CN112891622A - 一种多孔钙镁双相陶瓷微球及其制备方法 - Google Patents
一种多孔钙镁双相陶瓷微球及其制备方法 Download PDFInfo
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- CN112891622A CN112891622A CN202110155794.9A CN202110155794A CN112891622A CN 112891622 A CN112891622 A CN 112891622A CN 202110155794 A CN202110155794 A CN 202110155794A CN 112891622 A CN112891622 A CN 112891622A
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- Prior art keywords
- magnesium
- microspheres
- calcium
- phase
- phosphate salt
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- 239000004005 microsphere Substances 0.000 title claims abstract description 91
- 239000000919 ceramic Substances 0.000 title claims abstract description 46
- ZFXVRMSLJDYJCH-UHFFFAOYSA-N calcium magnesium Chemical compound [Mg].[Ca] ZFXVRMSLJDYJCH-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 33
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 30
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims abstract description 25
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 claims abstract description 20
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- 108010010803 Gelatin Proteins 0.000 claims description 38
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- 239000008273 gelatin Substances 0.000 claims description 38
- 235000019322 gelatine Nutrition 0.000 claims description 38
- 235000011852 gelatine desserts Nutrition 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 9
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- QQFLQYOOQVLGTQ-UHFFFAOYSA-L magnesium;dihydrogen phosphate Chemical compound [Mg+2].OP(O)([O-])=O.OP(O)([O-])=O QQFLQYOOQVLGTQ-UHFFFAOYSA-L 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 4
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 claims description 4
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- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
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- MHJAJDCZWVHCPF-UHFFFAOYSA-L dimagnesium phosphate Chemical compound [Mg+2].OP([O-])([O-])=O MHJAJDCZWVHCPF-UHFFFAOYSA-L 0.000 claims description 2
- 229910000395 dimagnesium phosphate Inorganic materials 0.000 claims description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
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- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
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- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 2
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- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 claims description 2
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- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 claims description 2
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Abstract
本发明公开了一种多孔钙镁双相陶瓷微球及其制备方法。以磷酸钙盐和磷酸镁盐为主要原料,利用油包水型乳化交联法制备多孔钙镁双相陶瓷微球,并负载抗菌、抗肿瘤、抗骨质疏松或促成骨等药物。所得微球具有较为均匀的粒径分布,且其多孔结构可确保较大的药物装载率,同时具有持续的钙离子和镁离子释放能力、良好的生物相容性、良好的诱导骨生长性,良好的诱导血管生长性,且该双相陶瓷微球可持续性释放药物并发挥作用,可用于药物递送及骨填充。
Description
技术领域
本发明属于生物材料制备技术领域,特别涉及一种多孔钙镁双相陶瓷微球及其制备方法。
背景技术
我国每年新增骨损伤病例1000万例以上,其中超过300万例因骨缺损尺度超出骨组织自愈合能力而需进行植入性外科手术,其目的是充填骨缺损来刺激骨愈合。目前,临床上常用的骨植入材料包括自体骨、异体骨及人工材料等。自体骨虽是骨移植的金标准,但自体骨来源极为有限且还会导致供区并发症,增加病患者的痛苦;而异体骨的来源虽较自体骨广,但其存在病源传播的危险和免疫排斥反应;因此人工材料由于其来源不受限且可不断研究改进的优势,受到研究人员的广泛关注。
磷酸钙材料由于具有良好的生物相容性、骨传导性以及可降解性,在无机骨修复材料中具有重要的地位。镁是人体必需的矿物元素,是维持神经、肌肉和心脏应激性的重要离子之一,主要分布于细胞内,可参与物质代谢和能量代谢,具有维护骨骼生长等作用。因此将磷酸钙材料与磷酸镁材料复合使用,不仅可以提升材料的生物相容性、骨诱导能力以及降解性能,也可为人体补充一定量的钙镁离子,赋予骨填充材料一定的功能性,拓宽其应用领域。
目前,骨修复材料多以粉体、微球或块状支架等形式应用于骨组织工程领域。其中,粉体通常缺少孔隙结构,不能为细胞提供良好的生长场所与营养运输;而块状陶瓷太脆,无法切割成特殊形状,限制了其在临界尺寸骨缺损中的应用。较前两者,微球流动性好,内部孔结构均匀,点接触不易团聚,与不规则颗粒相比,球形颗粒会减小炎症反应,促进骨再生。且当球形颗粒填满骨腔时,颗粒之间的空隙提供了相互连接的大孔,有利于细胞、骨组织和血管的生长。当微球中存在相互连通的微孔时,可提高微球的比表面积,可加速材料的降解,促进了营养和废物的运输,并促进了宿主组织的渗透。可见,微球形式的骨修复材料将更适用于其在药物缓释领域的应用。现常用的微球制备方法有喷雾干燥法、乳化交联法、模板法、自组装法等。其中乳化交联法工艺设备简单、制备条件温和;高速搅拌下的微球能很好地分散于水油体系中,不易团聚,球形良好。
为实现骨缺损修复与疾病治疗的双重目的,本发明采用油包水型乳化交联法,制备一种新型、多功能的多孔双相陶瓷微球。所制备的多孔双相陶瓷微球具有较为均匀的粒径分布(300-500μm),且其多孔结构可确保较大的药物装载率,同时具有持续的钙离子和镁离子释放能力、良好的生物相容性、良好的诱导骨生长性,良好的诱导血管生长性,一定的抗压强度,药物持续释放性,可用于药物递送及骨填充。
发明内容
本发明针对现有技术不足,提出一种多孔钙镁双相陶瓷微球及其制备方法,使得陶瓷微球同时具有一定的抗压强度,规则的球形形貌、多孔结构、可控的颗粒及晶粒尺寸、良好的药物负载及缓释能力、持续的钙离子和镁离子释放能力等特点。
本发明解决上述技术问题所采用的方案是:
一种多孔钙镁双相陶瓷微球的制备方法,包括以下步骤:
1)配制明胶水溶液;
2)向明胶水溶液中加入磷酸钙盐和磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)将液体石蜡和Span-80混合均匀,作为油相备用;
4)将水相缓慢滴加至油相中,搅拌后改冰水浴;
5)加入一定的交联剂,继续搅拌;
6)反应结束后,过滤、洗涤、干燥,得到明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球热处理以除去明胶,得到所述的多孔钙镁双相陶瓷微球。
优选地,所述磷酸钙盐包括α-磷酸三钙、β-磷酸三钙、羟基磷灰石、磷酸四钙、焦磷酸钙中的一种或几种;所述磷酸镁盐包括磷酸氢镁、氯化镁、磷酸三镁、硝酸镁、氢氧化镁和硫酸镁中的一种或几种;磷酸钙盐的粒径为500nm-2μm;磷酸镁盐的粒径为1-5μm。
优选地,步骤(1)明胶水溶液中明胶的质量分数为10-30wt%;步骤(2)所得水相溶液中,磷酸钙盐的质量分数为25-75wt%,磷酸镁盐的质量分数为25-75wt%;步骤(3)中的液体石蜡为20-60体积份,Span-80为2-6体积份。
优选地,步骤(4)中的搅拌速度为300-600r/min。
优选地,步骤(5)中所选择的交联剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)中的一种或几种的混合物;交联时间为0.5~1.5h。
优选地,步骤(7)中所述热处理设备为马弗炉烧结或管式炉烧结;热处理过程如下:先在200-500℃预烧1h-5h,升温速率为3℃/min-10℃/min,再在800-1100℃烧结2h-5h,升温速率为3℃/min-10℃/min,烧结结束后以5℃/min-100℃/min降温,最终冷却至室温,即得到多孔钙镁双相陶瓷微球。
优选地,将所述多孔双相陶瓷微球在药物溶液中浸泡一定时间进行载药,得到多孔钙镁双相陶瓷微球。
优选地,所述的药物为硫酸庆大霉素,万古霉素,利福平,阿仑膦酸钠,唑来膦酸钠、雷奈酸锶、硫酸软骨素中的一种或几种。
本发明的另一目的是提供一种多孔钙镁双相陶瓷微球,采用上述的方法制备得到。
本发明的另一目的是提供上述多孔钙镁双相陶瓷微球在骨修复材料领域的应用。
与现有技术相比,本发明的有益效果为:
1)本发明所采用的油包水型乳化交联法所制备的明胶/磷酸钙/磷酸镁复合微球具有良好的球形度,粒径分布均匀(300-500μm),且粒径可控,产量较高,可达85%以上,同时具有较高的载药包封率,可实现药物的长期缓释同时促进骨髓间充质干细胞的增殖。
2)本发明所制备的多孔双相载药陶瓷微球生物相容性好、性能稳定、可降解,同时结合磷酸钙材料和磷酸镁材料的优势,实现钙离子和镁离子的长期缓慢释放,具备促成骨、促血管、激活多种酶活性等功能,拓展了其应用领域。
3)本发明所制备的多孔双相载药陶瓷微球经烧结后,可除去制备过程中所添加的明胶,不仅保证了微球规则的球形度,并使微球内部具有贯通的孔隙结构,有利于药物的高效负载及细胞的黏附,方便临床使用。
4)本发明所制备的多孔双相载药陶瓷微球制备工艺简单,操作方便,易于推广。
附图说明
图1为本发明所得多孔钙镁双相陶瓷微球的实物图;
图2为本发明实施例1所得陶瓷微球与BMSCs细胞共培养1、3和5D后CCK8检测结果,其中CMCB-Ⅰ代表TCP与TMP的比例为3:1、CMCB-Ⅱ为1:1、CMCB-Ⅲ为1:3;
图3为本发明实施例1所得的不同烧结制度下所得陶瓷微球的表面SEM图;
图4为本发明实施例2所得未烧结微球的SEM图,其中从左到右放大倍数依次增大;
图5为本发明实施例3所得多孔双相陶瓷微球烧结后的XRD图。
具体实施方式
为更好的理解本发明,下面的实施例是对本发明的进一步说明,但本发明的内容不仅仅局限于下面的实施例。
实施例1
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入一定比例的磷酸钙盐和磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800-1100℃烧结,烧结时升温速率为5℃/min,烧结时间为2h-4h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在所配制的药物溶液中浸泡一定的时间即可得所述的载药微球。
改变步骤2)中磷酸钙盐和磷酸镁盐的混合粉末的比例,将所得微球与BMSCs细胞共培养,结果如图2所示。
改变步骤2)中磷酸钙盐和磷酸镁盐的混合粉末的比例,以及步骤7)中烧结制度,对所得载药微球进行表面形貌测试,结果如图3所示。
实施例2
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入6g磷酸钙盐和2g磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800-900℃烧结,烧结时升温速率为5℃/min,烧结时间为2h-4h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在庆大霉素药物溶液中浸泡一定的时间即可得所述的载药微球。
实施例3
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入4g磷酸钙盐和4g磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800-1000℃烧结,烧结时升温速率为3℃/min,烧结时间为2h-5h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在庆大霉素药物溶液中浸泡一定的时间即可得所述的载药微球。
实施例4
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入4g磷酸钙盐和4g磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800-1100℃烧结,烧结时升温速率为4℃/min,烧结时间为2h-5h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在庆大霉素药物溶液中浸泡一定的时间即可得所述的载药微球。
实施例5
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入2g磷酸钙盐和6g磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800℃烧结,烧结时升温速率为5℃/min,烧结时间为2h-5h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在庆大霉素药物溶液中浸泡一定的时间即可得所述的载药微球。
实施例6
本实施例中多孔钙镁双相陶瓷微球制备工艺如下:
1)称取5g的明胶,加15mL水,配制明胶水溶液;
2)在步骤(1)所制得的明胶水溶液中加入6g磷酸钙盐和2g磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)取50mL液体石蜡和5m LSpan-80,混合均匀,作为油相备用;
4)将步骤(1)制备的水相缓慢滴加至步骤(3)制备的油相中,以400r/min速度搅拌10-20min后改冰水浴;
5)加入0.5M的交联剂(EDC),继续搅拌30min后关闭搅拌;
6)反应结束后,过滤、洗涤、干燥,得到所述的明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球在200-500℃预烧5h,烧结时升温速率为3℃/min,再在800℃烧结,烧结时升温速率为5℃/min,烧结时间为2h-5h,烧结结束后的降温速率为5℃/min-100℃/min,最终冷却至室温,即得到多孔双相陶瓷微球;
8)将所得的微球在庆大霉素药物溶液中浸泡一定的时间即可得所述的载药微球。
以上所述是本发明的优选实施方式而已,当然不能以此来限定本发明之权利范围,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和变动,这些改进和变动也视为本发明的保护范围。
Claims (10)
1.一种多孔钙镁双相陶瓷微球的制备方法,其特征在于,包括以下步骤:
1)配制明胶水溶液;
2)向明胶水溶液中加入磷酸钙盐和磷酸镁盐的混合粉末,混合均匀,作为水相备用;
3)将液体石蜡和Span-80混合均匀,作为油相备用;
4)将水相缓慢滴加至油相中,搅拌后改冰水浴;
5)加入一定的交联剂,继续搅拌;
6)反应结束后,过滤、洗涤、干燥,得到明胶/磷酸钙-磷酸镁双相复合微球;
7)所得复合微球热处理以除去明胶,得到所述的多孔钙镁双相陶瓷微球。
2.根据权利要求1所述的制备方法,其特征在于,所述磷酸钙盐包括α-磷酸三钙、β-磷酸三钙、羟基磷灰石、磷酸四钙、焦磷酸钙中的一种或几种;所述磷酸镁盐包括磷酸氢镁、氯化镁、磷酸三镁、硝酸镁、氢氧化镁和硫酸镁中的一种或几种;磷酸钙盐的粒径为500nm-2μm;磷酸镁盐的粒径为1-5μm。
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)明胶水溶液中明胶的质量分数为10-30wt%;步骤(2)所得水相溶液中,磷酸钙盐的质量分数为25-75wt%,磷酸镁盐的质量分数为25-75wt%;步骤(3)中的液体石蜡为20-60体积份,Span-80为2-6体积份。
4.根据权利要求1所述的制备方法,其特征在于,步骤(4)中的搅拌速度为300-600r/min。
5.根据权利要求1所述的制备方法,其特征在于,步骤(5)中所选择的交联剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)中的一种或几种的混合物;交联时间为0.5~1.5h。
6.根据权利要求1所述的制备方法,其特征在于,步骤(7)中所述热处理设备为马弗炉烧结或管式炉烧结;热处理过程如下:先在200-500℃预烧1h-5h,升温速率为3℃/min-10℃/min,再在800-1100℃烧结2h-5h,升温速率为3℃/min-10℃/min,烧结结束后以5℃/min-100℃/min降温,最终冷却至室温,即得到多孔钙镁双相陶瓷微球。
7.根据权利要求1所述的制备方法,其特征在于,将所述多孔钙镁双相陶瓷微球在药物溶液中浸泡一定时间进行载药,得到多孔钙镁双相载药陶瓷微球。
8.根据权利要求7所述的制备方法,其特征在于,所述的药物为硫酸庆大霉素,万古霉素,利福平,阿仑膦酸钠,唑来膦酸钠、雷奈酸锶、硫酸软骨素中的一种或几种。
9.一种多孔钙镁双相陶瓷微球,其特征在于,采用权利要求1~8任一项所述的方法制备得到。
10.如权利要求9所述的多孔钙镁双相陶瓷微球的应用,其特征在于,用于骨修复材料。
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