CN103957947B - 使用聚乙二醇粘合剂的可生物吸收的止血装置 - Google Patents
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Abstract
本发明公开了一种止血垫,其包含可生物吸收的支撑材料;冻干的凝血酶粉末、冻干的纤维蛋白原粉末以及能够熔融的粘合剂粉末,所有的粉末均设置在所述可生物吸收的支撑材料上。能够熔融的粘合剂诸如PEG将所述冻干的凝血酶粉末和所述冻干的纤维蛋白原粉末粘结到所述可生物吸收的支撑材料,以改善脆碎度、可润湿性和使用性能,诸如针对伤口部位处的止血治疗或封闭而言。
Description
技术领域
本发明整体涉及用于促进止血和组织封闭的试剂和装置,更具体地讲,涉及包含携带冻干促止血蛋白(诸如纤维蛋白原和凝血酶)的可生物吸收的支架的止血垫。
背景技术
血液是液体组织,包含分散在液相中的红细胞、白细胞、触觉小体和血小板。液相是血浆,其包括酸、脂质、溶解的电解质和蛋白质。悬浮在液相中的一种特定蛋白是纤维蛋白原。当出血发生时,纤维蛋白原与水和凝血酶(一种酶)反应以形成血纤维蛋白,所述血纤维蛋白不溶于血液中并聚合以形成凝块。
在广泛多样的情况下,动物包括人可遭受由于伤口或外科手术期间的出血。在一些情况下,出血是较少量的,并且除施加简单急救之外的正常血液凝结功能均是需要的。在其他情况下,可发生大量出血。这些情况通常需要专门的设备和材料以及受过训练的施用适当援助的人员。
在解决上述问题的努力中,已开发出用于控制过量出血的材料。可生物吸收的局部止血剂(TAH)广泛应用于外科手术应用当中。TAH涵盖基于各种织造或非织造织物或海绵的产品,通常由可至少部分地吸收性材料制成,范围从天然聚合物到合成聚合物以及它们的组合,包括基于丙交酯-乙交酯的共聚物,例如Polyglactin910、氧化纤维素(OC)、氧化再生纤维素(ORC)、明胶、胶原、几丁质、壳聚糖等。为了改善止血性能,可将基于上述材料的支架与生物来源的凝血因子(例如凝血酶和/或纤维蛋白原)结合。
目前市场上可获得的或处于开发中的多种止血制剂利用冻干纤维蛋白原,其通常与冻干凝血酶结合,并且止血制剂以干粉、半液体糊剂、液体制剂的形式施用或任选地设置在支承支架(例如可生物吸收的织物支架)上。
对于位于可生物吸收支架上的含有冻干凝血酶和纤维蛋白原的止血敷片或止血垫来说,需要提升装置的性能和性质,具体地讲需要与止血垫的改善的润湿性相关的强化,以便冻干蛋白质能够更快地重构并更快地止血;降低的脆碎度,即,在处理和/或切割止血垫的过程中,减少活性粉末脱落;以及改善的组织粘合和伤口封闭性质。
名称为“Hemoactive compositions and methods for their manufacture anduse(止血活性组合物及其制造和使用方法)的美国专利No.7,320,962公开了一种用于抑制出血或递送试剂的干燥且具有止血活性的材料,其包含:在接触血液时形成水凝胶的生物相容性的交联聚合物;以及在接触血液时增溶的生物相容性的非交联聚合物;其中交联聚合物分散在非交联聚合物的干燥基质中。该参考文献还公开了存在于至少非交联聚合物中的增塑剂,并提出所述增塑剂选自聚乙二醇、山梨醇和甘油。
名称为“Hemoactive compositions and methods for their mannfacture anduse”(止血活性组合物及其制造和使用方法)的美国专利No.6,706,690公开了一种在接触血液时形成水凝胶的干燥材料,所述材料包含:在接触血液时形成水凝胶的生物相容性的交联聚合物;在接触血液时溶解的生物相容性的非交联聚合物;存在于生物相容性的非交联聚合物中的增塑剂;并且其中交联聚合物分散在非交联聚合物的干燥基质中,其中生物相容性的非交联聚合物在与血液接触时,将在15分钟或更短的时间内溶解。该参考文献还公开了以材料的1重量%至20重量%存在于非交联聚合物中的增塑剂,并提出所述增塑剂选自聚乙二醇、山梨醇和甘油。
名称为“FREE-STANDING BIODEGRADABLE PATCH”(自支撑的可生物降解敷片)的美国专利申请No.201I/0071499A1公开了一种装置,包括:含有固态纤维蛋白原和固态凝血酶的膜,其中该膜是自支撑的,并且被配置成在与水分接触时形成血纤维蛋白敷片,并且还提出了所述膜还包含增塑剂。所述专利进一步公开了其中膜含有约5至约30重量%的聚乙二醇的装置。
名称为“Hemostatic woven fabric”(止血织造织物)的美国专利申请No.2009/0053288A1公开了一种具有改性蒺黎编织图案并且还包含止血剂的织造织物。该参考文献还公开了进一步包含选自甘油、丙二醇、聚乙二醇(PEG)、海藻糖以及它们的组合的防腐剂的织造织物。
名称为“Hemostatic textile”(止血织物)的美国专利申请No.2007/0160653A1公开了一种止血织物,其包含:含有玻璃纤维和一种或多种次级纤维的材料,所述次级纤维选自丝纤维、聚酯纤维、尼龙纤维、陶瓷纤维、竹原纤维或再生竹纤维、棉纤维、人造丝纤维、亚麻纤维、丙交酯和/或乙交酯聚合物、丙交酯/乙交酯共聚物、凝血酶或含有凝血酶的成分;以及一种或多种止血剂,其选自RL血小板、RL血细胞、血纤维蛋白和纤维蛋白原;所述止血织物能够在施用于伤口时激活机体内的止血系统。该参考文献还公开了进一步包含选自甘油、丙二醇、聚乙二醇(PEG)、海藻糖以及它们的组合的防腐剂的止血织物。
名称为“COMPOSITION FOR SEALING WOUNDS”(用于封闭伤口的组合物)的PCT专利公布No.WO1997028832A1公开了一种止血绷带,其包含使用粘性的非水溶液型粘合剂(诸如粘性多糖、二醇或凡士林)附着至纤维质基质的粉末状纤维蛋白原和凝血酶。所述非水溶液型粘合剂在绷带被体液(诸如血液)润湿之前阻止纤维蛋白原和凝血酶之间发生水解反应,并提出了该绷带能够被制出并长期储存,在此期间保持止血活性。该参考文献还公开了一种用于减少来自伤口的血液流动的组合物,其包含:载体;通过粘合剂附着至载体的凝血成分,所述粘合剂选自处于凝血酶与纤维蛋白原不相互作用以生成血纤维蛋白的pH下的水以及生物相容性的粘性非水溶液型粘合剂,所述凝血成分以足以治疗的量存在,以便在组合物接触体液从而激活血小板凝聚时,凝结并减少来自伤口的血液流动。该参考文献还公开了其中在20℃下为非水液体的粘合剂将凝血成分附着至载体的组合物。该参考文献还公开了一种组合物,其中所述非水溶液型粘合剂选自丙二醇、甘油、凡士林和聚乙二醇。
该参考文献还提出了一种止血伤口敷料,其包含:适于作为施用的垫片放置在开放性流血伤口之上或插入其中的纤维质基质;存在于基质表面上的粉末状凝血因子的混合颗粒的混合物,所述颗粒在暴露于处于生理pH下的含水介质时彼此充分紧密接触以形成凝块,所述颗粒通过粘性非水溶液型粘合剂(在20℃下的粘度为至少100厘泊)附着至基质,并且在其暴露于处于生理pH下的含水介质之前阻止在混合颗粒之间发生凝结反应。
该参考文献还公开了一种止血伤口敷料,其包含:适于作为施用的垫片放置在开放性流血伤口之上或插入其中的纤维质基质;遍布基质存在的粉末状凝血因子的混合颗粒的混合物,所述颗粒在暴露于处于生理pH下的含水介质时充分紧密接触以形成凝块,所述颗粒通过粘性非水溶液型粘合剂附着至基质,所述粘性非水溶液型粘合剂在颗粒暴露于处于生理pH下的含水介质之前阻止在混合颗粒之间发生凝结反应,其中所述粘合剂选自多糖、聚乙二醇、丙二醇、甘油和凡士林,所述粘合剂已采用液体的形式(包含不到3重量%的水)被施用于基质。
发明内容
简言之,在一个实施例中,本发明涉及具有改善的脆碎度和润湿性的止血垫以及制造这种止血垫的方法,所述止血垫包含:可生物吸收的或生物吸收性支撑材料;冻干的凝血酶粉末、冻干的纤维蛋白原粉末以及聚乙二醇粉末(PEG),它们全部设置在可生物吸收的支撑材料上;其中PEG粉末将冻干的凝血酶粉末与冻干的纤维蛋白原粉末粘结到可生物吸收的支撑材料,但不完全包裹住冻干的凝血酶粉末和/或冻干的纤维蛋白原粉末颗粒。“可生物吸收的”和“生物吸收性”在本文可互换使用,意指可被机体分解且不需要机械移除的材料。
在一个实施例中,本发明涉及一种制造止血垫的方法,包括以下步骤:(a)在非水流体中形成冻干凝血酶粉末、冻干纤维蛋白原粉末和聚乙二醇粉末的悬浮液;(b)将悬浮液涂覆到由生物吸收性材料制成的支架上;(c)让流体蒸发,使支架携带凝血酶粉末、纤维蛋白原粉末和聚乙二醇粉末的一部分;(d)将支架加热至超过聚乙二醇熔点,但不超过使凝血酶和纤维蛋白原明显变性的温度;(e)将支架冷却至环境温度以形成止血垫。
在一个实施例中,本发明涉及一种向伤口部位提供止血治疗或组织封闭的方法,包括以下步骤:(a)形成如上所述的止血垫,(b)将止血垫施用于伤口部位。
附图说明
图1示出了组织剥离测试数据和PEG添加剂的效果。
图2示出了若干测试体系的渗漏测试数据。
图3示出了采用不同浓度PEG3进行测试的脆碎度结果。
具体实施方式
简言之,在一个实施例中,本发明涉及具有改善的脆碎度和润湿性的止血垫以及制造这种止血垫的方法,所述止血垫包含:可生物吸收的支撑材料;冻干的凝血酶粉末、冻干的纤维蛋白原粉末以及聚乙二醇粉末,它们全部设置在可生物吸收的支撑材料上;其中PEG粉末将冻干的凝血酶粉末与冻干的纤维蛋白原粉末粘结到可生物吸收的支撑材料,但不完全包裹住冻干的凝血酶和冻干的纤维蛋白原粉末颗粒。
根据本发明的一个实施例,使用能够熔融的PEG(任选地在CMC的存在下)形成冻干的蛋白质与可生物吸收的支撑材料的更强效粘合以及所得止血垫的更好润湿性/粘合性,由此熔化并重新固化的PEG将近侧颗粒或粉末与支架纤维粘结,但不会将粉末/颗粒完全覆盖或包裹住,以便允许水分进入且易于在外科手术环境中将这些生物试剂活化。这产生了使脆碎度降低,伴随组织粘合和封闭性改善的低成本解决方案。
在一个实施例中,本发明涉及一种止血或组织封闭材料或垫片。在另一个实施例中,本发明还涉及一种向伤口部位提供止血治疗或组织封闭的方法,包括以下步骤:(a)形成如上所述的止血或组织封闭材料或垫片,以及(b)将所述止血或组织封闭材料施用于伤口部位。
包含冻干的纤维蛋白原和凝血酶的止血垫
根据一个实施例,本发明涉及一种位于可生物吸收支架或基质上的包含冻干的促止血试剂(任选地冻干)的止血垫。优选的止血支架是天然的或经基因工程改造的可生物吸收的聚合物或合成的可生物吸收的聚合物,或它们的混合物。
天然的或经基因工程改造的可生物吸收的聚合物的例子是蛋白质、多糖以及它们的组合。多糖包括但不限于:纤维素、氧化纤维素、氧化再生纤维素(ORC)、烷基纤维素如甲基纤维素、烷基羟烷基纤维素、羟烷基纤维素、纤维素硫酸酯、羧甲基纤维素的盐、羧甲基纤维素、羧乙基纤维素、甲壳质、羧甲基甲壳质、透明质酸、透明质酸的盐、藻酸盐、藻酸、丙二醇藻酸盐、糖原、葡聚糖、硫酸葡聚糖、凝胶多糖、果胶、普鲁兰多糖、黄原胶、软骨素、硫酸软骨素、羧甲基葡聚糖、羧甲基壳聚糖、壳聚糖、淀粉、直链淀粉、支链淀粉、聚-N-葡糖胺、聚甘露糖醛酸、聚葡糖醛酸、聚古洛糖醛酸,以及任何上述物质的衍生物。
合成的可生物吸收的聚合物的例子是聚酯聚合物、共聚物和/或它们的组合。聚酯通常在单体的开环聚合反应中合成,所述单体包括但不限于乳酸、丙交酯(包括L-、D-、内消旋和D,L混合物)、乙醇酸、乙交酯、ε-己内酯、对二氧杂环己酮(1,4-二氧六环-2-酮)和三亚甲基碳酸酯(1,3-二氧杂环己烷-2-酮)。
促止血试剂包括蛋白质、前凝血酶、凝血酶、纤维蛋白原、血纤维蛋白、纤连蛋白、肝素酶、因子X/Xa、因子VII/VIIa、因子IX/IXa、因子XI/XIa、因子XII/XIIa、组织因子、巴曲酶、安克洛酶、蛇静脉酶、血管性血友病因子、胶原、弹性蛋白、白蛋白、明胶、血小板表面糖蛋白、加压素、加压素类似物、肾上腺素、选择素、促凝血毒液、纤溶酶原激活物抑制剂、血小板活化剂、具有止血活性的合成肽和/或它们的组合。
本发明的实验测试中使用的在可生物吸收的支架上包含冻干的凝血酶和纤维蛋白原的止血垫被称为增强的包含止血生物制剂的垫子,其由已被针刺进ORC背衬层的Polyglactin910(PG910)纤维的复合基质组成。基质的PG910侧涂覆有处于干燥的未反应状态的人纤维蛋白原和凝血酶粉末。当将增强的包含止血生物制剂的垫子施用于出血部位时,蛋白质易于水化(在几秒钟内),导致纤维蛋白原转变为血纤维蛋白,进而形成血纤维蛋白凝块。在组织表面上形成血纤维蛋白促进止血以及与组织的粘合。重要的是,蛋白质在施用于组织之前保持未反应状态。由于在生产或存储期间暴露于水而使纤维蛋白原过早地转变为血纤维蛋白(提前活化)可能对性能和稳定性产生负面影响。
授予Shetty等人的名称为“Reinforced bioabsorable multilayered fabricfor use in medical devices”(用于医疗装置的增强型可生物吸收的多层织物)的美国专利7,666,803出于所有目的其全文以引用方式并入本文中,并提出了一种多层织物,该多层织物包含第一可生物吸收的非织造织物和包含氧化多糖的第二可生物吸收的织造或针织织物。
授予Gorman等人的名称为“REINFORCED BIOABSORBABLE MULTILAYEREDHEMOSTATIC WOUND DRESSING”(增强型可生物吸收的多层止血伤口敷料)的美国专利申请公布2009/0246238A1出于所有目的其全文以引用方式并入本文中,并提出了一种制备多层伤口敷料的方法,该多层伤口敷料具有第一可生物吸收的非织造织物、一层或多层第二可生物吸收的织造或针织织物、凝血酶和/或纤维蛋白原,该方法包括以下步骤:(a)将可生物吸收的聚合物纤维或纱线卷曲,使其在约10至30个卷曲/英寸的范围内;(b)将卷曲的纤维或纱线切割至介于约0.1和2.5英寸之间的短纤维长度;(c)梳理所述短纤维,以形成第一可生物吸收的非织造织物,同时在约15至24℃的室温下将湿度控制到约20至60%;(d)将第一可生物吸收的非织造织物附接到第二可生物吸收的织造或针织织物;(e)将凝血酶和/或纤维蛋白原施加到第一可生物吸收的非织造织物。该参考文献还公开了一种制备包含可生物吸收的非织造织物、凝血酶和/或纤维蛋白原的伤口敷料的方法,包括以下步骤:(a)将凝血酶和/或纤维蛋白原悬浮在全氟烃中以形成悬浮液;以及(b)将所述悬浮液施加到可生物吸收的非织造织物。
授予Gorman等人的名称为“Method for making an bioabsorable hemostat”(用于制备可生物吸收的止血器的方法)的欧洲专利公布EP2,052,746A2出于所有目的其全文以引用方式并入本文,并公开了一种制备伤口敷料的方法,其特征在于所述方法包括:将凝血酶和/或纤维蛋白原粉末悬浮在全氟烃载流体中,其中粉末不溶解,然后将所得的悬浮液施加到第一可生物吸收的非织造织物。
授予Gorman等人的名称为“Method for making an absorbable hemostat”(制备可吸收止血器的方法)的已公布美国专利申请2006/0088589A1出于所有目的其全文以引用方式并入本文中,并公开了一种制备伤口敷料的方法,其特征在于所述方法包括:将凝血酶和/或纤维蛋白原粉末悬浮在全氟烃载流体中,其中粉末不溶解,然后将所得的悬浮液施加到第一可吸收的非织造织物。
在实践本发明所实施的实验中使用如上述参考文献所述制备的包含止血生物制剂的垫子。
包含止血生物制剂的垫子的基质组分由位于一层Polyglactin910(PG910)非织造纤维下的针织ORC背衬层构组成。在制造基质的过程中,将PG910纤维粗疏成絮状并针刺进ORC背衬层中,以制备增强的包含止血生物制剂的垫子的基质。
包含止血生物制剂的垫子的生物组分优选地为冻干形式的人纤维蛋白原和人凝血酶药物物质。纤维蛋白原和凝血酶物质可以作为一种选择从非人类动物来源获得,或者采用已知的方式合成得到。根据下文呈现的数据,实验中使用的含有止血生物制剂的垫子的组成将清晰明了。除如下所述量的活性粉末之外,本发明的包含止血生物制剂的垫子任选地还涂覆有不同量的PEG3000和CMC,如稍后将在文中所述。包含纤维蛋白原的垫子的生物组分优选地为冻干形式的人纤维蛋白原和人凝血酶。它们分别包含生物活性成分纤维蛋白原和凝血酶,以及其他赋形剂。施用于包含纤维蛋白原的垫子的人纤维蛋白原和人凝血酶的组成为2-20mg/cm2纤维蛋白原和1-1501U/cm2凝血酶。包含止血生物制剂的垫子的支架或基质组分的组成为约5-30mg/cm2的ORC(作为背衬层);和5-30mg/cm2的PG910(作为载体层),总基质的重量为约10-60mg/cm2。
施用于包含止血生物制剂的垫子的人纤维蛋白原和人凝血酶的组成为约2-20mg/cm2纤维蛋白原和1-150IU/cm2凝血酶,且存在其他赋形剂,诸如氯化钙,任选的精氨酸、甘氨酸、白蛋白、甘露醇、缓冲盐以及通常存在于血浆衍生产品中的其他任选蛋白质组分。
实例1:包含止血生物制剂的垫子的测试样品的制造
随后的工序与上文引用的美国专利申请公布2009/0246238A1和欧洲专利公布EP2,052,746A2中所述的类似,将聚(乙交酯-共-丙交酯)(PGLA,90/10mol/mol)熔纺成纤维。将80旦尼尔的复丝纱线合并成800旦尼尔的合并纱线。在大约110℃下将合并纱线卷曲。将卷曲的纱线切割成长度为约1.25英寸的短纤维,精确称量20克卷曲的短纤维并均匀地铺设在多辊粗梳机的进料传送带上。控制环境条件(温度:21℃/55%RH)。随后梳理短纤维,以形成非织造絮状物。然后将该絮状物从拾取辊中取出,并切割成4等分。将这些等分垂直于收集方向重新送入粗梳机。在该第二次通过之后,对絮状物进行称量(19.8g:织物收率99%),然后将其压制成毡。将该紧凑的毡精确地铺设到ORC织物上,然后经由针刺法将它们牢固地附接。修剪该多层织物,并在三个分立的异丙醇浴中对其进行洗涤以除去纺织油剂和任何机油。将经洗涤的多层织物置于烘箱中在70℃下干燥30分钟,冷却并称量。
随后将经洗涤的多层织物切割成4×4英寸的小片。将1.70克比活性(Clauss法)为0.3g/g的BAC-2(欧姆瑞克斯生物医药有限公司(Omrix Biopharmaceuticals,Inc.))、0.30克含凝血酶的粉末(同样来自欧姆瑞克斯生物医药有限公司(Omrix Biopharmaceuticals,Inc))以及任选地0.40克聚乙二醇(PEG)和任选地0.30克羧甲基纤维素(CMC)粉末与约14毫升的非水流体氢氟醚HFE-7000充分混合。将浆液倾入凹槽稍大于4×4英寸的托盘中,以供容纳织物之用。随后将织物置于浆液中浸涂,以使粉末充分沉积在织物上。将所得的多层止血垫风干至少15分钟。
随后,使含有PEG的测试样品(有些样品还任选地包含CMC)在超过PEG熔点的温度下经受热处理。将样品放置在温度设定为65-70℃的标准真空烘箱中,并加热大约15分钟。通过加热至超过PEG熔点的温度,涂覆在可生物吸收的支架上的冻干凝血酶和纤维蛋白原颗粒以及任选地CMC颗粒将熔合到支架。随后使测试样品冷却至室温。
氢氟醚(HFE)流体为3M NovecTM工程流体HFE-7000(3M NovecTM EngineeredFluid HFE-7000),其为可商购自3M公司的1-甲氧基七氟丙烷。HFE-7000是一种惰性、不易燃、低沸点的流体。在制造期间,HFE-7000用作凝血酶和纤维蛋白原以及任选地PEG和/或CMC粉末的惰性递送载体,并且在制造过程中通过蒸发可基本上完全除去。在本发明的止血垫的制造过程中,任何其他惰性、不易燃、低沸点的非水流体也可用作凝血酶和纤维蛋白原以及任选地PEG和/或CMC粉末的惰性递送载体。
任何能够熔融的具有生物相容性并可生物吸收的粉末也可用于实践本发明,前提条件是其在环境温度下为固体并且熔融温度低于冻干蛋白质明显变性的温度。优选的粘合剂为平均分子量为1000至20,000道尔顿的PEG,更优选地为PEG3000至8000。当前的例子使用得自福鲁卡公司(Fluka)的PEG3000,其熔点为约56-59℃,且数均粒度为45微米。在优选的实施例中,按粘合剂颗粒的数量计,该颗粒的至少95%的粒度在约25-60微米的范围内,更优选地在35-55微米的范围内。
CMC(30,000PA,澄清且稳定)得自陶氏沃尔夫纤维素公司(Dow WolffCellulosics),并具有20微米的平均粒度。
BAC-2(生物活性组分2)是一种血液衍生产品,主要包含纤维蛋白原,其余部分包含白蛋白、缓冲盐以及通常存在于血浆衍生产品中的其他蛋白质组分。
根据上述过程制造了三类包含止血生物制剂的垫子的样品,然后对其进行实验测试:
a)含有纤维蛋白原和凝血酶的包含止血生物制剂的垫子;
b)含有纤维蛋白原、凝血酶和PEG的包含止血生物制剂的垫子;
c)含有纤维蛋白原、凝血酶、PEG和CMC的包含止血生物制剂的垫子。
含有少量PEG的包含止血生物制剂的垫子出乎意料地表现出改善的性质,包括改善的剥离强度、脆碎度和润湿性。这些改善在功能上的结果是封闭性和组织粘合性得到了增强,伴随着活性物质脆碎度的下降。
实例2:组织剥离测试
使用了活性组分的以下可变的浓度水平:
含有BAC-2纤维蛋白原的粉末:每4×4英寸包含止血生物制剂的垫子样品含有5.0和6.7mg/cm2的纤维蛋白原或1.27克和1.7克的含有纤维蛋白原的BAC-2粉末。
含有凝血酶的粉末:每4×4英寸包含止血生物制剂的垫子样品含有300mg含有凝血酶的粉末。
PEG:每4英寸×4英寸包含止血生物制剂的垫子样品含有0mg、100mg、400mg。
CMC:每4英寸×4英寸包含止血生物制剂的垫子样品含有0mg、300mg。
组织剥离测试按以下步骤进行。将宽0.75英寸、长约4英寸的包含止血生物制剂的垫子的测试样品放置在潮湿的牛真皮组织上。立即将施加180mm Hg压力的加压砝码放置在包含止血生物制剂的垫子的测试样品上方,然后在附着至组织的情况下进行三分钟孵育。孵育后将砝码移除,将包含止血生物制剂的垫子样品夹持在十字头上,然后以90度角将其从真皮组织剥离,并使用张力计测量剥离力。
现在参见表1和图1,其呈现了组织剥离测试的结果。
表1:组织剥离测试结果
对表1呈现数据的分析表明,PEG3000以100mg至400mg范围内的量存在显著地提升了包含止血生物制剂的垫子的组织剥离强度,且PEG越多,剥离强度越高。对所述数据的进一步分析表明,类似地,除一组测试外,CMC30k以300mg的量存在提升了包含止血生物制剂的垫子的组织剥离强度。
现在参见图1,其中组织剥离测试的单个数据点以及平均值明确地示出了400mg的PEG对组织剥离的作用。图表呈现了具有标称量的纤维蛋白原和凝血酶(分别为1700mg和300mg)的包含止血生物制剂的垫子相对于另外具有400mg PEG3000的包含止血生物制剂的垫子的数据。对数据的分析表明,PEG3000的存在显著地提升了包含止血生物制剂的垫子的组织剥离强度。
实施3:渗漏测试
渗漏测试按以下步骤进行:使包含止血生物制剂的垫子的测试样品在处于加压砝码下方的同时于猪血浆中经受三分钟孵育。然后将样品放置在具有4.5mm孔的平坦金属夹具上,并将具有匹配孔的透明塑料盖夹持在包含止血生物制剂的垫子之上。随后使样品经受作为以恒定流速递送穿过所述孔的液压流体的猪血浆。因此,渗漏是允许的唯一一种失效模式,并且将峰值压力记录为输出。
现在参见表2和图2,其呈现了两种不同量的BAC2的渗漏测试的结果:每4×4英寸包含止血生物制剂的垫子样品包含1.7g和1.27g含有纤维蛋白原的BAC-2粉末;0mg和400mgPEG3000;以及0mg和300mg CMC30k;所有量均针对每4英寸×4英寸包含止血生物制剂的垫子样品计。
表2:渗漏测试结果
对数据的分析表明,相对于未添加PEG的包含止血生物制剂的垫子(样品14),PEG3000的存在显著地提升了包含止血生物制剂的垫子在渗漏测试中的强度(样品12、13、24)。平均渗漏测试压力提升在从约6倍强至约14倍强的范围内。
实例4:脆碎度测试
现在参见表3和图3,其呈现了在对包含止血生物制剂的垫子进行处理之后四种不同PEG3000浓度(0、100、200和400mg;所有浓度均针对每4英寸×4英寸包含止血生物制剂的垫子样品计)的脆碎度测试结果。
对处理之后粉末重量损耗的脆碎度测试按以下步骤进行:使包含止血生物制剂的垫子的测试样品经受采用的极端处理实践。首先,记录4×4英寸包含止血生物制剂的垫子的重量。然后,单手握住止血垫,使其位于工作台顶部上方约三英寸处,且经涂覆的一侧面向下。使用手术剪将垫子剪切成大致两个2×4英寸的小片。使未被握持的小片下落至工作台顶部上的外科用无尘套上。然后将两个2×4英寸的小片中的每一个保持在工作台顶部上的外科用无尘套上方12英寸处,接着使两者分别下落三次。将两个小片置于天平上称量,并根据与初始的4×4英寸样品进行质量平衡而计算出粉末损耗百分比。所使用的样品包含各种量的PEG,但不包含CMC。结果在表3中示出。
表3脆碎度测试:处理后的粉末重量损耗
垫子样品编号 | BAC2(g) | 凝血酶(mg) | PEG3000(mg) | 粉末损耗百分比 |
5 | 1.700 | 300 | 0 | 16.0 |
6 | 1.700 | 300 | 100 | 2.6 |
7 | 1.700 | 300 | 200 | 2.2 |
8 | 1.700 | 300 | 400 | 1.4 |
对表3数据的分析表明,在脆碎度测试中,PEG3000的存在导致包含止血生物制剂的垫子(样品6、7、8)的脆碎度相对于未添加PEG的包含止血生物制剂的垫子(样品5)显著下降,同时粉末损耗从在最高PEG含量(400mg)时下降至约1/11,到在存在最低PEG量(对应于100mg PEG)时下降至约1/6。
随后如实例2中所述对经受了上述极端处理实践的样品进行组织剥离测试。该测试证明了相对于每4×4英寸装置含有0mg PEG的样品,含有100mg、200mg和400mg PEG量的样品的脆碎度降低与润湿性及组织剥离强度增强的协同效应。针对经受了上述标准化极端处理的包含止血生物制剂的垫子的测试样品测量了组织剥离力,结果反应出脆碎度降低与粘附性提升的协同组合。对图3呈现的实验结果的分析表明,PEG3000的存在显著提升了样品经受极端处理后的剥离力。PEG的正剂量响应在组织剥离的结果中得到证实,其中增加PEG含量导致组织剥离强度增加,且相对于不含有PEG的样品,含有400mg PEG的样品的组织剥离强度增加至2-2.5倍。
实例5:血纤维蛋白胶凝测试
测量样品使纤维蛋白原溶液凝块的时间的血纤维蛋白胶凝测试(试管倾斜法)按以下步骤进行。将纤维蛋白原(ERL FIB3)溶解在浓度为10mg/mL的200mM Tris缓冲盐溶液中。将本发明的包含止血生物制剂的垫子或对照用包含止血生物制剂的垫子的样品(测得为约1cm2)放置在12×75mm硼硅酸盐玻璃试管的底部处。将样品经涂覆的一侧面向上放置于试管中。然后将2mL 10mg/mL的纤维蛋白原溶液添加至试管,随后对试管加盖,并立即将试管架放入37℃水浴中。每十秒手动倒置试管一次,然后将其放回水浴内的试管架中。每次倒置时都进行观察,终点为观察到凝胶完全形成(即,试管内无明显的大量流体运动)的时间。
测试结果如下。对于不含有PEG且不含有CMC的对照用包含止血生物制剂的垫子样品,两次测试中样品使纤维蛋白原溶液凝块的时间为230秒和270秒。对于含有400mgPEG3000和300mg CMC的本发明的包含止血生物制剂的垫子(所有浓度均按每4英寸×4英寸的包含止血生物制剂的垫子样品计),两次测试中样品使纤维蛋白原溶液凝块的时间为90秒和120秒。
结果表明纤维蛋白原溶液凝块更快,因此含有PEG和CMC的包含止血生物制剂的垫子中的凝血酶较快润湿/疏水性较低/实用性更佳。
实例6:进水研究
进水研究按以下步骤进行。通过注射器将水滴递送到测得为约1cm2的包含止血生物制剂的垫子样品的经活性涂覆的一侧上。随后测量水滴芯吸进样品中的时间。
测试结果如下。对于不含有PEG的名义上的包含止血生物制剂的垫子,观察到水滴芯吸进样品中的时间为分钟级,即,长于约1-2分钟。对于含有400mg PEG3000和300mg CMC的本发明的包含止血生物制剂的垫子,水滴芯吸进样品中的时间为毫秒级。
结果表明含有PEG和CMC的包含止血生物制剂的垫子润湿更快,且疏水性较低。
虽然上述实例展示了本发明的某些实施例,但它们不应被理解为限制本发明的范围,而应理解为有助于完善本发明的描述。
Claims (20)
1.一种止血垫,包含:
a) 可生物吸收的支撑材料;
b) 冻干的凝血酶粉末,
c) 冻干的纤维蛋白原粉末,和
d) 能够熔融的粘合剂粉末,
其中所述凝血酶和纤维蛋白原粉末设置在所述可生物吸收的支撑材料上,并且所述能够熔融的粘合剂粉末将所述凝血酶粉末和所述纤维蛋白原粉末粘结到所述可生物吸收的支撑材料,
其中所述能够熔融的粘合剂不完全包裹所述冻干的凝血酶粉末和/或所述冻干的纤维蛋白原,并且其中所述能够熔融的粘合剂为具有25℃至100℃的熔点的亲水性、生物相容性和可生物吸收的材料。
2.根据权利要求1所述的止血垫,其中所述能够熔融的粘合剂包含平均分子量为1500道尔顿至20,000道尔顿的聚乙二醇聚合物。
3.根据权利要求1所述的止血垫,其中所述能够熔融的粘合剂基本上由平均分子量为2500道尔顿至8000道尔顿的聚乙二醇聚合物组成。
4.根据权利要求1所述的止血垫,其中所述能够熔融的粘合剂基本上由平均分子量为2500道尔顿至4000道尔顿的聚乙二醇聚合物组成。
5.根据权利要求3所述的止血垫,其中用于所述粘合剂粉末的所述聚乙二醇聚合物的平均分子量为3000道尔顿。
6.根据权利要求2所述的止血垫,其中所述粘合剂颗粒的数均粒度为45微米。
7.根据权利要求2所述的止血垫,其中所述冻干的凝血酶粉末的重量分数为10%-15%,所述冻干的纤维蛋白原粉末的重量分数为55%-85%,并且所述聚乙二醇的重量分数为2%-20%,各重量分数均相对于所述止血垫上的所述凝血酶、纤维蛋白原和聚乙二醇粉末的总重量计,其中所述止血垫上的所述凝血酶、纤维蛋白原和聚乙二醇粉末的总重量分数为100%。
8.根据权利要求2所述的止血垫,其中所述可生物吸收的支撑材料为织造的或非织造的合成的或天然的可生物吸收材料或它们的组合。
9.根据权利要求2所述的止血垫,其中所述可生物吸收的支撑材料为双层材料,其包含一层非织造的Polyglactin 910纤维,所述纤维已被针刺进一层针织的氧化再生纤维素中,其中所述粉末仅设置在非织造Polyglactin 910纤维的所述层上。
10.根据权利要求2所述的止血垫,其中通过将所述止血垫的温度升高至高于所述聚乙二醇聚合物的熔点的点,将所述冻干的凝血酶粉末和所述冻干的纤维蛋白原粉末粘结到所述可生物吸收的支撑材料。
11.根据权利要求2所述的止血垫,其中所述止血垫包含每平方英寸所述止血垫中200-600IU的凝血酶,如施用时所测得,所述止血垫以每平方英寸所述止血垫中20-80mg的量包含纤维蛋白原,如施用时所测得,并且所述聚乙二醇以每平方英寸所述止血垫中6-25mg的量存在。
12.根据权利要求2所述的止血垫,还包含CMC粉末。
13.根据权利要求12所述的止血垫,其中所述CMC粉末的数均粒度为20微米,并且其中所述CMC粉末以每平方英寸所述止血垫中15-20mg的量存在。
14.一种制造止血垫的方法,所述方法包括以下步骤:
(a) 形成冻干的凝血酶粉末、冻干的纤维蛋白原粉末和聚乙二醇粉末的非水悬浮液;
(b) 将所述悬浮液涂覆到由生物吸收性材料制成的支架上
(c) 使所述悬浮液蒸发,同时所述支架携带所述凝血酶粉末、所述纤维蛋白原粉末和所述聚乙二醇粉末的一部分;
(d) 将所述支架加热至超过所述聚乙二醇粉末熔点的温度;
(e) 将所述支架冷却至低于所述聚乙二醇的熔点的温度以形成所述止血垫,
其中所述聚乙二醇粉末不完全包裹所述冻干的凝血酶粉末和/或所述冻干的纤维蛋白原。
15.根据权利要求14所述的方法,其中所述步骤(d)和(e)导致所述聚乙二醇熔化以及所述聚乙二醇固化,以将所述冻干的凝血酶粉末和所述冻干的纤维蛋白原粉末粘结到所述支架上。
16.根据权利要求14所述的方法,其中所述聚乙二醇粉末基本上由平均分子量为1500道尔顿至20,000道尔顿的聚乙二醇粉末组成,并且所述生物吸收性材料为织造的或非织造的合成的或天然的可生物吸收材料或它们的组合,并且所述聚乙二醇粉末的数均粒度为45微米。
17.根据权利要求16所述的方法,其中所述聚乙二醇粉末基本上由平均分子量为2500道尔顿至4000道尔顿的聚乙二醇粉末组成。
18.根据权利要求14所述的方法,其中所述生物吸收性材料为双层材料,其包含一层非织造的Polyglactin 910纤维,所述纤维已被针刺进一层针织的氧化再生纤维素中,并且其中所述粉末仅设置在非织造Polyglactin 910纤维的所述层上。
19.根据权利要求14所述的方法,其中所述非水悬浮液包含HFE-7000,并且通过将所述支架浸入所述悬浮液中或将所述悬浮液喷涂到所述支架上来进行将所述悬浮液涂覆到所述支架上的所述步骤。
20.根据权利要求14所述的方法,其中所述悬浮液还包含CMC粉末颗粒。
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AU2012346104B2 (en) | 2015-11-12 |
US20130149343A1 (en) | 2013-06-13 |
BR112014013337A2 (pt) | 2017-06-13 |
CN103957947A (zh) | 2014-07-30 |
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CA2857138A1 (en) | 2013-06-06 |
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