CN109568673B - 一种新型抗生素骨水泥及其制备方法 - Google Patents
一种新型抗生素骨水泥及其制备方法 Download PDFInfo
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- CN109568673B CN109568673B CN201811406103.2A CN201811406103A CN109568673B CN 109568673 B CN109568673 B CN 109568673B CN 201811406103 A CN201811406103 A CN 201811406103A CN 109568673 B CN109568673 B CN 109568673B
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- bone cement
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- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000000463 material Substances 0.000 claims abstract description 33
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 30
- HWSSEYVMGDIFMH-UHFFFAOYSA-N 2-[2-[2-(2-methylprop-2-enoyloxy)ethoxy]ethoxy]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCOCCOC(=O)C(C)=C HWSSEYVMGDIFMH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 27
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- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Inorganic materials O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
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- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- WFUGQJXVXHBTEM-UHFFFAOYSA-N 2-hydroperoxy-2-(2-hydroperoxybutan-2-ylperoxy)butane Chemical compound CCC(C)(OO)OOC(C)(CC)OO WFUGQJXVXHBTEM-UHFFFAOYSA-N 0.000 description 1
- 208000012260 Accidental injury Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
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- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
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- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 description 1
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 1
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
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- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 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 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
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Abstract
本发明提供了一种新型抗生素骨水泥及其制备方法。材料包括组分A和组分B；所述组分A包括：双酚A双甲基丙烯酸缩水甘油酯、二甲基丙烯酸三甘醇酯、显影剂、无机填料、引发剂及抗生素；所述组分B包括：双酚A乙氧基二甲基丙烯酸酯、二甲基丙烯酸三甘醇酯、显影剂、无机填料、促进剂及抗生素。本发明还涉及前述材料的制备方法。本发明制备得到了多种含有不同抗生素的骨水泥产品，其中热稳定性较差的抗生素在PMMA骨水泥中使用时会受热失活，抗菌性下降或消失，而在本发明的产品中仍保持优异的抗菌性，扩展了骨水泥用抗生素的范围；并且与市售的含抗生素的PMMA骨水泥相比，本发明产品的抗菌谱更宽、抗菌性更强、毒副作用更小。
Description
技术领域
本发明涉及生物医用材料领域，具体地，涉及一种新型抗生素骨水泥及其制备方法。
背景技术
长期以来，全世界因疾病、衰老、意外伤害或战争而造成的骨组织缺损和破坏的患者数以百万计。目前，在椎体成形、关节置换等手术中主要使用PMMA骨水泥，其主要成分是丙烯酸酯类共聚物及其单体。然而，该类产品在使用过程中会释放出大量的热，最高温度达到80℃甚至更高，超过人体组织的耐受范围，造成周围组织坏死；椎体成形手术中并发症就是PMMA进入椎管损伤神经，其中热灼伤是一个重要因素。同时，热灼伤引起的周围组织坏死，会导致假体的无菌松动。
另外，在多年的临床实践中发现，部分患者在关节假体处及周围骨组织和软组织中发生感染。为了治疗这些感染，通常使用含有抗生素的PMMA骨水泥进行翻修。然而，该类产品同样存在使用时温度过高的缺陷；并且，由于很多种抗生素对温度敏感，受热时药效下降甚至失活，使得PMMA骨水泥很难选用抗菌谱、抗菌效果、毒性等综合性能较好的抗生素，比如抗菌谱广、毒性小的β-内酰胺类抗生素就很难应用于PMMA骨水泥；另外，由于适用于PMMA骨水泥的抗生素品种较少，使得PMMA骨水泥产品很难充分发挥不同品种抗生素之间的协同作用，不利于产品抗菌性的提高，如强生的庆大霉素骨水泥只含有庆大霉素、贺利氏的Copal G+V只含有庆大霉素和万古霉素；同时，由于长期使用一种或固定几种抗生素，一定程度上增大了细菌变异产生耐药性的概率，已经发现一些MRSA、VRE、VBE等细菌对万古霉素产生了耐药性，由多重耐药菌引起的关节假体感染翻修的数量也一直在增加。扩展可以应用于骨水泥产品的抗生素品种，以及提高骨水泥产品的抗菌性，对于骨水泥厂家一直是一种极大的挑战。
此前，我公司已开发出一种凝胶状快速聚合骨填充材料及制备方法（专利申请号：CN10201800053589.4），其主要成分为双酚A双甲基丙烯酸缩水甘油酯和双酚A乙氧基二甲基丙烯酸酯，该产品使用时的最高温度远低于PMMA骨水泥，能够很好的应用于首次骨组织修复手术中。然而，当时并未研究该体系产品与抗生素尤其是热稳定性较差的抗生素的相互作用，以及抗生素在该体系产品中的稳定性和释放特性，尚未开发出具有优异抗菌性的低温聚合骨填充材料，限制了其在骨组织翻修手术中的应用。
发明内容
针对现有技术中的缺陷，本发明的目的是提供一种新型抗生素骨水泥及制备方法。
根据本发明的一个方面，提供一种新型抗生素骨水泥，包括组分A和组分B，以质量百分数计算，
所述组分A包括以下组分：
双酚A双甲基丙烯酸缩水甘油酯 10-65份，
二甲基丙烯酸三甘醇酯 10-65份，
过氧化物引发剂 0.1-2份，
抗生素 0-10份；
显影剂 10-30份，
无机填料 10-30份，
所述组分B包括以下组分：
双酚A乙氧基二甲基丙烯酸酯 10-65份，
二甲基丙烯酸三甘醇酯 10-65份，
促进剂 0.1-2份，
抗生素 0-10份，
显影剂 10-30份，
无机填料 10-30份，
所述组分A与组分B的质量比为1：1，且组分A及组分B中，抗生素含量不同时为0。
优选地，本发明所涉及的双酚A双甲基丙烯酸缩水甘油酯可以用双酚A乙氧基二甲基丙烯酸酯代替，也可以用双酚A双甲基丙烯酸缩水甘油酯与双酚A乙氧基二甲基丙烯酸酯混合材料代替。
优选地，所述组分A中的过氧化物引发剂为过氧化苯甲酰、过氧化苯甲酰叔丁酯或过氧化甲乙酮的一种或多种。
优选地，所述组分B中的促进剂为N,N-二甲基对甲苯胺。
所述组分A及组分B中，抗生素为可以耐受40℃的抗生素品种，为青霉素、头孢菌素、喹诺酮类抗生素、庆大霉素中的一种或多种。
优选地，所述组分A及组分B中，显影剂为硫酸钡、二氧化锆的一种或多种，粒径分布1-50μm。
优选地，所述组分A及组分B中，无机填料为自磷酸钙、硫酸钙或生物玻璃的一种或多种。
本发明还涉及前述的具有优异抗菌性的低温聚合骨填充材料的制备方法，所述方法包括如下步骤：
步骤一，组分A的配制：
（1）将双酚A双甲基丙烯酸缩水甘油酯与二甲基丙烯酸三甘醇酯搅拌混合12 h以上，使其混合均匀；
（2）将过氧化物引发剂加入基体材料继续混合12 h以上；
（3）加入显影剂、无机材料、抗生素电动混合搅拌成膏状物质，完成组分A配制；
步骤二，组分B配制：
（1）将双酚A乙氧基二甲基丙烯酸酯与二甲基丙烯酸三甘醇酯搅拌混合12 h以上，使其混合均匀；
（2）将促进剂加入基体材料继续混合12 h以上；
（3）加入显影剂、无机材料、抗生素电动混合搅拌成膏状物质，完成组分B配制；
步骤三，将组分A和组分B加入双组份灌装机，匀速注射到包装盒内并封口。本发明的原理：组分A和组分B均为膏体状态，当将两者混合后注射到病人患处，过氧化物引发剂与促进剂N,N-二甲基对甲苯胺组成了聚合反应引发体系，使得三种单体双酚A双甲基丙烯酸缩水甘油酯（Bisphenol-a-glycidyl dimethacrylate简称Bis-GMA）、双酚A乙氧基二甲基丙烯酸酯（Bisphenol-a-ethoxy dimethacrylate简称Bis-EMA）、二甲基丙烯酸三甘醇酯（Triethylene glycol dimethacrylic acid简称TEGDMA）通过自由基反应形成三维交联网状结构的聚合物大分子，固化为有一定力学强度的固体；抗生素可以从骨水泥产品表面释放出来，发挥抗菌作用；显影剂用于诊断和观察骨水泥在体内的位置和状态；无机填料可以增强骨水泥的力学性能，其中生物玻璃等无机填料还可以促进骨组织的生长。
与现有技术相比，本发明具有如下的有益效果：（1）一些热稳定性较差的抗生素，不能用于PMMA骨水泥，在本发明产品中却可以发挥良好的抗菌性，扩展了骨水泥用抗生素的范围；（2）通过调节加入抗生素的品种，对市场上现有的抗生素PMMA骨水泥有抗药性的细菌，本发明产品也具有良好的抗菌性，扩大了骨水泥产品的抗菌谱；（3）加入不同品种的抗生素，可以发挥抗生素间的协同作用，提高了骨水泥产品的抗菌效果。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
本实施例涉及一种新型抗生素骨水泥及制备方法，其制备方法包括如下步骤：
步骤一，组分A配制：
（1）基体材料配制：将双酚A双甲基丙烯酸缩水甘油酯（Bis-GMA）、二甲基丙烯酸三甘醇酯（TEGDMA）使用电动搅拌器搅拌混合12 h以上，使其混合均匀。Bis-GMA占配料总体质量的30份，TEGDMA占配料总体质量28份。
（2）根据基体材料配制后将过氧化苯甲酰加入基体材料继续混合12 h以上。引发剂占配料总体质量0.5份。
（3）将（2）混料后加入二氧化锆占总体质量17.5份、生物玻璃占总体质量20份，阿莫西林钠占总体质量4份，电动混合搅拌成膏状物质，以上完成组分A制作。
步骤二，组分B配制：
（1）基体材料配制：将双酚A乙氧基二甲基丙烯酸酯（Bis-GMA）、二甲基丙烯酸三甘醇酯（TEGDMA）使用电动搅拌器搅拌混合12 h以上，使其混合均匀。Bis-GMA占配料总体质量的20份，TEGDMA占配料总体质量20份。
（2）根据（1）基体材料配制后将促进剂N,N-二甲基对甲苯胺加入基体材料继续混合12 h以上。促进剂占配料总体质量0.3份。
（3）将（2）混料后加入二氧化锆占总体质量25份、生物玻璃占总体质量34.7份，电动混合搅拌成膏状物质，以上完成组分B制作。
步骤三，将组分A和组分B按照1：1比例加入双组份灌装机，匀速注射到包装盒内并封口。
应用：将A、B组分混合后得到可注射骨水泥。将实施例1所得材料进行性能测试，测得结果表示，使用过程中温度较低，力学性能良好，对金黄色葡萄球菌有明显的抑制作用。
对比例1
使用市售的Palacos ®R骨水泥，向其粉剂中加入阿莫西林钠，占整体骨水泥的质量分数为2份，按照其使用说明书与液剂混合。将对比例1所得材料进行性能测试，测得结果表示，使用过程中温度较高，导致抗生素失活，对金黄色葡萄球菌没有明显的抑制作用。
实施例2
本实施例涉及一种新型抗生素骨水泥及制备方法，其制备方法包括如下步骤：
步骤一，组分A配制：
（1）基体材料配制：将双酚A乙氧基二甲基丙烯酸酯（Bis-GMA）、二甲基丙烯酸三甘醇酯（TEGDMA）使用电动搅拌器搅拌混合12 h以上，使其混合均匀。Bis-GMA占配料总体质量的20份，TEGDMA占配料总体质量40份。
（2）根据基体材料配制后将过氧化苯甲酰叔丁酯加入基体材料继续混合12 h以上。引发剂占配料总体质量0.3份。
（3）将（2）混料后加入硫酸钡占总体质量23份、生物玻璃占总体质9.7份，盐酸环丙沙星占总体质量5份，硫酸庆大霉素2份，电动混合搅拌成膏状物质，以上完成组分A制作。
步骤二，组分B配制：
（1）基体材料配制：将双酚A乙氧基二甲基丙烯酸酯（Bis-GMA）、二甲基丙烯酸三甘醇酯（TEGDMA）使用电动搅拌器搅拌混合12 h以上，使其混合均匀。Bis-GMA占配料总体质量的30份，TEGDMA占配料总体质量20份。
（2）根据（1）基体材料配制后将促进剂N,N-二甲基对甲苯胺加入基体材料继续混合12 h以上。促进剂占配料总体质量0.5份。
（3）将（2）混料后加入硫酸钡占总体质量27.5份、生物玻璃占总体质量20份，阿莫西林钠占总体质量2份，电动混合搅拌成膏状物质，以上完成组分B制作。步骤三，将组分A和组分B按照1：1比例加入双组份灌装机，匀速注射到包装盒内并封口。
应用： 将A、B组分混合后得到可注射骨水泥。将实施例2所得材料进行性能测试，测得结果表示，使用过程中温度较低，力学性能良好，对厌氧菌有明显的抑制作用。
对比例2
使用强生公司市售的庆大霉素骨水泥，按照其使用说明书混合粉剂和液剂。将对比例2所得材料进行性能测试，测得结果表示，使用过程中温度较高，且该产品对厌氧菌没有明显的抑制作用。
表1 实施例及对比例所制备的骨水泥材料性能测试结果
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (1)
1.一种新型抗生素骨水泥，包括组分A和组分B，其中：
所述组分A包括以下组分：
双酚A双甲基丙烯酸缩水甘油酯30份，
二甲基丙烯酸三甘醇酯28份，
过氧化物引发剂0.5份，
阿莫西林钠4份，
二氧化锆17.5份，
生物玻璃20份，
所述组分B包括以下组分：
双酚A乙氧基二甲基丙烯酸酯20份，
二甲基丙烯酸三甘醇酯20份，
N,N-二甲基对甲苯胺0.3份，
二氧化锆25份，
生物玻璃34.7份，
所述组分A与组分B的质量比为1：1；
所述新型抗生素骨水泥的制备方法包括如下步骤：
步骤一，组分A的配制：
(1)将双酚A双甲基丙烯酸缩水甘油酯与二甲基丙烯酸三甘醇酯搅拌混合12h以上，使其混合均匀；
(2)将过氧化物引发剂加入基体材料继续混合12h以上；
(3)加入显影剂、无机材料、抗生素电动混合搅拌成膏状物质，完成组分A配制；
步骤二，组分B配制：
(1)将双酚A乙氧基二甲基丙烯酸酯与二甲基丙烯酸三甘醇酯搅拌混合12h以上，使其混合均匀；
(2)将促进剂加入基体材料继续混合12h以上；
(3)加入显影剂、无机材料、抗生素电动混合搅拌成膏状物质，完成组分B配制；
步骤三，将组分A和组分B加入双组分灌装机，匀速注射到包装盒内并封口。
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Effective date of registration: 20231102 Address after: 200120 floor 2, building 2, No. 139, xuanqiu Road, Xuanqiao Town, Pudong New Area, Shanghai Patentee after: HARMONY BIOTECH LTD. Address before: Room 302, Floor 1 and 3, Building 6, No. 1525 Minqiang Road, Songjiang District, Shanghai, 201600 Patentee before: SHANGHAI LEGEND MEDICAL TECHNOLOGY CO.,LTD. |