CN115414481B - 一种具有药物磁控脉冲释放功能的微球及其制备方法和应用 - Google Patents
一种具有药物磁控脉冲释放功能的微球及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种具有药物磁控脉冲释放功能的微球，所述微球由多个MnFe2O4纳米球堆积而成，在完全干燥下尺寸为100‑250nm。所得微球具有均一、稳定的尺寸，丰富、有序的介孔结构，不仅可实现较高的药物负载率，保证药物活性和稳定性，在交变磁场作用下，还具有灵敏的磁热升温效果，在一定的温度条件下，调控药物分子热运动，进而实现药物的脉冲释放，在生物医用材料领域具有良好的应用前景。
Description
技术领域
本发明涉及生物医用材料技术领域，具体涉及一种具有药物磁控释放功能的微球及其制备方法和应用。
背景技术
随着经济社会不断发展与生活节奏的加快，人类长期以来面临着各种疾病的困扰，即使科技不断发展进步，医疗水平逐渐提高完善，但药物治疗仍然是临床上常用、最基本的方法之一，但全身给药存在吸收慢，生物利用度低，易产生依赖性和耐药性，对肝脏、肾脏和消化系统产生毒副作用等弊端。因此，新型药物载体引起学者们的广泛关注，如脂质体、胶束、微球、纳米片等，具有减少药物损失，提高药物活性，渗透性强，可修饰加工等优点，但仍存在载药量有待提高、制备过程复杂、难以精准调控、治疗效果差等问题。
脉冲释药系统作为一种新兴的供药模式，可根据病人的临床需要定时、定量给药，减少患者的不良反应和耐药性(如辛伐他汀等药物由于自身作用机制等原因需特定时间给药)；亦可根据药物的具体作用特点和方式进行给药，进而提高治疗效果(如特立帕肽是FDA批准的唯一的促骨形成类骨质疏松治疗药物，但作用效果与其浓度和给药方式密切相关，只有低浓度或间歇高浓度给药才能促进成骨)。常用的脉冲给药系统包括：本体溶蚀、表面溶蚀、酶激活、渗透压、超声波等，但其时滞性及精准度差等问题仍有待解决。
发明内容
鉴于此，本发明的目的是提供一种具有药物磁控脉冲释放功能的微球及其制备方法和应用。所述的药物磁控脉冲释放功能的微球具有均一、稳定的尺寸，丰富、有序的介孔结构用以负载药物，在交变磁场作用下有良好的磁热响应性能并脉冲式释放药物。
本发明解决上述技术问题所采用的方案是：
一种具有药物磁控脉冲释放功能的微球，所述微球由多个MnFe2O4纳米球堆积而成，在完全干燥下尺寸为100-250nm。
本发明还提供上述具有药物磁控脉冲释放功能的微球的制备方法，包括如下步骤：
1)将六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、表面活性剂加入去离子水中搅拌至完全溶解；
2)在160-240℃下水热反应8-12h；
3)将水热反应产物洗涤干燥后得MnFe2O4微球。
优选地，步骤1)所述六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠的质量比为1：(0.2-3)：(1-3)。
优选地，步骤1)所得混合溶液中，铁离子的浓度为0.03～0.1mmol/ml。
优选地，步骤1)所得混合溶液中，尿素浓度为0.01～0.125g/ml。
优选地，步骤1)所得混合溶液中，表面活性剂的浓度为0.0008～0.025g/ml。
优选地，所述表面活性剂为PEG3000、PEG6000中的任一种或几种。
本发明还提供上述微球的应用，用于负载药物，并通过其磁热响应性能实现药物的脉冲释放。
优选地，所述微球负载药物的方法包括：将药物配制成溶液，与MnFe2O4微球混合均匀，经载药处理并干燥后即得载药MnFe2O4微球。
优选地，用于配置药物溶液的分散溶剂任选自去离子水、PBS、生理盐水、乙醇、丙酮、DMSO、吐温80、甲醇、PEG、二甲亚砜。
优选地，所述载药处理方式任选自搅拌载药、真空灌注、电荷吸附、分散载药、蒸发载药。
优选地，用于负载的药物任选自特立帕肽、辛伐他汀、四环素、庆大霉素、阿霉素。
优选地，实现药物脉冲释放的方式包括向载药的MnFe2O4微球给予外磁场刺激，以实现药物的脉冲释放。
Fe3+在柠檬酸三钠还原作用下部分被还原为Fe2+，尿素分解释放NH3和CO2气体，NH3为反应体系提供碱性环境，生成Fe(OH)3和Fe(OH)2，它们进一步脱水生成Fe3O4初始晶粒，随反应时间延长，所形成的Fe3O4晶粒不断迁移、聚集，进而形成由多个纳米微球颗粒堆积而成的微球结构，在这一过程，由于Mn2+的离子半径接近于Fe2+，因此Mn2+可以很容易地进入晶格并取代Fe2+，且Mn2+可以和生成的MnFe2O4微球表面的羟基自由基发生络合反应，为进一步形成MnFe2O4微球提供基础。
本发明提供了一种具有药物磁控脉冲释放功能的MnFe2O4微球，制备过程简单，应用范围广，实用性强。所得微球具有均一、稳定的尺寸，丰富、有序的介孔结构，药物负载率可达35％-45％，包封率可达80％-95％。不仅可实现较高的药物负载率，保证药物活性和稳定性，在交变磁场作用下，还具有灵敏的磁热升温效果，在一定的温度条件下，调控药物分子热运动，进而实现药物的脉冲释放，在生物医用材料领域具有良好的应用前景。
附图说明
图1为实施例1所得MnFe2O4微球的SEM图。
图2为实施例1所得MnFe2O4微球的氮气吸附-脱氢曲线。
图3为实施例1所得载药MnFe2O4微球的磁热升温曲线。
图4为实施例1所得载药MnFe2O4微球的脉冲释药曲线。
图5为实施例2所得MnFe2O4微球的XRD图。
图6为对比例1所得MnFe2O4微球的XRD图。
具体实施方式
为更好的理解本发明，下面的实施例是对本发明的进一步说明，但本发明的内容不仅仅局限于下面的实施例。
实施例1
本实施例的制备过程包括：
1)将质量比为1：2：1：1.5：0.7的六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、PEG3000加入60ml去离子水中搅拌至完全溶解，在180℃下水热反应8h，洗涤干燥后得MnFe2O4微球，微球形貌如附图1所示，可见微球由多个纳米级球堆叠而成，球形度较好，尺寸均一，介孔明显。对所得微球进行全自动比表面及孔隙度分析测试(附图2)，得知比表面积为49.35m2/g，孔径主要分布在18-25nm，孔体积为0.22cm3/g，较大的比表面积及良好的介孔结构有利于实现药物负载及控释。
2)将特立帕肽药物溶于PBS配成溶液，与步骤1)制备的MnFe2O4微球按1：100质量比混合均匀，经真空灌注、干燥处理后即得载药MnFe2O4微球。
3)将步骤2)制得的载药MnFe2O4微球施加2mT的正弦交变磁场，测得微球随磁场的升温曲线如附图3所示，从图中可知，微球有灵敏的磁热升温性能。同时检测药物在交变磁场下的释放效果，结果如图4所示，从图中可知，通过控制交变磁场开/关，可实现特立帕肽的磁控脉冲释放。
实施例2
本实施例的制备过程包括：
1)将质量比为1：0.5：1.5：2：1的六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、PEG3000加入40ml去离子水中搅拌至完全溶解，在180℃下水热反应8h，洗涤干燥后得MnFe2O4微球；对所得微球进行XRD检测，结果如图5所示，显示6个较明显的衍射峰，分别对应于MnFe2O4的(111)、(220)、(311)、(400)、(422)和(511)晶面，与MnFe2O4的标准卡片(JCPDS Card No.10-0319)吻合较好，说明产物纯度高，无其他杂质及副产物。对所得微球进行全自动比表面及孔隙度分析测试，得知比表面积为45.62m2/g，孔径主要分布在15-20nm，孔体积为0.19cm3/g。
2)将特立帕肽药物溶于PBS配成溶液，与步骤1)制备的MnFe2O4微球按1：100质量比混合均匀，经真空灌注、干燥处理后即得载药MnFe2O4微球。
3)将步骤2)制得的载药MnFe2O4微球给予2mT的正弦交变磁场刺激，发现其磁热升温温度低于实施例1(附图3)，其药物在交变磁场下的释放呈现与实施例1相同的磁控脉冲释放效果，药物释放浓度略低于实施例1。
实施例3
本实施例的制备过程包括：
1)将质量比为1：3：2：4：1的六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、PEG6000加入50ml去离子水中搅拌至完全溶解，在200℃下水热反应10h，洗涤干燥后得MnFe2O4微球。
2)将阿霉素药物溶于去离子水配成溶液，与步骤1)制备的MnFe2O4微球按1：50质量比混合均匀，经搅拌分散、干燥处理后即得载药MnFe2O4微球。
3)将步骤2)制得的载药MnFe2O4微球施加4mT的正弦交变磁场，观察到与实施例1相同的磁控脉冲释放效果。
实施例4
本实施例的制备过程包括：
1)将质量比为1：2.5：3：5：1的六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、PEG6000加入70ml去离子水中搅拌至完全溶解，在220℃下水热反应8h，洗涤干燥后得MnFe2O4微球。
2)将四环素药物溶于去离子水配成溶液，与步骤1)制备的MnFe2O4微球按1：200质量比混合均匀，经搅拌分散、干燥处理后即得载药MnFe2O4微球。
3)将步骤2)制得的载药MnFe2O4微球施加4mT的正弦交变磁场，观察到与实施例1相同的磁控脉冲释放效果。
对比例1
制备方法与实施例1相同，不同之处在于，步骤1)六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、PEG3000的质量比为1：2：0.7：1.5：0.7。
对所得微球进行XRD检测，结果如图6所示，除显示MnFe2O4的特征衍射峰以外，还发现新增2个明显的衍射峰，经与标准卡片对比发现其归属于碳酸锰的特征峰，说明产物纯度低，混有副产物碳酸锰。对所得微球施加与实施例1相同的交变磁场，磁热升温效果及灵敏性更差，特立帕肽的释放曲线难以呈现精准的磁控脉冲释放趋势。
以上所述是本发明的优选实施方式而已，当然不能以此来限定本发明之权利范围，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和变动，这些改进和变动也视为本发明的保护范围。
Claims (9)
1.一种具有药物磁控脉冲释放功能的微球的制备方法，其特征在于，所述微球由多个MnFe2O4纳米球堆积而成，在完全干燥下尺寸为100-250nm；所述微球的制备方法包括如下步骤：
1）将六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠、尿素、表面活性剂加入去离子水中搅拌至完全溶解；所得混合溶液中，铁离子的浓度为0.03~0.1 mmol/ml；尿素浓度为0.01~0.125g / ml；所述表面活性剂为PEG3000、PEG6000中的任一种或几种；
2）在160-240℃下水热反应8-12h；
3）将水热反应产物洗涤干燥后得MnFe2O4微球。
2.根据权利要求1所述的制备方法，其特征在于，步骤1）所述六水合氯化铁、四水合氯化锰、二水合柠檬酸三钠的质量比为1：（0.2-3）：（1-3）。
3. 根据权利要求1所述的制备方法，其特征在于，步骤1）所得混合溶液中，表面活性剂的浓度为0.0008~0.025 g/ ml。
4.根据权利要求1~3所述的制备方法所得微球的应用，其特征在于，用于负载药物，并通过其磁热响应性能实现药物的脉冲释放。
5.根据权利要求4所述的应用，其特征在于，负载药物的方法包括：将药物配制成溶液，与MnFe2O4微球混合均匀，经载药处理并干燥后即得载药MnFe2O4微球。
6.根据权利要求5所述的应用，其特征在于，用于配置药物溶液的分散溶剂任选自去离子水、PBS、生理盐水、乙醇、丙酮、DMSO、吐温80、甲醇、PEG、二甲亚砜。
7.根据权利要求5所述的应用，其特征在于，所述载药处理方式任选自搅拌载药、真空灌注、电荷吸附、分散载药、蒸发载药。
8.根据权利要求4所述的应用，其特征在于，用于负载的药物任选自特立帕肽、辛伐他汀、四环素、庆大霉素、阿霉素。
9.根据权利要求4所述的应用，其特征在于，实现药物脉冲释放的方式包括向载药的MnFe2O4微球给予外磁场刺激，以实现药物的脉冲释放。
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