CN111773433A - 一种载药纳米气泡骨水泥的制备方法 - Google Patents
一种载药纳米气泡骨水泥的制备方法 Download PDFInfo
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Abstract
本发明公开了一种载药纳米气泡骨水泥的制备方法，包括使用双乳液溶剂蒸发法制备载药纳米气泡，制备含有不同比例载药纳米气泡的骨水泥，优化骨水泥中载药纳米气泡的含量，制备最优的载药纳米气泡骨水泥，探究其细胞学行为并应用到动物伤口模型中监测其治疗效果，拟解决抗生素不能持续释放以及病灶部位血药浓度下降等问题，骨水泥中的载药纳米气泡因包埋位置不同，降解速率不相同，万古霉素可以持续释放，满足临床治疗所需，药物的持续释放不受外界环境中药物浓度的影响，且分散于骨水泥内部的药物也可随周围的孔道流出，给病灶部位提供一个相对稳定的治疗环境。
Description
技术领域：
本发明属于临床医学技术领域，尤其涉及一种载药纳米气泡骨水泥的制备方法。
背景技术：
骨感染在临床上是一个治疗难题，感染局部骨质硬化，有时存在死骨形成的死腔、血液循环差，全身给药的抗菌药物局部浓度低，疗效不佳的问题。提高骨感染局部的抗菌药物浓度，是治疗骨感染的重要问题。
目前主要通过万古霉素全身给药，组织分布浓度低，其骨浓度仅为静脉血药浓度的7％-13％，为达到骨组织中的治疗浓度，需要提高血药浓度，因此指南推荐其治疗骨感染，血药浓度需要达到15-20mg·L-1，而大剂量长疗程、累计剂量高，与该药导致的肾损伤、白细胞减少、药物热等不良反应密切相关。临床上使用万古霉素加入骨水泥治疗骨感染，取得了较为满意的疗效。在手术清创的同时给予负载抗生素缓释系统已经成为临床治疗骨感染的治疗方法之一。根据研究结果表明，骨水泥内部的抗生素不能被释放出来，导致随着时间的推移，局部血药浓度的明显下降。
发明内容：
针对上述问题，本发明要解决的技术问题是提供一种载药纳米气泡骨水泥的制备方法，包括以下步骤：
(1)使用双乳液溶剂蒸发法制备载药纳米气泡：
首先，将250毫克PLGA溶于50毫升的二氯甲烷中，超声处理10分钟，得到PLGA纳米气泡；
再加入250微升含有万古霉素的聚乙烯醇溶液，继续超声处理1分钟，将处理后的上述溶液逐滴加入到10毫升1％的聚乙烯醇溶液中，超声处理1分钟；
再将所得溶液逐滴加入到含有35毫升去离子水的敞口烧杯中，于室温下搅拌过夜，离心得到沉淀物，用去离子水洗涤三次，置于冷冻干燥机中冻干，得到载药纳米气泡，密封保存备用；
(2)制备含有不同比例载药纳米气泡的骨水泥：
在聚甲基丙烯酸甲酯骨水泥形成的骨水泥浆体中，加入不同量的载药纳米气泡，超声处理后，用注射器将上述液体滴入到液氮中制备含有不同比例载药纳米气泡的骨水泥复合小球，所得的骨水泥复合小球用无水乙醇洗涤数次，真空干燥；
(3)优化骨水泥中载药纳米气泡的含量：
通过扫描电镜和透射电镜监测骨水泥中纳米气泡的降解过程，优化骨水泥中纳米气泡的含量；
通过荧光光谱仪实时监测骨水泥中万古霉素的释放行为；
(4)制备最优的载药纳米气泡骨水泥，探究其细胞学行为并应用到动物伤口模型中监测其治疗效果：
骨水泥中载药纳米气泡的最佳含量为：
万古霉素99.2mg；
PLGA纳米气泡16g；
骨水泥浆体40g。
优选的，所述PLGA纳米气泡的尺寸在150nm到500nm之间。
优选的，所述步骤(3)中监测骨水泥中纳米气泡的降解过程中监测的释药周期为4-6周。
本发明有益效果：本发明的一种载药纳米气泡骨水泥的制备方法，拟解决抗生素不能持续释放以及病灶部位血药浓度下降等问题。传统方法中将药物直接分散于骨水泥中，药物的释放周期大约在一周以内，而本发明中，骨水泥中的载药纳米气泡因包埋位置不同，导致降解速率不相同，其完全降解大约需要4-6周左右，此期间万古霉素可以持续释放，可以满足临床治疗所需；药物的持续释放主要取决于纳米气泡的降解速率，不受外界环境中药物浓度的影响，且分散于骨水泥内部的药物也可随周围的孔道流出，给病灶部位提供一个相对稳定的治疗环境。
附图说明：
图1为本发明制备过程示意图；
图2为本发明制备方法流程图。
具体实施方式：
为使本发明的目的、技术方案和优点更加清楚明了，下面通过具体实施例及附图来描述本发明。但是应该理解，这些描述只是示例性的，而并非要限制本发明的范围。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本发明的概念。
如图1-2，本实施例的一种载药纳米气泡骨水泥的制备方法，包括以下步骤：
(1)使用双乳液溶剂蒸发法制备载药纳米气泡：
首先，将250毫克PLGA溶于50毫升的二氯甲烷中，超声处理10分钟，得到PLGA纳米气泡；
再加入250微升含有万古霉素的聚乙烯醇溶液，继续超声处理1分钟，将处理后的上述溶液逐滴加入到10毫升1％的聚乙烯醇溶液中，超声处理1分钟；
再将所得溶液逐滴加入到含有35毫升去离子水的敞口烧杯中，于室温下搅拌过夜，离心得到沉淀物，用去离子水洗涤三次，置于冷冻干燥机中冻干，得到载药纳米气泡，密封保存备用；
(2)制备含有不同比例载药纳米气泡的骨水泥：
在聚甲基丙烯酸甲酯骨水泥形成的骨水泥浆体中，加入不同量的载药纳米气泡，超声处理后，用注射器将上述液体滴入到液氮中制备含有不同比例载药纳米气泡的骨水泥复合小球，所得的骨水泥复合小球用无水乙醇洗涤数次，真空干燥；
(3)优化骨水泥中载药纳米气泡的含量：
通过扫描电镜和透射电镜监测骨水泥中纳米气泡的降解过程，优化骨水泥中纳米气泡的含量；
通过荧光光谱仪实时监测骨水泥中万古霉素的释放行为；
(4)制备最优的载药纳米气泡骨水泥，探究其细胞学行为并应用到动物伤口模型中监测其治疗效果：
骨水泥中载药纳米气泡的最佳含量为：
万古霉素99.2mg；
PLGA纳米气泡16g；
骨水泥浆体40g。
具体地，PLGA纳米气泡的尺寸在150nm到500nm之间。载药纳米气泡的体外降解周期在4周左右，因此监测4-6周的载药纳米气泡骨水泥的释药周期。载药纳米气泡骨水泥对小鼠S180肉瘤细胞和MG-63人骨肉瘤细胞有明显的抑制作用。
本发明的一种载药纳米气泡骨水泥的制备方法，制备磷酸钙骨水泥多孔小球，拟解决抗生素不能持续释放以及病灶部位血药浓度下降等问题。2019-2010年，制备载药纳米气泡骨水泥，摸索出成熟的制备流程及最佳条件；研究PLGA纳米气泡的含量对磷酸钙骨水泥的结构、形貌等的影响，探究PLGA纳米气泡破裂和PLGA材料降解分别对骨水泥多孔结构形成的影响及其体外释药行为；2010-2011年，建立动物伤口模型，探究载药纳米气泡骨水泥在伤口处的生物相容性并监测其治疗效果。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。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 (3)
1.一种载药纳米气泡骨水泥的制备方法，其特征在于：包括以下步骤：
(1)使用双乳液溶剂蒸发法制备载药纳米气泡：
首先，将250毫克PLGA溶于50毫升的二氯甲烷中，超声处理10分钟，得到PLGA纳米气泡；
再加入250微升含有万古霉素的聚乙烯醇溶液，继续超声处理1分钟，将处理后的上述溶液逐滴加入到10毫升1％的聚乙烯醇溶液中，超声处理1分钟；
再将所得溶液逐滴加入到含有35毫升去离子水的敞口烧杯中，于室温下搅拌过夜，离心得到沉淀物，用去离子水洗涤三次，置于冷冻干燥机中冻干，得到载药纳米气泡，密封保存备用；
(2)制备含有不同比例载药纳米气泡的骨水泥：
在聚甲基丙烯酸甲酯骨水泥形成的骨水泥浆体中，加入不同量的载药纳米气泡，超声处理后，用注射器将上述液体滴入到液氮中制备含有不同比例载药纳米气泡的骨水泥复合小球，所得的骨水泥复合小球用无水乙醇洗涤数次，真空干燥；
(3)优化骨水泥中载药纳米气泡的含量：
通过扫描电镜和透射电镜监测骨水泥中纳米气泡的降解过程，优化骨水泥中纳米气泡的含量；
通过荧光光谱仪实时监测骨水泥中万古霉素的释放行为；
(4)制备最优的载药纳米气泡骨水泥，探究其细胞学行为并应用到动物伤口模型中监测其治疗效果：
骨水泥中载药纳米气泡的最佳含量为：
万古霉素99.2mg；
PLGA纳米气泡16g；
骨水泥浆体40g。
2.根据权利要求1所述的一种载药纳米气泡骨水泥的制备方法，其特征在于：所述PLGA纳米气泡的尺寸在150nm到500nm之间。
3.根据权利要求1所述的一种载药纳米气泡骨水泥的制备方法，其特征在于：所述步骤(3)中监测骨水泥中纳米气泡的降解过程中监测的释药周期为4-6周。
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