CN1467234A - 一种医用共聚水凝胶及制备方法 - Google Patents
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- A—HUMAN NECESSITIES
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Abstract
一种医用共聚水凝胶及制法。本发明的水凝胶是丙烯酰胺甲基丙烯酸羟乙酯的共聚物，其制法是丙烯酰胺和甲基丙烯酸羟乙酯二种单体与交联剂N，N亚甲基双丙烯酰胺在无热原水溶液中经自由基聚合反应而得到的共聚物。本发明的共聚物除保留现有技术中单一的丙烯酰胺聚合而制成的水凝胶的有益性能外，提高了水凝胶的强度与弹性，便于使用中为适应人体不同部位的软、硬程度的调整。
Description
技术领域
本发明属于医用高分子材料技术领域。
背景技术
为恢复因疾病而受影响的人体器官的功能或整容的需要，用于填充人体缺损部位的填充材料在不断的发展。由于最初的硅胶，聚四氟乙烯糊，牛胶原等。直至今天看好的交联聚丙烯酰胺水凝胶，如中国专利申请公开94195147.2<生物相容性水凝胶>；法国专利申请公开10631289951<软组织植入物及用途和应用此植入物的水凝胶>。植入人体的方法也从切口埋入的方式发展到用注射器注入的方式。如苏联发明证书所公开的SU1697756A1，<在声韧带粘膜下注射3％的聚丙酰胺凝胶>。
虽然用于人体的填充材料不断更新，但并非完美无缺。与本发明最接近的也就是当前最受推崇的交联聚丙烯酰胺水凝胶，在为适应人体不同部位而调整相应软硬程度时，会使强度和弹性变差。人体具有很复杂的结构，人体的各个组织其功能迥然不同，因此，尽管人体的软组织结构成份十分相近，但由于不同部位的功能不同，力学状态不一样，软组织的性能干差万别，这样，作为软组织替代材料的水凝胶也应具有和不同部位相匹配的物理性能，如软、硬度、湿态强度、弹性等。这一点，现有的交联聚丙烯酰胺水凝胶就显出了不足。这种水凝胶的软硬调整，靠的是调整水凝胶的含水率和改变交联度的办法。提高含水率能有效的提高水凝胶的柔软性，但植入人体后凝胶体积会有所收缩，势必影响治疗效果，减少交联度也可以提高水凝胶的柔软性，但凝胶的强度、弹性下降，也影响治疗效果。反之，在提高这种水凝胶的硬度时就需要增加丙烯酰胺的残留量和增加交联度。增加丙酰胺的单体含量的办法会使水凝胶中丙烯酰胺单体含量上升，较彻底去除凝胶中丙烯酰胺单体并非易事，由此导致水凝胶的生物相容性不理想，植入人体后副反应明显增高。同时，植入人体后替代组织的弹性效果还要下降，这在临床是不希望看到的。提高交联度在一定范围内能提高这种水凝胶的硬度，但会使水凝胶变脆、弹性下降，在注射时，特别是针头较细时，常发生胶粒破裂，影响植入后的使用效果。
发明内容
本发明的目的是提供一种有调整软硬，同时具有理想的强度与弹性，又不降低其他性能的水凝胶及其制备方法，克服现有的用丙烯酰胺一种单体聚的水凝胶的上述的不足。
本发明的水凝胶是由丙烯酰胺Caciylamide)和甲基丙烯酸羟乙酯(hy-dmyerhyl methaerylate)二种单体与交联剂N，N’-亚甲基双丙烯酰胺(N，N’-ethylene-Bis-acrylamide)或N，N’二烯丙基酒石酸二酰胺的溶液经自由基聚合反应的共聚物。
其结构式为：其中：
A：丙烯酰胺反应后结构为
B：甲基丙烯酸羟乙酯反应后结构为
C：NN＝亚甲基双丙烯酰胺
其中主要单体是丙烯酰胺，甲基丙烯酸羟乙酯为共聚单体。交联剂N，N’亚甲基双丙烯酰胺的作用是使二种单体共聚后形成体型的网状结构，使聚合物保持水凝胶状态，具有一定弹性与一定的吸水性而不溶于水。
本发明的水凝胶的制备方法包括以下内容：
将丙烯酰胺和甲基丙烯酸羟乙酯溶于无菌、无热源二次蒸馏水与医用乙醇混合的剂中。引发体系用摧化剂，加速剂，促进剂三元组成，反应中总固体含量为2.5-8Wt/％，其中丙烯酰胺与甲基丙烯酸羟乙酯的分子比为1∶0.01-1∶0.40摧化剂用量为单体总重量的0.01-2.0％。加速剂为单体总重量的0.001-1.0％。促进剂为单体总重量的0.001-0.1％。交联剂为单体总重量的0.001-5.0％，其余成分为溶剂。其中的催化剂可使用过硫酸铵或过硫酸钾。加速剂可以是亚硫酸氢钠或偏亚硫酸钠。促进剂包括三乙醇胺或三乙胺及其含取代基的N，N乙二胺类。交联剂为N，N一亚甲基双丙烯酰胺或N，N二烯丙基酒石酸二酰胺，用量为单体总重量的0.001-5.0％。
聚合反应在氮气气氛下20-30℃条件下进行，反应时间4-30小时。
反应结束后得到的水凝胶经无菌、无热原二次蒸馏水浸泡、洗涤，得本发明的水凝胶。若需提高纯度，可用医用乙醇萃取，过滤萃取物，将滤出的固体低温干燥，粉碎，用生理盐水或缓冲溶液配制成医用水凝胶。
本发明的依据和积极效果：
聚甲基丙烯酸羟乙酯作为一种医用水凝胶有优异的生物相溶性。从六十年代开始在医学上应用。主要应用有接触眼镜、义齿基托软垫底、眼内软性人工晶体、人工肾吸附剂的包膜材料、固定化酶的基材、喷雾型烧伤敷料、眼科的其他材料如角膜等。作为体内植入物，用量较大，使用人数较多的是软性眼内人工晶体公开的文献有Chehade-M.et al：fntraocular lens materials and styles：areview.Aust-N-Z-J-Ophthalmol，1997，25(4).255-263和俞梦孙等主编，<中国生物医学工程的今天与明天>，第七章：人工晶体进展天津科技翻译出版公司，1998，80-87。其安全性已被临床所肯定。公开的文献有Lanis9K：ct al：Lens epithckal growth on theanterior Surface of hydrogel lolls.An in vivostudy.Acta-0phthalmol-Scand，1998，76：184和Percival-s.etal：Plve-year follow-up of a prospective study comparinghydrogel with PMMA single piecc Lenses，Eur-J-Implant-Ref-Surg.1994，6：10-13。美国及欧共体已批准美国Storz等眼科器材公司生产的甲基丙烯酸羟乙酯水凝胶眼内人工晶体上市销售。我国也有应用的研究报告。公开文献有杜冰、林振德、邹玉平，水凝胶折叠人工晶体植入人眼1年后的临床观察，<透析与人工器官>杂志201，12(1)40-43。与聚丙烯酰胺水凝胶相比，聚甲基丙烯酸羟乙酯具有强度(可达40kg/cm)是前者的10倍以上，吸水后富有弹性，能耐高温灭菌等特点。单一的丙烯酰胺聚合水凝胶用作人体入物已被广泛使用。同时丙烯酰胺与甲基丙烯酸羟乙酯有很好的共聚性能。公开的文献有罗致诚主编<中国医学百科全书>生物医学工程，上海科学技术出版社，1989，150-151。所以用两种单体共聚在化学反应上可行的。
两种单体共聚的水凝胶较单一丙烯酰胺水凝胶分子结构的变化是聚丙烯酰胺水凝胶，主要的特征基团是酰胺基，红外光谱中可看到在1650cm处有强的吸收峰为C-O伸缩。
加入甲基丙烯酸羟乙酯后，聚丙烯酰胺共聚水凝胶中出现聚丙烯酰胺水凝胶中没有的特征基团羟基(OH)，红外光谱中可以发现在3640cm、1050cm处有中至强的吸收峰为0H伸缩及C-O伸缩。
共聚水凝胶较聚丙烯酰胺水凝胶物理性能的变化。
以总固体含量5％交联剂0.8％(与单体总量相比)的凝胶为例5cm×5cm×5cm凝胶，若是聚丙烯酰胺水凝胶，承压强度为550g，共聚水凝胶(丙烯酰胺与甲基丙烯酸羟乙酯的克分子比为3∶1)，承压能力提高到850克。在200克负载下，纵向形变聚丙烯酰胺水凝胶为12％，共聚水凝胶为5％。
上述数据说明共聚对改善水凝胶的强度与弹性是有效的。
本发明的产品所达到的技术标准及如下：
1、外观透明(无色)肉眼见无杂质的凝胶；
2、PH7.0±0.5；
3、重金属含量以铅计小于0.1mg/l；
4、热稳定性250℃DSC差热分析未发现变化；
5、细胞毒性不大于一级；
6、无致敏反应；
7、无皮肤刺激；
8、无全身急性毒性；
9、溶血率小于5％；
10、无遗传毒性。
弹性与变形测定方法
1.5％总固体含量，交联剂0.8％(与单体总量相比)反应制备的凝胶。切成5cm×5cm×5cm的立方体。上面放一块200％g重薄不锈钢板，记录试压前后纵向高度(ho-hl)。
在上述不锈钢板上加上砝码，每次增加50g，直至凝胶破碎。此时。法码重量-200g为凝胶的承压能力。
本发明给出以下制造方法实施例：
实施例1、低浓度医用共聚水凝胶的制备
将30.0g丙烯酰胺与0.5g甲基丙烯酸羟乙酯溶于800ml克分子比为1∶0.05的无菌、无热原蒸馏水与医用乙醇的混合剂中，经5μm及0.2μm过滤器过滤。加入经0.2m过滤器滤过的10ml 0.5％N，N亚甲基双丙烯酰胺无菌、无热原双蒸水溶液以及10ml 0.5％的过滤硫酸胺、8ml 0.45的亚硫酸氢钠、8ml 0.2％三乙醇胺的无菌、无热原双蒸水溶液，再用上述混合溶剂稀释至1000ml。在25-35℃条件下充纯氮去除溶液中的氧气并搅拌溶液，保温24小时。形成的凝胶经过无菌，无热原蒸溜水充分，反复浸泡，洗涤，即得本发明的水凝胶，若需进一步提高纯度，可接着用医用乙醇萃取，过滤萃取物，将滤出的固体低温干燥，进一步粉碎，再用生理盐水或磷酸氢钠平衡缓冲液配制成3.05％的交联共聚水凝胶。
实施例2、高浓度医用共聚水凝胶的制备
将27.5g丙烯酰胺与2.5g甲基丙烯酸羟乙酯溶于200g克分子比1∶0.05的无菌、无热原蒸馏水与医用乙醇的混合溶剂中，经5μm及0.2μm过滤器过滤。加入经0.2μm过滤器过滤的15ml 0.8N，N亚甲基双丙酰胺及12ml 0.6的过硫酸钠、10ml 0.4％亚硫酸氢钠、10ml 0.2％二乙醇胺的无菌、无热原双蒸馏水溶液，同时用上述混合溶液稀释至350ml，在30-50℃条件下充纯氮去除溶液中氧气并搅拌溶液，保温24小时，形成水凝胶后的后处理步骤同实施例1。最终配制成8.6％的共聚水凝胶。
实施例3、中浓度医用共聚水凝胶制备
将40g丙烯酰胺与5.0g甲基丙烯酸羟乙酯溶于800g克分子比为1∶0.1的灭菌、无热原蒸馏水与医用乙醇混合溶剂中，经5.0μm及0.2μm过滤器过滤，加入经0.2μm过滤器过滤的20ml 0.5％N，N亚甲基比丙烯酰胺无菌、无热原双蒸水溶液以及15ml 1％的过硫酸胺10ml 0.4％亚硫酸氢钠、10ml 0.2％四甲基乙二胺的灭菌、无热原双蒸水溶液，用上述混合溶剂稀释至1000ml其他步骤同实施例2。
Claims (2)
1、一种医用共聚水凝胶，其特征是：该水凝胶为丙烯酰胺和甲基丙烯酸羟乙酯二种单体与交联剂N，N亚甲基双丙烯酰胺或N，N二烯丙基酒石酸胺的共聚物，其结构式为：其中：
A：丙烯酰胺反应后结构为
B：甲基丙烯酸羟乙酯反应后结构为
C：NN＝亚甲基双丙烯酰胺
2、一种医用共聚水凝胶的制法，
其特征是将丙烯酰胺和甲基丙烯酸羟乙酯溶于无菌、无热原蒸馏水与医用乙醇混合的剂中，引发体系用摧化剂，加速剂，促进剂三元组成，反应中总固体含量为2.5-8Wt/％，其中丙烯酰胺与甲基丙烯酸羟乙酯的分子比为1∶0.01-1∶0.40催化剂用量为单体总重量的0.01-2.0％，加速剂为单体总重量的0.001-1.0％，促进剂为单体总重量的0.001-0.1％，交联剂为单体总重量的0.001-5.0％，其余成分为溶剂，其中的催化剂可使用过硫酸铵或过硫酸钾，加速剂可以是亚硫酸氢钠或偏亚硫酸钠，促进剂包括三乙醇胺或三乙胺及其含取代基的N，N乙二胺类，交联剂为N，N一亚甲基双丙烯酰胺或N，N二烯丙基酒石酸二酰胺，用量为单体总重量的0.001-5.0％，
聚合反应在氮气气氛下20-30℃条件下进行，反应时间4-30小时，结束后得到的水凝胶经无菌、无热原二次蒸馏水浸泡、洗涤，得医用水凝胶。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397347B (zh) * | 2007-09-27 | 2011-03-23 | 北京师范大学 | 一种高强度水凝胶、其制备方法以及用途 |
| CN102006894A (zh) * | 2008-03-18 | 2011-04-06 | 麦德托尼克瓦斯科尔勒公司 | 医学装置应用的不可降解水凝胶 |
| CN101293942B (zh) * | 2008-04-22 | 2011-06-01 | 东华大学 | 紫外引发法制备快速响应的互穿网络复合水凝胶的方法 |
| CN110144183A (zh) * | 2019-05-05 | 2019-08-20 | 广州大学 | 一种可反复使用且不伤基材表面的水凝胶胶黏剂及其制备和应用 |
| CN116217795A (zh) * | 2023-02-21 | 2023-06-06 | 台州市黄岩鸿瀚工贸有限公司 | 一种空气杀菌消毒和除醛、除异味凝胶及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116396442B (zh) * | 2023-06-01 | 2023-08-15 | 四川大学华西医院 | 一种原位相分离光固化打印高精度凝胶材料及其制备方法 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397347B (zh) * | 2007-09-27 | 2011-03-23 | 北京师范大学 | 一种高强度水凝胶、其制备方法以及用途 |
| CN102006894A (zh) * | 2008-03-18 | 2011-04-06 | 麦德托尼克瓦斯科尔勒公司 | 医学装置应用的不可降解水凝胶 |
| CN101293942B (zh) * | 2008-04-22 | 2011-06-01 | 东华大学 | 紫外引发法制备快速响应的互穿网络复合水凝胶的方法 |
| CN110144183A (zh) * | 2019-05-05 | 2019-08-20 | 广州大学 | 一种可反复使用且不伤基材表面的水凝胶胶黏剂及其制备和应用 |
| CN110144183B (zh) * | 2019-05-05 | 2021-04-23 | 广州大学 | 一种可反复使用且不伤基材表面的水凝胶胶黏剂及其制备和应用 |
| CN116217795A (zh) * | 2023-02-21 | 2023-06-06 | 台州市黄岩鸿瀚工贸有限公司 | 一种空气杀菌消毒和除醛、除异味凝胶及其制备方法 |
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| KR100995717B1 (ko) | 2010-11-19 |
| CN1226318C (zh) | 2005-11-09 |
| KR20040007327A (ko) | 2004-01-24 |
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