CN107050525A - 一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法 - Google Patents

一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法 Download PDF

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CN107050525A
CN107050525A CN201710271234.3A CN201710271234A CN107050525A CN 107050525 A CN107050525 A CN 107050525A CN 201710271234 A CN201710271234 A CN 201710271234A CN 107050525 A CN107050525 A CN 107050525A
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gelatin
coaxial
pla
plcl
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朱利民
桑青青
吴焕岭
刘凯琳
李赫宇
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Donghua University
National Dong Hwa University
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Abstract

本发明涉及一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，将明胶、碳酸氢钠溶解在溶剂中，得到壳层溶液；将聚乳酸己内酯PLCL溶解在溶剂中，得到芯层溶液；将上述溶液中分别加入抗菌药和抗癌药，搅拌溶解，得到纺丝液，然后进行同轴静电纺，干燥，即得。本发明的实验条件为常温常压，制备过程简单，易于控制，且制作成本低。

Description

一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架 的制备方法
技术领域
本发明属于载药纤维支架的制备领域，特别涉及一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法。
背景技术
静电纺丝技术，即静电雾化或电喷的一种特殊方法，是在高压电场作用下的纺丝过程。而同轴静电纺丝技术是在静电纺丝的基础上发展而来的，主要的改进措施是将原先的单一喷丝口改进为同心轴的复合毛细管，解决了将不同原料进行物理共混时必须是混合体系的局限性，这种加工方法操作简单并且制备的纤维在均匀性和连续性方面都要好于其他加工方法。芯-壳结构纤维的壳层被赋予良好的生物相容性、感光性、pH敏感性，温敏性等，纤维芯层则具备良好的机械性能以及使载在芯层的药物释放缓慢的作用。另外，当芯层载入生物、化学、光学或电学活性物质后，又可增加芯-壳结构纤维的催化、传感等功能。因此，芯-壳结构纤维在组织工程，生物医用，化工等领域具有广阔的应用潜力。
明胶是由胶原蛋白部分水解而获得的高分子量多肽混合物，是多种氨基酸排列成长链的高分子蛋白质，由20种常见氨基酸合成，约30％为甘氨酸，20％是亚氨基酸(脯氨酸或経脯氨酸)，形成了一种(Gly－X－Y)n的重复模式，甘氨酸－脯氨酸－哲脯氨酸是胶原中最为普遍的三肽序列。生物相容性好，降解性好。
聚乳酸己内酯(PLCL)一种脂肪族聚酯共聚物，由PLA和CL的开环聚合而成，通过改变PLLA和PCL链段的比例可以有效控制产物的断裂强度、断裂伸长和降解速率。PLCL是疏水性材料，在体内可降解，被大量应用在组织工程中。
碳酸氢钠又称小苏打，白色细小晶体。固体50℃以上开始逐渐分解生成碳酸钠、二氧化碳和水，440℃时完全分解。另外，在酸性环境在可以与氢离子发生反应，生成水与二氧化碳，此反应在中性环境下并不能进行。碳酸氢钠是强碱与弱酸中和后生成的酸式盐，溶于水时呈现弱碱性。
环丙沙星又名丙氟哌酸，是西德拜耳药厂于1983年开发成功的一种化学合成的广谱抗菌药物。其作用机理是通过抑制细菌的DNA回旋酶而起到快速杀菌的作用，对革兰氏阴性菌、革兰氏阳性菌、支原体等都有很强的抗菌活性。它广泛应用于动物和人类的多种感染性疾病的治疗，具有抗菌谱广、抗菌作用强等特点。
盐酸阿霉素(Doxouribicn)是抗肿瘤抗生素，通过抑制癌细胞遗传物质核酸的合成，抗瘤谱较广，对多种肿瘤细胞均有杀灭作用。
发明内容
本发明所要解决的技术问题是提供一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，该方法实验原理简单，操作简单，对环境要求低，人为误差小，可获得生物相容性好，具有一定缓释效果的纤维材料，有望应用于组织工程支架。
本发明的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，包括：
(1)将明胶、碳酸氢钠溶解在溶剂中，得到壳层溶液；
(2)将聚乳酸己内酯PLCL溶解在溶剂中，得到芯层溶液；
(3)将上述溶液中分别加入抗菌药和抗癌药，搅拌溶解，得到纺丝液，然后进行同轴静电纺，干燥，即得pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架。
所述步骤(1)、(2)的溶剂均为六氟异丙醇HFIP，HFIP的质量浓度为90～95％(w/w)，含水量小于0.1％。
所述步骤(1)中壳层溶液中明胶的浓度为14-16％(w/v)。
所述步骤(1)中碳酸氢钠为碳酸氢钠饱和溶液。
所述步骤(1)中碳酸氢钠相对于明胶的浓度为4-6％(w/w)。
所述步骤(2)中芯层溶液PLCL的浓度为4-6％(w/v)(g/mL)。
所述步骤(3)中抗菌药物为环丙沙星，抗癌药物为盐酸阿霉素DOX。
抗癌药DOX在使用过程中始终保持避光状态。
环丙沙星和明胶的质量比为9-11％(w/w)；DOX与PLCL的质量比为4-6％(w/w)。
所述步骤(3)中搅拌溶解的温度为25℃，搅拌时间为24-36h。
同轴静电纺的装置即利用同轴喷头和两个推进器进行纺丝。
所述步骤(3)中同轴静电纺具体工艺参数为：注射器规格为5mL；同轴针头内部直径约为0.6-0.7mm，外部直径约为1.4-1.4mm；喷出流速壳层为0.6-0.8mL/h，芯层为0.2-0.4mL/h；电压为15-20kV，接收距离为25-30cm，纺丝时间为5-9h，铝箔收集；其中静电纺丝环境温度为25℃，湿度为30-40％。
所述步骤(3)中干燥是在真空干燥箱中进行，温度为25℃，干燥时间为12-24h。
有益效果
(1)本发明实验原理简单，操作简单，对环境要求低，人为误差小，可获得生物相容性好，具有一定药物缓释效果的纤维材料，有望应用于癌症治疗的组织工程支架。
(2)本发明所使用的原材料价廉，较易得到。
附图说明
图1载药同轴纤维支架的SEM图；其中a为同轴纤维的SEM图；b为其直径分布柱状图；
图2载药同轴纤维支架的TEM图；
图3载药前后同轴纳米纤维的FTIR图；
图4载药前后同轴纤维的XRD衍射图。
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)秤取0.453g明胶溶于3mL六氟异丙醇(HFIP)中。
(2)将碳酸氢钠配制为饱和溶液，量取0.217mL碳酸氢钠饱和溶液，加入上述溶液中，后加入0.0454g环丙沙星，用磁力搅拌器搅拌28h，直至溶质在溶剂中完全溶解，得到壳层明胶纺丝液；
(3)秤取0.153g PLCL(PCL:PLLA＝1:1)溶于3mL六氟异丙醇(HFIP)中，后加入0.0751g DOX，用磁力搅拌器搅拌28h，直至溶质在溶剂中完全溶解，得到芯层PLCL纺丝液；
(4)用5mL注射器抽取上述纺丝液，固定在同轴静电纺装置上，调节纺丝参数进行电纺，喷出流速壳层为0.7mL/h，芯层为0.3mL/h，静电压为16kV，接收距离为29cm，所处环境温度为25℃，湿度为30-40％，纺丝时间为7h。
(5)依照以上步骤将得到载药的同轴聚乳酸己内酯(PLCL)/明胶双载药纤维支架，放在真空干燥箱中干燥24h，剪成2*2cm大小，用扫描电镜(SEM,JSM-5600,JOEL,Japan)对纤维进行观察，得到纤维的SEM图，利用Image J和Origin对纤维直径进行分析，结果如图1a，图1b为其直径分布柱形图从图中可见纤维表面光滑，无结节及串珠出现，且粗细相对均匀，纤维直径分布在750nm左右。
实施例2
(1)秤取0.452g明胶溶于3mL六氟异丙醇(HFIP)中；
(2)将碳酸氢钠配制为饱和溶液，量取0.218mL碳酸氢钠饱和溶液，加入上述溶液中，后加入0.0455g环丙沙星，用磁力搅拌器搅拌30h，直至溶质在溶剂中完全溶解，得到壳层明胶纺丝液；
(3)秤取0.154g PLCL(PCL:PLLA＝1:1)溶于3mL六氟异丙醇(HFIP)中，后加入0.0753g DOX，用磁力搅拌器搅拌30h，直至溶质在溶剂中完全溶解，得到芯层PLCL纺丝液。
(4)用5mL注射器抽取上述纺丝液，固定在同轴静电纺装置上，调节纺丝参数进行电纺，喷出流速壳层为0.8mL/h，芯层为0.4mL/h，静电压为18kV，接收距离为28cm，所处环境温度为25℃，湿度为30-40％，纺丝时间为8h。
(5)照以上步骤，在纺丝过程中，用铜网在喷丝口处上下扫三次，每次时间不超过2s，使纤维喷在铜网上，在铜网上得到载药的同轴聚乳酸己内酯(PLCL)/明胶双载药纤维支架，用场发射透射电镜(TEM,H-800instrument,Hitachi,Japan)对铜网上的纤维进行观察，得到纤维的TEM图，结果如图2，从图中可见明显的同轴结构，单根纤维的表面光滑，粗细均匀。
实施例3
(1)秤取0.751g明胶溶于5mL六氟异丙醇(HFIP)中；
(2)将碳酸氢钠配制为饱和溶液，量取0.362mL碳酸氢钠饱和溶液，加入上述溶液中，后加入0.076g环丙沙星，用磁力搅拌器搅拌29h，直至溶质在溶剂中完全溶解，得到壳层明胶纺丝液；
(3)秤取0.201g PLCL(PCL:PLLA＝1:1)溶于4mL六氟异丙醇(HFIP)中，后加入0.011DOX，用磁力搅拌器搅拌29h，直至溶质在溶剂中完全溶解，得到芯层PLCL纺丝液。
(4)用5mL注射器抽取上述纺丝液，固定在同轴静电纺装置上，调节纺丝参数进行电纺，喷出流速壳层为0.9mL/h，芯层为0.4mL/h，静电压为19kV，接收距离为27cm，所处环境温度为25℃，湿度为30-40％，纺丝时间为10h。
(5)依照以上步骤所得到同轴聚乳酸己内酯(PLCL)/明胶双载药纤维支架，剪取2*3cm的纤维支架，利用傅里叶变换红外光谱(FTIR；Nicolet Instrument Corporation,WI))对纤维进行表征，利用Origin软件处理数据，结果如图3，可见，纯明胶在3296cm-1处由于-OH的伸缩振动出现明显特征峰，在1659cm-1和1539cm-1由于酰胺I和酰胺Ⅱ出现两宽峰；纯PLCL在1758cm-1和2943cm-1处分别有-COOC-和-CH2-的特征吸收峰；环丙沙星在3050cm-1、1620cm-1、1600cm-1处分别是-OH、酮基、和苯环的特征吸收峰；盐酸阿霉素在3310cm-1、1350cm-1和1070cm-1分别是-NH2，C-H和C-O-C的特征峰，纤维支架在3050cm-1,1350cm-1和1070cm-1里均出现各特征峰，所以环丙沙星和盐酸阿霉素成功载到同轴纤维支架上。
实施例4
(1)秤取0.454g明胶溶于3mL六氟异丙醇(HFIP)中；
(2)将碳酸氢钠配制为饱和溶液，量取0.217mL碳酸氢钠饱和溶液，加入上述溶液中，后加入0.0453g环丙沙星，用磁力搅拌器搅拌27h，直至溶质在溶剂中完全溶解，得到壳层明胶纺丝液；
(3)秤取0.153g PLCL(PCL:PLLA＝1:1)溶于3mL六氟异丙醇(HFIP)中，后加入0.0752g DOX，用磁力搅拌器搅拌27h，直至溶质在溶剂中完全溶解，得到芯层PLCL纺丝液。
(4)用5mL注射器抽取上述纺丝液，固定在同轴静电纺装置上，调节纺丝参数进行电纺，喷出流速壳层为0.87mL/h，芯层为0.4mL/h，静电压为16kV，接收距离为28cm，所处环境温度为25℃，湿度为30-40％，纺丝时间为7h。
(5)照以上步骤得到载药的同轴聚乳酸己内酯(PLCL)/明胶双载药纤维支架，用X射线衍射(XRD；Rigaku,Japan)对纤维进行表征，利用Origin软件处理数据，得到纤维的XRD图，结果如图4，环丙沙星和盐酸阿霉素在2θ为10°and 30°均出现大量杂乱无章的峰，说明两药物是结晶结构，明胶在23.14°出现一峰，PLCL在16.18°(VS)和22.03°(S)出现一强峰和弱峰。当药物载入纤维，仅在22.16°出现一个弱峰，说明药物的加入并没有改变纤维支架的非结晶结构。

Claims (10)

1.一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，包括：
(1)将明胶、碳酸氢钠溶解在溶剂中，得到壳层溶液；
(2)将聚乳酸己内酯PLCL溶解在溶剂中，得到芯层溶液；
(3)将上述溶液中分别加入抗菌药和抗癌药，搅拌溶解，得到纺丝液，然后进行同轴静电纺，干燥，即得pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架。
2.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(1)、(2)的溶剂均为六氟异丙醇HFIP，HFIP的质量浓度为90～95％(w/w)，含水量小于0.1％。
3.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(1)中壳层溶液中明胶的浓度为14-16％(w/v)。
4.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(1)中碳酸氢钠为碳酸氢钠饱和溶液。
5.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(1)中碳酸氢钠相对于明胶的浓度为4-6％(w/w)。
6.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(2)中芯层溶液的浓度为4-6％(w/v)。
7.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(3)中抗菌药物为环丙沙星，抗癌药物为盐酸阿霉素DOX。
8.根据权利要求7所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：环丙沙星和明胶的质量比为9-11％(w/w)；抗癌药与PLCL的质量比为4-6％(w/w)。
9.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(3)中同轴静电纺具体工艺参数为：注射器规格为5mL；同轴针头内部直径约为0.6-0.7mm，外部直径约为1.4-1.4mm；喷出流速壳层为0.6-0.8mL/h，芯层为0.2-0.4mL/h；电压为15-20kV，接收距离为25-30cm，纺丝时间为5-9h，铝箔收集；其中静电纺丝环境温度为25℃，湿度为30-40％。
10.根据权利要求1所述的一种pH敏感性同轴聚乳酸己内酯PLCL/明胶双载药纤维支架的制备方法，其特征在于：所述步骤(3)中搅拌溶解的温度为25℃，搅拌时间为24-36h；干燥是在真空干燥箱中进行，温度为25℃，干燥时间为12-24h。
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