CN116763980A - 一种磷酸盐基药物缓释载体及其制备方法 - Google Patents
一种磷酸盐基药物缓释载体及其制备方法 Download PDFInfo
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Abstract
本发明涉及无机材料领域，尤其是涉及一种磷酸盐基药物缓释载体及其制备方法。本发明通过原料调整，选用3D打印方法，制备得到孔径集中于200‑300μm的缓释载体，孔径更为合理，缓释效果更佳，且原料成本低，工艺流程简单。
Description
技术领域
本发明涉及无机材料领域，尤其是涉及一种磷酸盐基药物缓释载体及其制备方法。
背景技术
磷酸镁水泥是一种早强、快凝的胶凝材料，其水化产物胶粘性好，且生物相容性好，因此常备用作骨水泥。磷酸镁水泥主要由氧化镁、磷酸盐和液相组成，基于酸碱中和反应生成磷酸镁盐。
磷酸镁水泥作为医用材料需要有一定的孔隙，多孔结构有利于组织生长和营养成分的渗入，也可进行药物负载达到缓释，虽然磷酸镁水泥固化体本身为多孔结构，但是其孔多为纳米级，自身并无法满足孔隙要求，因此常常采用人工法进行造孔。
多孔磷酸镁水泥已有部分研究，但研究并不广泛，现有技术CN108863290A公开以明胶和壳聚糖制备了一种微球材料，具有控制药物释放、延长药物疗效的作用，从而提高药物的稳定性，降低药物的不良反应，同时其自身具有抗炎作用，明胶-壳聚糖微球生物相容性好，明胶-壳聚糖微球/磷酸钙骨水泥在体液环境中时，微球溶化成液体，明胶和壳聚糖会以液体状态缓慢析出，使整个支架被明胶和壳聚糖包裹，CN108379666A则公开一种明胶微球/磷酸镁基骨水泥药物缓释载体及其制备方法，先制备1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐交联的载药明胶微球；再将所得载药明胶微球与磷酸镁基骨水泥粉相混合均匀，再与磷酸镁基骨水泥液相调和固化，得到所述的明胶微球/磷酸镁基骨水泥药物缓释载体，然而，两者需采用特殊原料，成本高，制备工艺相对复杂。
3D打印技术是一种以数字模型文件为基础，运用可粘合材料，通过逐层打印方式来构造物体的技术，它与传统的去除材料加工技术不同，因此又称为添加制造，与传统制造方式相比，3D打印技术无需设计模具，建造速度快，单个实物制作费用低，并可大量节省原材料，目前3D打印技术在生物工程与医学领域也进行了应用，提供了更多的材料制造解决方案。现有技术CN113233887A公开一种可控多孔磷酸钙支架及其制备方法，所述磷酸钙支架的成分包括钙磷陶瓷和磷酸钙骨水泥，所述磷酸钙支架上设置有孔结构，所述孔结构包括宏孔结构、微孔结构和通孔结构，所述磷酸钙支架包括晶体结构，所述晶体结构之间设置有通孔结构，所述磷酸钙支架的外形根据患者缺损部位进行匹配设计，通过改进了牺牲材料的制备方法，选用精度更高的3D打印技术，可以制备出更加复杂多样的孔结构，CN110694109A提供一种复合载药高分子微球的磷酸钙骨水泥支架，其制备方法包括以下步骤：采用微乳液法制备载药的可降解高分子微球；配制粘结剂溶液；将载药高分子微球、磷酸钙骨水泥粉末和粘结剂溶液混合，获得混合浆料；将设计的多孔支架三维模型输入到三维打印设备机；将步骤S2配制的混合浆料置于三维打印机的料筒中，从打印机的喷头挤出的纤维根据设计的模型进行堆叠，得到多孔样品；将多孔样品置于20-80℃、相对湿度为90％-100％的环境中养护1-14天，然后干燥，得到复合载药高分子微球的磷酸钙骨水泥支架，CN112245656A通过可设计钙源及镁源比例，结合三维设计软件，选择打印模型并调整打印参数，旨在构建出不同含镁量的可用于3D打印的磷酸钙镁骨水泥复合支架，具备药物缓释功能及促血管化潜力，CN109437826A公开一种可3D打印的磷酸镁骨水泥及其制备方法和应用，所述骨水泥包含烧结氧化镁，磷酸二氢盐，聚戊二酸丙二醇酯，聚己内酯，缓凝剂、水。但是，上述方法同样存在制备工艺复杂，原材料价格昂贵的缺陷，并且，制备得到的磷酸镁水泥孔径分步不合理不可控，限制了药物缓释效果。
发明内容
本发明为解决上述现有技术中的问题，公开一种磷酸镁水泥基药物缓释载体，通过原料调整，选用3D打印方法，制备得到孔径集中于200-300μm的缓释载体，孔径更为合理，缓释效果更佳，且原料成本低，工艺流程简单。
具体的，本发明磷酸盐基药物缓释载体，由以下重量份原料经3D打印制备而成：
重烧氧化镁200-300份，
烧结氧化镁50-100份，
磷酸二氢钾150-300份，
碳酸锌40-60份，
硼砂15-30份，
双氧水30-50份，
磷酸二氢铵10-30份，
水200-250份。
优选的，磷酸盐基药物缓释载体由以下重量份原料经3D打印制备而成：
重烧氧化镁220-280份，
烧结氧化镁60-100份，
磷酸二氢钾160-290份，
碳酸锌40-55份，
硼砂20-30份，
双氧水34-50份，
磷酸二氢铵10-25份，
水210-240份。
优选的，所述重烧氧化镁由碳酸镁经煅烧、粉磨制成。更优选的，所述煅烧为1500-1550℃煅烧1-3h，所述粉磨为粉磨至比表面积制成4-5m2/g。
优选的，所述烧结氧化镁由碳酸镁经烧结、细磨制成。更优选的，所述烧结为1300-1350℃烧结1-3h，所述细磨为细磨至比表面积制成5-6m2/g。
本发明磷酸镁水泥选用重烧氧化镁、烧结氧化镁和磷酸二氢钾作为主要原料，磷酸镁水泥所用氧化镁一般采用重烧氧化镁，氧化镁的选用对磷酸镁水泥凝结时间、力学性能具有重要影响，本发明由于采用3D打印方法进行成型，为满足浆料挤出和堆叠效果，且同时兼顾气泡对成型效果的影响，本发明研究表明，采用重烧氧化镁和烧结氧化镁作为活性氧化镁，利用不同煅烧温度和细度对氧化镁水化活性和水化进程的影响，可满足多孔磷酸镁水泥3D打印施工和后期力学性能的要求。
本发明采用硼砂作为调凝剂，对磷酸镁水泥浆料凝结时间进行调控。碳酸锌的添加可提高多孔缓释载体的力学性能，提高气泡分布均匀性，降低气泡造成的力学性能下降。
优选的，所述碳酸镁为分析纯。
优选的，所述双氧水质量浓度为20-30％。本发明采用化学发泡法引入气泡，不同品种发泡剂在磷酸镁水泥中引入的气泡是不同的，本发明研究发现，200-300μm气孔更有利于磷酸镁水泥对药物的存储和缓释，经过大量实验研究，本发明采用双氧水作为发泡剂，无毒且不会引入杂质，为控制双氧水在磷酸镁水泥中的发泡均匀性和气泡大小，并结合3D打印工艺要求，本发明添加少量磷酸二氢铵，铵根离子可对双氧水在磷酸镁水泥中的发泡过程进行调控，实现平稳发泡，气泡均匀，制备合理孔径的气泡，满足3D打印成型要求，磷酸根也可为磷酸镁水泥水化提供磷酸根。
优选的，所述水为去离子水。
本发明还涉及上述磷酸盐基药物缓释载体的制备方法，具体的，包括如下步骤：
1)按重量份称取各原料，备用，
2)将重烧氧化镁、烧结氧化镁、磷酸二氢钾、碳酸锌、硼砂混合均匀，得干料，
3)将磷酸二氢铵与水混合均匀，得液料，
4)将干料与液料混合均匀后，倒入双氧水迅速搅拌均匀后静置5-10min后，利用3D打印机喷头挤出，得到层叠体，
5)将层叠体进行养护、破碎、筛分，得到缓释载体。
本发明利用3D打印工艺制备得到多孔磷酸镁水泥层叠体，进行养护后可根据药物粒径要求进行破碎、筛分，简单高效，成本低。
此外，本发明还涉及上述磷酸盐基药物缓释载体在药物缓释中的应用。
具体实施方式
对本发明磷酸镁水泥进行气孔孔径、抗压强度进行测试，其中气孔孔径测试采用氮吸附法绘制气孔孔径曲线，以200-300μm孔径在总气泡中占比作为结果，抗压强度为利用养护后层叠体的7d抗压强度。
实验过程中重烧氧化镁由分析纯碳酸镁经1550℃煅烧2h、粉磨至比表面积4.6m2/g，烧结氧化镁由分析纯碳酸镁经1300℃烧结2h、细磨至比表面积5.5m2/g，双氧水浓度为30％，水为去离子水。
实施例1
磷酸盐基药物缓释载体由以下重量份原料经3D打印制备而成：重烧氧化镁230份，烧结氧化镁90份，磷酸二氢钾200份，碳酸锌50份，硼砂23份，双氧水39份，磷酸二氢铵15份，水220份。
经检测，磷酸镁水泥浆料3D打印成型效果良好，层叠体无坍塌现象，抗压强度9.5MPa，200-300μm孔径在总气泡中占比96.6％。
实施例2
磷酸盐基药物缓释载体由以下重量份原料经3D打印制备而成：重烧氧化镁260份，烧结氧化镁80份，磷酸二氢钾260份，碳酸锌40份，硼砂25份，双氧水40份，磷酸二氢铵20份，水230份。
经检测，磷酸镁水泥浆料3D打印成型效果良好，层叠体无坍塌现象，抗压强度10.2MPa，200-300μm孔径在总气泡中占比98.3％。
对比例1
缓释载体，原料为：重烧氧化镁340份，磷酸二氢钾260份，碳酸锌40份，硼砂25份，双氧水40份，磷酸二氢铵20份，水230份。
经检测，磷酸镁水泥浆料3D打印成型塌模严重，无法进行3D打印制作。
对比例2
缓释载体，原料为：重烧氧化镁280份，烧结氧化镁100份，磷酸二氢钾260份，硼砂25份，双氧水40份，磷酸二氢铵20份，水230份。
经检测，磷酸镁水泥浆料3D打印成型效果一般，层叠体无大面积坍塌现象，抗压强度5.2MPa，200-300μm孔径在总气泡中占比63.7％。
对比例3
缓释载体，原料为：重烧氧化镁260份，烧结氧化镁80份，磷酸二氢钾260份，碳酸锌40份，硼砂25份，十二烷基苯磺酸钠40份，磷酸二氢铵20份，水230份。
经检测，磷酸镁水泥浆料3D打印成型塌模严重，无法进行3D打印制作。
对比例4
缓释载体，原料为：重烧氧化镁260份，烧结氧化镁80份，磷酸二氢钾280份，碳酸锌40份，硼砂25份，双氧水40份，水230份。
经检测，磷酸镁水泥浆料3D打印成型塌模严重，无法进行3D打印制作。
最后应说明的是：以上各实施方式仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施方式对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施方式所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施方式技术方案的范围。
Claims (10)
1.一种磷酸盐基药物缓释载体，其特征在于，由以下重量份原料经3D打印制备而成：
重烧氧化镁200-300份，
烧结氧化镁50-100份，
磷酸二氢钾150-300份，
碳酸锌40-60份，
硼砂15-30份，
双氧水30-50份，
磷酸二氢铵10-30份，
水200-250份。
2.根据权利要求1所述磷酸盐基药物缓释载体，其特征在于，由以下重量份原料经3D打印制备而成：
重烧氧化镁220-280份，
烧结氧化镁60-100份，
磷酸二氢钾160-290份，
碳酸锌40-55份，
硼砂20-30份，
双氧水34-50份，
磷酸二氢铵10-25份，
水210-240份。
3.根据权利要求1所述磷酸盐基药物缓释载体，其特征在于，所述重烧氧化镁由碳酸镁经煅烧、粉磨制成。
4.根据权利要求3所述磷酸盐基药物缓释载体，其特征在于，所述煅烧为1500-1550℃煅烧1-3h，所述粉磨为粉磨至比表面积制成4-5m2/g。
5.根据权利要求1所述磷酸盐基药物缓释载体，其特征在于，所述烧结氧化镁由碳酸镁经烧结、细磨制成。
6.根据权利要求5所述磷酸盐基药物缓释载体，其特征在于，所述烧结为1300-1350℃烧结1-3h，所述细磨为细磨至比表面积制成5-6m2/g。
7.根据权利要求3-6任一所述磷酸盐基药物缓释载体，其特征在于，所述碳酸镁为分析纯。
8.根据权利要求1所述磷酸盐基药物缓释载体，其特征在于，所述双氧水质量浓度为20-30％。
9.根据权利要求1所述磷酸盐基药物缓释载体，其特征在于，所述水为去离子水。
10.根据权利要求1-9任一所述磷酸盐基药物缓释载体的制备方法，其特征在于，包括如下步骤：
1)按重量份称取各原料，备用，
2)将重烧氧化镁、烧结氧化镁、磷酸二氢钾、碳酸锌、硼砂混合均匀，得干料，
3)将磷酸二氢铵与水混合均匀，得液料，
4)将干料与液料混合均匀后，倒入双氧水迅速搅拌均匀后静置5-10min后，利用3D打印机喷头挤出，得到层叠体，
5)将层叠体进行养护、破碎、筛分，得到缓释载体。
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