醇和环氧乙烷的摩尔比为1：500，反应温度为50℃，反应时间为48h；
(3)将超支化聚醚-多臂聚乙二醇与L-高半胱氨酸进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与L-高半胱氨酸的摩尔比为1：25，反应温度为40℃，反应时间为24h；
(4)将超支化聚醚-多臂聚乙二醇与2-(氯甲基)丙烯酸乙酯进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与2-(氯甲基)丙烯酸乙酯的摩尔比为1:25，反应温度为40℃，反应时间为24h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为质量百分浓度为0.9％的氯化钠水溶液。
实施例4
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与双季戊四醇按摩尔比为1:5混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，双季戊四醇和环氧丙醇的摩尔比为1:80，反应温度为60℃，反应时间为48h；
(2)制备超支化聚醚-多臂聚乙二醇
将氢化钾与超支化聚醚多元醇按摩尔比为1:25混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚醚多元醇和环氧乙烷的摩尔比为1:400，反应温度为80℃，反应时间为24h；
(3)将超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯的摩尔比为1：40，反应温度为100℃，反应时间为24h；
(4)将超支化聚醚-多臂聚乙二醇与巯基乙醇进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与巯基乙醇的摩尔比为1:40，反应温度为90℃，反应时间为24h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为pH值为7.4的磷酸盐缓冲液。
实施例5
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与乙二醇按摩尔比为1:8混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，乙二醇和环氧丙醇的摩尔比为1:36，反应温度为65℃，反应时间为56h；
(2)制备超支化聚醚-多臂聚乙二醇
将氢化钾与超支化聚醚多元醇按摩尔比为1:38混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚醚和环氧乙烷的摩尔比为1:600，反应温度为80℃，反应时间为24h；
(3)将超支化聚醚-多臂聚乙二醇与甲基丙烯酸酐进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与甲基丙烯酸酐的摩尔比为1：60，反应温度为100℃，反应时间为62h；
(4)将超支化聚醚-多臂聚乙二醇与巯基乙酸进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与巯基乙酸的摩尔比为1:40，反应温度为90℃，反应时间为24h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为pH值为7.4的磷酸盐缓冲液。
实施例6
可用于眼内长期填充的原位交联超支化聚醚类水凝胶，其制备方法包括以下步骤：
(1)制备超支化聚醚多元醇
将甲醇钾与双季戊四醇按摩尔比为1:5混合，组成引发剂体系引发环氧丙醇的开环聚合，制得超支化聚醚多元醇(具体为超支化聚缩水甘油醚)；其中，双季戊四醇和环氧丙醇的摩尔比为1:60，反应温度为80℃，反应时间为24h；
(2)制备超支化聚醚-多臂聚乙二醇
将甲醇钾与超支化聚醚多元醇按摩尔比为1:15混合，组成引发剂体系引发环氧乙烷的开环聚合，制得超支化聚醚-多臂聚乙二醇；其中，超支化聚醚多臂和环氧乙烷的摩尔比为1：800，反应温度为80℃，反应时间为24h；
(3)将超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯进行反应，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与2-(溴甲基)丙烯酸乙酯的摩尔比为1：15，反应温度为60℃，反应时间为24h；
(4)将超支化聚醚-多臂聚乙二醇与L-高半胱氨酸进行反应，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中，超支化聚醚-多臂聚乙二醇与L-高半胱氨酸的摩尔比为1:15，反应温度为80℃，反应时间为24h；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为25℃，反应溶剂为pH值为7.2的磷酸盐缓冲液。
按照本发明的方法制得的超支化聚醚-多臂聚乙二醇的结构如图1所示，其具体结构可以从图1中得到确认。
下面对实施例6得到的原位交联超支化聚醚类水凝胶进行如下测试：
1、用流变仪测量原位交联超支化聚醚类水凝胶的储存模量(G')和损耗模量(G”)，结果见图2。由图2可知，改变其频率，G'恒大于G”且差值较大，说明得到的凝胶在一定时间内结构很稳定。
2、用紫外光谱扫描原位交联超支化聚醚类水凝胶，其透光率结果见图3，由图3可知，原位交联超支化聚醚水凝胶的透光率达到85％，具有较高的透光性。
3、将原位交联超支化聚醚水凝胶置于生理盐水中，在37℃分别孵育0天和60天，其表观图见图4中的左图，然后分别再将其冻干后通过SEM扫描后得到内部形貌图(中间和右图)，由图可知，其内部结构疏松多孔，且在60天内无降解，再一次证明了其稳定性好的特点。
试验例1细胞安全性试验
采用大鼠视网膜色素上皮细胞D407细胞做安全性试验，具体过程依次包括以下步骤：
1、选取大鼠视网膜色素上皮细胞D407细胞系进行常规培养，培养液为DMEM/F12＝1∶1，加入胎牛血清(终浓度为10％)，取传至3-6代的细胞用于实验。
2、用0.25％的胰酶消化细胞，混匀，制成细胞悬液，消化制成细胞悬液后按5×106/ml接种于无菌6孔培养板，放入37℃5％CO2的恒温培养箱内培养，至细胞融合到70％孔底面积，给予无血清的培养液培养12h。
3、弃掉培养液，每孔重新加入新鲜的无血清培养液1ml，同时加入实施例6制得的原位交联超支化聚醚类水凝胶，对照组不加，培养箱内继续培养24h。
4、用冷的PBS洗涤2次，然后用0.25％胰酶消化至细胞开始脱落，20％胎牛血清终止消化，再用冷PBS洗涤2次，于1000rpm离心5分钟，弃上清，用100ul凋亡结合缓冲液重悬浮细胞；细胞悬液转移至流式管，加5ul Annexin V和10ul PI，室温避光作用15分钟。
5、加入400ul结合缓冲液，上机(流式细胞仪)检测。
结果显示：在凝胶组，早期凋亡细胞比率2.3％，晚期凋亡细胞比率为1.02％；在正常对照组，早期凋亡细胞比率为4.58％，晚期凋亡细胞比率为4.15％。
上述结果表明，本发明提供的新材料原位交联凝胶没有明显的细胞毒性反应。
试验例2动物眼内填充安全性试验
选取白兔做动物试验，具体过程依次包括以下步骤：
(1)麻醉白兔。
(2)沿角膜缘剪开半侧球结膜，19G巩膜穿刺刀造灌注孔和玻切孔。
(3)插入灌注头，打开灌注，灌注液的配方如下：500ml乳酸林格氏液中加入50％葡萄糖4ml，地塞米松(5mg/1ml)1.6ml，盐酸肾上腺素(1mg/1ml)0.Sml，妥布霉素(8万U/1ml)0.2ml。
(4)玻璃体切割头伸入玻璃体腔，切除全部玻璃体。
(5)将实施例6制得的原位交联超支化聚醚类水凝胶注入玻璃体腔。
(6)缝合巩膜口和球结膜。
(7)结膜囊涂抹泰利必妥眼膏。
手术半年后，进行眼底照相检查，可见视网膜及脉络膜表现正常，无出血、渗出等病理性改变；视网膜电图检查显示双眼a/b波振幅和潜伏期相近，原位超支化聚醚类水凝胶眼无明显视网膜毒性功能损害；处死兔子，剖开眼球，可见玻璃体腔内存在符合玻璃体透明/不定型的特点，表面无渗出膜、出血覆盖；对兔眼视网膜用苏木素-伊红染色，可见视网膜各层次结构正常，细胞排列紧密，未见水肿、出血等改变。
综上，细胞试验证实本发明提供的原位交联水凝胶的无细胞毒性；动物试验显示，长达半年的时间，本发明提供的原位交联水凝胶在玻璃体切除后的兔眼内仍保持凝胶形式存在，并且保持透明；视网膜和脉络膜的各层组织结构存在，未见出血、水肿等病理改变，尤为重要的是，视网膜的功能也大致正常；动物体内试验也证实本材料在眼内填充是安全的。
Claims (10)
1.可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，包括以下步骤：
(1)制备超支化聚醚多元醇
将含活泼氢的金属化合物与含羟基或氨基化合物混合，然后与环氧类化合物反应，反应温度为0-150℃，反应时间为24-72h，制得超支化聚醚多元醇；其中，含活泼氢的金属化合物与含羟基或氨基化合物的摩尔比为1:1-20，含羟基或氨基化合物与环氧类化合物的摩尔比为1:30-1000；
(2)制备超支化聚醚-多臂聚乙二醇
将含活泼氢的金属化合物与超支化聚醚多元醇混合，然后与环氧乙烷反应，反应温度为0-150℃，反应时间为24-72h，制得超支化聚醚-多臂聚乙二醇；其中，含活泼氢的金属化合物与超支化聚醚多元醇的摩尔比为1:1-40，超支化聚醚多元醇与环氧乙烷的摩尔比为1:50-1000；
(3)将超支化聚醚-多臂聚乙二醇与含双键的分子进行反应，反应温度为0-100℃，反应时间为24-100h，得到末端为双键改性的超支化聚醚-多臂聚乙二醇；其中超支化聚醚-多臂聚乙二醇与含双键的分子的摩尔比为1:2-100；
(4)将超支化聚醚-多臂聚乙二醇与含巯基的分子进行反应，反应温度为0-100℃，反应时间为24-100h，得到末端为巯基改性的超支化聚醚-多臂聚乙二醇；其中超支化聚醚-多臂聚乙二醇与含巯基的分子的摩尔比为1:2-100；
(5)将步骤(3)所得物和步骤(4)所得物经原位交联反应制得超支化聚醚类水凝胶；其中，反应温度为15-37℃。
2.根据权利要求1所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(1)中含活泼氢的金属化合物与含羟基或氨基化合物的摩尔比为1:1-8，含羟基或氨基化合物与环氧类化合物的摩尔比为1:30-80，反应温度为50-80℃，反应时间为24-56h。
3.根据权利要求1或2所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(1)中含活泼氢的金属化合物为甲醇钾；含羟基或氨基化合物为三羟甲基丙烷、季戊四醇、双季戊四醇或乙二醇；环氧类化合物为环氧丙醇。
4.根据权利要求1所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(2)中含活泼氢的金属化合物与超支化聚醚多元醇的摩尔比为1:2-40，超支化聚醚多元醇与环氧乙烷的摩尔比为1:150-800。
5.根据权利要求1或4所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(2)中含活泼氢的金属化合物为甲醇钾或氢化钾；反应温度为50-80℃，反应时间为24-48h。
6.根据权利要求1所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(3)中超支化聚醚-多臂聚乙二醇与含双键的分子的摩尔比为1:20-60，反应温度为25-100℃，反应时间为24-65h。
7.根据权利要求1或6所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(3)中含双键的分子为甲基丙烯酸酐、2-(溴甲基)丙烯酸乙酯或2-(氯甲基)丙烯酸乙酯。
8.根据权利要求1所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(4)中超支化聚醚-多臂聚乙二醇与含巯基的分子的摩尔比为1:15-40，反应温度为25-100℃，反应时间为24-48h。
9.根据权利要求1或8所述的可用于眼内长期填充的原位交联超支化聚醚类水凝胶的制备方法，其特征在于，步骤(4)中含巯基的分子为巯基乙酸、巯基乙醇、2-巯基丙酸或L-高半胱氨酸。
10.如权利要求1-9任一项所述的方法制备得到的可用于眼内长期填充的原位交联超支化聚醚类水凝胶。
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