CN113181418B - 一种医用粘合剂及其制备方法 - Google Patents
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Abstract
本发明公开了一种医用粘合剂及其制备方法,该制备方法包括将2‑氯乙基胺与明胶反应,得到明胶‑乙基胺;在催化剂作用下,明胶‑乙基胺和邻二羟基苯羧酸进行反应,得到明胶‑邻二羟基苯衍生物;将明胶‑邻二羟基苯衍生物与TG酶混合,再添加金属离子溶液进行交联反应,既得所述医用粘合剂;该粘合剂在潮湿环境下仍具有良好的粘附性并能够快速固化,且稳定性好,此外所需原料简单易得、经济实惠,有效控制终产品的成本,利于临床推广;同时,经细胞毒性试验、家兔颈动脉包裹、溶血实验等证实了本发明制得的粘合剂具有安全、无毒,且降解产物无毒的效果。
Description
技术领域
本发明涉及粘合剂技术领域,具体涉及一种医用粘合剂及其制备方法。
背景技术
创伤或手术后无法控制的出血是全球死亡率的主要原因,血管吻合术后的出血和渗血一只困扰着心脏病专家。尤其是大血管吻合手术难以控制的出血,导致了患者的高并发症、高死亡率。当前,外科手术缝合是唯一用于主动脉破裂密封的临床方法,但缝合后的渗血却难以控制,以往只能通过压迫止血来解决。
随着材料科学的最新发展,已经有许多实验化学试剂进行了手术止血的测试,各种医用粘合剂,如纤维蛋白胶,白蛋白-戊二醛粘合剂混合物和氰基丙烯酸酯等为外科手术提供了便利。但是都具有一定的局限性,纤维蛋白粘合剂是从人血浆中提取制造的,因此成本比合成材料更昂贵;并且与血液制品相关的潜在疾病的传播给其带来了严重安全隐患;更为重要的是,在充满血液和组织液的湿润生理环境中,纤维蛋白粘合剂存在粘合强度较差和机械强度不足等缺陷。含醛产品的高毒性则严重限制了相关粘合剂产品在人体中的应用。氰基丙烯酸酯快速聚合时产生的聚合热易使组织受二次损伤,固化后的弹性和柔韧性较差,且储存期短、易发生凝固,这些缺点限制了氰基丙烯酸酯类粘合剂在临床医学中的广泛应用,尤其是体内软组织的修复。
发明内容
本发明的目的在于提供一种医用粘合剂及其制备方法,该粘合剂能够在生理条件下快速固化,并具有一定的组织粘附强度以及优良的机械性能、止血性能和抗感染性能,同时,该粘合剂能够被机体降解吸收,且安全、无菌、无毒,能够广泛用于临床。
为了实现本发明的上述目的,特采用以下技术方案:
本发明第一方面提供一种医用粘合剂的制备方法,所述制备方法包括如下步骤:
(a)将2-氯乙基胺与明胶反应,得到明胶-乙基胺;
(b)在催化剂作用下,明胶-乙基胺和邻二羟基苯羧酸进行反应,得到明胶-邻二羟基苯衍生物;
(c)将明胶-邻二羟基苯衍生物与TG酶混合,再添加金属离子溶液进行交联反应,既得所述医用粘合剂。
优选地,所述步骤(a)中,2-氯乙基胺与明胶反应包括:
将2-氯乙基胺溶液与明胶水溶液混合进行反应,其中,2-氯乙基胺溶液与明胶水溶液的体积比为1∶(1~10);2-氯乙基胺溶液浓度为0.01~1.2M,明胶水溶液浓度为0.01~15g/ml;
优选地,反应条件如下:
反应温度为40~70℃,反应pH值大于10,反应时间为0.5~40h。
优选地,所述步骤(b)中,在催化剂作用下,明胶-乙基胺和邻二羟基苯羧酸进行反应包括:
在催化剂作用下,在明胶-乙基胺溶液中添加邻二羟基苯羧酸进行反应,其中,明胶-乙基胺溶液浓度为0.1~8g/ml。
优选地,所述步骤(b)中,催化剂的终浓度为0.001~10g/ml;
优选地,所述催化剂为EDC和NHS,所述EDC和NHS的质量比为1∶(0~2)。
优选地,所述步骤(b)中,邻二羟基苯羧酸包括但不限于3,4-二羟基苯甲酸、3,4-二羟基苯乙酸、2,3-二羟基苯乙酸和3,4-二羟基苯丙酸。
优选地,所述步骤(b)中,反应条件如下:
反应温度为30~65℃,反应时间为1~30h;反应液pH值为4~7。
优选地,所述步骤(c)中,明胶-邻二羟基苯衍生物与TG酶的质量比为(18~200)∶(1~18);
优选地,所述明胶-邻二羟基苯衍生物与所述金属离子溶液的质量比为1∶(1~20);
优选地,所述金属离子溶液中金属离子的含量为5%~40%。
优选地,所述步骤(c)中,金属离子溶液中金属离子为铁离子、钙离子、锌离子、铝离子和镁离子等二价及更高价离子中的任意一种或多种。
优选地,所述明胶替换为乳清蛋白、白蛋白或植物蛋白。
本发明第二方面提供一种医用粘合剂,所述医用粘合剂通过上述制备方法制得。
与现有技术相比,本发明的有益效果至少包括:
本发明中明胶-邻二羟基苯衍生物具有儿茶酚基团,能够使制备得到的粘合剂在潮湿环境下仍具有良好的粘附性,而且其含有的邻苯二酚基团和金属阳离子的快速反应能够快速固化,可以减少出血及缩短手术时间,并通过TG-酶的添加,能够促进复合物羧基与氨基形成酰基的反应,从而确保了制备粘合剂的长期稳定性,保障了在切口、血管吻合口愈合之前粘附性不会丧失,并具有更好的安全性;此外,本发明所需的材料为明胶、乙基胺、邻二羟基苯羧酸、TG酶,金属阳离子等,上述原料均为简单易得、经济实惠的原材料,有效控制终产品的成本,利于临床推广;同时,经细胞毒性试验、家兔颈动脉包裹、溶血实验等证实了本发明制得的粘合剂具有安全、无毒,且降解产物无毒的效果。
本发明中明胶-邻二羟基苯衍生物、TG酶均可溶于PBS溶液,产品在混合之前具有良好的流动性,保证了应用区域的准确性。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍。在所有附图中,类似的元件或部分一般由类似的附图标记标识。附图中,各元件或部分并不一定按照实际的比例绘制。
图1为本发明实施例1中明胶-3,4-二羟基苯甲酸的核磁氢谱;
图2为实验例中家兔颈动脉吻合实验状态图以及不同处理方式的出血量;
图3为实验例中家兔肝脏创伤止血状态图以及不同处理方式的出血量。
具体实施方式
下面将结合实施例对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案,因此只作为示例,而不能以此来限制本发明的保护范围。
需要注意的是,除非另有说明,本申请使用的技术术语或者科学术语应当为本发明所属领域技术人员所理解的通常意义。
实施例1
本实施例为一种医用粘合剂的制备方法,该制备方法包括如下步骤:
(a)按照体积比为1∶1将浓度为1M的2-氯乙基胺溶液加入浓度为0.1g/ml的明胶水溶液中并搅拌30min,再调节pH值至10.5并在55℃下反应24h,得到明胶-乙基胺;
(b)采用PBS缓冲液配制浓度为0.6g/ml的明胶-乙基胺溶液,并调节pH值至4.2,再添加EDC至终浓度为0.005g/ml、NHS至终浓度为0.003g/ml、3,4-二羟基苯甲酸至终浓度为0.02g/ml,然后在37℃下进行反应24h,随后,将反应液在去离子水中透析两天、冻干,得到明胶-3,4-二羟基苯甲酸;
(c)按照明胶-3,4-二羟基苯甲酸与TG酶的质量比为5∶1将明胶-3,4-二羟基苯甲酸与TG酶混合,再添加40%的氯化铁溶液进行交联反应,既得上述医用粘合剂;
其中,明胶-3,4-二羟基苯甲酸与氯化铁溶液的质量比为1∶10;
本实施例步骤(b)中制备得到的明胶-3,4-二羟基苯甲酸进行核磁氢谱检测,检测结果如图1所示,由图1可确定制备得到明胶-3,4-二羟基苯甲酸。
实施例2
本实施例为一种医用粘合剂的制备方法,该制备方法包括如下步骤:
(a)按照体积比为1∶1.2将浓度为1.2M的2-氯乙基胺溶液加入浓度为0.15g/ml的乳清蛋白水溶液中并搅拌30min,再调节pH值至11.0并在52℃下反应26h,得到乳清蛋白-乙基胺;
(b)采用PBS缓冲液配制浓度为6g/ml的乳清蛋白-乙基胺溶液,并调节pH值至5.6,再添加EDC至终浓度为0.012g/ml、NHS至终浓度为0.016g/ml、3,4-二羟基苯乙酸至终浓度为0.09g/ml,然后在35℃下进行反应26h,随后,将反应液在去离子水中透析两天、冻干,得到乳清蛋白-3,4-二羟基苯乙酸;
(c)按照乳清蛋白-3,4-二羟基苯乙酸与TG酶的质量比为3∶1将乳清蛋白-3,4-二羟基苯乙酸与TG酶混合,再添加40%的氯化铁溶液进行交联反应,既得上述医用粘合剂;
其中,乳清蛋白-3,4-二羟基苯乙酸与氯化铁溶液的质量比为1∶5。
实施例3
本实施例为一种医用粘合剂的制备方法,该制备方法包括如下步骤:
(a)按照体积比为1∶0.8将浓度为0.8M的2-氯乙基胺溶液加入浓度为0.05g/ml的明胶水溶液中并搅拌30min,再调节pH值至12.0并在58℃下反应22h,得到明胶-乙基胺;
(b)采用PBS缓冲液配制浓度为0.5g/ml的明胶-乙基胺溶液,并调节pH值至4.6,再添加EDC至终浓度为0.01g/ml、NHS至终浓度为0.02g/ml、3,4-二羟基苯丙酸至终浓度为0.01g/ml,然后在39℃下进行反应22h,随后,将反应液在去离子水中透析两天、冻干,得到明胶-3,4-二羟基苯丙酸;
(c)按照明胶-3,4-二羟基苯丙酸与TG酶的质量比为7∶1将明胶-3,4-二羟基苯丙酸与TG酶混合,再添加40%的氯化铁溶液进行交联反应,既得上述医用粘合剂;
其中,明胶-3,4-二羟基苯丙酸与氯化铁溶液的质量比为1∶15。
实施例4
本实施例为一种医用粘合剂的制备方法,该制备方法包括如下步骤:
(a)按照体积比为1∶1将浓度为1M的2-氯乙基胺溶液加入浓度为0.1g/ml的白蛋白水溶液中并搅拌30min,再调节pH值至11.5并在55℃下反应24h,得到白蛋白-乙基胺;
(b)采用PBS缓冲液配制浓度为0.6g/ml的白蛋白-乙基胺溶液,并调节pH值至4.2,再添加EDC至终浓度为0.005g/ml、NHS至终浓度为0.003g/ml、3,4-二羟基苯甲酸至终浓度为0.1g/ml,然后在37℃下进行反应24h,随后,将反应液在去离子水中透析两天、冻干,得到白蛋白-3,4-二羟基苯甲酸;
(c)按照白蛋白-3,4-二羟基苯甲酸与TG酶的质量比为8∶1将白蛋白-3,4-二羟基苯甲酸与TG酶混合,再添加40%的氯化铁溶液进行交联反应,既得上述医用粘合剂;
其中,白蛋白-3,4-二羟基苯甲酸与氯化铁溶液的质量比为1∶10。
本发明上述实施例制备得到的医用粘合剂在潮湿环境下仍具有良好的粘附性,而且其含有的邻苯二酚基团和金属阳离子的快速反应能够快速固化,可以减少出血及缩短手术时间,并通过TG-酶的添加,能够促进复合物羧基与氨基形成酰基的反应,从而确保了制备粘合剂的长期稳定性,保障了在切口、血管吻合口愈合之前粘附性不会丧失,并具有更好的安全性。
现通过如下具体实验例对本发明制备得到的医用粘合剂的性能加以验证并作进一步详细说明。
实验例1家兔颈动脉缝合后应用实施例1粘合剂止血研究
家兔术前禁饮食2小时,采用水合氯醛0.03mg/g,腹腔注射麻醉后,固定体位;取颈部正中切口,依次切开皮肤、皮下筋膜、颈阔肌,牵开胸锁乳突肌,暴露颈动脉;游离颈动脉,上至颈动脉分叉处,向下游离足够长度;经耳缘静脉注射肝素;血管夹阻断颈动脉,中间剪断;记录开始吻合时间,吻合血管,吻合结束后再次记录时间;于血管下置入薄膜,给与实施例1制备的粘合剂110μl,待凝胶后开放血管夹,开放后用棉球吸附出血并称重;缝合肌肉,关闭切口。重复三次,出血量分别为:0.1g、0g、0.1g,吻合时间分别为:16min04s,14min20s、13min14s。
实验例2家兔颈动脉缝合后应用Bioglue止血研究
家兔术前禁饮食2小时;采用水合氯醛0.03mg/g,腹腔注射麻醉后,并固定体位;在颈部正中切口,依次切开皮肤、皮下筋膜、颈阔肌,牵开胸锁乳突肌,暴露颈动脉;游离颈动脉,上至颈动脉分叉处,向下游离足够长度;经耳缘静脉注射肝素;血管夹阻断颈动脉,中间剪断;记录开始吻合时间,吻合血管,吻合结束后再次记录时间;于血管下置入薄膜,给与Bioglue110μl,待凝胶后开放血管夹,开放后用棉球吸附出血并称重;缝合肌肉,关闭切口。重复三次,出血量分别为:0.1g、0.2g,0.3g。
实验例3阿司匹林喂养家兔颈动脉缝合后应用实施例1粘合剂止血研究
家兔术前禁饮食2小时;采用水合氯醛0.03mg/g,腹腔注射麻醉后,并固定体位;在颈部正中切口,依次切开皮肤、皮下筋膜、颈阔肌,牵开胸锁乳突肌,暴露颈动脉;游离颈动脉,上至颈动脉分叉处,向下游离足够长度;经耳缘静脉注射肝素;血管夹阻断颈动脉,中间剪断;记录开始吻合时间,吻合血管,吻合结束后再次记录时间;于血管下置入薄膜,给与实施例1粘合剂110μl,待凝胶后开放血管夹,开放后用棉球吸附出血并称重;缝合肌肉,关闭切口。重复三次,出血量分别为:0.15g、0.1g、0.15g。
同样,按照单纯缝合组、阿司匹林喂养单纯缝合组,分别完成实验例4、5。单纯缝合组实验结果:出血量为3.6g、2.41g、3.8g;阿司匹林喂养单纯缝合组的实验结果为:4.5g、4.3g、4.1g。
家兔颈动脉吻合实验状态以及各组出血量结果如图2所示,图中,(a)正常颈动脉;(b)阻断并剪断颈动脉;(c)吻和剪断的颈动脉,尚未开放;(d)吻和完成后开放颈动脉;(e)应用粘合剂后开放颈动脉;(f)各实验组的出血量比较;
由图2可知,粘合剂组的血管吻合后出血量明显少于单纯缝合组,并且与Bioglue组具有一致的良好的止血性能。其中,阿司匹林喂养行单纯缝合组的出血量最大,主要为吻合口大量渗血所致,但在应用本粘合剂后,出血量则明显减少,说明本粘合剂在家兔应用阿司匹林后同样具有良的效果。
实验例6肝脏创伤止血研究
术前禁饮食2小时;水合氯醛0.03mg/g,腹腔注射麻醉后,固定体位;上腹部正中切口,依次切开皮肤、白线、腹膜,暴露肝脏,于肝脏下置入干纱布,并于肝脏表面切开0.5cm切口;实验组于切口处立即给予实施例1制备的粘合剂,对照组则不给予处理措施;五分钟后取出纱布并称重,逐层关闭切口。重复实验4次,实验组出血量结果分别为:0g、0.2g、0g、0.3g,对照组出血量分别为:4.5g、5g、3.4g、4.2g。
家兔肝脏创伤止血状态图以及两组出血量比较如图3所示:图中,图3肝脏止血实验(a)正常肝脏;(b)创伤后肝脏;(c)未应用粘合剂5分钟后肝脏;(d)应用粘合剂5分钟后肝脏;(e)肝脏损伤对照组与应用粘合剂组的出血量比较;
由图3可知,两组的出血量具有明显的差异,应用本发明的实验组的出血量要明显少于对照组,证明了本发明具有良好的止血效果,并且在湿性环境下依旧可以保持完整的粘附性。
最后应说明的是:以上各实施例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例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例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例技术方案的范围,其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (14)
1.一种医用粘合剂的制备方法,其特征在于,包括如下步骤:
(a)将2-氯乙基胺与明胶反应,得到明胶-乙基胺;
(b)在催化剂作用下,明胶-乙基胺和邻二羟基苯羧酸进行反应,得到明胶-邻二羟基苯衍生物;
(c)将明胶-邻二羟基苯衍生物与TG酶混合,再添加金属离子溶液进行交联反应,即得所述医用粘合剂。
2.根据权利要求1所述的制备方法,其特征在于,所述步骤(a)中,2-氯乙基胺与明胶反应包括:
将2-氯乙基胺溶液与明胶水溶液混合进行反应,其中,2-氯乙基胺溶液与明胶水溶液的体积比为1∶(1~10);2-氯乙基胺溶液浓度为0.01~1.2M,明胶水溶液浓度为0.01~15g/mL。
3.根据权利要求1所述的制备方法,其特征在于,所述步骤(a)中,反应条件如下:
反应温度为40~70℃,反应pH值大于10,反应时间为0.5~40h。
4.根据权利要求1所述的制备方法,其特征在于,所述步骤(b)中,在催化剂作用下,明胶-乙基胺和邻二羟基苯羧酸进行反应包括:
在催化剂作用下,在明胶-乙基胺溶液中添加邻二羟基苯羧酸进行反应,其中,明胶-乙基胺溶液浓度为0.1~8g/mL。
5.根据权利要求1所述的制备方法,其特征在于,所述步骤(b)中,催化剂的终浓度为0.001~10g/mL。
6.根据权利要求1所述的制备方法,其特征在于,所述步骤(b)中,所述催化剂为EDC和NHS,所述EDC和NHS的质量比为1∶(0~2)。
7.根据权利要求1所述的制备方法,其特征在于,所述步骤(b)中,邻二羟基苯羧酸包括但不限于3,4-二羟基苯甲酸、3,4-二羟基苯乙酸、2,3-二羟基苯乙酸和3,4-二羟基苯丙酸。
8.根据权利要求1所述的制备方法,其特征在于,所述步骤(b)中,反应条件如下:
反应温度为30~65℃,反应时间为1~30h;反应液pH值为4~7。
9.根据权利要求1所述的制备方法,其特征在于,所述步骤(c)中,明胶-邻二羟基苯衍生物与TG酶的质量比为(18~200)∶(1~18)。
10.根据权利要求1所述的制备方法,其特征在于,所述步骤(c)中,所述明胶-邻二羟基苯衍生物与所述金属离子溶液的质量比为1∶(1~20)。
11.根据权利要求1所述的制备方法,其特征在于,所述步骤(c)中,所述金属离子溶液中金属离子的含量为5%~40%。
12.根据权利要求1所述的制备方法,其特征在于,所述步骤(c)中,金属离子溶液中金属离子为铁离子、钙离子、锌离子、镁离子、铝离子的二价及更高价离子中的任意一种或多种。
13.根据权利要求1所述的制备方法,其特征在于,所述明胶替换为乳清蛋白、白蛋白或植物蛋白。
14.一种医用粘合剂,其特征在于,通过权利要求1~9任一所述的制备方法制得。
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CN105541963A (zh) * | 2015-08-31 | 2016-05-04 | 深圳出入境检验检疫局食品检验检疫技术中心 | 一种在蛋白质上修饰烯酰基团的方法 |
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