CN116370715A - 一种含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法 - Google Patents
一种含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法 Download PDFInfo
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Abstract
本发明涉及骨充填材料技术领域,具体为一种含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法。其制备方法包括:(1)按比例称量无水硫酸钙粉末和他汀类药物粉末,然后将两者混合放置于调拌板上,在常温下用调刀水平反复调拌后,再上下反复调拌;其中,无水硫酸钙粉末和他汀类药物粉末的重量比为1:0.005~0.01;(2)在常温下,按比例快速称量去端多肽胶原凝胶,所述去端多肽胶原凝胶为固体果冻状;所述去端多肽胶原凝胶与无水硫酸钙和他汀类药物混合粉末的重量比为1:2~2:1;(3)将称量好的去端多肽胶原凝胶置于放有调拌板上,在常温下,用调刀反复按压调拌,即得含他汀类药物的可塑形多孔生物复合骨充填材料。
Description
技术领域
本发明涉及骨充填材料技术领域,特别是涉及一种可塑形多孔生物复合骨充填材料及制备方法。
背景技术
骨组织是人体分布最广泛、最普遍的器官之一,其功能的丧失是导致生活质量下降的主要原因之一。目前由于严重创伤、感染、骨肿瘤等因素导致的大块骨吸收、缺损日益成为临床医生所面临的一个重大挑战。而随着人口老龄化问题越来越严重,随之而来的骨病(例如骨质疏松症、骨关节炎和骨髓炎)以及由原发肿瘤切除术和骨科手术(如全关节置换术和植入物固定)引起的创伤相关损伤的发病率增加,这些导致对于骨填充和修复材料需求的不断增加。
目前,治疗骨缺损最主要的方法为自体或异体骨移植,但因供体缺乏、手术创伤性较大、高成本、受骨缺损部位形状限制等问题,也给患者和临床医生带来了很大的难题。国际上每年大约有200万例脊柱,骨盆骨和其他躯干骨的骨移植手术,然而无论是自体骨或者异体骨移植,都有约50%的植入物面临着因各种原因导致失败的发生。骨与关节相关疾病如骨质疏松症、关节炎、肥胖、糖尿病、癌症等的高发,对骨组织造成损伤,并最终影响人体骨骼的健康和功能。因此,如何减少骨缺损患者的手术成功率、减轻患者经济负担、提高患者生活质量就成为当下急需解决的问题。
口腔方面的骨缺损对于患者带来的危害也是显而易见的。首先是导致患者牙齿缺失,继而影响患者吐字、发音不清伴、软组织缺损、影响进食,进而可能引起患者容貌的改变,最终造成病人心理和精神上的负担。牙齿缺失会严重影响患者咀嚼、辅助发音的功能和美观,同时还可能影响口颌***的健康及患者的心理健康。牙齿缺失已经证实是肥胖、糖尿病、心血管疾病、部分类型肿瘤和阿尔兹海默症的危险因素。
对于骨缺损的治疗自体骨移植(将同一患者身体的一个部位的组织移植到另一个部位)是最成功的,也是金标准。但它面临着许多限制,如:收集组织的可用性差、慢性供体部位疼痛、发病率和并发症等。而且,在进行额外的复杂手术时会产生巨大的伤害和疼痛,同时取骨可能会导致供体部位发病。同种异体骨(将组织从一个不同基因型的患者移植到另一名患者)和异种移植物(从另一个物种的供体移植组织)也是现在临床中应用较为广泛的替代材料之一,但由于免疫介导的排斥反应、传染病传播的风险、不能满足治疗大块骨缺损的等缺点,一定程度上限制了其应用前景。
鉴于以上原因,合成材料的发现开启了骨移植医学领域的新时代。这类生物材料因其出色的生物相容性、可吸收性、骨传导性、可塑性等优点而越来越受到关注,包括聚甲基丙烯酸甲酯(PMMA)、磷酸钙骨水泥(CPC)和硫酸钙(CAS)等。尤其是钙磷人工骨生物材料因其良好的生物相容性、可原位固化、可注射性等优点,可以注入各种几何形状的骨缺损部位进行原位塑形固化,大大提升了临床中对骨缺损治疗的成功率。但随着临床的应用、研究的深入,同样也发现了一些问题,如:PMMA存在聚合温度高、生物相容性差、不可降解等缺点;CPC存在成骨时间较长、机械性能较差等缺点。另一方面,此类材料多运用于整形外科、骨科等,可注射骨生物材料在口腔中的运用缺少之又少。
可注射性磷酸钙和硫酸钙骨替代物为最常见的钙磷生物材料。这类复合材料降解的同时为血管和成骨细胞长入提供空间和引导性支架,即其降解吸收过程同步于骨的爬行替代过程,骨替代物吸收时间于骨折达到临床愈合时间一致。尤其因为其可注射性,对于口腔内的骨缺损治疗尤为方便。它不仅操作简单,并且经粘膜注射或通过微创开窗注射降低了感染风险,更减轻了患者的身心负担。
硫酸钙(CAS)由于其生物相容性和骨传导特性,以及其低廉的价格及可注射性,在口腔科、骨科等外科重建手术中具有用于微创手术的潜力。而且,因其比CPC更坚硬、支撑作用更强、已经逐渐成为临床常用的骨缺损替代产品。CAS用作骨缺损充填修复材料已经有百年之久,但由于早期CAS的制作工艺的限制,CAS的纯度不高导致临床使用效果不佳。但随着技术的不断发展,已经使得CAS以超高纯度的晶体结构存在。研究表明,CAS具有良好的组织相容性,对周围组织不产生炎症和刺激作用,更重要的是CAS在体内降解时间为1-4个月,这与新骨形成时间相一致,这也为新骨再生创造了有利条件。另一方面,有研究表明CAS成骨机理包括一下两方面:CAS充填骨缺损,恢复骨外形,防止软组织长入,且在降解同时为血管和成骨细胞长入提供空间和传导支架。CAS降解吸收过程同步于骨的爬行替代过程,最终在植骨区形成连续的骨组织;CAS具有骨诱导活性,其机理为CAS降解吸收过程中局部形成微酸环境,引起局部脱钙、骨基质成骨诱导因子释放。CAS在体内降解时局部形成高钙环境,为新骨形成提供钙源的同时,还能促进成骨细胞增殖、分化。因此,CAS是具有骨传导性、骨诱导性及成骨作用,并且无毒、无免疫源性,可以再短时间内完全生物降解的成骨材料。
但同时也有研究表明CAS有固化速度快从而抑制骨再生的缺点。因此,为了将CAS优点极大的发挥出来,这也就需要开发出一种结合其他材料的新型复合材料。
他汀类药物通过甲羟戊酸途径在刺激骨再生方面发挥作用,它们抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶从而影响成骨细胞中的生长因子,例如:上调BMP-2和VEGF的表达。有研究表明,他汀类药物可促进骨愈合及新骨(NB)形成、增强骨强度并增加骨体积等作用。此外,研究发现当全身或局部注射时,他汀类药物可促进植入物周围的骨形成。但是,在没有有效药物递送***(DDS)的情况下单独使用时,他汀类药物的作用仅能维持5天。也就需要一种更好的药物释放材料,使氟伐他汀可以在体内长期稳定释放生物活性物质。
CN106390192A公开了一种生物型骨水泥,由粉剂和液剂组成,其中粉剂组成重量百分比为:硫酸钙0.1-50%;亲水生物材料0.01-10%;丙烯酸类树脂0.1-50%;显影剂1.0-30%;引发剂0.001-5%;液剂组成重量百分比为:丙烯酸类单体10-99%;促进剂0.01-5%;抗氧化剂0-1%。但是,该材料中硫酸钙并非主体材料,仅作为添加物;其抗折强度过高,其应用范围为身体骨骼,并不能用于口腔颌骨。而且,该材料的反应过程中释放温度,最低也在48℃,如果在反应过程中置于骨缺损处,容易造成伤口周围的细胞死亡;另外,其彻底硬化时间较长。
去端肽胶原具有高保湿能力和优异的生物相容性,它常被用作培养细胞的组织工程支架。另一方面,去端肽胶原具有引导组织再生的积极作用,它可以促进成骨细胞分化和I型胶原蛋白的产生,从而起到引起骨再生的作用。因此,发明人研究团队利用这些特点,使用去端肽胶原作为溶剂与CAS混合,从而改善并提升CAS性能。
发明人参与的研究团队于《Injectable Porous Bioresorbable CompositeContaining Fluvastatin for Bone Augmentation》(ACS Biomater.Sci.Eng.2019,5,5422-5429)中,采用了硫酸钙、液体的去端多肽胶原及氟伐他汀,但是因测试实验均是将样品于37℃放置7天后再进行测试。该产品硬化时间过长,缝合时软组织压力会使材料变形,降低了材料治疗效果,从而降低了手术时使用的可能性。
因此,如何对上述材料进行改进成为了本领域亟需解决的技术难题之一。
发明内容
针对上述问题,本发明的目的是提供一种含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法。
为了解决上述技术问题,本申请提供了如下技术方案:
一种含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,包括以下步骤:
(1)按比例称量无水硫酸钙粉末和他汀类药物粉末,然后将两者混合放置于调拌板上,在常温下用调刀水平反复调拌后,再上下反复调拌;其中,无水硫酸钙粉末和他汀类药物粉末的重量比为1:0.005~0.01;
(2)在常温下,按比例快速称量去端多肽胶原凝胶,所述去端多肽胶原凝胶为固体果冻状;所述去端多肽胶原凝胶与无水硫酸钙和他汀类药物混合粉末的重量比为1:2~2:1;
(3)将称量好的去端多肽胶原凝胶置于放有调拌板上,在常温下,用调刀反复按压调拌,即得含他汀类药物的可塑形多孔生物复合骨充填材料。
其中,所述步骤(1)中,用调刀以1-3次/s的速度,水平反复调拌20-30s后,再上下反复调拌20-30s。
其中,所述步骤(3)中,用调刀以0.5-1次/s速度反复按压调拌25-90s。
其中,所述无水硫酸钙粉末的纯度≥99.99%。
其中,所述他汀类药物粉末的纯度≥98%。
其中,所述去端多肽胶原凝胶的来源为牛或猪,纯度>99%,脂肪含量<1%;分子量为270-300KD,储存温度为2-8℃。
其中,所述常温的温度为18-37℃。
其中,所述他汀类药物包括氟伐他汀或瑞舒伐他汀。
与现有技术相比,本发明的含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法至少具有以下有益效果:
本发明的含他汀类药物的可塑形多孔生物复合骨充填材料仅需1小时内(实际凝固时间均小于30分钟,凝固后30分钟内完成测试)即能达到抗压强度20Mpa,应用到临床治疗中,放到骨缺损处时只需极短时间即可硬化(具有一定支撑性),这样当缝合时软组织压力不会使得材料变形,提高了材料治疗效果,大大提高了手术时使用的可能性。
延长操作时间与材料固化速度是相对矛盾的性质,而本发明材料很好的解决了此项矛盾。该材料增加了充填到骨缺损部位过程中的操作时间,在充填操作结束后又大大缩短了自身固化的时间。
本发明的含他汀类药物的可塑形多孔生物复合骨充填材料兼具了可塑形、可吸收性、多孔搭载性、延长操作时间、缩短材料固化速度、提高成骨水平等特点,可以起到很好的引导骨再生的能力。
下面结合附图对本发明的含他汀类药物的可塑形多孔生物复合骨充填材料及制备方法作进一步说明。
附图说明
图1为含他汀类药物的可塑形多孔生物复合骨充填材料的调配过程照片;其中,A:材料混合前示意图;B:去端多肽胶原凝胶混合前示意图;C:材料混合后形态示意图;D:材料充填到圆形玻璃模具示意图;
图2为含他汀类药物的可塑形多孔生物复合骨充填材料的调配过程温度照片;其中,A:材料混合开始时温度测定;B:材料混合过程中最高温度测定;C:材料未凝固时温度测定;D:材料凝固后温度测定;E:材料凝固1小时后温度测定;
图3为抗压强度测试照片;
图4为实施例1-10的实验结果统计图。
具体实施方式
实施例1
结合图1-2所示,一种含氟伐他汀的可塑形多孔生物复合骨充填材料的制备方法,包括以下步骤:
(1)按比例称量无水硫酸钙粉末和氟伐他汀粉末,然后将两者混合放置于调拌板上,在常温(18-37℃)下用不锈钢调刀以1-3次/s的速度,水平反复调拌20-30s后,再上下反复调拌20-30s。其中,无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.005;
(2)在常温(18-37℃)下,按比例快速称量去端多肽胶原凝胶,所述去端多肽胶原凝胶为固体果冻状;所述去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为1:1;
(3)将称量好的去端多肽胶原凝胶置于放有调拌板上,在常温下,用不锈钢调刀以0.5-1次/s速度反复按压调拌25-90s,即得含氟伐他汀的可塑形多孔生物复合骨充填材料,即可填入骨缺损部位。
其中,去端多肽胶原凝胶的来源为牛或猪,纯度>99%,脂肪含量<1%,分子量为270-300KD,储存温度为2-8℃。
实施例2
与实施例1相比,区别在于:去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为3:2。
实施例3
与实施例1相比,区别在于:去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为2:1。
实施例4
与实施例1相比,区别在于:去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为2:3。
实施例5
与实施例1相比,区别在于:去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为1:2。
实施例6
与实施例1相比,区别在于:无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.01。
实施例7
与实施例1相比,区别在于:无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.01;去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为3:2。
实施例8
与实施例1相比,区别在于:无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.01;去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为2:1。
实施例9
与实施例1相比,区别在于:无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.01;去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为2:3。
实施例10
与实施例1相比,区别在于:无水硫酸钙粉末(纯度≥99.99%)和氟伐他汀粉末(纯度≥98%)的重量比为1:0.01;去端多肽胶原凝胶与无水硫酸钙和氟伐他汀混合粉末的重量比为1:2。
对实施例1-10的可塑形时间、凝固时间、平均温度、最高温度、抗压强度(凝固后30分钟内完成测量)及新生成骨率进行测试,抗压强度测试如图3所示,结果如图4及表1所示。
表1
注:CAS:无水硫酸钙;FS:氟伐他汀;ACG:去端多肽胶原凝胶。
与发明人在《Injectable Porous Bioresorbable Composite ContainingFluvastatin for Bone Augmentation》(ACS Biomater.Sci.Eng.2019,5,5422-5429)中的产品相比,本发明制备的产品的凝固时间大大缩短,其余各项指标亦有不同程度提高。
在2019年发表的文章中确定无水硫酸钙:去端多肽胶原按3:2为最优结果,但其凝固时间仍需要34分钟,而有研究表明临床治疗中凝固时间≤15分钟最为合适。至于其它比例虽然凝固时间短,但物理性质不佳无法应用。在口腔临床治疗中,手术时间不宜过长,所以材料的凝固时间不宜过长。如果骨充填材料在未凝固之前就缝合创口,材料易受软组织等外界条件挤压变形,导致治疗效果达不到预期效果。本发明实验中在不影响材料其他方面性能前体下,大幅缩短凝固时间,最优方案中(实施例1的比例1:1)凝固时间缩短到11分钟左右。分析其机理大致为:凝胶易受阳离子影响,在一定范围内凝胶强度随阳离子浓度增加而增强。当凝胶接触Ca2+时,Ca2+诱导形成良好的均一网络结构,并且Ca2+可以降低凝胶中大分子间的斥力,使得凝胶内部扭结、缠绕形成网络结构,进而更好的包裹无水硫酸钙颗粒,使得两者反应更快、更均匀,两者相互影响提高材料性能。
另外,为达到理想效果,使得材料完全凝固,2019年发表的文章中的体外实验均是在材料合成后于37℃放置7天后进行(参见文中2.3.1、2.3.2和2.4,如2.3.1中明确说明“37℃真空烤箱中7天”;2.3.2机械性能测试(即抗压强度)中明确提到“圆柱形试样如上所述制作”;2.2中明确提到“需将模具放入37℃真空烤箱中”,其凝固条件均比本发明更为严格、复杂。本发明均在室温条件下进行凝固,无需真空烤箱)。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (10)
1.一种含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于,包括以下步骤:
(1)按比例称量无水硫酸钙粉末和他汀类药物粉末,然后将两者混合放置于调拌板上,在常温下用调刀水平反复调拌后,再上下反复调拌;其中,无水硫酸钙粉末和他汀类药物粉末的重量比为1:0.005~0.01;
(2)在常温下,按比例快速称量去端多肽胶原凝胶,所述去端多肽胶原凝胶为固体果冻状;所述去端多肽胶原凝胶与无水硫酸钙和他汀类药物混合粉末的重量比为1:2~2:1;
(3)将称量好的去端多肽胶原凝胶置于放有调拌板上,在常温下,用调刀反复按压调拌,即得含他汀类药物的可塑形多孔生物复合骨充填材料。
2.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述步骤(1)中,用调刀以1-3次/s的速度,水平反复调拌20-30s后,再上下反复调拌20-30s。
3.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述步骤(3)中,用调刀以0.5-1次/s速度反复按压调拌25-90s。
4.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述无水硫酸钙粉末的纯度≥99.99%。
5.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述他汀类药物粉末的纯度≥98%。
6.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述去端多肽胶原凝胶的来源为牛或猪,纯度>99%,脂肪含量<1%。
7.根据权利要求6所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述去端多肽胶原凝胶的分子量为270-300KD,储存温度为2-8℃。
8.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述常温的温度为18-37℃。
9.根据权利要求1所述的含他汀类药物的可塑形多孔生物复合骨充填材料的制备方法,其特征在于:所述他汀类药物包括氟伐他汀或瑞舒伐他汀。
10.权利要求1-9任一所述制备方法制得的含他汀类药物的可塑形多孔生物复合骨充填材料。
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