CN110183588A - 一种高强度光固化人工晶状体及其制作方法 - Google Patents
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Abstract
本发明提供一种高强度光固化人工晶状体及其制作方法。将聚氨酯丙烯酸酯预聚体与活性稀释剂、光引发剂、紫外光吸收剂混合后，注入拥有人工晶状体形状的可透光模具间，经固定波长的光固化聚合和脱模纯化处理，即可制造出软质可折叠人工晶状体。本发明制造的人工晶状体强度高、韧性佳，无需后期打磨抛光等处理，无细胞毒性，柔软可折叠，适合作为医用人工晶状体。
Description
技术领域
本发明属于医学用人工晶状体的制备领域，特别涉及用聚氨酯-丙烯酸酯类材料作为主体快速制作高强度光固化人工晶状体的方法。
背景技术
现人眼内用软性人工晶状体主要采用硅凝胶、亲水性聚丙烯酸酯及疏水性聚丙烯酸酯等材料，特别是聚丙烯酸酯类人工晶状体已经成为临床选择主流。聚丙烯酸酯类人工晶体在工业上多仍采用热聚合方式，在热引发剂的作用下通常需要将材料在高温条件固化24小时以上，聚合反应时间长，耗能多；人工晶状体材料聚合后多为材料片，材料去毒后仍需后期机器切削、打磨、抛光等，生产周期长；且聚丙烯酸酯类人工晶体在使用过程中有襻断裂的情况发生，反映此类材料的力学性能有待加强。
聚氨酯是一类综合性能优秀的材料，其已经广泛应用于生物医学领域。其具有优良的韧性和弹性，加工性能好，加工形式多样；毒性符合医用要求，生物相容性好，无致畸变作用，无过敏反应。在Bozukova D等人的研究中，已成功用热聚合的方式制作出可生物用的纯聚氨酯人工晶状体,但其合成周期长，透光率仍有上升空间。
光固化是一种节能环保的高分子聚合方式，在人工晶状体的制作方面也有运用，比如美国专利5290892中的光引发制作晶状体材料。光固化引发剂分紫外光波段光引发剂和可见光波段光引发剂两类，为了减少紫外光对视网膜及黄斑组织的损害，人工晶状体材料中多加入紫外光屏蔽剂，屏蔽剂的作用使得紫外光段引发剂无法迅速有效聚合人工晶状体材料。在专利CN1264472中，描述了在蓝光光源下用可见光引发剂聚合人工晶状体材料。此方法快速，但固化后材料片仍需要切削打磨、抛光等工艺，生产周期长。
发明内容
本发明目的针对现有技术中人工晶状体的强度和透明性不能兼顾，且生产周期长耗能多的问题，提供一种高强度光固化人工晶状体及其制作方法。
本发明采用如下技术方案：一种高强度光固化人工晶状体，所述光固化人工晶状体至少由20-90重量份的聚氨酯丙烯酸酯预聚体、10-80重量份的活性稀释剂、0.1-5重量份的光引发剂、0.1-3重量份的紫外光吸收剂混合后，经过光固化得到。
一种光固化人工晶状体的制备方法：包括以下步骤：
(1)将聚氨酯丙烯酸酯预聚体与活性稀释剂、光引发剂、紫外光吸收剂混合。
(2)将步骤(1)里的混合物注入透明模具中。透明模具内人工晶状体形状为任何符合人体工学的眼内植入物形状，模具内人工晶状体光学部分为镜面级光滑。
(3)将步骤(2)的模具在光照下进行光固化。作为本领域的公知常识，光固化的光线波长应覆盖光引发剂的工作波长，光固化时间为5-60分钟。
(4)将步骤(3)中固化好的成品脱模，纯化去除未反应单体，真空干燥。
得到的光固化人工晶状体通常采用密封灭菌保存，灭菌方式包括但不限于紫外灭菌、放射线灭菌、环氧乙烷灭菌。
进一步地，步骤(1)中的聚氨酯丙烯酸酯预聚体通过如下方法得到：在氮气气氛下，在催化剂及阻聚剂的作用下，将聚醚多元醇逐滴加入到异氰酸酯中，反应完全，反应时间2-5小时，反应温度30-60℃，再将羟基丙烯酸树脂逐滴加入，反应温度40-80℃，反应时间3-6小时，其中异氰酸酯、聚醚多元醇、羟基丙烯酸树脂按照摩尔比N:1:(2N-1.9)投料，N为任意大于等于2的常数；或是先将羟基丙烯酸树脂先逐滴加入异氰酸酯中反应完全，再将聚醚多元醇逐滴加入反应至结束。红外光谱监测产物至异氰酸根特征峰消失。聚氨酯丙烯酸酯预聚体可为自制或者直接购买商业成品。
进一步地，所述异氰酸酯为芳香族异氰酸酯或脂肪族异氰酸酯，具体包括但不限于甲苯二异氰酸酯、异佛尔酮二异氰酸酯、二苯基甲烷二异氰酸酯、二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯、赖氨酸二异氰酸酯；所述聚醚多元醇具体包括但不限于各分子量的聚乙二醇、聚丙二醇、聚四氢呋喃二醇；所述羟基丙烯酸树脂包括但不限于丙烯酸-2-羟基乙酯、丙烯酸-2-羟基丙酯、甲基丙烯酸羟乙酯、甲基丙烯酸羟丙酯。
进一步地，活性稀释剂由一种或多种单体组成，所述单体带不饱和双键单官能团或带不饱和双键多官能团，包括但不限于功能性丙烯酸酯类、乙烯基醚类。
进一步地，光引发剂应本体及光裂解产物无毒，可为一种或多种搭配使用；例如：Irgacure819、Irgacure TPO。
进一步地，紫外光吸收剂能至少截止380nm以下波长光但吸收范围不超过400nm以上波长的单体，房水条件下不发生析出、转移、毒性。例如：苯并三唑、三嗪类紫外线吸收剂。
进一步地，步骤(4)的纯化方式包括但不限于冷萃取、热萃取、高温蒸馏。
本发明的有益效果在于：
(1)本发明制备的人工晶状体透光率高、力学性能好，生物相容性好；
(2)本发明的制备方法成本低，方法简单可行，制作工序耗时短，经济环保。
附图说明
图1为材料水接触角；
图2为人工晶状体成品；
图3为人工晶状体透光率；
图4为人工晶状体抗拉强度；
图5为人工晶状体断裂伸长率；
图6为纯聚氨酯丙烯酸酯材料透光率。
具体实施方式
实施例1：本实施例制备一种有高力学性能的亲水性可折叠人工晶状体。
制备方法包括以下步骤：
(1)制备一种聚氨酯丙烯酸酯预聚物：异氰酸酯:聚醚多元醇:羟基丙烯酸酯的摩尔比为2:1:2.1。反应容器为250ml四口烧瓶，连接顶置式机械搅拌器、回流冷凝管、恒压滴液漏斗、温度计，通氮气，加热装置为油浴锅。在四口烧瓶中投入8.8912g异佛尔酮二异氰酸酯及催化剂二月桂酸二丁基锡0.0172g，在60℃逐滴添加20.0000g聚四氢呋喃二醇-1000。反应2小时后，缓慢加入5.3357g丙烯酸-2-羟基丙酯及0.0534g对苯二酚，升温至80℃继续反应3小时，得到透明粘稠液体，密封阴凉处保存。
(2)制备光固化树脂组分：将0.9524g①制备的产物、0.0529g N-乙烯基吡咯烷酮、0.0529g丙烯酸异丁酯、0.0529g Irgacure819、0.0011g RUVA93充分混合成低粘度树脂，静置去除气泡。
(3)将(2)制备的低粘度树脂用针筒小心注入模具内，模具密封固定，放入光固化箱，使用500W高压汞灯在距离30cm处照射5分钟。
(4)关闭汞灯，取出打开模具，用镊子取出固化好的人工晶状体，浸入石油醚-乙醚混合溶液(体积比85:15)中1小时洗去未反应单体，再用双蒸水清洗，置于真空干燥箱内在25℃完全干燥。将干燥后的人工晶状体密封，使用环氧乙烷消毒。
制备出的人工晶状体材料为亲水性材料(PUA IOL)，如图1所示，外形符合植入标准，如图2所示，折光率为1.487，可见光透光率超过90％，可阻挡380nm以下的紫外光(如图3所示)，其力学性能明显优于丙烯酸酯类人工晶状体(Acrylic IOL)，如图4、图5所示；细胞相容性好(如表1所示)。
表1人工晶状体CCK-8细胞毒性测试(P>0.05)
| OD 450nm | Acrylic IOL | PUA IOL | Blank control |
| hLEC | 0.764±0.04 | 0.756±0.03 | 0.758±0.02 |
| APRE-19 | 0.702±0.10 | 0.710±0.06 | 0.708±0.05 |
实施例2：本实施例制备一种有高力学性能的亲水性可折叠人工晶状体。
制备方法包括以下步骤：
(1)制备一种聚氨酯丙烯酸酯预聚物：异氰酸酯:聚醚多元醇:羟基丙烯酸酯的摩尔比为3:1:4.1。反应容器为250ml四口烧瓶，连接顶置式机械搅拌器、回流冷凝管、恒压滴液漏斗、温度计，通氮气，加热装置为油浴锅。在四口烧瓶中投入丙烯酸-2-羟基乙酯4.7609g及0.0476g对苯二酚，在30℃逐滴添加5.2385g甲苯二异氰酸酯，反应5小时后，缓慢加入4.0000g聚乙二醇-400，升温至40℃继续反应6小时，得到透明粘稠液体，密封阴凉处保存。
(2)制备光固化树脂组分：将0.2685g①制备的产物、0.5370g甲基丙烯酸异冰片酯、1.8795g丙烯酸-2-羟基丙酯、0.0269g Irgacure TPO、0.8070g RUVA BAPO充分混合成低粘度树脂，静置去除气泡。
(3)将(2)制备的低粘度树脂用针筒小心注入模具内，模具密封固定，放入光固化箱，使用500W高压汞灯在距离50cm处照射60分钟。
(4)关闭汞灯，取出打开模具，用镊子取出固化好的人工晶状体，浸入石油醚-乙醚混合溶液(体积比85:15)中1小时洗去未反应单体，再用双蒸水清洗，置于真空干燥箱内在25℃完全干燥。将干燥后的人工晶状体密封，使用辐照消毒。
经测试，制备得到的人工晶状体材料折光率为1.487，可见光透光率超过90％，可阻挡380nm以下的紫外光，其力学性能明显优于丙烯酸酯类人工晶状体，细胞相容性极好。
对比例：本实施例制备一种纯聚氨酯丙烯酸酯预聚体型人工晶状体。
制备方法包括以下步骤：
(1)制备一种聚氨酯丙烯酸酯预聚物：异氰酸酯:聚醚多元醇:羟基丙烯酸酯的摩尔比为2:1:2.1。反应容器为250ml四口烧瓶，连接顶置式机械搅拌器、回流冷凝管、恒压滴液漏斗、温度计，通氮气，加热装置为油浴锅。在四口烧瓶中投入8.8912g异佛尔酮二异氰酸酯及催化剂二月桂酸二丁基锡0.0172g，在60℃逐滴添加20.0000g聚乙二醇-1000。反应2小时后，缓慢加入5.3357g丙烯酸-2-羟基丙酯及0.0534g对苯二酚，升温至80℃继续反应3小时，得到透明粘稠液体，密封阴凉处保存。
(2)制备光固化树脂组分：将1.2543g(1)制备的产物、0.0012g Irgacure819充分混合，静置去除气泡。
(3)将(2)制备的树脂小心注入模具内，模具密封固定，放入光固化箱，使用500W高压汞灯在距离30cm处照射10分钟。
(4)关闭汞灯，取出打开模具，用镊子取出固化好的人工晶状体，浸入乙醚中30分钟洗去未反应单体，再用双蒸水清洗，置于真空干燥箱内在25℃完全干燥。将干燥后的人工晶状体密封，使用环氧乙烷消毒。
成品的可见光透过率为80％(如图6所示)，因未添加紫外线吸收剂，380nm以下波长的光线无法吸收。
结论：本发明以聚氨酯丙烯酸酯、亲水性单体为主体的人工晶状体，透光率明显高于纯聚氨酯丙烯酸酯类材料，折光率适中，更适合作为光学晶状体使用，且无明显细胞毒性、力学性能与传统丙烯酸酯类材料相比大幅提升。
Claims (8)
1.一种高强度光固化人工晶状体，其特征在于：所述光固化人工晶状体至少由20-90重量份的聚氨酯丙烯酸酯预聚体、10-80重量份的活性稀释剂、0.1-5重量份的光引发剂、0.1-3重量份的紫外光吸收剂混合后，经过光固化得到。
2.一种如权利要求1所述的光固化人工晶状体的制备方法，其特征在于：包括以下步骤：
(1)将聚氨酯丙烯酸酯预聚体与活性稀释剂、光引发剂、紫外光吸收剂混合。
(2)将步骤(1)里的混合物注入透明模具中。透明模具内人工晶状体形状为任何符合人体工学的眼内植入物形状，模具内人工晶状体光学部分为镜面级光滑。
(3)将步骤(2)的模具在光照下进行光固化。
(4)将步骤(3)中固化好的成品脱模，纯化去除未反应单体，真空干燥。
3.根据权利要求2所述的光固化人工晶状体的制备方法，其特征在于：步骤(1)中的聚氨酯丙烯酸酯预聚体通过如下方法得到：在氮气气氛下，在催化剂及阻聚剂的作用下，将聚醚多元醇逐滴加入到异氰酸酯中，反应完全，反应时间2-5小时，反应温度30-60℃，再将羟基丙烯酸树脂逐滴加入，反应温度40-80℃，反应时间3-6小时，其中异氰酸酯、聚醚多元醇、羟基丙烯酸树脂按照摩尔比N:1:(2N-1.9)投料，N为任意大于等于2的常数；或是先将羟基丙烯酸树脂先逐滴加入异氰酸酯中反应完全，再将聚醚多元醇逐滴加入反应至结束。
4.根据权利要求3所述的光固化人工晶状体的制备方法，其特征在于：所述异氰酸酯为芳香族异氰酸酯或脂肪族异氰酸酯，具体包括但不限于甲苯二异氰酸酯、异佛尔酮二异氰酸酯、二苯基甲烷二异氰酸酯、二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯、赖氨酸二异氰酸酯；所述聚醚多元醇具体包括但不限于各分子量的聚乙二醇、聚丙二醇、聚四氢呋喃二醇；所述羟基丙烯酸树脂包括但不限于丙烯酸-2-羟基乙酯、丙烯酸-2-羟基丙酯、甲基丙烯酸羟乙酯、甲基丙烯酸羟丙酯。
5.根据权利要求2所述的光固化人工晶状体的制备方法，其特征在于：活性稀释剂由一种或多种单体组成，所述单体带不饱和双键单官能团或带不饱和双键多官能团，包括但不限于功能性丙烯酸酯类、乙烯基醚类。
6.根据权利要求2所述的光固化人工晶状体的制备方法，其特征在于：光引发剂应本体及光裂解产物无毒，可为一种或多种搭配使用。
7.根据权利要求2所述的光固化人工晶状体的制备方法，其特征在于：紫外光吸收剂能至少截止380nm以下波长光但吸收范围不超过400nm以上波长的单体，房水条件下不发生析出、转移、毒性。
8.根据权利要求2所述的光固化人工晶状体的制备方法，其特征在于：步骤(4)的纯化方式包括但不限于冷萃取、热萃取、高温蒸馏。
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Application publication date: 20190830 |