CN108295050A - 一种具有骨修复作用的骨结核药物控释微球及制备方法 - Google Patents
一种具有骨修复作用的骨结核药物控释微球及制备方法 Download PDFInfo
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Abstract
本发明涉及一种具有骨修复作用的骨结核药物控释微球及制备方法，在结构设计上将诱导骨生长的活性组分置于内部，在抑菌后期发挥作用的疏水性药物利福平负载于中间聚乳酸层，亲水性抗结核药物异烟肼包埋在壳聚糖中置于外层，因此实现上述三种组分的有序逐层释放。在药物逐级抑菌之后，再释放导骨生长的活性组分，实现骨修复，综合治疗骨结核。载体组分也经过精心选择，磷、钙、胶原蛋白等均是成骨所必须的物质，壳聚糖和聚乳酸具有良好的生物相容性，且可在病灶处降解并被吸收。因此，该缓释微球对骨结核治疗具有很强的针对性，为骨结核的临床治疗提供高效的新材料，应用潜力及价值巨大。
Description
技术领域
本发明属于新材料合成领域，涉及一种具有骨修复作用的骨结核药物控释微球及制备方法。
背景技术
骨结核是一种常见的肺外结核，约占结核总发病率的3～5％，为解决这一医疗难题，局部缓释给药、扩大清除术及“病灶清除+缓释抑菌”等疗法相继被提出并应用于临床。上述治疗方案在一定程度上对骨结核的治疗起到积极的作用，但骨结核治疗会造成局部骨缺损，这种情况下结构组织重建困难，因而在不同步进行骨修复的情况下可能会引起残留结核菌的生长，使得结核病往复。
抗结核药物化疗往往需要长期全身给药，常用的抗结核药物包括异烟肼、利福平、吡嗪酰胺、链霉素等，但上述药物在各脏器组织的积聚会产生严重的毒副作用，因此缓释给药是较好的解决药物副作用的手段。现在被用于缓释给药治疗骨结核治疗的载体很多，包括壳聚糖、聚乳酸(PLGA)、磁性复合颗粒等。由于药物间存在物性上的差异，较难通过简单的办法将其负载在同一载体上，而负载单一药物又违背结核治疗中由于药物杀菌特性不同需要联合给药的原则。目前，鲜少见到将多种抗菌药物负载于同一载体，尚未见到将骨诱导生长因子与多种结核药物同时负载在一个载体上，实现非同步可控释放的报道。
发明内容
要解决的技术问题
为了避免现有技术的不足之处，本发明提出一种具有骨修复作用的骨结核药物控释微球及制备方法。
技术方案
一种具有骨修复作用的骨结核药物控释微球，其特征在于：骨结核药物控释微球为三层核/壳结构，结构组分采用下式描述：
Bio-A/Bio-B/Zn3(PO4)2/Ca3(PO4)2@RFP/PLGA@INH/CS
其中：Bio-A和Bio-B为两种不同的活性物质；
磷酸钙Ca3(PO4)2为成骨主要无机组分；
磷酸锌Zn3(PO4)2为促进杂化组分和成骨有效组分，锌的引入可以大大缩短杂化骨架形成时间，并使得杂化材料形貌规整；
聚乳酸PLGA为可生物降解载药层，降解产物可调节pH值，产物pH为弱酸性；
利福平RFP为第二阶段抗结核药物；
壳聚糖CS为可生物降解载药层，降解产物可调节pH值，产物pH为弱碱性；
异烟肼INH为第一阶段抗结核药物。
所述活性物质A和活性物质B的质量比为20:1。
所述活性物质Bio-A为：胶原蛋白CA、人血清白蛋白HSA、赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸中的一种或几种的任意比混合。
所述活性物质Bio-B为：骨形成蛋白BMP、骨生长肽OGP、转化生长因子家族TGFs、成纤维细胞生长因子FGF、血小板衍生生长因子PDGF、血管内皮生长因子VEGF、胰岛素样生长因子IGF中的一种或几种的任意比混合。
一种所述具有骨修复作用的骨结核药物控释微球的制备方法，其特征在于步骤如下：
步骤1：称取活性物质Bio-A和活性物质Bio-B溶解在磷酸盐缓冲溶液中，得到溶液I；其中活性物质Bio-A与活性物质Bio-B的质量比为20:1；所述活性物质A和活性物质B的总质量浓度为0.2～0.5g/L；
步骤2：配制浓度为100～140g/L的锌盐与钙盐混合溶液，得到溶液II；其中锌盐和钙盐的质量比为1:0.2～0.25；
步骤3：在搅拌条件下向溶液I中加入溶液II，室温反应1～3h后，经过离心、水洗、冷冻干燥即得杂化骨架；其中溶液I与溶液II的体积比为15～20:1；
步骤4：将聚乳酸PLGA、利福平RFP和步骤3制得的杂化骨架溶解、分散到二氯甲烷中得到溶液III；其中聚乳酸的质量浓度为20～50g/L，利福平的质量浓度为1～3g/L，杂化骨架的质量浓度为10～20g/L；
步骤5：配置浓度为1.5g/L的十二烷基磺酸钠水溶液，然后搅拌下向其中加入溶液III，室温下挥发5～8h，经过离心、水洗、干燥即得内核载药体；所述十二烷基磺酸钠水溶液与溶液III的体积比为10-20～1；
步骤6：将步骤5制得的内核载药体超声分散在溶有异烟肼INH的壳聚糖CS溶液中，得到溶液IV；其中内核载药体的质量浓度为10～20g/L，异烟肼的质量浓度为1～3g/L，壳聚糖溶液中壳聚糖的质量浓度为2～4g/L，含醋酸的质量浓度为1～2g/L；
步骤7：将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即制备得到具有骨修复作用的新型骨结核药物控释微球；氢氧化钾水溶液的质量浓度不低于5g/L。
所述步骤5的搅拌速度不低于800r/min。
所述步骤7的经微流控装置制备时连续相和分散相的流速比不低于2。
所述步骤2的锌盐是醋酸锌、硝酸锌、氯化锌或葡萄糖酸锌。
所述步骤2的钙盐是醋酸钙、氯化钙、葡萄糖酸钙、乳酸钙或硝酸钙。
有益效果
本发明提出的一种具有骨修复作用的骨结核药物控释微球及制备方法，通过结构设计和制备方法集成，将两种抗结核药物(异烟肼、利福平)和诱导骨生长的活性组分有机结合，得到了一种新型的具有骨修复作用的骨结核药物控释微球。该微球在结构设计上将诱导骨生长的活性组分置于内部，在抑菌后期发挥作用的疏水性药物利福平负载于中间聚乳酸层，亲水性抗结核药物异烟肼包埋在壳聚糖中置于外层，因此实现上述三种组分的有序逐层释放。在药物逐级抑菌之后，再释放导骨生长的活性组分，实现骨修复，综合治疗骨结核。载体组分也经过精心选择，磷、钙、胶原蛋白等均是成骨所必须的物质，壳聚糖和聚乳酸具有良好的生物相容性，且可在病灶处降解并被吸收。因此，该缓释微球对骨结核治疗具有很强的针对性，为骨结核的临床治疗提供高效的新材料，应用潜力及价值巨大。
附图说明
图1是具有骨修复作用的新型骨结核药物控释微球结构示意图
图2是杂化骨架的SEM照片：
A：BMP/CA/Ca3(PO4)2/Zn3(PO4)2；
B：BMP/HRSA/Ca3(PO4)2/Zn3(PO4)2；
C：OGP/HRSA/Ca3(PO4)2/Zn3(PO4)2；
D：OGP/CA/Ca3(PO4)2/Zn3(PO4)2
图3是内核载药体的SEM照片
图4是具有骨修复作用的新型骨结核药物控释微球的光学显微镜照片
具体实施方式
现结合实施例、附图对本发明作进一步描述：
实施例1：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0381g胶原蛋白和0.0019g骨形成蛋白(BMP)溶解在200mL磷酸盐缓冲溶液中，得到溶液I；称取0.8g醋酸锌和0.2g醋酸钙溶解在10mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应3h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.2g聚乳酸、0.01g利福平和0.1g杂化骨架溶解、分散到10mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发5h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为800r/min；将1g内核载药体超声分散在100mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中内异烟肼的质量浓度为1g/L，壳聚糖溶液中壳聚糖的质量浓度为2g/L，含醋酸的质量浓度为1g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为2，氢氧化钾水溶液的质量浓度为5g/L。
实施例2：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0952g人血清白蛋白和0.0048g骨生长肽(OGP)溶解在200mL磷酸盐缓冲溶液中，得到溶液I；称取1.12g硝酸锌和0.28g氯化钙溶解在10mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应2h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.1g聚乳酸、0.015g利福平和0.05g杂化骨架溶解、分散到5mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发6h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为900r/min；将2g内核载药体超声分散在100mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为3g/L，壳聚糖溶液中壳聚糖的质量浓度为4g/L，含醋酸的质量浓度为2g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为4，氢氧化钾水溶液的质量浓度为10g/L。
实施例3：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0571g赖氨酸和0.0029g转化生长因子家族(TGFs)溶解在200mL磷酸盐缓冲溶液中，得到溶液I。；称取1.5g氯化锌和0.3g葡萄糖酸钙溶解在15mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应1h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.21g聚乳酸、0.014g利福平和0.105g杂化骨架溶解、分散到7mL二氯甲烷中，得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发8h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为800r/min；将1.5g内核载药体超声分散在100mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为1g/L，壳聚糖溶液中壳聚糖的质量浓度为4g/L，含醋酸的质量浓度为1g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为2，氢氧化钾水溶液的质量浓度为7g/L。
实施例4：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0762g色氨酸和0.0028g成纤维细胞生长因子(FGF)溶解在200mL磷酸盐缓冲溶液中，得到溶液I；称取1.0833g葡萄糖酸锌和0.2167g乳酸钙溶解在10mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应1.5h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.21g聚乳酸、0.018g利福平和0.108g杂化骨架溶解、分散到6mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发8h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为1000r/min；将1.3g内核载药体超声分散在100mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为1.8g/L，壳聚糖溶液中壳聚糖的质量浓度为2.5g/L，含醋酸的质量浓度为1.6g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为6，氢氧化钾水溶液的质量浓度为10g/L。
实施例5：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0660g苯丙氨酸和0.0033g血小板衍生生长因子(PDGF)溶解在200mL磷酸盐缓冲溶液中，得到溶液I；称取1.0g氯化锌和0.2g葡萄糖酸钙溶解在12mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应3h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.198g聚乳酸、0.027g利福平和0.099g杂化骨架溶解、分散到9mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发5.5h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为800r/min；将2.55g内核载药体超声分散在150mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为3g/L，壳聚糖溶液中壳聚糖的质量浓度为2.5g/L，含醋酸的质量浓度为1.6g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为4，氢氧化钾水溶液的质量浓度为7g/L。
实施例6：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0476g甲硫氨酸和0.0024g血管内皮生长因子(VEGF)溶解在200mL磷酸盐缓冲溶液中，得到溶液I；称取1.232g氯化锌和0.308g葡萄糖酸钙溶解在11mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应3h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.246g聚乳酸、0.012g利福平和0.096g杂化骨架溶解、分散到6mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液100mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发5h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为1200r/min；将0.75g内核载药体超声分散在50mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为1g/L，壳聚糖溶液中壳聚糖的质量浓度为2g/L，含醋酸的质量浓度为2g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为3，氢氧化钾水溶液的质量浓度为9g/L。
实施例7：具有骨修复作用的新型骨结核药物控释微球的制备
称取0.0714g缬氨酸和0.0036g胰岛素样生长因子(IGF)溶解在150mL磷酸盐缓冲溶液中，得到溶液I；称取0.832g氯化锌和0.208g葡萄糖酸钙溶解在8mL去离子水中，得到溶液II；将溶液I加入到三角瓶中，搅拌条件下向其中加入溶液II，室温反应1h后，经过离心、水洗、冷冻干燥即得杂化骨架；称取0.2g聚乳酸、0.015利福平和0.1g杂化骨架溶解、分散到5mL二氯甲烷中得到溶液III；配置浓度为1.5g/L的十二烷基磺酸钠水溶液50mL，加入到三口瓶中，机械搅拌下向其中加入溶液III，室温下挥发6h，经过离心、水洗、干燥即得内核载药体；其中搅拌速度为900r/min；将1.5g内核载药体超声分散在150mL溶有异烟肼的壳聚糖溶液中，得到溶液IV。其中异烟肼的质量浓度为2g/L，壳聚糖溶液中壳聚糖的质量浓度为4g/L，含醋酸的质量浓度为1g/L；将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即可制备得到具有骨修复作用的新型骨结核药物控释微球。其中连续相和分散相的流速比为5，氢氧化钾水溶液的质量浓度为10g/L。
Claims (8)
1.一种具有骨修复作用的骨结核药物控释微球，其特征在于：骨结核药物控释微球为三层核/壳结构，结构组分采用下式描述：
Bio-A/Bio-B/Zn3(PO4)2/Ca3(PO4)2@RFP/PLGA@INH/CS
其中：Bio-A和Bio-B为两种不同的活性物质，磷酸钙Ca3(PO4)2为成骨主要无机组分，磷酸锌Zn3(PO4)2为促进杂化组分和成骨有效组分，聚乳酸PLGA为可生物降解载药层，利福平RFP为第二阶段抗结核药物，壳聚糖CS为可生物降解载药层，异烟肼INH为第一阶段抗结核药物；
所述活性物质A和活性物质B的质量比为20:1。
2.根据权利要求1所述具有骨修复作用的骨结核药物控释微球，其特征在于：所述活性物质Bio-A为：胶原蛋白CA、人血清白蛋白HSA、赖氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸、缬氨酸中的一种或几种的任意比混合。
3.根据权利要求1所述具有骨修复作用的骨结核药物控释微球，其特征在于：所述活性物质Bio-B为：骨形成蛋白BMP、骨生长肽OGP、转化生长因子家族TGFs、成纤维细胞生长因子FGF、血小板衍生生长因子PDGF、血管内皮生长因子VEGF、胰岛素样生长因子IGF中的一种或几种的任意比混合。
4.一种权利要求1～3所述任一项具有骨修复作用的骨结核药物控释微球的制备方法，其特征在于步骤如下：
步骤1：称取活性物质Bio-A和活性物质Bio-B溶解在磷酸盐缓冲溶液中，得到溶液I；其中活性物质Bio-A与活性物质Bio-B的质量比为20:1；所述活性物质A和活性物质B的总质量浓度为0.2～0.5g/L；
步骤2：配制浓度为100～140g/L的锌盐与钙盐混合溶液，得到溶液II；其中锌盐和钙盐的质量比为1:0.2～0.25；
步骤3：在搅拌条件下向溶液I中加入溶液II，室温反应1～3h后，经过离心、水洗、冷冻干燥即得杂化骨架；其中溶液I与溶液II的体积比为15～20:1；
步骤4：将聚乳酸PLGA、利福平RFP和步骤3制得的杂化骨架溶解、分散到二氯甲烷中得到溶液III；其中聚乳酸的质量浓度为20～50g/L，利福平的质量浓度为1～3g/L，杂化骨架的质量浓度为10～20g/L；
步骤5：配置浓度为1.5g/L的十二烷基磺酸钠水溶液，然后搅拌下向其中加入溶液III，室温下挥发5～8h，经过离心、水洗、干燥即得内核载药体；所述十二烷基磺酸钠水溶液与溶液III的体积比为10-20～1；
步骤6：将步骤5制得的内核载药体超声分散在溶有异烟肼INH的壳聚糖CS溶液中，得到溶液IV；其中内核载药体的质量浓度为10～20g/L，异烟肼的质量浓度为1～3g/L，壳聚糖溶液中壳聚糖的质量浓度为2～4g/L，含醋酸的质量浓度为1～2g/L；
步骤7：将溶液IV作为分散相，正己烷作为连续相，氢氧化钾水溶液为接收液及离子交联剂，经微流控装置即制备得到具有骨修复作用的新型骨结核药物控释微球；氢氧化钾水溶液的质量浓度不低于5g/L。
5.根据权利要求4所述的方法，其特征在于：所述步骤5的搅拌速度不低于800r/min。
6.根据权利要求4所述的方法，其特征在于：所述步骤7的经微流控装置制备时连续相和分散相的流速比不低于2。
7.根据权利要求4所述的方法，其特征在于：所述步骤2的锌盐是醋酸锌、硝酸锌、氯化锌或葡萄糖酸锌。
8.根据权利要求4所述的方法，其特征在于：所述步骤2的钙盐是醋酸钙、氯化钙、葡萄糖酸钙、乳酸钙或硝酸钙。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110338921A (zh) * | 2019-07-15 | 2019-10-18 | 南方医科大学口腔医院 | 一种牙科种植体及其制备方法 |
| CN111407727A (zh) * | 2020-03-26 | 2020-07-14 | 浙江大学 | 哺乳动物雷帕霉素靶蛋白（mTOR）阻断剂在制备治疗钙化性肌腱病药物中的应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219241A (zh) * | 2007-11-27 | 2008-07-16 | 清华大学 | 具骨诱导因子控释功能的生物活性骨修复材料及制备方法 |
| CN102188756A (zh) * | 2011-05-12 | 2011-09-21 | 天津市海河医院 | 一种含药缓释降解骨支架的制备方法 |
| US20170182080A1 (en) * | 2014-03-14 | 2017-06-29 | Bo Han | Functional scaffold for tissue repair and regeneration |
-
2018
- 2018-01-29 CN CN201810083985.7A patent/CN108295050A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219241A (zh) * | 2007-11-27 | 2008-07-16 | 清华大学 | 具骨诱导因子控释功能的生物活性骨修复材料及制备方法 |
| CN102188756A (zh) * | 2011-05-12 | 2011-09-21 | 天津市海河医院 | 一种含药缓释降解骨支架的制备方法 |
| US20170182080A1 (en) * | 2014-03-14 | 2017-06-29 | Bo Han | Functional scaffold for tissue repair and regeneration |
Non-Patent Citations (3)
| Title |
|---|
| NENAD IGNJATOVIĆ 等: "Chitosan-PLGA polymer blends as coatings for hydroxyapatite nanoparticles and their effect on antimicrobial properties,osteoconductivity and regeneration of osseous tissues", 《MATERIALS SCIENCE AND ENGINEERING C》 * |
| ZHAOHUI GE 等: "Development and In Vitro Release of Isoniazid and Rifampicin-Loaded Bovine Serum Albumin Nanoparticles", 《MED SCI MONIT》 * |
| 李大伟: "骨结核治疗用局部长效药物缓释复合材料研究", 《中国博士学位论文全文数据库》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110338921A (zh) * | 2019-07-15 | 2019-10-18 | 南方医科大学口腔医院 | 一种牙科种植体及其制备方法 |
| CN110338921B (zh) * | 2019-07-15 | 2021-06-29 | 南方医科大学口腔医院 | 一种牙科种植体及其制备方法 |
| CN111407727A (zh) * | 2020-03-26 | 2020-07-14 | 浙江大学 | 哺乳动物雷帕霉素靶蛋白（mTOR）阻断剂在制备治疗钙化性肌腱病药物中的应用 |
| CN111407727B (zh) * | 2020-03-26 | 2021-03-23 | 浙江大学 | 哺乳动物雷帕霉素靶蛋白（mTOR）阻断剂在制备治疗钙化性肌腱病药物中的应用 |
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