CN116637064A - 一种用于大量负载且快速透皮递送蛋白质类药物的凝胶微针阵列及其制备方法 - Google Patents
一种用于大量负载且快速透皮递送蛋白质类药物的凝胶微针阵列及其制备方法 Download PDFInfo
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- A61M2037/0053—Methods for producing microneedles
Abstract
本发明公开了一种大量负载并快速透皮递送蛋白质类药物的凝胶微针阵列及其制备方法，该方法利用利用蛋白质类药物在不同pH环境下的净电荷性质差异，以低pH下大量吸附‑生理环境下快速释放的模式透皮递送蛋白，实现药物蛋白的高效、快速的透皮递送。在该微针阵列插入皮肤后，释放蛋白质类药物。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种可大量负载且快速透皮递送蛋白质类药物的凝胶微针阵列及其制备方法。
背景技术
近年来，越来越多的蛋白与多肽类药物被应用到临床治疗上。但蛋白质在胃肠道内极易被降解且难以被吸收，广泛应用的皮下或静脉注射需要经过严格培训，且会引发明显疼痛，特别是对于需要频繁给药的药物。研究人员开发了多种简便无痛的给药方式，如吸入给药、黏膜给药、以及透皮递送等。其中，微针透皮递送技术由于其无痛微创、操作便利等特点，有望成为注射给药的良好替代。微针是一系列微米级的针头，长度一般为200-4000μm，可以以微创方式刺入皮肤，不会引起明显痛觉与不可逆损伤，同时在皮肤表面形成微米级孔道，允许蛋白质类药物进入位于皮肤内层的皮肤微循环。微针不会接触真皮深层的血管和神经，是无痛微创的，且使用方便简单。
基于不同的药物递送策略，微针通常可分为五类，包括固体、空心、涂层、溶解和可溶胀微针。固体微针难以控制给药量，且使用不便；空心微针制造复杂，疼痛感明显；涂层微针的涂层可能发生脱落，给药效果不好控制；可溶解微针机械强度与溶解时间难以兼顾，且容易吸潮。目前，已报道的用于蛋白药物透皮传递的微针系统，是通过将蛋白药物混溶于微针聚合物基质中，或是涂覆在微针表面，其普遍具有载药量低、药物活性难以保留、给药速度慢等缺陷。可溶胀微针生物安全性好，制备简单，不溶且高度亲水，可大量吸水溶胀，但仅依靠水凝胶本身的溶胀性能进行载药和释放太过缓慢。因此，开发出一种同时满足制备简单、载药量大、高效快速给药、生物安全性好等要求的微针给药载体依然是一个需要解决的难题。
发明内容
本发明公开了一种快速透皮递送蛋白质类药物的微针阵列及其制备方法。本发明利用蛋白质在不同pH环境下的净电荷性质差异及其与聚阴离子聚合物之间的静电作用，在低pH蛋白质溶液中，空白凝胶微针通过静电吸引大量吸附蛋白质药物。本发明所公开的快速透皮递送蛋白质类药物的微针阵列在生理环境下时，负载的蛋白质药物的净电荷电性发生变化，与微针产生静电排斥，快速释放蛋白，实现药物蛋白的高效、快速的透皮递送。
本发明的技术方案：
本发明提供了一种微针阵列，其结构包括凝胶微针基质与所负载的蛋白质药物，其特征在于，蛋白质药物通过静电相互作用在低pH下被微针基质凝胶大量吸附，生理环境下快速释放，具有pH敏感性。
优选地，所述微针阵列的针体长度为200-2000微米。
优选地，所述微针阵列基底的材料为阴离子聚合物交联成的凝胶网络。
优选地，所述阴离子聚合物包括羧甲基纤维素、透明质酸、硫酸软骨素、肝素、聚谷氨酸、甲基丙烯酸透明质酸或海藻酸。
优选地，所述交联剂包括柠檬酸、丙烯酸酐、戊二醛、京尼平、或甲基丙烯酸酐。
优选地，所述蛋白质类药物的等电点低于7.0。
优选地，所述蛋白质类药物包括胰岛素及其类似物、胰高血糖素样肽1及其类似物、肿瘤坏死因子、凝血因子、干扰素α2b、L-天冬酰胺酶、白介素-1β、葡糖苷酶、人粒细胞集落刺激因子(G-CSF)、胶原蛋白、生长激素、表皮生长因子、角蛋白、白蛋白。
本发明还提供了一种微针阵列的制备方法，将阴离子聚合物与交联剂混合溶液反复多次加入模具干燥，交联固化得到空白微针。其特征在于，将空白微针阵列浸泡在低pH蛋白质药物溶液中并最终干燥，使微针内大量负载蛋白质药物，蛋白质药物与聚阴离子聚合物通过静电相互作用形成，将载药微针置于生理环境下时，微针内负载的蛋白质药物净电荷电性发生反转，蛋白质药物与聚阴离子聚合物通过静电排斥作用快速释放，具有pH敏感性。
优选地，所述聚阴离子聚合物的浓度为0.5-50％。
优选地，所述交联剂的浓度为0-50％。
优选地，所述干燥的温度为1-80℃，干燥时间为1小时-24小时。
优选地，所述蛋白质类药物溶液pH应低于蛋白质类药物的等电点，此溶液pH下所述蛋白质的净电荷的电性为正。
优选地，所述蛋白质类药物的溶液浓度应为1ug/ml-1g/ml。
本发明具有如下的有益效果：
根据本发明制备的微针阵列利用了蛋白质药物在等电点两侧所具有净电荷的差异，实现了蛋白质药物在微针上的大量负载与快速透皮递送。
附图说明
通过阅读以下附图，本发明的原理、特征和优点将会变得更明显：
图1.根据本发明制备的微针阵列透皮递送蛋白质类药物的示意图。在酸性环境下，净电荷为正的蛋白质类药物与净电荷为负的阴离子聚合物通过静电作用结合，被大量吸附进微针内部。负载了蛋白质类药物的微针阵列插入皮肤后，蛋白质类药物净电荷发生电性反转，与聚阴离子聚合物相互排斥，导致蛋白质类药物迅速释放到皮肤内。
图2A-2D.负载了蛋白质药物(胰岛素)的羧甲基纤维素凝胶微针与空白微针在扫描电镜观察下的形态差异。图2A，空白的羧甲基纤维素凝胶微针阵列20倍放大后的表面形态。图2B，负载胰岛素的羧甲基纤维素微针20倍放大后的表面形态。图2C，空白的羧甲基纤维素凝胶微针阵列500倍放大后的表面形态。图2D，负载胰岛素的羧甲基纤维素凝胶微针500倍放大后的表面形态。
图3.负载了荧光标记的Cy3-胰岛素的羧甲基纤维素凝胶微针阵列应用于小猪皮的荧光图像。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不应视为限定本发明的范围。
实施例1制备负载了胰岛素的羧甲基纤维素凝胶微针阵列
具体制备步骤为：将羧甲基纤维素和柠檬酸混合溶液滴加进微针模具中，并在3500rpm下离心3分钟，然后缓慢干燥，温度为35℃。在干燥过程中每隔1小时向模具中添加一次羧甲基纤维素和柠檬酸混合溶液，重复6-10次，使其干燥后能填满针腔。完全干燥后，取少量20％PVA溶液加入微针模具中，涂抹于干燥好的微针背面。将亲水改性的聚甲基丙烯酸甲酯片放入模具中，轻压使PVA溶液透过网格空隙，去除气泡并将聚甲基丙烯酸甲酯片与微针粘连。干燥完全后将微针从模具中取出，将其置于110℃烘箱中5分钟，使水凝胶网络交联。取出后冷却至室温，即得空白凝胶微针。将胰岛素溶于盐酸缓冲溶液(pH＝2)中，浓度为1mg/mL。将空白凝胶微针浸泡在pH 2的胰岛素溶液中10分钟，室温干燥。
实施例2制备负载了生长激素的甲基丙烯酸透明质酸凝胶微针阵列
具体制备步骤为：将2.0g透明质酸溶解于100ml去离子水中，充分搅拌均匀。随后，将溶液置于4℃环境中，向溶液中滴入66ml DMF和2.4ml甲基丙烯酸酐，搅拌均匀。向溶液添加1M NaOH将其pH控制在8-9之间，并置于4℃环境下持续搅拌12小时。然后向溶液中添加4.94g氯化钠，加入100％乙醇使甲基丙烯酸透明质酸沉淀。将沉淀用乙醇洗涤沉淀物三次，沉淀溶于去离子水后用去离子水透析三天，最后将透析后的溶液冷冻干燥获得甲基丙烯酸透明质酸。将1g甲基丙烯酸透明质酸和0.01g光引发剂(Irgacure 2959)溶于20mL离子水中，搅拌均匀。然后将溶液浇铸到微针模具中，并在3500rpm下离心3分钟，然后干燥24h。完全干燥后，甲基丙烯酸透明质酸微针贴片从模具中取出，置于紫外线下(波长为360nm，强度＝20.0mW cm-2)交联时间5分钟，得到甲基丙烯酸透明质酸凝胶微针。将空白凝胶微针浸泡在pH 2的生长激素溶液中10分钟，室温干燥。
实施例3负载了胰岛素的羧甲基纤维素凝胶微针阵列
采用实施例2相同的方法，制备负载了胰岛素的羧甲基纤维素凝胶微针阵列。将微针阵列表面干燥后喷金进行扫描电镜观察，可见如图2所示的微针阵列表面形态，空白微针阵列排列整齐，针尖明显，针尖无损伤，形态良好，其微针表面较为光滑。在酸性溶液下载药干燥后，凝胶微针的针头两侧轻微鼓起，并且部分针尖部分有些许裂纹，但这几乎不影响微针的机械强度。并且，载药微针表面由于溶胀以及载药相比于空白微针较为粗糙。
实施例4负载了胰岛素的微针阵列体外透皮递送胰岛素
将负载了Cy3-胰岛素的羧甲基纤维素凝胶微针施加到猪皮肤的表面，并持续按压5分钟，然后立刻将凝胶微针从猪皮肤上移除。使用手术刀将凝胶微针作用的猪皮肤区域切下，并将其迅速地浸泡在OCT包埋剂中，然后置于液氮内冷冻，并使用冷冻切片机将其切割成10μm厚的猪皮肤切片，使用金相显微镜对样品观察微针插入以及胰岛素递送情况。如图3所示，红色荧光表明胰岛素很快从微针中释放到皮肤中且向皮内渗透。
本发明具体应用途径很多，以上所述仅是本发明的优选实施方式。应当指出的是，以上实施例仅用于说明本发明，而并不用于限制本发明的保护范围。对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
Claims (10)
1.一种微针阵列，其结构包括凝胶微针基质与所负载的蛋白质药物，其特征在于，蛋白质药物通过静电相互作用在低pH下被微针基质凝胶大量吸附，生理环境下快速释放，具有pH敏感性。
2.根据权利要求1所述的微针阵列，其中所述微针阵列基底的材料为阴离子聚合物交联成的凝胶网络。
3.根据权利要求1或权利要求2所述的微针阵列，其中所述阴离子聚合物包括羧甲基纤维素、透明质酸、硫酸软骨素、肝素、聚谷氨酸、甲基丙烯酸透明质酸或海藻酸。
4.根据权利要求1或权利要求2所述的微针阵列，其中所述交联剂包括柠檬酸、丙烯酸酐、戊二醛、京尼平、或甲基丙烯酸酐。
5.根据权利要求1所述的微针阵列，其中所述蛋白质药物的等电点低于7.0。
6.根据权利要求5所述的微针阵列，其中所述蛋白质药物包括胰岛素及其类似物、胰高血糖素样肽1及其类似物、肿瘤坏死因子、凝血因子、干扰素α2b、L-天冬酰胺酶、白介素-1β、葡糖苷酶、人粒细胞集落刺激因子(G-CSF)、胶原蛋白、生长激素、表皮生长因子、角蛋白、白蛋白。
7.如权利要求1所述的微针阵列的制备方法，将阴离子聚合物与交联剂混合溶液反复多次加入模具干燥，交联固化得到空白微针。其特征在于，将空白微针阵列浸泡在低pH蛋白质药物溶液中并最终干燥，使微针内大量负载蛋白质药物，蛋白质药物与阴离子聚合物通过静电相互作用形成，将载药微针置于生理环境下时，微针内负载的蛋白质药物净电荷电性发生反转，蛋白质药物与聚阴离子聚合物通过静电排斥作用快速释放，具有pH敏感性。
8.根据权利要求7所述的微针阵列的制备方法，其中所述蛋白质类药物溶液pH应低于蛋白质类药物的等电点，此溶液pH下所述蛋白质的净电荷的电性为正。
9.根据权利要求7所述的微针阵列的制备方法，其中所述蛋白质类药物的溶液浓度应为1ug/ml-1g/ml。
10.根据权利要求7所述的微针阵列的制备方法，其中所述浸泡的温度为1-37℃，浸泡时间为10分钟-10小时。
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