CN107233318A - 具有多级缓控释效果的羟基磷灰石载药微球的制备方法 - Google Patents

具有多级缓控释效果的羟基磷灰石载药微球的制备方法 Download PDF

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CN107233318A
CN107233318A CN201710407574.4A CN201710407574A CN107233318A CN 107233318 A CN107233318 A CN 107233318A CN 201710407574 A CN201710407574 A CN 201710407574A CN 107233318 A CN107233318 A CN 107233318A
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hydroxyapatite
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bearing microsphere
drug bearing
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于翔
张�浩
杨柳
徐茜
卢晓龙
赵俊杰
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Henan Institute of Engineering
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Abstract

本发明公开一种具有多级缓控释效果的羟基磷灰石载药微球的制备方法，属于生物医用材料领域。所述的制备方法如下：1）通过静电液滴法制备羟基磷灰石/壳聚糖微球，然后通过高温烧结后得到多孔羟基磷灰石微球；2）将步骤1）中的多孔羟基磷灰石微球浸入到药液中，然后通过冷冻干燥得到载药羟基磷灰石微球；3）将2）中的载药羟基磷灰石微球与PLGA与药物的混合溶液混合，在低温条件下过滤，得到表面含有PLGA的载药羟基磷灰石微球。本发明的制备方法简单，重复性好，适合工业化生产；且所制备的微球载药量高，具有长期的缓控释效果，在治疗骨缺损的慢性感染及炎症具有较为广阔的应用前景。

Description

具有多级缓控释效果的羟基磷灰石载药微球的制备方法
技术领域
本发明属于药物缓释骨缺损修复领域，具体涉及一种具有多级缓控释效果的羟基磷灰石载药微球的制备方法及应用。
背景技术
目前，由于疾病或者创伤引起的骨缺损给人们的生活带来了极大不便，且骨缺损在治疗的过程中极易发生感染，形成感染性骨缺损。感染性骨缺损的治疗方式目前一般包括两种：一种是在缺损区域填充支架材料，同时肌肉注射抗生素药物，这种方式能够对感染性骨缺损起到良好的治疗效果，但是也存在着抗生素的治疗次数较多，给病人的生活带来不便，同时抗生素的利用率较低，容易造成肾毒症；另一种方法是，在支架材料中混入抗生素药物起到促进骨生长和抑制感染的效果，但是这种方法也存在着一定的问题：支架材料若孔隙率较低，降解速率较慢，药物释放的速率较慢，达不到抗感染的效果；而若是支架材料的孔隙率较高，药物释放过快，达不到药物缓控释的目的。因此需要找到一种能够对药物能够缓控释的方法，同时能够促进骨缺损的修复。
羟基磷灰石(HA)是人体硬组织的主要无机成分，具有良好的生物相容性，在临床上已广泛用于生物硬组织的修复和替换，如骨缺损的填充、耳小骨替换和脊椎骨替换等，是良好的骨缺损修复材料。此外，已经有大量研究表明，利用水热法、喷雾法、模板法等将羟基磷灰石制备成的多孔羟基磷灰石微球，具有较高的孔隙率能够负载大量的药物，从而起到缓释的作用。但是这些方法也存在着药物在前期释放速率较慢的问题，起不到对药物进行控释的效果，这些方法制备羟基磷灰石微球较为麻烦。此外，骨组织是有有机物和无机物组成的杂化体系。因此，需要找到一种能够与骨组织结构和成分均较为类似的材料进行载药，同时这种材料能够达到对药物具有缓控释效果，只有这样才能够对感染性骨缺损起到较好的治疗效果。
发明内容
本发明所要解决的技术问题是针对单纯的羟基磷灰石载药微球只能够对药物进行缓释而不能够对药物进行控释的问题提供一种具有多级缓控释效果的羟基磷灰石载药微球的制备方法，同时本发明制备的羟基磷灰石载药微球在结构上对骨组织进行了仿生设计，能够对感染性骨缺损提供较好的治疗效果。
为解决上述技术问题，本发明采用以下技术方案：
一种具有多级缓控释效果的羟基磷灰石载药微球的制备方法，步骤如下：
（1）将羟基磷灰石粉末加入90℃的明胶溶液中，混合均匀后，利用液滴冷凝法制备明胶/羟基磷灰石微球；
（2）将步骤（1）制得的明胶/羟基磷灰石微球经过高温烧结得到多孔羟基磷灰石微球，将多孔羟基磷灰石微球置于药液A中12-24h以吸附药液A，然后将吸附药液A后的多孔羟基磷灰石微球进行冷冻干燥得到多孔羟基磷灰石载药微球；
（3）配制高分子溶液，向其中加入一定量的药物粉末，混合均匀后得到药液B，将步骤（2）得到的多孔羟基磷灰石载药微球放入药液B中，在多孔羟基磷灰石载药微球表面均匀地包覆一层高分子/药物复合膜制得复合微球，然后将复合微球冷冻干燥，得到具有多级缓控释效果的羟基磷灰石载药微球。
所述步骤（1）中明胶溶液的浓度为0.02g/mL-0.04 g/mL。
所述步骤（1）中明胶与羟基磷灰石粉末的质量比为1:2-1:4。
所述的液滴冷凝法为将明胶/羟基磷灰石热溶液逐滴滴入到液氮中。
所述步骤（2）中的明胶/羟基磷灰石微球的烧结温度为900℃，烧结时间为2h。
所述步骤（2）药液A中的药物为抗菌消炎或抗感染类药物，包括但不限于盐酸万古霉素、盐酸四环素，药液A的质量浓度为5-10%。
所述步骤（2）中的多孔羟基磷灰石微球在药液A中的质量体积浓度为0.2g/mL-0.5g/mL。
所述步骤（3）中的高分子为PLA、PLGA或PCL，高分子溶液的浓度为0.05g/mL -0.15g/mL；所述药物粉末为抗菌消炎或抗感染类药物，包括但不限于盐酸万古霉素、盐酸四环素；所述高分子与药物粉末的质量比为1:1-1:2。
所述步骤（2）和步骤（3）中冷冻干燥的温度为-40℃冷冻干燥的时间为24h。
所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法制得的羟基磷灰石载药微球应用于感染性骨缺损的治疗。
与现有技术相比，本发明的有益之处在于：
本发明解决了传统法的羟基磷灰石载药微球只能够对药物进行缓释，而不能够进行控释的缺点。本发明所制备的复合微球在传统的多孔微球的基础上包覆了一层可生物降解的高分子膜，当复合微球植入到感染性骨缺损部位后，高分子膜中的药物可以缓慢释放，而多孔羟基磷灰石中的药物可以逐渐扩散到高分子膜中，从而保持高分膜中药物浓度的恒定，从而达到对药物的缓控释的效果。同时本发明所制备的多级缓控释效果的羟基磷灰石载药微球从结构和成分上对骨组织进行仿生，能够有效的对感染性骨缺损进行治疗。该方法条件温和，工艺简单，无残留，适合大量生产。
具体实施方式
下面结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围，该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
本实施例的具有多级缓控释效果的羟基磷灰石载药微球的制备方法下：
（1）配制100mL浓度为0.02g/mL的明胶热溶液（90℃），然后加入4g羟基磷灰石粉末，混合均匀后，利用注射器将明胶/纳米磷灰石混合溶液逐滴滴到液氮中即得到明胶/羟基磷灰石微球；
（2）将上述的明胶/羟基磷灰石微球经过在900℃烧结2h后得到多孔羟基磷灰石微球，然后将2g多孔羟基磷灰石微球浸入到10mL浓度为5%的盐酸万古霉素分散液中24h，将吸附药液后的微球进行冷冻干燥（-40℃，24h）即可得到多孔羟基磷灰石载药微球；
（3）配制浓度为0.05g/mL的PLA稀溶液10mL，向其中加入0.5g盐酸万古霉素粉末，混合均匀后，将步骤（2）中的载药微球放入其中，在其表面均匀的包覆一层高分子/药物复合膜，然后将复合微球冷冻干燥（-40℃，24h）后即可得到具有多级缓控释效果的羟基磷灰石载药微球。
实施例2
本实施例的具有多级缓控释效果的羟基磷灰石载药微球的制备方法下：
（1）配制100mL浓度为0.03g/mL明胶热溶液（90℃），然后加入9g羟基磷灰石粉末，混合均匀后，利用注射器将明胶/纳米磷灰石混合溶液逐滴滴到液氮中即得到明胶/羟基磷灰石复合微球；
（2）将上述的明胶/羟基磷灰石复合微球经过在900℃烧结2h后得到多孔羟基磷灰石微球，然后将4g多孔羟基磷灰石微球浸入到10mL浓度为7.5%的盐酸万古霉素分散液中18h，然后将吸附药液后的微球进行冷冻干燥（-40℃，24h）即可得到多孔羟基磷灰石载药微球；
（3）配制浓度为0.1g/mL的PLA稀溶液10mL，向其中加入1.5g盐酸万古霉素粉末，混合均匀后，将步骤（2）中的载药微球放入其中，在其表面均匀的包覆一层高分子/药物复合膜，然后将复合微球冷冻干燥（-40℃，24h）后即可得到具有多级缓控释效果的羟基磷灰石载药微球。
实施例3
本实施例的具有多级缓控释效果的羟基磷灰石载药微球的制备方法下：
（1）配制100mL浓度为0.04g/mL明胶热溶液（90℃），然后加入16g羟基磷灰石粉末，混合均匀后，利用注射器将明胶/纳米磷灰石混合溶液逐滴滴到液氮中即得到明胶/羟基磷灰石复合微球；
（2）将上述的明胶/羟基磷灰石复合微球经过在900℃烧结2h后得到多孔羟基磷灰石微球，然后将5g多孔羟基磷灰石微球浸入到10mL浓度为10%的盐酸万古霉素分散液中12h，然后将吸附药液后的微球进行冷冻干燥（-40℃，24h）即可得到多孔羟基磷灰石载药微球；
（3）配制浓度为0.15g/mL的PLA稀溶液10mL，向其中加入3g盐酸万古霉素粉末，混合均匀后，将步骤（2）中的载药微球放入其中，在其表面均匀的包覆一层高分子/药物复合膜，然后将复合微球冷冻干燥（-40℃，24h）后即可得到具有多级缓控释效果的羟基磷灰石载药微球。
实施例4
本实施例的具有多级缓控释效果的羟基磷灰石载药微球的制备方法下：
（1）配制100mL浓度为0.02g/mL明胶热溶液（90℃），然后加入6g羟基磷灰石粉末，混合均匀后，利用注射器将明胶/纳米磷灰石混合溶液逐滴滴到液氮中即得到明胶/羟基磷灰石复合微球；
（2）将上述的明胶/羟基磷灰石复合微球经过在900℃烧结2h后得到多孔羟基磷灰石微球，然后将2g多孔羟基磷灰石微球浸入到10mL浓度为10%的盐酸四环素分散液中18h，然后将吸附药液后的微球进行冷冻干燥（-40℃，24h）即可得到多孔羟基磷灰石载药微球；
（3）配制浓度为0.05g/mL的PLGA稀溶液10mL，向其中加入1g盐酸四环素粉末，混合均匀后，将步骤（2）中的载药微球放入其中，在其表面均匀的包覆一层高分子/药物复合膜，然后将复合微球冷冻干燥（-40℃，24h）后即可得到具有多级缓控释效果的羟基磷灰石载药微球。
实施例5
本实施例的具有多级缓控释效果的羟基磷灰石载药微球的制备方法下：
（1）配制100mL浓度为0.03g/mL明胶热溶液（90℃），然后加入12g羟基磷灰石粉末，混合均匀后，利用注射器将明胶/纳米磷灰石混合溶液逐滴滴到液氮中即得到明胶/羟基磷灰石复合微球；
（2）将上述的明胶/羟基磷灰石复合微球经过在900℃烧结2h后得到多孔羟基磷灰石微球，然后将2g多孔羟基磷灰石微球浸入到10mL浓度为5%的盐酸四环素分散液中12h，然后将吸附药液后的微球进行冷冻干燥（-40℃，24h）即可得到多孔羟基磷灰石载药微球；
（3）配制浓度为0.15g/mL的PCL稀溶液10mL，向其中加入1.5g盐酸四环素粉末，混合均匀后，将步骤（2）中的载药微球放入其中，在其表面均匀的包覆一层高分子/药物复合膜，然后将复合微球冷冻干燥（-40℃，24h）后即可得到具有多级缓控释效果的羟基磷灰石载药微球。
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (10)

1.一种具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于，步骤如下：
（1）将羟基磷灰石粉末加入90℃的明胶溶液中，混合均匀后，利用液滴冷凝法制备明胶/羟基磷灰石微球；
（2）将步骤（1）制得的明胶/羟基磷灰石微球经过高温烧结得到多孔羟基磷灰石微球，将多孔羟基磷灰石微球置于药液A中12-24h以吸附药液A，然后将吸附药液A后的多孔羟基磷灰石微球进行冷冻干燥得到多孔羟基磷灰石载药微球；
（3）配制高分子溶液，向其中加入一定量的药物粉末，混合均匀后得到药液B，将步骤（2）得到的多孔羟基磷灰石载药微球放入药液B中，在多孔羟基磷灰石载药微球表面均匀地包覆一层高分子/药物复合膜制得复合微球，然后将复合微球冷冻干燥，得到具有多级缓控释效果的羟基磷灰石载药微球。
2.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（1）中明胶溶液的浓度为0.02g/mL-0.04 g/mL。
3.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（1）中明胶与羟基磷灰石粉末的质量比为1:2-1:4。
4.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述的液滴冷凝法为将明胶/羟基磷灰石热溶液逐滴滴入到液氮中。
5.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（2）中的明胶/羟基磷灰石微球的烧结温度为900℃，烧结时间为2h。
6.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（2）药液A中的药物为抗菌消炎或抗感染类药物，包括但不限于盐酸万古霉素、盐酸四环素，药液A的质量浓度为5-10%。
7.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（2）中的多孔羟基磷灰石微球在药液A中的质量体积浓度为0.2g/mL-0.5g/mL。
8.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（3）中的高分子为PLA、PLGA或PCL，高分子溶液的浓度为0.05g/mL -0.15g/mL；所述药物粉末为抗菌消炎或抗感染类药物，包括但不限于盐酸万古霉素、盐酸四环素；所述高分子与药物粉末的质量比为1:1-1:2。
9.根据权利要求1所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法，其特征在于：所述步骤（2）和步骤（3）中冷冻干燥的温度为-40℃冷冻干燥的时间为24h。
10.利用权利要求1~9任一所述的具有多级缓控释效果的羟基磷灰石载药微球的制备方法制得的羟基磷灰石载药微球应用于感染性骨缺损的治疗。
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