CN114831926B - 一种双层微针阵列及其制备方法 - Google Patents
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Abstract
本发明涉及一种双层微针阵列及其制备方法，利用聚乙二醇二丙烯酸酯（PEGDA）分子量不同导致的水溶性差异，制备层高比例可控的双层微针阵列。本发明提供的制备方法具有操作简单、通用性强、便于大规模生产等优点，制备的微针阵列可以同时加载亲疏水性药物，并且避免了传统双层微针制备过程中聚二甲基硅氧烷模板部分孔洞未填充的问题。对于疾病治疗、创面修复、组织再生等生物医学领域具有潜在的应用前景及现实意义。
Description
技术领域
本发明涉及生物医学材料领域，具体涉及一种双层微针阵列及其制备方法。
背景技术
透皮给药系统是指药物通过皮肤的给药途径，实现局部或全身治疗，1981年获准临床使用,是继口服和注射后的第三大给药系统。透皮给药可以减少血药浓度的波动和毒副作用，并且提高患者的依从性。而且，透皮给药可以避免肝脏的首过效应和胃肠道代谢。然而，角质层作为小分子药物和生物大分子经皮转运的主要屏障，降低了透皮给药系统的渗透性和生物利用度，从而导致治疗效果下降。由于角质层屏障的存在，用于临床的透皮给药系统通常限于分子量<500 Da的亲脂性药物。
微针是一种微创装置，由高度约为50-900 μm的微米大小的针阵列组成。其可以穿透角质层并在皮肤中产生机械微通道，从而显着提高透皮给药系统的递送效率,并且不会刺激神经末梢而产生疼痛。在过去的二十年中，已经开发了各种类型的微针系统，包括固体微针，药物涂层微针，聚合物载药微针和中空载药微针。其中，聚合物载药微针因其良好的生物相容性，优异的生物降解性和足够的载药量而受到广泛关注。与可重复使用的不锈钢固体微针或空心微针相比，用可生物降解的聚合物制造的聚合物微针避免了有害的尖锐医疗废物的产生。与涂层微针相比，聚合物微针可以将药物分子封装到整个微针中，可以极大地提高微针的载药量。迄今为止，微针递送系统已广泛用于癌症治疗、疾病诊断、糖尿病治疗、以及抗炎和镇痛治疗等领域。
发明内容
本发明提供一种具有双层结构的微针阵列，通过利用聚乙二醇二丙烯酸酯（PEGDA）分子量不同导致的水溶性差异制备得到，操作简单、通用性强、便于大规模生产，制备的微针阵列可以同时加载亲疏水性药物，并且避免了传统双层微针制备过程中聚二甲基硅氧烷模板部分孔洞未填充的问题。
本发明的技术方案具体如下：
一种双层微针阵列及其制备方法，其特征在于：包括以下步骤：
（1） 首先配置含有数均分子量为250的聚乙二醇二丙烯酸酯PEGDA250、光引发剂和乙醇的微针原材料溶液A，所述的PEGDA250的体积分数为25%-99%，所述的光引发剂为2-羟基-2-甲基苯丙酮，所述的光引发剂在微针原材料溶液A中的体积分数为0.5%-1%，所述的药物1的质量分数为0%-10%；配制含有数均分子量为700的聚乙二醇二丙烯酸酯PEGDA700、光引发剂和水的微针原材料溶液B，所述的PEGDA700的体积分数为40%-60%，所述的光引发剂为2-羟基-2-甲基苯丙酮，所述的光引发剂在微针原材料溶液B的体积分数为0.5%-1%，所述的药物1的质量分数为0%-10%；
（2） 通过真空的方法将微针原材料溶液A填充到具有微米级孔洞的聚二甲基硅氧烷模板表面，吸走孔洞外周多余的微针原材料溶液A后，通过高温50℃下同时真空处理10min到20 min以充分挥发乙醇，使模板孔洞形成半填充状态；
（3） 接着向所述步骤（2）的具有微米级孔洞的聚二甲基硅氧烷模板表面继续填充微针原材料溶液B，通过真空的方法将微针原材料溶液B填充到模板孔洞中，并完全覆盖在微针原材料溶液A的上层，由于两种聚乙二醇二丙烯酸酯PEGDA存在水溶性差异，因此会形成分层现象，然后利用紫外照射固化两种原材料溶液；最后，进行模板脱离，即可得到双层微针阵列。
进一步地，所述聚二甲基硅氧烷模板的孔洞阵列的为倒四棱锥形。
进一步地，微针针尖的半径为100-400 μm，长度为400-1000 μm，相邻微针的间距为100-800 μm。
进一步地，所述步骤（3）的双层微针阵列的尖端由两部分组成，通过微针原材料溶液A和微针原材料溶液B固化后形成，两部分长度比例范围为1:2至1:1，长度比例由微针原材料溶液A中的乙醇溶液的质量分数决定。
进一步地，所述步骤（2）中微针原材料溶液A填充，包含以下步骤：微针原材料溶液A通过真空处理3 min到10 min以充分填充在聚二甲基硅氧烷模板孔洞中；所述步骤（3）中微针原材料溶液B填充，包含以下步骤：微针原材料溶液B通过真空处理5 min到15 min填充聚二甲基硅氧烷模板孔洞。
进一步地，所述步骤（3）的紫外固化的紫外照射时间为20 s到2 min，光照强度为17 mW·cm-2。
本发明主要优点有：
（1）首次利用PEGDA分子量不同导致的水溶性差异制备层高比例可控的双层微针；
（2）制备的双层微针阵列可以同时加载亲疏水性药物，并且可以通过调节针尖原材料溶液中的有机相质量分数来调控药物在微针的大体位置；
（3）传统光聚合双层微针的制备需要精准控制针尖原材料溶液的使用量，易导致聚二甲基硅氧烷模板的一些孔洞因针尖原材料溶液太少而没有得到填充。本发明可以通过调节针尖原材料溶液中的乙醇溶液的质量分数控制针尖载药量及针尖高度，因此在真空法填充模板的过程中，可以增加针尖原材料溶液的使用量，避免了聚二甲基硅氧烷模板部分孔洞未填充的问题。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚，本发明提供如下附图：
图1 双层微针阵列的制备过程流程图。
图2 为本发明实施例3的含有两种不同数均分子量的PEGDA的混合水溶液的分层照片。
图3 为本发明实施例1的尖端负载香豆素6和藻蓝素的层高比例为1:2的双层微针阵列的显微镜图。
图4 为本发明实施例1的尖端负载香豆素6和藻蓝素的层高比例为1:2的双层微针阵列的实物图。
图5 本发明实施例2的尖端负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列的显微镜图。
图6 本发明的实施例2的尖端负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列的实物图。
图7 本发明的实施例2的尖端负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列的荧光照片。
具体实施方式
以下结合具体实施例对上述方案做进一步说明。应理解，这些实施例是用于说明本发明而不限于限制本发明的范围。凡根据本发明精神实质所做的等效变换或修饰，都应涵盖在本发明的保护范围之内。实施例中未注明的实施条件通常为常规实验中的条件。
实施例1
双层微针阵列的制备过程流程图如图1所示。
一种尖端负载香豆素6和藻蓝素的层高比例为1:2的双层微针阵列，其制备包括如下步骤：
S1.配置载药微针原材料溶液A1：配置含有PEGDA250、2-羟基-2-甲基苯丙酮、香豆素6和乙醇的混合溶液，所述的PEGDA250的体积分数为25%，所述的2-羟基-2-甲基苯丙酮的体积分数为1%，所述的香豆素6的质量分数为0.2%；
S2.用移液枪将500 μl载药微针原材料溶液A1滴加在具有微米级孔洞的聚二甲基硅氧烷模板表面，真空处理5 min，使其充分填充在聚二甲基硅氧烷模板孔洞中；然后用移液枪吸走微米级孔洞外周的的多余的载药微针原材料溶液A1后，通过高温50℃下同时真空处理10 min以充分挥发聚二甲基硅氧烷模板孔洞中的乙醇；
S3.配置载药微针原材料溶液B：配置含有PEGDA700、2-羟基-2-甲基苯丙酮、藻蓝素和水的混合溶液，所述的PEGDA700的体积分数为50%，所述的2-羟基-2-甲基苯丙酮的体积分数为1%，所述的藻蓝素的质量分数为1%；
S4.用移液枪将500 μl载药微针原材料溶液B滴加在上述的聚二甲基硅氧烷模板表面，真空处理10 min，使其充分填充在聚二甲基硅氧烷模板孔洞中，并完全覆盖在载药微针原材料溶液A1溶液上层；
S5.紫外照射1 min，使聚二甲基硅氧烷模板孔洞内的载药微针原料液A1及载药微针原材料溶液B固化，得到负载香豆素6和藻蓝素的层高比例为1:2的双层微针阵列，如图3和图4所示。
实施例2
一种尖端负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列，其制备包括如下步骤：
S1.配置载药微针原材料溶液A2：配置含有PEGDA250、2-羟基-2-甲基苯丙酮、香豆素6和乙醇的混合溶液，所述的PEGDA250的体积分数为98%，所述的2-羟基-2-甲基苯丙酮的体积分数为1%，所述的香豆素6的质量分数为0.3%；
S2.用移液枪将500 μl载药微针原材料溶液A2滴加在具有微米级孔洞的聚二甲基硅氧烷模板表面，真空处理8 min，使其充分填充在聚二甲基硅氧烷模板孔洞中；然后用移液枪吸走微米级孔洞外周的的多余的载药微针原材料溶液A2，通过高温50℃下同时真空处理10 min以充分挥发聚二甲基硅氧烷模板孔洞中的乙醇；
S3.配置载药微针原材料溶液B：配置含有PEGDA700、2-羟基-2-甲基苯丙酮、藻蓝素和水的混合溶液，所述的PEGDA700的体积分数为50%，所述的2-羟基-2-甲基苯丙酮的体积分数为1%，所述的藻蓝素的质量分数为1%；
S4.用移液枪将500 μl载药微针原材料溶液B滴加在上述的聚二甲基硅氧烷模板表面，真空处理12 min，使其充分填充在聚二甲基硅氧烷模板孔洞中，并完全覆盖在载药微针原材料溶液A2溶液上层；
S5.紫外照射1 min，使聚二甲基硅氧烷模板孔洞内的载药微针原料液A2及载药微针原材料溶液B固化，得到负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列，如图5和图6所示。
实施例3
含有两种不同数均分子量的PEGDA的混合水溶液分层验证：
为了验证本发明的双层微针阵列是利用PEGDA分子量不同导致的水溶性差异制备得到，我们配制了含有不同体积分数的PEGDA250和PEGDA700的水溶液并观察其分层现象。首先，配制含有0.5 mg/ml的姜黄素的PEGDA250溶液300 ul；然后，配制含有体积分数为50%的PEGDA700的水溶液300 ul，并向其中混合0.5 mg/ml的亚甲蓝；将上述两种溶液混合均匀，并超声处理3 min后于室温环境下静置5 min，观察其分层现象，结果如图2所示。由图2可见，混合溶液的上层为绿色，是由于PEGDA700溶解了部分姜黄素导致的颜色重叠。负载姜黄素的PEGDA250溶液与负载亚甲蓝的PEGDA700的水溶液明显分层，说明本发明制备的双层微针阵列的分层原因是由于PEGDA250具有疏水性。
实施例4
本发明制备的双层微针阵列的载药性验证：
为了验证本发明制备的双层微针阵列可以有效地负载亲疏水性药物，我们将实施例2的尖端负载香豆素6和藻蓝素的层高比例为1:1的双层微针阵列置于紫外光下观察，结果如图7所示。由图7可见，制备的双层微针显示出两种不同的较强的荧光（香豆素6显示绿色荧光，藻蓝素显示红色荧光），说明本申请的双层微针阵列可同时负载亲疏水性药物并保存其荧光性质。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其做出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.一种双层微针阵列的制备方法，其特征在于：包括以下步骤：
（1） 首先配置含有数均分子量为250的聚乙二醇二丙烯酸酯PEGDA250、光引发剂、药物1和乙醇的微针原材料溶液A，所述的PEGDA250的体积分数为25%-99%，所述的光引发剂为2-羟基-2-甲基苯丙酮，所述的光引发剂在微针原材料溶液A中的体积分数为0.5%-1%，所述的药物1的质量分数为0%-10%；配制含有数均分子量为700的聚乙二醇二丙烯酸酯PEGDA700、光引发剂、药物2和水的微针原材料溶液B，所述的PEGDA700的体积分数为40%-60%，所述的光引发剂为2-羟基-2-甲基苯丙酮，所述的光引发剂在微针原材料溶液B的体积分数为0.5%-1%，所述的药物2的质量分数为0%-10%；
（2） 通过真空的方法将微针原材料溶液A填充到具有微米级孔洞的聚二甲基硅氧烷模板表面，吸走孔洞外周多余的微针原材料溶液A后，通过高温50℃下同时真空处理10 min到20 min以充分挥发乙醇，使模板孔洞形成半填充状态；
（3） 接着向所述步骤（2）的具有微米级孔洞的聚二甲基硅氧烷模板表面继续填充微针原材料溶液B，通过真空的方法将微针原材料溶液B填充到模板孔洞中，并完全覆盖在微针原材料溶液A的上层，由于两种聚乙二醇二丙烯酸酯PEGDA存在水溶性差异，因此会形成分层现象，然后利用紫外照射固化两种原材料溶液；最后，进行模板脱离，即可得到双层微针阵列；所述的双层微针阵列的针尖半径为100-400 μm，长度为400-1000 μm，相邻微针的间距为100-800 μm；所述步骤（3）的双层微针阵列的尖端由两部分组成，通过微针原材料溶液A和微针原材料溶液B固化后形成，两部分长度比例范围为1:2至1:1。
2.根据权利要求1所述的双层微针阵列的制备方法，其特征在于：所述的具有微米级孔洞的聚二甲基硅氧烷模板的孔洞为孔洞阵列，并且形状为倒四棱锥形。
3. 根据权利要求1所述的双层微针阵列的制备方法，其特征在于：所述步骤（2）中微针原材料溶液A填充，包含以下步骤：微针原材料溶液A通过真空处理3 min到10 min以充分填充在聚二甲基硅氧烷模板孔洞中；所述步骤（3）中微针原材料溶液B填充，包含以下步骤：微针原材料溶液B通过真空处理5 min到15 min填充聚二甲基硅氧烷模板孔洞。
4. 根据权利要求1所述的双层微针阵列，其特征在于：所述步骤（3）的紫外固化的紫外照射时间为20 s到2 min，光照强度为17 mW·cm-2。
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