CN117586535A - 一种形状均一可控的多孔聚合物微粒、制备方法及其自愈合载药的应用 - Google Patents
一种形状均一可控的多孔聚合物微粒、制备方法及其自愈合载药的应用 Download PDFInfo
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Abstract
本发明公开了一种形状均一可控的多孔聚合物微粒、制备方法及其自愈合载药的应用,属于生物医药技术领域,该多孔聚合物微粒的制备过程中使用微粒阵列模具,所述微粒阵列模具包括基板,基板上设有开口朝上的第一凹槽,在第一凹槽的底壁设置有第二凹槽阵列;配制聚合物溶液和背衬溶液,使聚合物溶液填充微粒阵列模具的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分;进一步低温处理固化脱模得到微粒阵列‑背衬;将微粒阵列‑背衬浸渍在溶液中,干燥后得到所述的形状均一可控的多孔聚合物微粒。本发明方法制备过程简便,安全可靠,得到的多孔聚合物微粒形貌可控且均一,孔隙效果明显,载药过程温和高效且适用于各种药物的装载和递送。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种形状均一可控的多孔聚合物微粒、制备方法及其自愈合载药的应用。
背景技术
具有三维立体形状的聚合物微粒被广泛应用于药物递送和组织工程等生物医学领域。与传统的制剂相比,将药物封装到聚合物微粒中有多个好处。例如,聚合物微粒可以保护药物在释放之前不被降解或失活,提高药物在体内的稳定性;此外,聚合物微粒通常具有缓释特点,可以使药物缓慢持续释放,使体内的血药浓度以长效维持在有效治疗水平之上,增强并且延长治疗效果、降低副作用、减少给药次数,从而提高用药依从性。相比于较大尺寸的植入式材料,载药微粒凭借其微米级别的尺寸可通过注射方式进入体内,从而避免了高侵入的手术带来的出血、感染等风险,进一步提高患者的接受度。
现有的载药微粒形状最常见的为球形,即载药微球。乳化法是制备载药微球最广泛被采用的方法。然而,此制备方法面临着许多问题:首先,制备过程中需要高速搅拌或超声波等手段,设备成本较高;其次,乳化法制备的微球形状不规则、大小不均匀,制备过程易造成微球的聚集;再次,微球载药需要在乳化过程中加入药物,而乳化过程引入的有机溶剂会大大损害药物的稳定性,尤其是生物活性分子药物,使得微球对于药物的负载类型有限;最后,乳化法制备微球的药物装载率效率低。这些问题导致了载药微球在体内的药物分布、释放速率、疗效和副作用等关键因素的不确定性。如公开号为CN105079876A的中国专利文献公开了一种多孔载药复合微球支架材料,该方法将可降解医用聚合物溶于有机溶剂中,加入无机粉体超声分散后,再加入造孔剂,乳化,得到乳液;再将乳液加入到甲基纤维素溶液中,除去溶剂,得到微球;最后将微球浸泡于药物溶液中,取出,干燥,得到多孔载药微球,其粒径在10~600μm的范围内。
另外,载药微粒形状上的单一和不可控也导致无系统研究微粒的几何形状对微粒体内分布、运输以及代谢等生理反应的影响。尽管有一些非球形的载药微粒系统通过热成型以及3D打印等技术被开发出来,但这些方法生产工序繁杂、设备要求高、适用材料的局限性以及高温或有机溶剂等苛刻条件,影响了其在药物递送领域的应用。
综上所述,开发一种制备过程简便、形状均一可控、载药过程温和高效的多孔聚合物微粒,对于推动载药微粒在药物递送与组织工程等生物医学领域的研究和临床转化具有重要意义。
发明内容
为了解决现有载药微粒制备过程复杂、形状不可控、可负载的药物种类有限以及稳定性差等问题,本发明提供了一种形状均一可控的多孔聚合物微粒的制备方法,该方法对设备要求低,制备过程简便,安全可靠,得到的多孔聚合物微粒形貌可控且均一,孔隙效果明显,载药过程温和高效并且可适用于各种药物的装载和递送,在保健、医疗、美容等领域具有广泛的应用前景。
具体采用的技术方案如下:
一种形状均一可控的多孔聚合物微粒的制备方法,包括以下步骤:
(1)使用微粒阵列模具,所述微粒阵列模具包括基板,基板上设有第一凹槽,第一凹槽开口朝上,在所述的第一凹槽的底壁设置有第二凹槽阵列,第二凹槽阵列用于聚合物微粒的成型;第二凹槽阵列中的每个凹槽的尺寸大小一致;
(2)配制聚合物溶液和背衬溶液,使聚合物溶液填充微粒阵列模具的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分;进一步低温处理固化脱模后得到微粒阵列-背衬;
(3)将微粒阵列-背衬浸渍在溶液中,使背衬溶解,聚合物微粒与背衬分离并且分散到溶液中,聚合物微粒在该溶液中发生溶剂置换,干燥后得到所述的形状均一可控的多孔聚合物微粒。
优选的,所述的第二凹槽的形状包括但不限于半球形、球形、立方体形等。
所述的聚合物包括但不限于聚乳酸、聚己内酯、聚羟基乙酸、聚二噁烷酮、聚羟基脂肪酸酯、聚乙醇酸、聚苯乙烯、聚氯乙烯、聚乙烯、聚氨酯、聚碳酸酯、聚丙烯、聚乳酸-羟基乙酸共聚物、聚二噁烷酮-己内酯共聚物、聚乳酸-己内酯共聚物、聚甲基丙烯酸甲酯、聚醚砜、聚酰胺、丙烯腈-丁二烯-苯乙烯共聚物醋酸纤维素、聚丙烯酸、聚丁二烯、聚氟乙烯、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯腈等。
所述的聚合物溶液的浓度为1mg/mL~10g/mL。
优选的,所述的聚合物溶液中,溶剂包括甲醇、氯仿、丙酮、1,4-二氧六环、二氯甲烷、二硫化碳、二甲基甲酰胺、二甲基亚砜、苯、甲苯、乙醚、四氢呋喃、四氯化碳、乙酸乙酯、乙醇、环已酮、2-硝基丙烷、N,N-二甲基乙酰胺中的至少一种。
所述的背衬溶液为水相溶液,溶质为水溶性物质。
优选的,所述的背衬溶液为水、缓冲液、氯化钠溶液、氯化钾溶液、透明质酸溶液、明胶溶液、蔗糖溶液、海藻糖溶液中的一种。
所述的低温处理条件为温度0℃~-196℃,时间0.1h~100h。
优选的,步骤(3)中,所述的溶液为水相溶液,优选为水、缓冲液、氯化钠溶液、氯化钾溶液、透明质酸溶液、明胶溶液、蔗糖溶液、海藻糖溶液中的一种。
优选的,微粒阵列-背衬在溶液中的浸渍时间为1min~100h。
本发明还提供了所述的形状均一可控的多孔聚合物微粒的制备方法制得的形状均一可控的多孔聚合物微粒。
本发明还提供了所述的形状均一可控的多孔聚合物微粒自愈合载药的应用,优选的,将所述的形状均一可控的多孔聚合物微粒浸泡到药物溶液中,通过自由扩散或真空作用,使药物进入到多孔聚合物微粒中,随后干燥得到预载药物的多孔聚合物微粒;将预载药物的多孔聚合物微粒进行升温处理使孔洞自愈合,即可完成载药过程。
进一步优选的,升温处理包括红外光照射、紫外灯照射或加热处理;升温处理时间为1min~100h,升温处理的目标温度为15℃~80℃。
本发明还提供了一种载药聚合物微粒,由所述的形状均一可控的多孔聚合物微粒自愈合载药后得到。
与现有技术相比,本发明的有益效果在于:
(1)本发明相比于传统微粒制备技术,制备过程高效便捷,制得的聚合物微粒形状可控且均一,同时聚合物微粒具有良好的多孔结构,孔隙率高;
(2)本发明制备的多孔聚合物微粒具有良好的多孔结构,在载药过程中,通过自由扩散或真空作用,使药物进入微粒中,并且通过孔洞的自愈合特性实现药物的封装,载药过程相比于传统方法(直接将药物在微粒制备过程中装载)更加高效、载药量可控(通过调控药物溶液初始浓度可以实现准确控制载药量),载药环境温和,避免了药物与有机溶剂的接触,能够极大程度提高所载药物尤其是大分子生物制剂的稳定性。
附图说明
图1为不同的阳模具结构示意图。
图2位利用微粒阵列模具(阴模具)制备长方体多孔聚合物微粒的流程示意图。
图3为实施例1中长方体多孔聚合物微粒的形貌图。
图4为实施例1中长方体多孔聚合物微粒的SEM图片。
图5为实施例1中长方体多孔聚合物微粒负载模型药物FTIC-OVA后的荧光图片。
图6为实施例3圆锥体多孔聚合物微粒的光学图片。
图7为实施例4半球体多孔聚合物微粒的光学图片。
图8为实施例2圆柱体多孔聚合物微粒的光学图片。
具体实施方式
下面结合实施例与附图,进一步阐明本发明。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。
实施例1-4中,首先预制具有不同形状微粒阵列的阳模具(如图1所示),通过倒膜法制备获得实验中使用的微粒阵列模具,该微粒阵列模具包括基板,基板上设有第一凹槽,第一凹槽开口朝上,底壁水平;在所述的第一凹槽的底壁设置有第二凹槽阵列,第二凹槽阵列中的每个凹槽的尺寸大小一致,第二凹槽阵列用于聚合物微粒的成型;
具体的,利用微粒阵列模具(阴模具)制备长方体多孔聚合物微粒的流程示意图如图2所示。
实施例1
(1)配制100mg/mL的聚乳酸-己内酯共聚物的1,4-二氧六环溶液,用PBS溶液作为背衬溶液,使聚合物溶液填充微粒阵列模具(第二凹槽的形状为长方体)的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分,进一步在-20℃下低温处理4h后固化脱模得到微粒阵列-背衬;
(2)将微粒阵列-背衬浸渍在PBS溶液中2h,使背衬溶解,聚合物微粒与背衬分离并且分散到PBS溶液中,聚合物微粒在PBS溶液中发生溶剂置换,干燥后得到长方体多孔聚合物微粒。
实施例2
(1)配制500mg/mL的聚己内酯的二氯甲烷溶液,用20mg/mL蔗糖水溶液作为背衬溶液,使聚合物溶液填充微粒阵列模具(第二凹槽的形状为圆柱体)的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分,进一步在-50℃低温处理3h后固化脱模得到微粒阵列-背衬;
(2)将微粒阵列-背衬浸渍在30mg/mL蔗糖水溶液中1h,使背衬溶解,聚合物微粒与背衬分离并且分散到蔗糖水溶液中,聚合物微粒在蔗糖水溶液中发生溶剂置换,干燥后得到圆柱体多孔聚合物微粒。
实施例3
(1)配制300mg/mL的聚乳酸的四氢呋喃溶液,用100mg/mL透明质酸水溶液作为背衬溶液,使聚合物溶液填充微粒阵列模具(第二凹槽的形状为圆锥体)的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分,进一步在-80℃下低温处理22h后固化脱模得到微粒阵列-背衬;
(2)将微粒阵列-背衬浸渍在50mg/mL透明质酸水溶液中5h,使背衬溶解,聚合物微粒与背衬分离并且分散到透明质酸水溶液中,聚合物微粒在透明质酸水溶液中发生溶剂置换,干燥后得到圆锥体多孔聚合物微粒。
实施例4
(1)配制800mg/mL的聚酰胺的乙酸乙酯溶液,用30mg/mL海藻糖水溶液作为背衬溶液,使聚合物溶液填充微粒阵列模具(第二凹槽的形状为半球体)的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分,进一步在-196℃下低温处理1h后固化脱模得到微粒阵列-背衬;
(2)将微粒阵列-背衬浸渍在50mg/mL海藻糖水溶液中10h,使背衬溶解,聚合物微粒与背衬分离并且分散到海藻糖水溶液中,聚合物微粒在海藻糖水溶液中发生溶剂置换,干燥后得到半球体多孔聚合物微粒。
样品分析
实施例1中制得的长方体多孔聚合物微粒的形貌如图3所示,形状均一,通过扫描电镜(图4)观察到其具有均匀的多孔结构。
采用荧光标记的卵清蛋白(FITC-OVA)作为模型药物,配制成10mg/mL的药物溶液,将制备的长方体多孔聚合物微粒浸泡到FITC-OVA溶液中2h,通过自由扩散作用,使药物进入到多孔聚合物微粒中,随后取出干燥得到预载药物的多孔聚合物微粒,再通过红外辐照使其目标温度达到40℃诱导孔洞自愈合,完成载药过程;载药后的长方体多孔聚合物微粒的形貌如图5所示。
通过选择不同的模具,可以相应制备出特定形状的多孔聚合物微粒,例如圆锥体、半球体和圆柱体的多孔聚合物微粒,分别如图6、图7和图8所示。
以上所述的实施例对本发明的技术方案进行了详细说明,应理解的是以上所述的仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充或类似方式替代等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种形状均一可控的多孔聚合物微粒的制备方法,其特征在于,包括以下步骤:
(1)使用微粒阵列模具,所述微粒阵列模具包括基板,基板上设有第一凹槽,第一凹槽开口朝上,在所述的第一凹槽的底壁设置有第二凹槽阵列,第二凹槽阵列用于聚合物微粒的成型;
(2)配制聚合物溶液和背衬溶液,使聚合物溶液填充微粒阵列模具的第二凹槽阵列部分,背衬溶液填充微粒阵列模具的剩余部分;进一步低温处理固化脱模后得到微粒阵列-背衬;
(3)将微粒阵列-背衬浸渍在溶液中,使背衬溶解,聚合物微粒与背衬分离并且分散到溶液中,聚合物微粒在该溶液中发生溶剂置换,干燥后得到所述的形状均一可控的多孔聚合物微粒。
2.根据权利要求1所述的形状均一可控的多孔聚合物微粒的制备方法,其特征在于,所述的聚合物包括聚乳酸、聚己内酯、聚羟基乙酸、聚二噁烷酮、聚羟基脂肪酸酯、聚乙醇酸、聚苯乙烯、聚氯乙烯、聚乙烯、聚氨酯、聚碳酸酯、聚丙烯、聚乳酸-羟基乙酸共聚物、聚二噁烷酮-己内酯共聚物、聚乳酸-己内酯共聚物、聚甲基丙烯酸甲酯、聚醚砜、聚酰胺、丙烯腈-丁二烯-苯乙烯共聚物醋酸纤维素、聚丙烯酸、聚丁二烯、聚氟乙烯、聚丙烯酸酯、聚甲基丙烯酸酯或聚丙烯腈。
3.根据权利要求1所述的形状均一可控的多孔聚合物微粒的制备方法,其特征在于,所述的聚合物溶液的浓度为1mg/mL~10g/mL。
4.根据权利要求1所述的形状均一可控的多孔聚合物微粒的制备方法,其特征在于,所述的聚合物溶液中,溶剂包括甲醇、氯仿、丙酮、1,4-二氧六环、二氯甲烷、二硫化碳、二甲基甲酰胺、二甲基亚砜、苯、甲苯、乙醚、四氢呋喃、四氯化碳、乙酸乙酯、乙醇、环已酮、2-硝基丙烷、N,N-二甲基乙酰胺中的至少一种。
5.根据权利要求1所述的形状均一可控的多孔聚合物微粒的制备方法,其特征在于,所述的背衬溶液和步骤(3)中的溶液均为水相溶液。
6.根据权利要求1所述的形状均一可控的多孔聚合物微粒的制备方法,其特征在于,所述的低温处理条件为温度0℃~-196℃,时间0.1h~100h。
7.根据权利要求1-6任一所述的形状均一可控的多孔聚合物微粒的制备方法制得的形状均一可控的多孔聚合物微粒。
8.根据权利要求7所述的形状均一可控的多孔聚合物微粒自愈合载药的应用。
9.根据权利要求8所述的形状均一可控的多孔聚合物微粒自愈合载药的应用,其特征在于,将所述的形状均一可控的多孔聚合物微粒浸泡到药物溶液中,通过自由扩散或真空作用,使药物进入到多孔聚合物微粒中,随后干燥得到预载药物的多孔聚合物微粒;进一步对预载药物的多孔聚合物微粒进行升温处理使孔洞自愈合,完成载药过程。
10.一种载药聚合物微粒,其特征在于,由权利要求7所述的形状均一可控的多孔聚合物微粒自愈合载药后得到。
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