CN116747318A - 一种药物共递送可降解多孔微球及其制备方法和应用 - Google Patents
一种药物共递送可降解多孔微球及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种药物共递送可降解多孔微球及其制备方法和应用。该方法包括以下步骤：将药物分子和无机纳米颗粒重悬并均匀分散于含有可降解聚合物的挥发性有机溶剂中，添加致孔剂后使用复乳‑溶剂挥发法，得到聚合物微球；使用碱溶液处理所述聚合物微球，以去除微球固化过程中外表层形成的连续膜层并同时刻蚀微球内部的多孔结构，从而得到负载药物分子且无机纳米颗粒镶嵌并部分暴露于孔洞骨架的药物共递送可降解多孔微球。由此获得的药物分子和无机纳米颗粒共递送系统能够克服传统药物递送方法的局限和阻碍，为实现多因素、多药物协同治疗提供可能。
Description
技术领域
本发明涉及生物医用材料技术领域，具体涉及一种药物共递送可降解多孔微球及其制备方法和应用。
背景技术
药物制剂需要解决的主要问题是增强药物对疾病的治疗作用并减少其副作用，也即将药物输送到病灶部位增加药物的疗效，并且避免药物的全身分布以减少其对正常组织的损害。因此开发载药量高、安全可控的药物递送系统具有重要的研究意义和临床应用价值。
近年来，以可降解聚合物材料为基材，负载药物后制备成微球分散体系，用作药物缓释、控释的研究日益增多。可降解聚合物材料在体内生物环境中通过水解、氧化、酶解等反应逐步降解，在释放出负载药物的同时生成对机体无毒无害的小分子降解产物并被代谢出体外，因此相较于非降解材料具有更好的生物相容性和生物安全性。使用可降解聚合物材料制备的微球药物递送系统，粒径一般在1～500μm之间，其尺寸高度可控，易于大规模合成和修饰。将药物包载在微球中，可保证药物在从微球内释放出来之前不受体内酶解、胃酸等生物环境的影响，从而显著提高药物的生物利用度。另外，还可以通过改变可降解聚合物材料的黏度及分子量等参数，灵活地控制载药微球的降解速度，以调节所包埋药物的释放速率，从而可以在病灶局部长期维持有效的药物浓度，达到提高药物靶向性、延缓或控制药物释放、减少给药频率、降低药物毒性等目的。载药微球可供注射、口服、滴鼻、皮下埋植或关节腔给药使用。另外对载药微球表面进行特异性修饰能使微球具有主动靶向性，精准定位到病灶区域或改变释放行为。由于微球药物递送系统良好的缓释能力以及主动靶向性，目前主要用于需要长时间频繁给药的适应症，比如肿瘤、帕金森病、镇痛、糖尿病、子宫内膜异位症、骨关节炎相关膝盖疼痛、牙周炎等。
发明内容
为解决上述技术问题，本发明提供一种药物共递送可降解多孔微球及其制备方法和应用。
为实现上述目的，本发明采用的技术方案如下：
本发明第一方面提供一种药物共递送可降解多孔微球的制备方法，该方法包括以下步骤：将药物分子和无机纳米颗粒重悬并均匀分散于含有可降解聚合物的挥发性有机溶剂中，添加致孔剂后使用复乳-溶剂挥发法，得到聚合物微球；使用碱溶液处理所述聚合物微球，以去除微球固化过程中外表层形成的连续膜层并同时刻蚀微球内部的多孔结构，从而得到负载药物分子且无机纳米颗粒镶嵌并部分暴露于孔洞骨架的药物共递送可降解多孔微球。
进一步的，所述药物分子包括消炎药、抗骨质疏松药、降糖药中的一种或多种；其中，消炎药包括地塞米松、阿司匹林；抗骨质疏松药包括阿仑膦酸钠；降糖药包括二甲双胍。
进一步的，所述无机纳米颗粒包括金属或合金纳米颗粒、氧化物纳米颗粒、无机盐纳米颗粒中的一种或多种；其中，金属或合金纳米颗粒包括金纳米颗粒；氧化物纳米颗粒包括SiO2、TiO2、ZnO、Fe2O3纳米颗粒；无机盐纳米颗粒包括CaCO3纳米颗粒。
进一步的，所述可降解聚合物包括聚己内酯(Polycaprolactone，PCL)、聚乙醇酸(Polyglycolicacid，PGA)、聚乳酸(Polylacticacid，PLA)、聚乳酸-羟基乙酸共聚物(Poly(lactic-co-glycolicacid)，PLGA)、聚三亚甲基碳酸酯(Poly(trimethylenecarbonate)，PTMC)、聚3-羟基丁酸酯(Poly(3-hydroxybutyrate)，PHB)中的一种或多种。
进一步的，所述挥发性的有机溶剂包括二氯甲烷、三氯甲烷、二甲基甲酰胺、二甲苯、四氢呋喃、乙酸乙酯中的一种或多种。
进一步的，该方法具体包括以下步骤：将聚乳酸-羟基乙酸共聚物溶解于二氯甲烷(Dichloromethane，DCM)中，得到二氯甲烷溶液；将药物分子和无机纳米颗粒添加至所述二氯甲烷溶液中，水浴超声处理至分散均匀，得到油相的二氯甲烷混合溶液；取所述二氯甲烷混合溶液添加体积比为20％至50％的浓度为0.05wt％的碳酸氢铵水溶液，进行乳化处理，形成初乳；将所述初乳逐滴添加入搅拌状态下的1wt％的聚乙烯醇的水溶液中，室温搅拌至所述二氯甲烷挥发完全，即可得到聚合物微球；将所述聚合物微球加入碱溶液中进行处理后，得到所述药物共递送可降解多孔微球。
进一步的，在将所述聚合物微球加入碱溶液中进行处理的步骤中，包括：将所述聚合物微球加入含有0.1M～0.5M的NaOH的水溶液中处理3～10分钟。需要说明的是，其中，NaOH的浓度越高，处理时间越长，则刻蚀效果更强。所以刻蚀以消除微球表面形成的连续膜层和部分刻蚀微球骨架，同时不损害微球整体构型为目标。
本发明第二方面提供根据上述的药物共递送可降解多孔微球的制备方法所制得的药物共递送可降解多孔微球。
本发明第三方面提供如上述的药物共递送可降解多孔微球在药物制剂领域中的应用。
本发明第四方面提供如上述的药物共递送可降解多孔微球在注射、口服、滴鼻、皮下埋植或关节腔给药领域中的应用。
与现有技术相比，本发明提供了一种同时负载药物分子和无机纳米颗粒的可降解多孔微球的制备方法。首先将药物分子和无机纳米颗粒分散于含有可降解聚合物的挥发性有机溶剂中，添加致孔剂以后进行乳化，进而通过复乳-溶解挥发法制备微球。在挥发性有机溶剂挥发完成后则得到固化的微球，随后使用碱溶液去除微球固化过程中表面形成的连续膜层并同时对微球内部孔洞结构进行部分刻蚀，从而得到同时负载药物分子和无机纳米颗粒的可降解多孔微球。通过控制微球制备过程药物分子和无机纳米颗粒的添加量，可以分别调控它们的释放趋势；通过控制复乳过程中的搅拌速度，可以调控微球的粒径；通过控制碱溶液的浓度以及处理的时间参数，可以调控微球的表面及内部的孔洞结构以及无机纳米颗粒的暴露程度，进而调控微球的降解趋势及释放趋势。
本发明提供了一种同时负载药物分子和无机纳米颗粒的可降解多孔微球的制备方法，具备以下优点：
1)本发明所制备的多孔微球同时负载药物分子和无机纳米颗粒；
2)本发明所制备的多孔微球内部孔道均匀分布，并且表面也呈多孔形态，从而增加微球内部与外界的物质交换效率；
3)本发明所制备的多孔微球中，无机纳米颗粒镶嵌于多孔结构骨架之中并部分暴露出来，有利于纳米颗粒物理特性的呈现；
4)本发明所述微球制备方法基于复乳-溶剂挥发法，工艺过程简单且成本低廉，易于实现大规模生产。
附图说明
图1是实施例1中所使用的SiO2纳米颗粒的扫描电子显微镜照片；
图2a是实施例3中所制备的PLGA微球的扫描电子显微镜照片(放大100)；
图2b是实施例3中所制备的PLGA微球的扫描电子显微镜照片(放大500)；
图2c是实施例3中所制备的PLGA微球的扫描电子显微镜照片(放大2000)；
图2d是实施例3中所制备的PLGA微球的扫描电子显微镜照片(放大5000)；
图3a是实施例4中所制备的PLGA微球的扫描电子显微镜照片(放大100)；
图3b是实施例4中所制备的PLGA微球的扫描电子显微镜照片(放大500)；
图3c是实施例4中所制备的PLGA微球的扫描电子显微镜照片(放大2000)；
图3d是实施例4中所制备的PLGA微球的扫描电子显微镜照片(放大5000)；
图3e是实施例4中所制备的PLGA微球内部的扫描电子显微镜照片(放大500)；
图3f是实施例4中所制备的PLGA微球内部的扫描电子显微镜照片(放大2000)；
图3g是实施例4中所制备的PLGA微球内部的扫描电子显微镜照片(放大5000)；
图3h是实施例4中所制备的PLGA微球内部的扫描电子显微镜照片(放大10000)；
图4是实施例5中，经不同处理的微球在磷酸盐缓冲液中孵育的过程中，所负载的药物分子地塞米松的释放趋势。
具体实施方式
发明人发现，药物分子通过静脉注射或者口服进入体内后药物全身分布，半衰期短，难以持续达到治疗的有效浓度，临床应用显示出有限的治疗效果和严重的副作用。为了克服这些障碍，人们开发了许多药物载体，如脂质体、水凝胶和微球颗粒等。与其他载体相比，基于可降解聚合物材料制备的微球药物递送系统具有许多优点，包括生物可降解性，生物相容性良好，高载药量和包封率等。更重要的是，包埋的药物通过聚合物基质的降解或侵蚀而释放，因此可以通过调整聚合物基质的降解行为来实现药物分子的可控、持续释放。聚合物微球的形状、尺寸和表面拓扑结构都对其生物学效应有着深远的影响。目前所使用的载药体系多为实心微球。相比之下多孔微球具有较大的比表面积，相互连接的内外部孔道结构可为药物的递送和传输提供便利，通过改变多孔微球的粒径及孔径的大小可有效调控药物的释放速率。
无机纳米颗粒是另外一种临床上已经得到广泛应用的药物制剂。无机纳米粒子具有比表面积大、表面易修饰、尺寸可调等特点。不但能够给药物分子和外源基因提供大量的吸附位点以实现药物和基因治疗的目的，还能被具有不同靶向功能的分子修饰，进而提高对肿瘤细胞的特异性识别和治疗。除此之外，无机纳米颗粒还具有光学及磁学等一系列优异的物理学性能，已被广泛用于癌症的化疗、基因治疗、光疗、磁热疗等领域。如金纳米粒子具有较高的光热转化效率，可在近红外激光的照射下进行肿瘤的光热消融；超顺磁性纳米氧化铁具有良好的磁学性能且生物相容性好，可以作为药物递送及癌症磁共振诊断中所使用的造影剂。
基于以上背景和现状，本发明提供一种能够同时负载药物分子和无机纳米颗粒的可降解多孔微球递送体系的制备方法。由此获得的药物分子和无机纳米颗粒共递送系统能够克服传统药物递送方法的局限和阻碍，为实现多因素、多药物协同治疗提供可能。
本发明提供了一种同时负载药物分子和无机纳米颗粒的可降解多孔微球的制备方法。该多孔微球具有均匀且相互连通的孔洞结构。多孔微球基质中负载了药物分子并且孔洞骨架中镶嵌着无机纳米颗粒，从而能够同时实现药物分子和无机纳米颗粒的可控递送和释放。该多孔微球递送系统载药量高，制备过程简单经济，适用于大批量生产。
下面结合具体实施方式对本发明进行详细说明。以下实施例中，选用甾体类消炎药地塞米松(Dexamethasone，DEX)作为药物分子，SiO2纳米颗粒作为无机纳米颗粒，将两种物质同时负载于可降解聚合物PLGA的多孔微球中，从而证明本发明所述方法的可行性。
实施例1
首先将PLGA溶解于挥发性有机溶剂DCM中，获得PLGA质量分数为5wt％的DCM溶液。取DEX和SiO2纳米颗粒添加于DCM溶液中，使DEX和SiO2相比于PLGA的质量分数分别为5％和0.5％，放入水浴中超声5分钟，使药物分子和SiO2纳米颗粒都能够均匀分散在DCM溶液中，得到DCM混合溶液。图1所示为所使用的SiO2纳米颗粒的扫描电子显微镜照片，可见SiO2纳米颗粒粒径分布均匀，直径在100nm左右。
实施例2
配制质量浓度为0.05wt％的碳酸氢铵水溶液为致孔剂。向5mL实施例1中的DCM混合溶液中加入1.5mL上述0.05wt％的碳酸氢铵水溶液，随后使用探头超声对其进行乳化。碳酸氢铵在超声波作用下，迅速分解为大量的NH3和CO2，小部分NH3和CO2溶于水，而剩余的大量气体则在超声波作用下，被油相隔离，从而得到大量乳白色的油包水(W/O)初乳液。
实施例3
使用聚乙烯醇(polyvinylalcohol，PVA)作为乳化剂，其分子链既有亲水部分又有疏水部分，能够在油水界面形成薄膜，从而保护油相液滴在磁力搅拌过程中更加稳定，使得所制备的微球成球性、分散性更好。称取5g的PVA溶解于500mL去离子水，将实施例2中得到的油包水初乳液逐滴滴加其中，滴加过程中保持磁力搅拌，得到水包油包水(W/O/W)复乳。室温搅拌4小时以上，溶液中的DCM完全挥发后，得到固化的PLGA微球。使用去离子水洗涤微球3次以上。
使用扫描电子显微镜观察微球的表面形貌。如图2a至图2d所示，所获得的PLGA微球虽然能看出来内部具有多孔结构，但是微球表面形成了一层连续的薄膜。
实施例4
对实施例3中所制备的微球进行碱蚀处理。将微球重悬于含有0.1M氢氧化钠(NaOH)的水溶液中，室温搅拌5分钟后，使用去离子水洗涤微球3次以上。NaOH通过促进PLGA微球表面的水解，不但去除了微球在固化过程中在表面形成的连续膜层，同时也使一部分负载在聚合物基体中的SiO2纳米颗粒能够暴露出来，使它们镶嵌于多孔的骨架结构上。
使用扫描电子显微镜观察微球的表面形貌。如图3a至图3d所示，经过NaOH碱蚀处理后，微球表面的连续膜层消失，增加了微球表面的孔洞结构，从而增强了微球内部与外界的物质交换能力也即药物递送效率。另外，PLGA基材内部负载的SiO2纳米颗粒部分暴露出来。再进一步观察微球的内部，如图3e至图3h所示，可以看到微球内部孔洞之间相互交错且分布均匀，并且有一部分SiO2纳米颗粒暴露并镶嵌于多孔骨架之中。
实施例5
将实施例3中的微球(Beforetreatment)和实施例4中的微球(Aftertreatment)分别加入透析袋并放置于30mL磷酸盐缓冲液(phosphatebufferedsaline，PBS)中，震荡孵育于37℃条件下，定时取5mL透析液并补充等量新鲜PBS，检测获得的透析液中从微球中释放出来的地塞米松的浓度并绘制释放曲线。
图4所示为两种微球中所负载的地塞米松的释放曲线。可以看到经过碱蚀处理以后，由于多孔微球与外界溶液有更高的传质效率，地塞米松的释放速度也会相对于处理前更快。
综上所述，本发明提供了一种同时负载药物分子和无机纳米颗粒的可降解多孔微球的制备方法。将药物分子和无机纳米颗粒均匀分散至含有可降解聚合物的挥发性有机溶剂中，通过复乳-溶剂挥发法制备聚合物微球以后，使用碱溶液对聚合物微球进行处理。在不影响微球基本构型的前提下，去除微球固化过程中在外表面形成的连续膜层，并部分暴露出聚合物中负载的无机纳米颗粒，从而获得负载有药物分子并且孔洞骨架上镶嵌有无机纳米颗粒的具有高度互连孔洞结构的多孔微球。
本领域的普通技术人员可以理解，上述各实施方式是实现本申请的具体实施例，而在实际应用中，可以在形式上和细节上对其作各种改变，而不偏离本申请的精神和范围。任何本领域技术人员，在不脱离本申请的精神和范围内，均可作各自更动与修改，因此本申请的保护范围应当以权利要求限定的范围为准。
Claims (10)
1.一种药物共递送可降解多孔微球的制备方法，其特征在于，该方法包括以下步骤：
将药物分子和无机纳米颗粒重悬并均匀分散于含有可降解聚合物的挥发性有机溶剂中，添加致孔剂后使用复乳-溶剂挥发法，得到聚合物微球；
使用碱溶液处理所述聚合物微球，以去除微球固化过程中外表层形成的连续膜层并同时刻蚀微球内部的多孔结构，从而得到负载药物分子且无机纳米颗粒镶嵌并部分暴露于孔洞骨架的药物共递送可降解多孔微球。
2.根据权利要求1所述的药物共递送可降解多孔微球的制备方法，其特征在于，所述药物分子包括消炎药、抗骨质疏松药、降糖药中的一种或多种；其中，消炎药包括地塞米松、阿司匹林；抗骨质疏松药包括阿仑膦酸钠；降糖药包括二甲双胍。
3.根据权利要求1所述的药物共递送可降解多孔微球的制备方法，其特征在于，所述无机纳米颗粒包括金属或合金纳米颗粒、氧化物纳米颗粒、无机盐纳米颗粒中的一种或多种；其中，金属或合金纳米颗粒包括金纳米颗粒；氧化物纳米颗粒包括SiO2、TiO2、ZnO、Fe2O3纳米颗粒；无机盐纳米颗粒包括CaCO3纳米颗粒。
4.根据权利要求1所述的药物共递送可降解多孔微球的制备方法，其特征在于，所述可降解聚合物包括聚己内酯、聚乙醇酸、聚乳酸、聚乳酸-羟基乙酸共聚物、聚三亚甲基碳酸酯、聚3-羟基丁酸酯中的一种或多种。
5.根据权利要求1所述的药物共递送可降解多孔微球的制备方法，其特征在于，所述挥发性的有机溶剂包括二氯甲烷、三氯甲烷、二甲基甲酰胺、二甲苯、四氢呋喃、乙酸乙酯中的一种或多种。
6.根据权利要求1所述的药物共递送可降解多孔微球的制备方法，其特征在于，该方法具体包括以下步骤：
将聚乳酸-羟基乙酸共聚物溶解于二氯甲烷中，得到二氯甲烷溶液；
将药物分子和无机纳米颗粒添加至所述二氯甲烷溶液中，水浴超声处理至分散均匀，得到油相的二氯甲烷混合溶液；
取所述二氯甲烷混合溶液添加体积比为20％至50％的浓度为0.05wt％的碳酸氢铵水溶液，进行乳化处理，形成初乳；
将所述初乳逐滴添加入搅拌状态下的1wt％的聚乙烯醇的水溶液中，室温搅拌至所述二氯甲烷挥发完全，即可得到聚合物微球；
将所述聚合物微球加入碱溶液中进行处理后，得到所述药物共递送可降解多孔微球。
7.根据权利要求6所述的药物共递送可降解多孔微球的制备方法，其特征在于，在将所述聚合物微球加入碱溶液中进行处理的步骤中，包括：将所述聚合物微球加入含有0.1M～0.5MNaOH的水溶液中处理3～10分钟。
8.根据权利要求1至7中任一项所述的药物共递送可降解多孔微球的制备方法所制得的药物共递送可降解多孔微球。
9.如权利要求8所述的药物共递送可降解多孔微球在药物制剂领域中的应用。
10.如权利要求8所述的药物共递送可降解多孔微球在注射、口服、滴鼻、皮下埋植或关节腔给药领域中的应用。
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