CN116421787A - 一种磷酸镁骨水泥 - Google Patents
一种磷酸镁骨水泥 Download PDFInfo
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Abstract
本发明公开了一种磷酸镁骨水泥，所述水泥包括粉相、缓释微胶囊、有机缓凝剂，所述粉相包括MgO、KH2PO4、Ca(H2PO4)2，所述缓释微胶囊、有机缓凝剂、粉相的质量比为5‑15:5‑7:100，所述缓释微胶囊的芯材为药物。本发明一种磷酸镁骨水泥利用琼脂作为微胶囊的将药物包裹起来，再复合到骨水泥中，可在避免药物与骨水泥相互作用的同时提高药物缓释性能，可以实现快速修复骨缺损部位和药物治疗的双重效果。
Description
技术领域
本发明涉及医用生物材料技术领域，尤其是一种磷酸镁骨水泥。
背景技术
由外伤、骨肿瘤、车祸、先天性疾病等导致的骨缺损一直是困扰和影响人类健康的重要医学难题，易造成骨不连接、延迟愈合甚至不愈合，以及局部功能障碍，需要大量优质骨移植材料以供临床修复。全球每年约进行200万例骨移植，其中自体骨移植因其优异的成骨诱导性、无免疫排斥反应而成为金标准，但其来源有限，二次手术也易带来其他风险；同种异体移植虽来源更广，但存在病原传播和免疫原性问题。因此，人工骨修复材料由于其来源不受限、可对机体组织进行修复与再生、可不断改进等优势，受到研究学者的广泛关注。
相对于需要预先成型并且以特定形状的颗粒或块体形式应用的金属材料、生物陶瓷材料、高分子材料和生物医用复合材料，骨水泥材料因其具有可塑形和自凝固的独特性能，既可以填充形状不规则的骨缺损，又可以用作微创手术的可注射材料，因而获得广泛关注和应用。磷酸镁骨水泥(Magnesium Phosphate Bone Cement，MPC)，主要由烧结氧化镁、磷酸盐和缓凝剂按一定比例配制而成，具有快凝、高早强的特性，早在1945年Brookhaven实验室就将MPC用作建筑物的快速修补材料。作为一类无机胶粘剂，MPC与磷酸钙骨水泥(CPC)类似，能在人体生理环境下自行固化，水化产物为磷酸盐类生物矿石，生物相容性好。研究表明，MPC具有良好的生物相容性和生物降解性，是一种理想的骨缺损修复材料。
骨缺损往往是由于骨肿瘤、骨结核等疾病导致一部分骨被切除，因此单独采用传统的骨水泥填充对骨疾病治疗没有明显的作用。另外，通常氧化镁和磷酸盐的反应速率很快，凝固时间很短，高的反应速率往往伴随着高的放热，在临床中，不利于医生的操作，同时植入物的温度过高对于人体组织也具有破环作用。因此，需要提供一种磷酸镁骨水泥。
发明内容
为了克服现有技术中的缺陷，提供一种磷酸镁骨水泥。
本发明通过下述方案实现：
一种磷酸镁骨水泥，所述水泥包括粉相、缓释微胶囊、有机缓凝剂，所述粉相包括MgO、KH2PO4、Ca(H2PO4)2，所述缓释微胶囊、有机缓凝剂、粉相的质量比为5-15:5-7:100，所述缓释微胶囊的芯材为药物。
所述MgO、KH2PO4、Ca(H2PO4)2的质量比为1:4-5:0.5-1。
所述缓释微胶囊的壁材为琼脂。
所述缓释微胶囊的制备方法为：
一、将琼脂和药物按照质量比2-3:1依次加入到纯水中溶解，然后预热至55℃，得到水相溶液；
二、将液体石蜡和油酸山梨坦混合后加热至55℃，一边定速搅拌一边加入缓慢滴加水相溶液，持续搅拌15-20分钟，随后进行冰水浴；
三、持续监测温度，当温度降至10℃时，保持温度并继续搅拌15分钟，随后加入葡萄糖溶液交联60-80分钟；
四、交联后加入絮凝剂絮凝10分钟，倒出乳浊液，然后用有机溶剂清洗去除油相，通风至有机溶剂挥发后即得缓释微胶囊。
所述液体石蜡与油酸山梨的体积比为1:10。
所述定速搅拌的转速为400-500r/min。
所述葡萄糖溶液的浓度为0.5g/ml。
所述有机缓凝剂为胶原多肽。
所述MgO为低活性MgO。
所述低活性MgO的制备方法为：将MgO在1600℃空气中进行高温焙烧；采用程序升温的方式，首先从室温以5℃/min的速度升温至300℃，保持2h，之后继续以20℃/min的速度升温至1600℃，焙烧4h，用风扇将产物快速冷却至室温，收集产物并研磨后使用200目样品筛过筛，得到低活性MgO。
本发明的有益效果为：
1.本发明一种磷酸镁骨水泥利用琼脂作为微胶囊的将药物包裹起来，再复合到骨水泥中，可在避免药物与骨水泥相互作用的同时提高药物缓释性能，可以实现快速修复骨缺损部位和药物治疗的双重效果。
2.本申请壁材的琼脂生物相容性及生物降解性好、无毒、无抗原性，与药物进行乳化-交联反应，可以得到性能最佳的微胶囊。
3.本申请胶原多肽含量的添加延长了骨水泥材料的初凝和终凝时间，降低了骨水泥水化固化过程中的最高温度，延后了出现最高温度的时间。
具体实施方式
下面对本发明优选的实施例进一步说明：
一种磷酸镁骨水泥，所述水泥包括粉相、缓释微胶囊、有机缓凝剂，所述粉相包括MgO、KH2PO4、Ca(H2PO4)2，所述缓释微胶囊、有机缓凝剂、粉相的质量比为5-15:5-7:100，所述缓释微胶囊的芯材为药物。在本实施例中，药物为对乙酰氨基酚，KH2PO4、Ca(H2PO4)2均采用湿法球磨24h后分别过200日与140目筛。
所述MgO、KH2PO4、Ca(H2PO4)2的质量比为1:4-5:0.5-1。
所述缓释微胶囊的壁材为琼脂。
所述缓释微胶囊的制备方法为：
一、将琼脂和药物按照质量比2-3:1依次加入到纯水中溶解，然后预热至55℃，得到水相溶液；
二、将液体石蜡和油酸山梨坦混合后加热至55℃，一边定速搅拌一边加入缓慢滴加水相溶液，持续搅拌15-20分钟，随后进行冰水浴；
三、持续监测温度，当温度降至10℃时，保持温度并继续搅拌15分钟，随后加入葡萄糖溶液交联60-80分钟；
四、交联后加入絮凝剂絮凝10分钟，倒出乳浊液，然后用有机溶剂清洗去除油相，通风至有机溶剂挥发后即得缓释微胶囊。
所述液体石蜡与油酸山梨的体积比为1:10。所述定速搅拌的转速为400-500r/min。所述葡萄糖溶液的浓度为0.5g/ml。所述有机缓凝剂为胶原多肽。在实际应用中，对本申请上述制备方法得到的缓释微胶囊进行分析检测，其中载药率与包封率分别为27-29％、33-36％，粒径分布在100～300μm的比例为60-62％。所述的载药率＝微球中药物含量/微球总质量；包封率＝微球中药物含量/投药量；制备出的缓释微胶囊进行过筛，称量粒径<l00μm、100～300μm、>300μm范围的微球质量，并除以总的微球质量，得出分布在每个粒径范围的微球的百分比。
将该粒径分布在100～300μm的缓释微胶囊与粉相、有机缓凝剂混合得到多孔缓凝复合磷酸镁基骨水泥。所述多孔缓凝复合磷酸镁基骨水泥在释药过程中，随着缓释微胶囊的降解，空隙率逐渐增加。在释放前期(0～10h)，药物释放速度较快，之后药物释放明显减缓；释药7d后，缓释微胶囊几乎降解完全，药物释放率达到60％～89％，达到了一定的药物缓释效果。本申请的磷酸镁骨水泥的缓释微胶囊可在药物缓释的同时形成多孔结构，不仅可提高药物利用率，亦可为细胞迁移及骨组织生长提供通道。
本申请添加有胶原多肽的磷酸镁骨水泥的初凝时间为8.2-9.5分钟，终凝时间为9.4-10.2分钟，与之对比的是没有添加胶原多肽的骨水泥的初凝时间为5.8±0.1分钟，终凝时间为6.1±0.1分钟。过快的凝固速率增加了医生手术操作的难度，而过慢的凝固速率则延长了手术操作的时间，增加了患者的痛苦。基于临床应用的考虑，骨水泥植入物的水化放热过程应加以控制。植入过程中，过高的温度会造成蛋白质的变性和细胞的死亡，导致组织的坏疽，从而导致植入手术的失败。本申请添加有胶原多肽，延长了磷酸镁骨水泥的初凝与终凝时间，同时也降低了磷酸镁骨水泥固化过程中的最高温度，实际测量结果显示最高温度由常规的63℃下降到低于42℃，同时使得达到最高温度的时间有所延后。
所述MgO为低活性MgO。所述低活性MgO的制备方法为：将MgO在1600℃空气中进行高温焙烧；采用程序升温的方式，首先从室温以5℃/min的速度升温至300℃，保持2h，之后继续以20℃/min的速度升温至1600℃，焙烧4h，用风扇将产物快速冷却至室温，收集产物并研磨后使用200目样品筛过筛，得到低活性MgO。
尽管已经对本发明的技术方案做了较为详细的阐述和列举，应当理解，对于本领域技术人员来说，对上述实施例做出修改或者采用等同的替代方案，这对本领域的技术人员而言是显而易见，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (10)
1.一种磷酸镁骨水泥，其特征在于：所述水泥包括粉相、缓释微胶囊、有机缓凝剂，所述粉相包括MgO、KH2PO4、Ca(H2PO4)2，所述缓释微胶囊、有机缓凝剂、粉相的质量比为5-15:5-7:100，所述缓释微胶囊的芯材为药物。
2.根据权利要求1所述的一种磷酸镁骨水泥，其特征在于：所述MgO、KH2PO4、Ca(H2PO4)2的质量比为1:4-5:0.5-1。
3.根据权利要求1所述的一种磷酸镁骨水泥，其特征在于：所述缓释微胶囊的壁材为琼脂。
4.根据权利要求3所述的一种磷酸镁骨水泥，其特征在于，所述缓释微胶囊的制备方法为：
一、将琼脂和药物按照质量比2-3:1依次加入到纯水中溶解，然后预热至55℃，得到水相溶液；
二、将液体石蜡和油酸山梨坦混合后加热至55℃，一边定速搅拌一边加入缓慢滴加水相溶液，持续搅拌15-20分钟，随后进行冰水浴；
三、持续监测温度，当温度降至10℃时，保持温度并继续搅拌15分钟，随后加入葡萄糖溶液交联60-80分钟；
四、交联后加入絮凝剂絮凝10分钟，倒出乳浊液，然后用有机溶剂清洗去除油相，通风至有机溶剂挥发后即得缓释微胶囊。
5.根据权利要求4所述的一种磷酸镁骨水泥，其特征在于：所述液体石蜡与油酸山梨的体积比为1:10。
6.根据权利要求4所述的一种磷酸镁骨水泥，其特征在于：所述定速搅拌的转速为400-500r/min。
7.根据权利要求4所述的一种磷酸镁骨水泥，其特征在于：所述葡萄糖溶液的浓度为0.5g/ml。
8.根据权利要求1所述的一种磷酸镁骨水泥，其特征在于：所述有机缓凝剂为胶原多肽。
9.根据权利要求1所述的一种磷酸镁骨水泥，其特征在于：所述MgO为低活性MgO。
10.根据权利要求9所述的一种磷酸镁骨水泥，其特征在于，所述低活性MgO的制备方法为：将MgO在1600℃空气中进行高温焙烧；采用程序升温的方式，首先从室温以5℃/min的速度升温至300℃，保持2h，之后继续以20℃/min的速度升温至1600℃，焙烧4h，用风扇将产物快速冷却至室温，收集产物并研磨后使用200目样品筛过筛，得到低活性MgO。
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