CN107308487A - 一种可生物降解高吸水医用复合止血海绵及其制备方法 - Google Patents
一种可生物降解高吸水医用复合止血海绵及其制备方法 Download PDFInfo
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Abstract
本发明属于医疗器械技术领域,尤其涉及一种可生物降解高吸水医用复合止血海绵及其制备方法。本发明所述的可生物降解高吸水医用复合止血海绵,止血材料采用共聚物组成,性能稳定;乌贼墨多糖提供强大而全面的止血功能,弥补壳聚糖不能激活凝血因子VII不足,十二烷基壳聚糖可以快速阻止动脉出血;胶原蛋白液引入氧化微晶纤维素,氧化微晶纤维素吸湿性和稳定性良好,能够通过接触激活作用促进凝血的进行,止血性能优异;采用安全无毒交联,止血海绵网状结构整齐,孔隙分布均匀,质地松软,韧性良好。
Description
技术领域
本发明属于医疗器械技术领域,尤其涉及一种可生物降解高吸水医用复合止血海绵及其制备方法。
背景技术
止血海绵作为一种常见的医用耗材,具有吸收渗液,快速止血,防治粘连,促进创面愈合等作用。止血海绵在临床上一般用于内脏手术时的毛细血管渗出性止血。止血海绵临床应用包括普通外科、心血管外科、整形外科、泌尿外科、骨科、皮肤科、烧伤科、妇科、口腔科、眼科等科室。止血海绵具有对组织伤害小、操作简便、止血迅速等特点,但现有技术中的止血海绵的生物相容性仍然不够理想,吸水性能较差,通常会导致吸液性能损失,渗出液无法及时吸收,止血效果不良,生物降解性能差而且会带来潜在的致癌危险。
发明内容
发明目的:为了克服以上问题,本发明的其中一个目的是提供一种可生物降解高吸水医用复合止血海绵。
技术方案:本发明所述的一种可生物降解高吸水医用复合止血海绵,包括以下重量份的组分:氧化微晶纤维素2-8份、胶原蛋白原液8-16份、十二烷基壳聚糖20-30份、乌贼墨多糖5-9份、聚乙二醇1-3份、ε-己内酯5-8份、葡萄糖酸锶1-3份、右旋糖酐铁1-2份、三七提取液1-5份、桉油精0.5-1.5份、交联剂1-3份、吐温-601-3份、乙醇25-40份、去离子水65-85份。
优选地,所述的胶原蛋白原液提取自鱼鳔、鱿鱼皮的一种。
优选地,所述的聚乙二醇的重均分子量Mw为1000-20000。
优选地,所述的交联剂为双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
优选地,所述的交联剂为重量比为0.5:2.5:1:0.5的双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
优选地,所述的三七提取液提取方法为三七根烘干粉碎后过80目筛后加入料液比为1:10的质量浓度为75%乙醇回流提取3次,合并提取液,在75-80℃下减压蒸发浓缩,回收乙醇,将浓缩液经大孔树脂柱吸附静置1-2h,用去离子水洗脱至洗涤液不出现紫环,再用质量浓度为90%乙醇溶液继续洗脱,得到三七提取液。
优选地,所述的十二烷基壳聚糖的制备方法如下:
1)将粘均分子量为50-100万、脱乙酰度95%-98%的壳聚糖溶于体积浓度为1%的乙酸水溶液中,搅拌至完全溶解;所述壳聚糖与所述乙酸水溶液的比例为2g:60-80mL;
2)向步骤1)获得的溶液中加入氢氧化钠水溶液调节pH至8-12,产生壳聚糖沉淀;过滤,将滤饼溶于二甲基甲酰胺中;所述滤饼干品与二甲基甲酰胺的比例为5g:100-150ml;按壳聚糖重复单元分子个数与月桂醛分子个数之比为4~2:1的比例加入月桂醛,用乙酸调节pH至5-7,室温下搅拌4-6h;在氮气下加入与月桂醛等摩尔的三乙酰氧基硼氢化钠,继续反应12-24h,过滤,滤饼依次用蒸馏水和无水乙醇洗涤,室温晾干,得到十二烷基壳聚糖。
本发明的另一个目的在于提供所述的可生物降解高吸水医用复合止血海绵的制备方法,包括以下步骤:
1)按照配方量将乌贼墨多糖溶液缓慢加入到十二烷基壳聚糖溶液中,混匀后备用;
2)称取配方用量的胶原蛋白液,加入配方量的氧化微晶纤维素,搅拌均匀备用;
3)将配方量的聚乙二醇熔融,加入配方量的ε-已内酯,在保护气中由催化剂催化进行聚合反应,得聚乙二醇-聚(ε-已内酯)共聚物;
4)将步骤1)和步骤2)和步骤3)分别制得的混合液混合搅拌均匀后加入配方量的葡萄糖酸锶、右旋糖酐铁、三七提取液、桉油精、吐温-60、乙醇、去离子水后搅拌均匀后再配方量的交联剂,以50-80rpm速度搅拌50-60min,去离子洗涤得交联产物;
5)将步骤4)制得的交联产物倒入模具中,然后浸泡于2wt%氯化钾溶液中4h,于-20℃预冻4h后取出再经冷冻干燥24-36h并经洗涤干燥,切割、包装和灭菌即得。
优选地,所述的步骤3)的保护气为氮气或氩气。反应条件温和,容易实现。
上述技术方案可以看出,本发明具有如下有益效果:本发明所述的可生物降解高吸水医用复合止血海绵,止血材料采用共聚物组成,性能稳定;乌贼墨多糖提供强大而全面的止血功能,弥补壳聚糖不能激活凝血因子VII不足,十二烷基壳聚糖可以快速阻止动脉出血;胶原蛋白液引入氧化微晶纤维素,氧化微晶纤维素吸湿性和稳定性良好,能够通过接触激活作用促进凝血的进行,止血性能优异;采用安全无毒交联,止血海绵网状结构整齐,孔隙分布均匀,质地松软,韧性良好。
具体实施方式
下面结合具体实施例,进一步阐明本发明。
实施例1
本实施例中所述的一种可生物降解高吸水医用复合止血海绵,包括以下重量份的组分:氧化微晶纤维素2份、鱼鳔胶原蛋白原液8份、十二烷基壳聚糖20份、乌贼墨多糖5份、聚乙二醇1份、ε-己内酯5份、葡萄糖酸锶1份、右旋糖酐铁1份、三七提取液1份、桉油精0.5份、交联剂1份、吐温-60 1份、乙醇25份、去离子水65份。
本实施例所述的聚乙二醇的重均分子量Mw为1000-20000。
本实施例所述的交联剂为重量比为0.5:2.5:1:0.5的双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
本实施例所述的三七提取液提取方法为三七根烘干粉碎后过80目筛后加入料液比为1:10的质量浓度为75%乙醇回流提取3次,合并提取液,在75℃下减压蒸发浓缩,回收乙醇,将浓缩液经大孔树脂柱吸附静置1h,用去离子水洗脱至洗涤液不出现紫环,再用质量浓度为90%乙醇溶液继续洗脱,得到三七提取液。
本实施例所述的十二烷基壳聚糖的制备方法如下:
1)将粘均分子量为50-100万、脱乙酰度95%的壳聚糖溶于体积浓度为1%的乙酸水溶液中,搅拌至完全溶解;所述壳聚糖与所述乙酸水溶液的比例为2g:60mL;
2)向步骤1)获得的溶液中加入氢氧化钠水溶液调节pH至8,产生壳聚糖沉淀;过滤,将滤饼溶于二甲基甲酰胺中;所述滤饼干品与二甲基甲酰胺的比例为5g:100ml;按壳聚糖重复单元分子个数与月桂醛分子个数之比为4:1的比例加入月桂醛,用乙酸调节pH至5,室温下搅拌4h;在氮气下加入与月桂醛等摩尔的三乙酰氧基硼氢化钠,继续反应12h,过滤,滤饼依次用蒸馏水和无水乙醇洗涤,室温晾干,得到十二烷基壳聚糖。
本实施例所述的可生物降解高吸水医用复合止血海绵的制备方法,包括以下步骤:
1)按照配方量将乌贼墨多糖溶液缓慢加入到十二烷基壳聚糖溶液中,混匀后备用;
2)称取配方用量的胶原蛋白液,加入配方量的氧化微晶纤维素,搅拌均匀备用;
3)将配方量的聚乙二醇熔融,加入配方量的ε-已内酯在氮气保护气中由催化剂催化进行聚合反应,得聚乙二醇-聚(ε-已内酯)共聚物;
4)将步骤1)和步骤2)和步骤3)分别制得的混合液混合搅拌均匀后加入配方量的葡萄糖酸锶、右旋糖酐铁、三七提取液、桉油精、吐温-60、乙醇、去离子水后搅拌均匀后再配方量的交联剂,以50rpm速度搅拌50min,去离子洗涤得交联产物;
5)将步骤4)制得的交联产物倒入模具中,然后浸泡于2wt%氯化钾溶液中4h,于-20℃预冻4h后取出再经冷冻干燥24h并经洗涤干燥,切割、包装和灭菌即得。
实施例2
本实施例中所述的一种可生物降解高吸水医用复合止血海绵,包括以下重量份的组分:氧化微晶纤维素8份、鱿鱼皮胶原蛋白原液16份、十二烷基壳聚糖30份、乌贼墨多糖9份、聚乙二醇3份、ε-己内酯8份、葡萄糖酸锶3份、右旋糖酐铁2份、三七提取液5份、桉油精1.5份、交联剂3份、吐温-60 3份、乙醇40份、去离子水85份。
本实施例所述的聚乙二醇的重均分子量Mw为1000-20000。
本实施例所述的交联剂为重量比为0.5:2.5:1:0.5的双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
本实施例所述的三七提取液提取方法为三七根烘干粉碎后过80目筛后加入料液比为1:10的质量浓度为75%乙醇回流提取3次,合并提取液,在80℃下减压蒸发浓缩,回收乙醇,将浓缩液经大孔树脂柱吸附静置2h,用去离子水洗脱至洗涤液不出现紫环,再用质量浓度为90%乙醇溶液继续洗脱,得到三七提取液。
本实施例所述的十二烷基壳聚糖的制备方法如下:
1)将粘均分子量为50-100万、脱乙酰度98%的壳聚糖溶于体积浓度为1%的乙酸水溶液中,搅拌至完全溶解;所述壳聚糖与所述乙酸水溶液的比例为2g: 80mL;
2)向步骤1)获得的溶液中加入氢氧化钠水溶液调节pH至12,产生壳聚糖沉淀;过滤,将滤饼溶于二甲基甲酰胺中;所述滤饼干品与二甲基甲酰胺的比例为5g:150ml;按壳聚糖重复单元分子个数与月桂醛分子个数之比为2:1的比例加入月桂醛,用乙酸调节pH至7,室温下搅拌6h;在氮气下加入与月桂醛等摩尔的三乙酰氧基硼氢化钠,继续反应24h,过滤,滤饼依次用蒸馏水和无水乙醇洗涤,室温晾干,得到十二烷基壳聚糖。
本实施例所述的可生物降解高吸水医用复合止血海绵的制备方法,包括以下步骤:
1)按照配方量将乌贼墨多糖溶液缓慢加入到十二烷基壳聚糖溶液中,混匀后备用;
2)称取配方用量的胶原蛋白液,加入配方量的氧化微晶纤维素,搅拌均匀备用;
3)将配方量的聚乙二醇熔融,加入配方量的ε-已内酯,在氩气保护气中由催化剂催化进行聚合反应,得聚乙二醇-聚(ε-已内酯)共聚物;
4)将步骤1)和步骤2)和步骤3)分别制得的混合液混合搅拌均匀后加入配方量的葡萄糖酸锶、右旋糖酐铁、三七提取液、桉油精、吐温-60、乙醇、去离子水后搅拌均匀后再配方量的交联剂,以80rpm速度搅拌60min,去离子洗涤得交联产物;
5)将步骤4)制得的交联产物倒入模具中,然后浸泡于2wt%氯化钾溶液中4h,于-20℃预冻4h后取出再经冷冻干燥36h并经洗涤干燥,切割、包装和灭菌即得。
实施例3
本实施例中所述的一种可生物降解高吸水医用复合止血海绵,包括以下重量份的组分:氧化微晶纤维素5份、鱼鳔胶原蛋白原液12份、十二烷基壳聚糖25份、乌贼墨多糖7份、聚乙二醇2份、ε-己内酯7份、葡萄糖酸锶2份、右旋糖酐铁1份、三七提取液3份、桉油精1份、交联剂2份、吐温-60 2份、乙醇33份、去离子水70份。
本实施例所述的聚乙二醇的重均分子量Mw为1000-20000。
本实施例所述的交联剂为重量比为0.5:2.5:1:0.5的双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
本实施例所述的三七提取液提取方法为三七根烘干粉碎后过80目筛后加入料液比为1:10的质量浓度为75%乙醇回流提取3次,合并提取液,在75℃下减压蒸发浓缩,回收乙醇,将浓缩液经大孔树脂柱吸附静置1.5h,用去离子水洗脱至洗涤液不出现紫环,再用质量浓度为90%乙醇溶液继续洗脱,得到三七提取液。
本实施例所述的十二烷基壳聚糖的制备方法如下:
1)将粘均分子量为50-100万、脱乙酰度96%的壳聚糖溶于体积浓度为1%的乙酸水溶液中,搅拌至完全溶解;所述壳聚糖与所述乙酸水溶液的比例为2g:70mL;
2)向步骤1)获得的溶液中加入氢氧化钠水溶液调节pH至10,产生壳聚糖沉淀;过滤,将滤饼溶于二甲基甲酰胺中;所述滤饼干品与二甲基甲酰胺的比例为5g:125ml;按壳聚糖重复单元分子个数与月桂醛分子个数之比为3:1的比例加入月桂醛,用乙酸调节pH至6,室温下搅拌5h;在氮气下加入与月桂醛等摩尔的三乙酰氧基硼氢化钠,继续反应16h,过滤,滤饼依次用蒸馏水和无水乙醇洗涤,室温晾干,得到十二烷基壳聚糖。
本实施例所述的可生物降解高吸水医用复合止血海绵的制备方法,包括以下步骤:
1)按照配方量将乌贼墨多糖溶液缓慢加入到十二烷基壳聚糖溶液中,混匀后备用;
2)称取配方用量的胶原蛋白液,加入配方量的氧化微晶纤维素,搅拌均匀备用;
3)将配方量的聚乙二醇熔融,加入配方量的ε-已内酯,在氮气保护气中由催化剂催化进行聚合反应,得聚乙二醇-聚(ε-已内酯)共聚物;
4)将步骤1)和步骤2)和步骤3)分别制得的混合液混合搅拌均匀后加入配方量的葡萄糖酸锶、右旋糖酐铁、三七提取液、桉油精、吐温-60、乙醇、去离子水后搅拌均匀后再配方量的交联剂,以65rpm速度搅拌55min,去离子洗涤得交联产物;
5)将步骤4)制得的交联产物倒入模具中,然后浸泡于2wt%氯化钾溶液中4h,于-20℃预冻4h后取出再经冷冻干燥30h并经洗涤干燥,切割、包装和灭菌即得。
对实施例1-3制备的止血海绵进行性能测试:
1.止血海绵家兔股动脉止血效果实验:用雌雄各6只,体重为1.5-2.0kg的家兔作为模式动物,随机分成两组,每组雌雄各3只,一组人为致使受创明显出血后用实施例1-3制备的止血海绵,另一组人为致使受创明显出血后用普通止血海绵,记录止血效果:使用本实施例制备的止血海绵的家兔90s内完成有效止血,止血率100%;使用普通止血海绵的家兔在300s内无法止血,止血率为0%。
2.止血海绵动物体内降解实验:大小体重均匀的雄性实验大鼠20只,随机分成两组,分别为1组和2组,1组使用实施例1-3制备的止血海绵,2组使用普通止血海绵。人为致使肝叶受创明显出血后分别使用止血海绵和普通海绵覆盖止血包扎观察;1周、4周和8周后解剖处死后观察腹腔记录覆盖部位吸收情况。1组降解速度明显快于2组,1组8周后止血海绵已完全消失,2组8周后降解不明显,几乎没有发生降解。
以上所述仅是本发明的优选实施方式,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,这些改进也应视为本发明的保护范围。
Claims (9)
1.一种可生物降解高吸水医用复合止血海绵,其特征在于:包括以下重量份的组分:氧化微晶纤维素2-8份、胶原蛋白原液8-16份、十二烷基壳聚糖20-30份、乌贼墨多糖5-9份、聚乙二醇1-3份、ε-己内酯5-8份、葡萄糖酸锶1-3份、右旋糖酐铁1-2份、三七提取液1-5份、桉油精0.5-1.5份、交联剂1-3份、吐温-601-3份、乙醇25-40份、去离子水65-85份。
2.根据权利要求1所述的一种可生物降解高吸水医用复合止血海绵,其特征在于:所述的胶原蛋白原液提取自鱼鳔、鱿鱼皮的一种。
3.根据权利要求1所述的可生物降解高吸水医用复合止血海绵,其特征在于:所述的聚乙二醇的重均分子量Mw为1000-20000。
4.根据权利要求1所述的可生物降解高吸水医用复合止血海绵,其特征在于:所述的交联剂为双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
5.根据权利要求4所述的可生物降解高吸水医用复合止血海绵,其特征在于:所述的交联剂为重量比为0.5:2.5:1:0.5的双乙酸钠、三偏磷酸钠、柠檬酸和氯化钙的混合物。
6.根据权利要求1所述的可生物降解高吸水医用复合止血海绵,其特征在于:所述的三七提取液提取方法为三七根烘干粉碎后过80目筛后加入料液比为1:10的质量浓度为75%乙醇回流提取3次,合并提取液,在75-80℃下减压蒸发浓缩,回收乙醇,将浓缩液经大孔树脂柱吸附静置1-2h,用去离子水洗脱至洗涤液不出现紫环,再用质量浓度为90%乙醇溶液继续洗脱,得到三七提取液。
7.根据权利要求1所述的一种可生物降解高吸水医用复合止血海绵,其特征在于:包括以下步骤:所述的十二烷基壳聚糖的制备方法如下:
1)将粘均分子量为50-100万、脱乙酰度95%-98%的壳聚糖溶于体积浓度为1%的乙酸水溶液中,搅拌至完全溶解;所述壳聚糖与所述乙酸水溶液的比例为2g:60-80mL;
2)向步骤1)获得的溶液中加入氢氧化钠水溶液调节pH至8-12,产生壳聚糖沉淀;过滤,将滤饼溶于二甲基甲酰胺中;所述滤饼干品与二甲基甲酰胺的比例为5g:100-150ml;按壳聚糖重复单元分子个数与月桂醛分子个数之比为4~2:1的比例加入月桂醛,用乙酸调节pH至5-7,室温下搅拌4-6h;在氮气下加入与月桂醛等摩尔的三乙酰氧基硼氢化钠,继续反应12-24h,过滤,滤饼依次用蒸馏水和无水乙醇洗涤,室温晾干,得到十二烷基壳聚糖。
8.根据权利要求1-7任一项所述的一种可生物降解高吸水医用复合止血海绵的制备方法,其特征在于:包括以下步骤:
1)按照配方量将乌贼墨多糖溶液缓慢加入到十二烷基壳聚糖溶液中,混匀后备用;
2)称取配方用量的胶原蛋白液,加入配方量的氧化微晶纤维素,搅拌均匀备用;
3)将配方量的聚乙二醇熔融,加入配方量的ε-已内酯,在保护气中由催化剂催化进行聚合反应,得聚乙二醇-聚(ε-已内酯)共聚物;
4)将步骤1)和步骤2)和步骤3)分别制得的混合液混合搅拌均匀后加入配方量的葡萄糖酸锶、右旋糖酐铁、三七提取液、桉油精、吐温-60、乙醇、去离子水后搅拌均匀后再配方量的交联剂,以50-80rpm速度搅拌50-60min,去离子洗涤得交联产物;
5)将步骤4)制得的交联产物倒入模具中,然后浸泡于2wt%氯化钾溶液中4h,于-20℃预冻4h后取出再经冷冻干燥24-36h并经洗涤干燥,切割、包装和灭菌即得。
9.根据权利要求8所述的一种可生物降解高吸水医用复合止血海绵的制备方法,其特征在于:所述的步骤3)的保护气为氮气或氩气。
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