CN117159811A - 一种表面处理组合物、医疗器械及其制备方法 - Google Patents
一种表面处理组合物、医疗器械及其制备方法 Download PDFInfo
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- CN117159811A CN117159811A CN202310705412.4A CN202310705412A CN117159811A CN 117159811 A CN117159811 A CN 117159811A CN 202310705412 A CN202310705412 A CN 202310705412A CN 117159811 A CN117159811 A CN 117159811A
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- surface treatment
- treatment composition
- heparin
- medical device
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Abstract
本发明公开了一种表面处理组合物、医疗器械及其制备方法。该表面处理组合物,用于血液中使用的医疗器械的外表面,至少包括由亲水材料和抗凝血材料复合成的材料,其中抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种。本发明提供的表面处理组合物具有稳定的亲水性和抗凝血性,在血液中持续时间超过4小时,甚至可达到24小时以上。
Description
本申请是2022年1月30日提交的名称为“一种表面处理组合物、具有该组合物的球囊微导管及制备方法”、申请号为202210114462.0的发明专利申请的分案申请。
技术领域
本发明涉及一种表面处理组合物,也涉及一种具有表面处理组合物的用于血液中使用的医疗器械,还涉及该医疗器械的制备方法,属于医疗器械技术领域。
背景技术
中国专利公开CN 103533967 A记载了具有润滑涂层的医疗器械和一种涂覆医疗器械的方法,润滑涂层被施加在底涂层之上,底涂层直接施加于医疗器械上。涂层可以包括提供涂层在器械上的增强附着的一种或更多种药剂。润滑涂层可以是与其本身交联并且与交联的聚合多官能单体或聚合物的网络互锁的亲水化合物的网络。此外,润滑涂层可以具有一种或更多种治疗剂或诊断剂,并且在一个实施方式中,在涂层的水合之后,药剂从润滑涂层中以高浓度释放相对快速地被洗脱。
中国专利公开CN 108939257A记载了一种头端可解脱球囊微导管,包括微导管主体,所述微导管主体的一端连通导管座,所述微导管主体的另一端还连接有可解脱的微导管头端;所述微导管主体外同轴设置有套管,所述套管两端分别连通至导管座和微导管主体上的可充盈球囊。所述可充盈球囊及所述套管的外表面均覆有亲水涂层。
血管内介入治疗用导管是血管内介入技术的主要器械之一。由于所有的介入导管必须与血液接触并沿着弯曲的血管到达远端病变部位,所以导管应具备良好的血液相容性、一定的柔软性和表面润滑性以达到减少对血管壁和血细胞损伤的目的,同时导管还应具备X射线或荧光可探测性。
导管常用的高分子材料Pebax因其具有优异的物理机械性能和相对良好的生物相容性,但医用Pebax材料的表面不具备润滑性且抗凝血性能不够持久。导管在使用过程中需与血液进行接触,因此血栓和感染是影响导管留置使用的主要问题。血液与高分子材料等异物接触时,会引起诸多不良反应,因此,构建良好血液相容性材料,赋予介入导管抗凝血特性,具有极大的临床使用价值。
然而,市场上使用的介入导管,多是在导管外表面进行涂层改性,在导管外表面覆盖亲水涂层。但是,由于在血管内介入手术中常用的导管的使用时间短,在手术操作结束时就将导管取出血管外,所以导管在血液中的浸没时间不长,不需要抗凝血涂层。
对于灌注化疗,尤其是肝动脉灌注化疗,需要将导管长时间留置在肝动脉,导管外表面会与血液长时间相接触,血液与高分子材料等异物接触时,会引起诸多不良反应,由导管内外表面引起的血栓和感染是影响导管使用的重要原因。随着介入导管的深入使用,单一涂层的导管不足以满足临床使用对器械的要求,为降低治疗过程的风险,减少患者的经济负担,构建外表面多功能涂层是介入导管未来发展的重要方向。
发明内容
本发明所要解决的一个技术问题在于提供一种表面处理组合物。
本发明所要解决的另一个技术问题在于提供一种具有表面处理组合物的在血液中使用的医疗器械。
本发明所要解决的又一个技术问题在于提供一种具有表面处理组合物的在血液中使用的医疗器械的制备方法。
为实现上述技术目的,本发明采用以下技术方案:
根据本发明实施例的第一方面,提供一种表面处理组合物,用于血液中使用的医疗器械的外表面,所述表面处理组合物至少包括由亲水材料和抗凝血材料复合成的材料,其中所述抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;所述亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种
根据本发明实施例的第二方面,提供一种具有表面处理组合物的医疗器械,使用在血液中,在其外表面形成有所述表面处理组合物;
所述表面处理组合物至少包括由亲水材料和抗凝血材料复合成的材料,其中所述抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;所述亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种。
其中较优地,所述表面处理组合物包括经聚乙烯亚胺或苯扎氯铵水溶液预处理并干燥后的抗凝血涂层,以及所述抗凝血涂层干燥后再形成的亲水涂层。
其中较优地,所述医疗器械是将真空干燥后的已涂覆肝素的管体浸入亲水涂层溶液中,并经紫外光固化处理得到的;
所述亲水涂层的溶液中还包括交联剂和引发剂。
其中较优地,所述聚乙烯吡咯烷酮的平均分子量在30000-130000之间。
根据本发明实施例的第三方面,提供一种上述医疗器械的制备方法,包括以下步骤:
步骤A:清洗医疗器械的管体,干燥;
步骤B:将管体放入1-20wt%聚乙烯亚胺或苯扎氯铵水溶液,在37℃水浴中浸泡0.5-1h,真空干燥;重复操作0-2次;
步骤C:将干燥的管体放入肝素水溶液中,在37℃水浴中浸泡1h,真空干燥;重复操作0-2次;
步骤D:配置亲水涂层溶液,将步骤C所述真空干燥后的已涂覆肝素的管体浸入亲水涂层溶液中,然后紫外光固化处理,得到所述医疗器械。
其中较优地,所述步骤B中,聚乙烯亚胺或苯扎氯铵水溶液中含有戊二醛或醛基化海藻酸钠。
其中较优地,所述步骤C中,肝素水溶液浓度为1-5wt%。
其中较优地,所述步骤D中,亲水涂层溶液为含有PVP的乙醇溶液。
其中较优地,所述步骤D中,亲水涂层溶液的重量份组成为:
采用本发明提供的表面处理组合物,经过上述方法制备得到的球囊微导管,当该球囊微导管用于血液内长期使用时,同时具有良好的亲水性和抗凝血性,并且亲水性和抗凝血性稳定,持续时间超过4小时,甚至可达到24小时以上。
附图说明
图1为本发明的一个实施例的球囊微导管示意图;
图2为本发明的表面处理组合物的抗凝血组分和亲水胶组分的分子结构示意图;
图3为本发明的表面处理组合物的肝素浓度-时间扩散曲线图。
具体实施方式
下面结合附图和具体实施例对本发明的技术内容进行详细具体的说明。
<第一实施例>
如图1所示,本发明所述球囊微导管,包括导管座5,应力扩散管4和管体。管体包括内管1、外管2和球囊3。内管1与外管2内形成贯通的腔体(未图示);内管1形成在外管2的远端并且在内管1与外管2连接处设置有球囊3,表面处理组合物形成在内管1、外管2和球囊3的外表面。球囊3通粘接方式固定在内管上。球囊3的外表面可以有表面处理组合物,也可以没有。
在介入手术中,将球囊导管从远端开始到近端依次被送入体内血管,再对球囊3进行扩张,在血管内形成封闭腔道。最后,根据介入手术的需要,通过腔体送入栓塞剂、化疗药物或造影剂等。
所述球囊微导管近端设置有Y型手柄6,所述球囊微导管的手柄6用于连接外部器械。所述球囊微导管的手柄6与管体成直线,相对管体的轴线成锐角倾斜。该球囊微导管不仅可临时改变血流方向(使血液停留在希望的位置以保证靶向治疗),阻止栓塞剂的漂移,还可长时间24h在人体内,用于灌注化疗,如肝动脉灌注化疗(HAI C)。
所述微导管的外管为高分子材料pebax材料,内管为编织管,由高分子材料pebax、不锈钢丝编织或绕簧、高分子材料聚四氟乙烯(PTFE)组成,导管座由高分子材料polycarbonate构成。内管与外管内形成的腔体,用于输送药物,例如栓塞剂、化疗药物或造影剂等。
所述表面处理组合物分两次涂复,先涂抗凝血涂层(也称为抗凝血材料),再涂亲水涂层(也称为:亲水材料)。亲水材料采用聚乙烯吡咯烷酮(PVP),该材料具有无毒和优良的生物相容性。一旦处于含水环境,如接触体液或血液后,亲水材料表面迅速吸水形成水化层,显著降低器械在运动过程中的摩擦阻力。并且,亲水性润滑涂层在插管时不脱落。抗凝血涂层为肝素、水蛭素、柠檬酸钠、氟化钾之中的一种或多种,在体内均发挥抗凝血作用。选择肝素而不是肝素的化合物,是因为肝素的抗凝血效果优于肝素的化合物。
PVP是由N-乙烯基-2-吡喏烷酮单体催化生成的水溶性聚合物,易溶于水和乙醇等极性有机溶剂。PVP主要起亲水作用,对生理凝血过程没有影响,既不受人体凝血因子的影响,也不对凝血因子产生影响。因此,PVP在本发明的表面处理组合物中起到亲水涂层的作用,可选择PVPK30-PVPK 120,其平均分子量在30000-130000。
如图2所示,PVP网格状分子结构有利于肝素分子渗入,使肝素分子修饰在PVP分子上。因此,本发明的表面处理组合物是由亲水材料和抗凝血材料的结合得到的复合材料。亲水材料同时具备高亲水性和一定粘度,使得肝素的释放可控。其中一优选实例中,PVP固含量在0.5~5%(质量比),粘度在5~50mPa.s-25℃/aq。
本领域普通技术人员也可以理解,除了PVP,还可以选用聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物(CAS号:9011-16-9)、聚二醇类(比如聚乙二醇(PEG))等作为亲水材料。
所述表面处理组合物的亲水材料采用PVP的乙醇溶液,或者由PVP与丙醇,异丙醇,丁醇等制成的PVP醇溶液。
众所周知,将肝素枝接到高分子材料的表面可以防止凝血酶的吸附,从而避免凝血。有数据表明,通过静脉注射肝素10分钟以内,血液凝固时间及部分凝血活酶(APTT)时间均明显延长,能够维持3~4小时的作用。因此在需要长效抗凝(超过4小时)的情况下,需要使血液中持续存在肝素分子。在本发明的表面处理组合物中,PVP形成的凝胶,发挥了控释剂的作用,其与肝素分子形成具有抗凝血功能的复合涂层,并且对肝素分子在血液中的扩散速度进行调控。
实施例1
将球囊微导管本体用乙醇清洗1h,再用蒸馏水清洗1h,放入真空干燥器中充分干燥12h。
配制5wt%聚乙烯亚胺水溶液,将导管本体放入100ml聚乙烯亚胺水溶液中,在37℃的水浴中浸泡1h;浸泡结束取出导管本体,在真空干燥器中充分干燥12小时。干燥后,将导管本体再次放入100ml聚乙烯亚胺水溶液中,在37℃的水浴中浸泡1h;浸泡结束取出导管本体,在真空干燥器中充分干燥12小时。干燥后,将导管本体第三次放入100ml聚乙烯亚胺水溶液中,在37℃的水浴中浸泡1h;浸泡结束取出导管本体,在真空干燥器中充分干燥12小时。
配制含有5wt%肝素的水溶液,将干燥后的导管本体放入100mL肝素的水溶液中,在37℃的水浴中浸泡1h。浸泡结束取出导管本体,在真空干燥器中充分干燥。将干燥后的已涂覆肝素的导管本体再次放入100mL肝素的水溶液(5wt%)中,在37℃的水浴中浸泡1h。浸泡结束取出导管本体,在真空干燥器中充分干燥。干燥后,将已二次涂覆肝素的导管本体再次放入100mL肝素的水溶液(5wt%)中,在37℃的水浴中浸泡1h。浸泡结束取出导管本体,在真空干燥器中充分干燥,得到干燥后的已涂覆三次肝素的导管本体。
其中,步骤C:将管体放入肝素水溶液中,在37℃水浴中浸泡1h,真空干燥;步骤D:配置亲水涂层溶液,将步骤C所述真空干燥后的导管本体浸入亲水涂层溶液中,然后紫外光固化处理,得到所述具有表面处理组合物的球囊微导管,这两个步骤根据所需药量可重复多次。例如,可以重复两次步骤C,然后再重复两步骤D;再例如先执行一次步骤C,再执行一次步骤D,然后再执行一次步骤C,最后再执行一次步骤D。
作为替代方案,也可将肝素水溶液和PVP的醇溶液混合后配成混合溶液,再将步骤B所述真空干燥后的管体浸入混合溶液中,取出后紫外光固化处理。
分别取以下组分配制亲水涂层溶液:
5克PVP K90;
0.5g交联剂PEGDA1000;
0.2g引发剂Irgacure2959;
0.1g的流平剂WX6214;
依次溶于94.2g无水乙醇中,搅拌均匀后,得到质量为100g的亲水涂层溶液。
将干燥后的已涂覆三次肝素的导管本体,完全浸入到亲水涂层溶液中,然后进行紫外光固化处理60秒,得到形成了具有亲水性能和抗凝血性能的复合涂层的球囊微导管。
所得球囊微导管在使用环境下,肝素分子扩散浓度曲线图见图3。如图3所示的实验中,在导管外形成有表面处理组合物(以PVP固含量为5%的亲水涂层溶液制备得到的表面处理组合物),通过亚甲基蓝褪色光度法,使用紫外可见分光光度计测量,得到的肝素分子扩散到外层生理盐水中的浓度。由图可见,6小时后,肝素浓度维持在一个稳定的水平,且持续时间维持至72小时以上。具体数据见表1:
表1:肝素浓度扩散时间表
本实施例制得的球囊微导管及球囊外表面设有里层的抗凝层和外层的亲水层组成的表面处理组合物,在长时间的接触血液过程中,亲水涂层中亲水材料与网络结构缠结吸水后形成水凝胶,能显著降低了导管表面的摩擦力。实测摩擦力为4.4g。摩擦力测试实验条件为:水浴温度37℃,硅胶片硬度55,提升速度10mm/s,夹持力300g,导管外径1mm,测试长度100mm,循环次数25次。
实施例2
具有表面处理组合物的球囊微导管的制备方法,该表面处理组合物为具有亲水性能和抗凝血性能的复合涂层。该方法包括以下步骤:
步骤A:清洗球囊微导管的管体,干燥;
步骤B:将管体放入1-20wt%聚乙烯亚胺或苯扎氯铵水溶液,在37℃水浴中浸泡0.5-1h,真空干燥;重复操作0-2次;
步骤C:将干燥的管体放入肝素水溶液中,在37℃水浴中浸泡1h,真空干燥;重复操作0-2次;
步骤D:配置亲水涂层溶液,将步骤C所述真空干燥后的管体浸入亲水涂层溶液中,然后紫外光固化处理;重复操作0-2次。
通过上述步骤得到所述具有表面处理组合物的球囊微导管。重复执行上述步骤B-D的时候,可以是先重复执行步骤B,再重复执行步骤C,最后再重复执行步骤D;也可以先执行步骤B-D,然后执行步骤B-D。
本实施例中所述的5wt%聚乙烯亚胺水溶液中,含有5%醛基化海藻酸钠。
实施例3-实施例8
参照实施例1制备具有亲水性能和抗凝血性能的复合层的球囊微导管。
不同之处在于,分别具有以下表所示组分比例。
上述各实施例中的试剂、原材料来源如下:
聚乙烯亚胺:上海攻碧克新材料科技有限公司
苯扎氯铵:上海阿拉丁生化科技股份有限公司
戊二醛:上海阿拉丁生化科技股份有限公司
海藻酸钠:上海阿拉丁生化科技股份有限公司
肝素钠:深圳海普瑞药业有限公司
PVP K90:上海攻碧克新材料科技有限公司
交联剂PEGDA1000:上海阿拉丁生化科技股份有限公司
引发剂Irgacure2959:巴斯夫(中国)有限公司
流平剂WX6214:海名斯德谦(上海)化工有限公司
无水乙醇:上海阿拉丁生化科技股份有限公司。
由于本发明所述球囊微导管具有表面处理组合物,使得所述球囊微导管适用于在体内的血液中长时间使用,例如长时间灌注化疗,例如12~72小时放置在血液中。根据凝血机理,血液相容性高分子材料制成的球囊微导管的表面,需要抑制凝血因子的活化,又能防止血小板的黏附、释放、聚集,二者缺一不可。引发剂会形成网络状,再用交联剂把PVP交联上,再嵌入肝素从而形成的表面处理组合物。
所述球囊微导管及球囊外表面设有里层的抗凝层和外层的亲水层组成的表面处理组合物,在长时间的接触血液过程中,亲水涂层中亲水材料与网络结构缠结吸水后形成水凝胶,能显著降低了导管表面的摩擦力,平均摩擦力能降低到4.5g以下。修饰的肝素分子在导管表面被血液浸润后浸入到水凝胶中,渗透到水凝胶网络结构中,同时起到在导管表面抗凝血效果。
本发明还提供一种表面处理组合物,用于血液中使用的医疗器械的外表面,所述表面处理组合物至少包括由亲水材料和抗凝血材料复合成的材料,其中所述抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;所述亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种。
上面对本发明进行了详细的说明。对本领域的一般技术人员而言,在不背离本发明实质内容的前提下对它所做的任何显而易见的改动,都将构成对本发明专利权的侵犯,将承担相应的法律责任。
Claims (10)
1.一种表面处理组合物,用于血液中使用的医疗器械的外表面,其特征在于:
所述表面处理组合物至少包括由亲水材料和抗凝血材料复合成的材料,其中所述抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;所述亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种。
2.一种具有表面处理组合物的医疗器械,使用在血液中,其特征在于:
在外表面形成有表面处理组合物,所述表面处理组合物至少包括由亲水材料和抗凝血材料复合成的材料,其中所述抗凝血材料是肝素、水蛭素、柠檬酸钠、氟化钾之中任意一种或多种;所述亲水材料为聚乙烯吡咯烷酮或含有聚羧酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、甲基乙烯基醚/马来酸酐共聚物、聚乙烯醇、聚乙二醇类之中任意一种或多种。
3.如权利要求1所述的医疗器械,其特征在于:
所述表面处理组合物包括经聚乙烯亚胺或苯扎氯铵水溶液预处理并干燥后的抗凝血涂层,以及所述抗凝血涂层干燥后再形成的亲水涂层。
4.如权利要求1所述的医疗器械,其特征在于:
所述医疗器械是将真空干燥后的已涂覆肝素的管体浸入亲水涂层溶液中,并经紫外光固化处理得到的;
所述亲水涂层的溶液中还包括交联剂和引发剂。
5.如权利要求1所述的医疗器械,其特征在于:
所述聚乙烯吡咯烷酮的平均分子量在30000-130000之间。
6.权利要求2-5中任意一项所述的医疗器械的制备方法,其特征在于包括以下步骤:
步骤A:清洗医疗器械的管体,干燥;
步骤B:将管体放入1-20wt%聚乙烯亚胺或苯扎氯铵水溶液,在37℃水浴中浸泡0.5-1h,真空干燥;重复操作0-2次;
步骤C:将干燥的管体放入肝素水溶液中,在37℃水浴中浸泡1h,真空干燥;重复操作0-2次;
步骤D:配置亲水涂层溶液,将步骤C所述的真空干燥后的已涂覆肝素的管体浸入亲水涂层溶液中,然后紫外光固化处理,得到所述医疗器械。
7.如权利要求6所述的制备方法,其特征在于:
所述步骤B中,聚乙烯亚胺或苯扎氯铵水溶液中含有戊二醛或醛基化海藻酸钠。
8.如权利要求6所述的制备方法,其特征在于:
所述步骤C中,肝素水溶液浓度为1-5wt%。
9.如权利要求6所述的制备方法,其特征在于:
所述步骤D中,亲水涂层溶液为含有PVP的乙醇溶液。
10.如权利要求9所述的制备方法,其特征在于:
所述步骤D中,亲水涂层溶液的重量份组成为:
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