CN116478388A - 一种室温透明可注射的pgs基液基聚合物及其制备方法和应用 - Google Patents
一种室温透明可注射的pgs基液基聚合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种室温透明可注射的PGS基液基聚合物及其制备方法和应用，所述聚合物的结构式如下：本发明制备得到的PGS基液基聚合物PGSS，侧链的引入打破了PGS分子链的规整性和结晶性，使PGSS在室温下表现为高度透明，同时PGS的玻璃化温度由原先的0℃降至‑20℃，使PGSS室温下表现出粘流、可注射性质。PGSS中的酯键的水解赋予其可降解特点，羧基易和治疗因子(包括生物活性小分子、蛋白或基因等)中的羟基、氨基等基团发生相互作用，随着PGSS的降解，实现对治疗因子的长效缓释。
Description
技术领域
本发明属于药物缓释用生物医用材料领域，特别涉及一种室温透明可注射的PGS基液基聚合物及其制备方法和应用。
背景技术
药物疗法可以通过药物分子抑制或消除治病因素，达到预防、缓解及治愈疾病的目的，是临床治疗的重要方法。因其使用方便、疗效快的独特优势，药物疗法被广泛应用于脑科、骨科、心外科、眼科等领域。口服、静脉注射等传统给药方式存在药物利用度低，毒副作用大，治疗效率低等问题。发展能够微创植入、局部定植、长效控释的药物缓释体系受到大家的日益关注。
现有药物递释体系有无机或有机微纳体系。无机递释体系包括无机金属基、碳基、介孔硅基微纳颗粒，具有比表面积大、形貌尺寸可控等特点。有机递释体系有微纳囊泡、颗粒、胶束、脂质体、树状大分子等具有易表面功能化改性的特点，但微纳递释体系在体内动态环境下的局部滞留率低，导致药物利用度降低，通常需要借助聚合物载体定植实现对药物的局部控释。水凝胶是常用的聚合物载体之一，展现出良好的可注射、局部定植和缓慢释放能力。但现有研究多是一种体系对同一类型药物的缓释研究，对不同种类药物的递释能力研究尚为匮乏。相较于单一药物，多类型药物复合往往能够发挥出更好的疗效，因此发明通用型局部药物缓释体系具有重大的研究和应用价值。除了通用、可注射之外，理想的递释体系还应该具有透光性、可降解等特点以满足不同应用场景的递释需求。如为了不影响眼的视觉功能，对递释体系的透光性提出了高的要求。缓释体系作为体内植入物，考虑到其后期去除问题，还应具有可降解性质。然而现有的递释体系尚无法满足需求，兼具有可注射、透明、可降解特征且可普适应用的药物递释体系亟待研发。
发明内容
本发明所要解决的技术问题是提供一种室温透明可注射的PGS基液基聚合物及其制备方法和应用，克服现有技术中聚合物基难以普适应用且难以兼顾可注射、透明、可降解特征。
本发明提供了一种室温透明可注射的PGS基液基聚合物，所述聚合物的结构式如下：
其中，n的范围为35-80；记作PGSS。
所述聚合物由摩尔比为0.5:1～4:1的第一单体与PGS预聚物反应而得；其中，所述第一单体为丁二酸酐、丁二酸中的一种。
本发明还提供了一种室温透明可注射的PGS基液基聚合物的制备方法，包括：
将癸二酸和甘油以1:1的摩尔比进行投料，于100℃-120℃、氮气氛围伴随磁力搅拌下反应24h得到PGS预聚物；将预先干燥的第一单体和PGS预聚物在无水溶剂中充分溶解混合，于氮气氛围80-120℃下伴随磁力搅拌反应30-60min，反应终止后用洗涤剂对反应混合物进行反复洗涤，抽真空处理后，得到PGS基液基聚合物。
所述无水溶剂为无水N、N-二甲基甲酰胺或无水二甲基亚砜。
本发明还提供了一种室温透明可注射的PGS基液基聚合物在药物递释体系中的应用。
所述PGS基液基聚合物与药物分子按体积比1000:0.1-1:200混合，得到药物递释体系。
所述药物分子为生物小分子、蛋白大分子、DNA、RNA中的一种。
所述生物小分子为阿昔替尼、Kartogenin、苄吡呤、拉坦前列素、噻吩洛尔β受体阻滞剂、盐酸左布诺洛尔中的一种；所述蛋白大分子为胰岛素、生长素、促肾上腺皮质激素中的一种；所述RNA为microRNA、siRNA、mRNA中的一种。
所述PGS基液基聚合物对拉坦前列素、胰岛素、microRNA均具有缓释作用，其缓释周期长达30天以上。
所述药物递释体系为透明体系，其透光率高达98％，与大鼠的天然玻璃体近似。
有益效果
本发明制备得到的PGS基液基聚合物PGSS，侧链的引入打破了PGS分子链的规整性和结晶性，使PGSS在室温下表现为高度透明，同时PGS的玻璃化温度由原先的0℃降至-20℃，使PGSS室温下表现出粘流、可注射性质。PGSS中的酯键的水解赋予其可降解特点，羧基易和治疗因子(包括生物活性小分子、蛋白或基因等)中的羟基、氨基等基团发生相互作用，随着PGSS的降解，实现对治疗因子的长效缓释。
附图说明
图1为本发明的PGS基液基聚合物PGSS的应用示意图。
图2为实施例1中PGSS的核磁谱图。
图3为实施例1中PGS和PGSS的DSC吸热和放热曲线。
图4为实施例1中PGSS和大鼠天然玻璃体的紫外可见吸收光谱。
图5为实施例1中PGSS的降解曲线。
图6为实施例1中PGSS对拉坦前列素的体外缓释曲线。
图7为实施例1中PGSS对microRNA的体外缓释曲线。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)PGS预聚物的合成
癸二酸单体重结晶后备用。重结晶癸二酸与缩水甘油按摩尔比1:1在120℃氮气氛围中，伴随磁力搅拌反应24h。去除氮气，反应混合物在抽真空条件下继续反应24h，制得白色蜡状固体PGS预聚物。
(2)PGSS的合成
在手套箱称取干燥后的PGS预聚物(1mol)和丁二酸酐(2mol)置于反应瓶中，同时添加无水N,N-二甲基甲酰胺，于110℃氮气氛围下伴随磁力搅拌反应50min。反应结束后，将反应产物用去离子水和四氢呋喃进行反复洗涤处理，然后室温25℃抽真空处理约48h，即得PGSS聚合物。
(3)PGSS基药物递释体系的制备和缓释评价
取适量拉坦前列素(浓度200μg)、PGSS(1mL)和磷酸缓冲溶液(3mL)混合均匀，置于36孔板中，于37℃进行缓释。在不同时间下(0.5d、1d、3d、5d、7d、14d、21d、28d)，从孔板中取出1.5mL缓释溶液，然后补给等量新鲜的磷酸缓冲溶液。使用液质联用仪制备拉坦前列素的标准曲线，基于标准曲线对缓释液中拉坦前列素的含量进行分析，得到不同时间下PGSS对拉坦前列素的缓释曲线。
称取500μg microRNA，将其溶于1mL磷酸缓冲溶液中。取10μL的microRNA溶液，1mL的PGSS置于36孔板中，添加3mL磷酸缓冲溶液对其稀释，于37℃进行缓释。在不同时间下(0.5d、1d、3d、5d、7d、14d、21d、28d)，分别取三个孔板的缓释溶液各1.5mL，用紫外分光光度计进行检测。microRNA中核酸的嘌呤和嘧啶碱基具有共轭双键，能吸收紫外光并在260nm处具有最大吸收峰。基于紫外吸收光谱得到的microRNA的标准曲线，计算不同时间下PGSS对microRNA的缓释量，三个值取平均。
(4)实验结果
由图2可知，核磁谱图明确了PGSS的结构。
图3为实施例1中PGS和PGSS的DSC吸热和放热曲线，说明了功能性侧基的引入显著降低了PGSS的玻璃化转变温度和结晶。
图4为实施例1中PGSS和大鼠天然玻璃体的紫外可见吸收光谱，证明了PGSS的透光率和天然玻璃体近似。
图5为实施例1中PGSS的降解曲线，说明了PGSS可降解性能。
图6为实施例1中PGSS对拉坦前列素的体外缓释曲线，说明了PGSS对小分子药物拉坦前列素具有缓慢释放作用，释放周期长达28天。
图7为实施例1中PGSS对microRNA的体外缓释曲线，说明了PGSS对基因microRNA具有缓慢释放作用，释放周期长达28天。
Claims (8)
1.一种室温透明可注射的PGS基液基聚合物，其特征在于：所述聚合物的结构式如下：
其中，n的范围为35-80。
2.根据权利要求1所述的PGS基液基聚合物，其特征在于：所述聚合物由摩尔比为0.5:1～4:1的第一单体与PGS预聚物反应而得；其中，所述第一单体为丁二酸酐、丁二酸中的一种。
3.一种如权利要求1-2任一所述的室温透明可注射的PGS基液基聚合物的制备方法，包括：
将癸二酸和甘油以1:1的摩尔比进行投料，于100℃、氮气氛围伴随磁力搅拌下反应24h得到PGS预聚物；将预先干燥的第一单体和PGS预聚物在无水溶剂中充分溶解混合，于氮气氛围80-120℃下伴随磁力搅拌反应30-60min，反应终止后用洗涤剂对反应混合物进行反复洗涤，抽真空处理后，得到PGS基液基聚合物。
4.根据权利要求3所述的制备方法，其特征在于：所述无水溶剂为无水N、N-二甲基甲酰胺或无水二甲基亚砜。
5.一种如权利要求1-2任一所述的室温透明可注射的PGS基液基聚合物在药物递释体系中的应用。
6.根据权利要求5所述的应用，其特征在于：所述PGS基液基聚合物与药物分子按体积比1000:0.1-1:200混合，得到药物递释体系。
7.根据权利要求6所述的应用，其特征在于：所述药物分子为生物小分子、蛋白大分子、DNA、RNA中的一种。
8.根据权利要求7所述的应用，其特征在于：所述生物小分子有阿昔替尼、Kartogenin、苄吡呤、拉坦前列素、噻吩洛尔β受体阻滞剂、盐酸左布诺洛尔中的一种；所述蛋白大分子为胰岛素、生长素、促肾上腺皮质激素中的一种；所述RNA为microRNA、siRNA、mRNA中的一种。
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