CN109107541B - 用于蛋白质结合的尿毒症毒素的透析的血液相容性吸附剂 - Google Patents
用于蛋白质结合的尿毒症毒素的透析的血液相容性吸附剂 Download PDFInfo
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- CN109107541B CN109107541B CN201810614783.0A CN201810614783A CN109107541B CN 109107541 B CN109107541 B CN 109107541B CN 201810614783 A CN201810614783 A CN 201810614783A CN 109107541 B CN109107541 B CN 109107541B
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Abstract
本发明涉及一种用于分离患者血液或血浆中含有的且关于其载体蛋白具有<500g/mol分子量的蛋白质结合的尿毒症毒素以便在血液透析过程中吸附所述尿毒症毒素的血液相容性吸附剂,所述血液相容性吸附剂包含基于环状低聚糖或其衍生物的以至少一层设置在固态载体组分上的聚合物。本发明还涉及一种用于血液透滤的装置,包括用于接收待纯化的血液体外回路和连接到患者血液循环的血液透析器和/或血液过滤器;其中提供血液相容性吸附剂用于分离患者血液或血浆中含有的且关于其载体蛋白具有<500g/mol分子量的蛋白质结合的尿毒症毒素;且其中在所述血液透析器内的血液侧上以至少一层设置在固态载体组分上的血液相容性吸附剂包含基于环状低聚糖或其衍生物的聚合物。
Description
技术领域
本发明涉及一种血液相容性吸附剂和一种用于血液透滤的装置。
背景技术
根据肾的生理学,通常已知健康肾的任务是通过尿液从身体排出如所谓的“尿物质”的代谢终产物和所谓的“尿毒症毒素”的毒素。肾去除不同分子量的广谱物质。尿毒症毒素的概述已由Vanholder等人在2003年发表。[参阅Vanholder等人,KidneyInternational,63(2003)1934-1943]。基于其分子量,尿毒症毒素主要分为三类:
A)具有<500g/mol的分子量的低分子量毒素;
B)具有平均分子量的毒素,还已知为“平均分子”,其具有500与12,000g/mol之间的分子量。例如,中等分子包括β2-微球蛋白(11800g/mol)。
C)第三类尿毒症毒素是具有>12,000g/mol的分子量的分子。
此外,关于尿毒症毒素的水溶性做出区分。具有低分子量的高度水溶性的尿毒症毒素的实例是尿素、肌酸酐、草酸盐、胍和尿酸。
水溶性较差的尿毒症毒素的实例是对甲酚、硫酸吲哚酚、苯酚、马尿酸和同型半胱氨酸。这些尿毒症毒素呈结合到蛋白质的形式主要存在于血清中。
在健康个体中,尿毒症毒素通过肾用尿液排出。然而,在慢性肾衰竭中,这些毒素保持在患者的血液中并且必须通过血液透析或腹膜透析去除。
虽然通过血液透析去除水溶性毒素诸如尿素或肌酸酐是非常有可能的,但是由于蛋白质结合,通过血液透析去除水溶性较差的疏水性尿毒症毒素是极其困难的,因为蛋白质结合的尿毒症毒素仅通过血液透析的血浆中的毒素-蛋白质复合物与游离毒素的化学平衡才可达到,所述平衡强烈倾向于所述复合物。这意味着尿毒症毒素的大部分结合到蛋白质,而仅小部分溶解在血浆中并且仅这些游离尿毒症毒素可被透析。
关于蛋白质结合的尿毒症毒素的生理化学的另外的研究已示出人类血清白蛋白在患者的血液中充当疏水性尿毒症毒素的结合配偶体并且因此呈毒素-白蛋白复合物形式。
由于其大约65,000g/mol的分子量,白蛋白被普通透析膜保留。因此通过血液透析不去除白蛋白。这意味着仅游离的、溶解的且非常小部分的尿毒症毒素可从患者的血液去除。在去除此小游离部分之后,白蛋白结合的与游离的尿毒症毒素之间的平衡恢复。
理论上,此再平衡可通过连续透析去除显著部分的游离尿毒症毒素。然而,毒素-白蛋白复合物的缔合常数以及不足以可实践的透析时间与此冲突。
因此长期以来,存在对于能够从患有慢性肾衰竭或慢性肾功能能不全的患者的血液中有效去除蛋白质结合的尿毒症毒素的透析方法的需要。
对此已存在多种现有技术方法,但是出于各种原因,它们均未在日常临床实践中被接受:
GB 1 466 702公开用于吸附消化道中的尿毒症毒素的聚合物涂覆的活性炭。
用于吸附来自血液的尿毒症毒素的聚合物涂覆的活性炭的用途从US 4,140,652已知。
WO 2009/157877公开一种用于通过吸附到ZrO2颗粒从透析流体去除毒素的方法。
此外,WO 2010/045474公开一种用于通过添加使毒素从蛋白质上的其结合位点移除并且因此使其对于透析可用的物质来分离蛋白质结合的尿毒症毒素的竞争性方法。
US 4,889,634还公开一种用于腹膜透析的含有羟丙基-β-环糊精的溶液。
概括地说,可得出结论,在透析条件下调整蛋白质结合的、尤其是白蛋白结合的尿毒症毒素与游离可用的尿毒症毒素之间的平衡是速度决定步骤。如以上提及的,虽然期待游离的与蛋白质结合的毒素之间的平衡将在从血液去除溶解毒素之后恢复并且如果透析时间足够长可去除相当大部分的毒素,但是此时间对于血液透析治疗不可用。
在透析过程中,由于其分子量并且因此还由于结合到其的毒素,白蛋白被普通透析膜保留。
然而,如果根据WO2015091842 A2[15],蛋白质结合的尿毒症毒素被转移到低分子量结合配偶体(而不是高分子量蛋白质配偶体),使得结合配偶体和尿毒症毒素的所得的复合物具有在可透析区域中的分子量,则当通过透析器时,存在于游离溶液中的毒素以及先前存在于结合的白蛋白中的毒素可被去除。在文献[15]的公开内容中,此类低分子量结合配偶体作为可透析佐剂被添加到透析。
根据文献[15],具体地提出例如将可透析赋形剂投配到透析器的血液供应软管中,使得在到透析器的途中建立结合配偶体与毒素之间的所需平衡。在此过程中,毒素从在白蛋白或其他蛋白质上的结合位点去除。结合配偶体与结合的毒素然后可高效地通过常规透析方法去除。作为此类竞争性赋形剂,除其他情况之外,WO2015091842 A2提出使用具有范围是500至5,000g/mol、优选地1,000至2,000g/mol的分子量的环糊精。
已知环糊精这种物质结合疏水性化合物。
环糊精是属于环状低聚糖的一类化合物。它们代表淀粉的环状降解产物。环糊精由α-1,4-糖苷键连接的葡萄糖分子组成。这引起具有中心腔的环形结构。根据连接的葡萄糖分子的数量,它们接受希腊字母作为前缀:
环糊精的特性诸如水溶性可被羟基的取代影响。例如,β-环糊精的水溶性通过甲基取代增加150个因子。此外,环糊精的吸附特性可通过选择性取代改变。例如,β-环糊精不可静脉内施用,因为其与胆固醇形成不可溶复合物。取代环糊精羟丙基-β环糊精(HPBCD)和磺丁基醚-β-环糊精(SBECD)不形成不可溶胆固醇复合物并且因此是用于根据文献[15]使用的优选环糊精。
除以上提及的环糊精化合物之外,存在是用于根据本发明的应用的候选物的各种环糊精基础物质的其他衍生物。它们对于本领域的技术人员从综述文章(诸如来自Brewster等人(Advanced Drug Delivery Reviews 59(2007)645-666)的综述文章)是已知的,并且通常通过引入环糊精分子的取代基的亲水基来区分。
原理上,除环糊精之外,也可考虑具有相当的结构特性的其他宏观环状系统。Biros等人(Chem.Soc.Rev.,2007,36,93-104)的综述对此给出概述。除环糊精之外,在此还描述杯[n]芳烃、二苯撑环烷烃和葫芦脲衍生物。
根据文献[15],可透析赋形剂溶解在透析或取代溶液中。在另一个实施方案中,可透析赋形剂可与诸如氯化钠的盐存在于物理混合物中。为了产生即用型溶液,混合物溶解在水中以用于注射,可能添加另外的电解质。此即用型溶液还适于作为根据WO2015091842A2的输注溶液。
文献[15]的教义还涉及一种通过添加可透析佐剂来去除蛋白质结合的毒素的装置和方法。
文献[15]的教义具体地涉及一种用于实施去除蛋白质结合的毒素的所述方法的装置,其包括用于接收待纯化的血液的体外回路并且包括血液透析器和/或血液过滤器,所述血液透析器和/或血液过滤器连接到血液循环,血液循环在血液透析器和/或血液过滤器的上游和任选地下游的各自具有用于供应取代流体的至少一个供应线。通过供应线在血液透析器和/或血液过滤器的上游供应的取代流体包含可透析赋形剂。
目前,不同的膜可用于通过血液透析和血液过(渗)滤消除尿毒症毒素。膜特性在确保高效透析处理方面发挥重要作用,[参阅1-5]。透析处理的效率可通过确定关于通常水溶性的且非蛋白质结合的小分子[2,4,5]的消除能力来估计[参阅5-6]。然而,最近的临床公布示出尿毒症的生物化学变化不仅通过水溶性/非蛋白质结合毒素触发[4],还通过蛋白质结合的物质/毒素诸如对甲酚、硫酸吲哚酚、马尿酸、3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)或苯酚衍生物触发[2,6]。这些毒素主要结合到白蛋白。
目前,对甲酚和硫酸吲哚酚是在透析患者的情况下最常研究的蛋白质结合毒素。单纯的扩散型(HD)、单纯的对流型(HF)和扩散型/对流型(HDF)透析不能保证有效消除。这主要是由于以下事实-如上提及的-必需蛋白质诸如白蛋白的保留当然必须被考虑在内,并且透析患者中通常使用的膜不提供此选择性。然而,对甲酚、硫酸吲哚酚和其他蛋白质结合毒素具有高心血管毒性,这直至目前对于透析处理还是问题。
在文献中,存在不同的论文,其描述不同分子大小的尿毒症毒素如何或多或少选择性地可从血液、人类血浆或血浆模仿溶液中被吸附。
基于活性碳的吸附
具有由丙烯酸和苯乙烯组成并且引起血液相容性涂层的共聚物的医学上可应用的活性炭的早期实例由Sparks等人(Sandoz AG)在1974年申请专利[7,DD 109 363]。此聚合物包覆的活性炭能够吸附不带电荷的低分子量尿毒症毒素(例如,尿素或肌酸酐)。在2015年,Tschulena等人(Fresenius AG)对直至现在仍是最有利的吸附剂粒料的粒料[8]申请专利。出于此目的,聚乙烯吡咯烷酮(PVP)、另外的交联剂和自由基引发剂的水溶液用于在加热下“接枝”由球形颗粒组成的活性碳;即,聚合物牢固地附接到活性炭并且与交联剂一起形成不带电荷的中孔结构,疏水性的且带电荷的低分子量尿毒症毒素(例如,硫酸吲哚酚、对甲酚硫酸酯、胆红素;Ap5A和苯乙酸)可通过所述中孔结构扩散。
在2016年,Stamatialis等人发表基于聚醚砜(PES)并且由两个组合层组成的低通量中孔纤维膜-“混合基质膜”(MMM)的开发。用于血液接触的内层由纯PES组成,而外层由具有细分在PES中的活性碳的复合材料构成。所述小组示出这些膜可用于在与没有活性炭层的膜相比使有效性翻倍的情况下去除人类血浆中的硫酸吲哚酚或对甲酚硫酸酯(人工添加并结合到白蛋白)。关于通过活性碳上的吸附去除尿毒症毒素的有效性与在常规透析中发生的扩散累加[9,10]。
Glorieux和Krieter等人的研究[11a和11b]报道健康人的血浆具有0.53±0.29mg/l的硫酸吲哚酚,并且患有慢性肾病的患者的血浆在透析处理之前具有44.5±15.3mg/l[11]。根据等人的研究[11,12],在透析处理之后,此值可减小至~39mg/l。如果结果与来自Stamatialis等人[9]的MMM相比,透析处理中的MMM将能够使此值降低至~32mg/l。
基于多孔芳基合成树脂的吸附
在1984年,Tlustakova等人对具有作为用于血液接触的生物相容性层的共价接枝的2-羟基乙基曱基丙烯酸酯(包括合适的交联剂)的基于苯乙烯、二乙烯基苯(DVB)和丙烯腈的多孔吸附剂的产生的首批实例中的一种申请专利[13]。此类型的过滤器目前仍在使用,例如用于LdL单采血液成分术。由于基于苯乙烯的树脂和待去除的物质的疏水性特征,这些吸附剂是特别有效的。最近,公司CytosorbentsCorp.生产一种用于从全血去除细胞因子(也是具有疏水性结构域的中等分子蛋白质)的吸附剂。颗粒的实际上负责吸附的核心也基于苯乙烯DVB聚合物,并且生物相容性保护层在此由高度多孔的PVP组成。因此,甚至可吸收具有较高分子量的细胞因子(8kDa至100%,18kDa至85%以及51kDa至55%)[14]。
用于复合物形成的环糊精(客体主体关系)
在2013年,Fislage等人(Fresenius Medical Care Deutschland股份有限公司)对通过使用具有针对其的可结合腔仿射的可透析赋形剂环糊精来去除具有疏水性结构域的白蛋白结合的毒素的全新方法申请专利[15]。因此,本发明基于溶液中的“再复合”。将202μmol/l的对甲酚(其在患有肾病的患者的血液中发现的量增加)添加到从在缓冲液中的638μmol/l的牛血清白蛋白(BSA)(对应于30g/l)产生的人工血浆。此对甲酚立即与BSA形成复合物。将此溶液在100ml/min的流动速率下泵送通过商购可获得的高通量透析器(Fresenius FX60类型)的内腔侧。在即将进入到透析器中之前,在10ml/min下连续投配羟丙基-β-环糊精(224g/l)的溶液,使得在整个溶液中实现22.4g/l(16mmol/l)的浓度。在透析器的出口处(体积流速110ml/min),与输入浓度相比,对甲酚的浓度明显降低至55%。
在2009年,Hammond等人发表基于聚(羧甲基-β-环糊精)的吸附剂的第一个实例[16]。此阴离子聚合电解质在由硅制成的模型表面上与作为粘合促进剂的生物可降解的阳离子聚合电解质组合通过叠层(LbL)工艺以交替方式固定。这些层用于使疏水性物质(抗生素、氟比洛芬和双氯芬酸)复合。环糊精本身的环上的弱的带负电的羧基形成用于聚合物粘合到基底的基础。
另外的方法
蛋白质与所讨论的疏水性毒素中的一种之间的结合基于复合物的形成,在血液的水性环境中的所述结合倾向于复合物[11,12,17,18]。硫酸吲哚酚、苯乙酸和对甲酚在生理条件(NaCI=0.15mol/l)下分别在96%、60%和97%下以结合形式存在。如果盐浓度增加至例如0.50mol/l的高渗范围,此平衡分别转变至88%、36%和91%。增加的盐含量干扰毒素与蛋白质之间的相互作用。因此,低分子毒素可通过透析膜去除。由于生理限制,此程序对于患者是有问题的。在相同的研究中,等人研究通过在体外环境中使用透析器作为两个电容器板之间的电介质或作为线圈的核心在高频率电磁场的帮助下影响疏水性毒素的消除的可能性。因此,发现所述影响显著小于当使用增加的盐浓度时的影响[11,12]。
先前现有技术方案的缺点
如果活性碳或具有疏水性行为的倾向的聚合物(例如,苯乙烯和二乙烯基苯的共聚物(Amberlite XAD-2))用作用于去除疏水性的低分子血液毒素或细胞因子的吸附剂,则全血不可与这些材料直接接触。这是一个很大的缺点。为了避免这一点,全血可使用血浆过滤器分开,使得与固态血液组分分离的血浆可通过此吸附剂纯化并且然后返回。然而,此方法需要复杂的泵和软管系统[19]。另一种可能性是使用以上提及的生物相容性亲水性聚合物中的一种“掩蔽”基础聚合物以允许与全血接触。对于此官能化,基底上的化学连接通常为所谓的“游离基接枝共聚”所需要。实现此连接是非常昂贵的。然而,保护层代表或多或少明显的扩散屏障,主要针对大分子。所述屏障在由Stamatialis等人提出的MMM的情况下是特别明显的。在所描述的体外实验中,~40μm PES将在血液侧上的加载有对甲酚的蛋白质与在透析液侧上的具有活性炭的吸附剂层分开[9,10]。高壁厚的膜(~100μm)还引起具有不利比率的纤维数量/束直径的厚纤维。用于产生所述膜的高材料消耗在此是清楚可见的并且因此是较高的成本因素。具有活性碳的常规吸附剂还具有它们不是非常具有选择性的缺点,即,对于待治疗的患者是重要的并且存在于血液中的蛋白质或水溶性较差的维生素也与有害分子一起被吸附。相似地,关于待吸附的物质的分子量没有选择性行为。在用于治疗脂肪平衡的代谢疾病(血脂异常)的单采血液成分术的疗法形式中,这些效应被消除,因为待去除的LDL等主要占据吸附位点。通常,另一个缺点是200至400ml的大血液体积和此吸附剂的高压损失。此特性导致大多数产品中小的可能的血液流动。总之,这些特性意味着与普通血液透析系统的整合是不可能的。
发明内容
基于根据WO2015091842 A2的技术发展水平[15],本发明的任务是:溶解来自白蛋白的蛋白质结合的毒素并且然后通过透析将其有效地去除而不将另外的赋形剂引入到患者和/或透析流体中,如根据文献[15]的教义所需要的。
此问题的解决方案是如权利要求1所述的血液相容性吸附剂。
附图说明
图1为单独的药筒与透析器的串联连接示意图;
图2为吸附剂在透析器的血液帽中;
图3为吸附剂在中空纤维膜的整个表面上。
具体实施方式
具体地,本发明涉及一种用于分离患者的血液或血浆中含有的并且关于其载体蛋白具有<500g/mol的分子量的蛋白质结合的尿毒症毒素以便使得所述尿毒症毒素通过血液透析可透析的血液相容性吸附剂,其中所述血液相容性材料包含基于环状低聚糖或其衍生物的以至少一层设置在固态载体组分上的聚合物。
在本发明的范围内,所述尿毒症毒素选自由以下组成的组:对甲酚、硫酸吲哚酚、苯酚、苯酚衍生物、同型半胱氨酸、尿呋喃酸(urofuranic acids)具体地3-羧基-4-甲基-5-丙基-2-呋喃丙酸、马尿酸以及对羟基马尿酸。
在优选的实施方案中,当待去除的尿毒症毒素结合到作为载体蛋白的人类白蛋白时,根据本发明的吸附剂是特别有效的。
在本发明的上下文中,优选使用血液相容性吸附剂,其中基于环状低聚糖的聚合物选自由以下组成的组:聚环糊精、聚-β-环糊精、聚(羧甲基-β-环糊精)和聚(三甲基铵-β-环糊精)以及使用表氯醇缩聚的环糊精。
在本发明的上下文内,固态载体组分优选地选自由以下组成的组:优选地非织造织物材料、中空纤维或平坦膜或基于以下的其他多孔材料:聚醚砜[PES]、聚砜[PSU]、聚醚醚酮[PEEK]、聚苯砜[PPSU]、聚甲醛[POM]、多酚、聚酰胺、具体地尼龙、聚苯乙烯、聚丙烯酸酯、聚碳酸酯或包含丙烯腈或甲基烯丙基磺酸盐的聚合物或其共聚物。
在本发明的范围内,基于环状低聚糖或其衍生物的聚合物通常使用叠层技术[LbL技术]以多层施加到固态载体组分。LbL技术对于专家例如从[16]是熟知的。
如果根据本发明的血液相容性吸附剂设计为布置在血液透析系统的透析器的上游的单独的药筒,其中设置在其中的织物、具体地非织造织物涂覆有聚合物,则产生所述血液相容性吸附剂的特定优点。
如果根据本发明的血液相容性吸附剂作为涂覆有聚合物的非织造织物整合在血液透析系统的透析器的血液帽中,则产生所述血液相容性吸附剂的另一个特别的优点。
本发明的上下文中描述的血液相容性吸附剂是整合到血液透析系统的透析器的中空纤维膜的孔系统中的那种血液相容性吸附剂。
本发明还涉及一种血液透滤设备,其包括用于接收待纯化的血液的体外回路和连接到患者的血液循环的血液透析器和/或血液过滤器;
其中提供血液相容性吸附剂用于分离患者的血液或血浆中含有的并且关于其载体蛋白具有<500g/mol的分子量的蛋白质结合的尿毒症毒素;并且其中在血液透析器内的血液侧上以至少一层设置在固态载体组分上的血液相容性吸附剂包含基于环状低聚糖或其衍生物的聚合物。
因此,本发明描述一种用于选择性地并且有效地去除具有疏水性和/或带电荷的结构域的多至~500Da的分子量的白蛋白结合的毒素(例如,硫酸吲哚酚、对甲酚、马尿酸、对羟基马尿酸或苯乙酸)以支持普通体外血液处理(例如,血液透析或肝脏透析)的吸附剂。
所述吸附剂由基于环糊精的血液相容性聚合物组成,所述聚合物使用LbL技术施加到具有大表面积的多孔材料。理想的载体是具有合适的目尺寸的非织造织物。此涂覆织物可串联连接在透析器的上游的小药筒中或整合到透析器的血液帽中。另一个可用的选项是使用血液相容性聚合物涂覆用于血液透析的高通量中空纤维膜的整个可达到的表面积。一方面,所述聚合物应由Hammond等人[16]作为阴离子聚合电解质首次引入的以上提及的聚(羧甲基-β-环糊精)组成。另一方面,所述聚合物由阳离子粘合促进剂聚乙烯亚胺(PEI)或理想地阳离子环糊精对应物诸如Morin等人[20]最近提出的聚(三甲基铵-β-环糊精)组成。后一种聚合电解质的明显优点是它不仅充当用于LbL工艺的结合剂像PEI,其本身还包含环糊精。因此,吸附剂的能力随着每个施加的层增加至所需的点。原理上,这两种聚合电解质可简单地通过使用表氯醇缩聚对应修饰的环糊精来产生。这些合成可在简单的反应条件下在水溶液中或也在有机溶剂中实施[21,22,23]。Cravotto等人和Hapiot等人还公开一种用于在球磨研磨的帮助下修饰环糊精作为没有水的固相反应的新的可能性[24,25]。
为了实现血液毒素从白蛋白到吸附剂的可能最好的转移,吸附剂对于对应毒素的结合常数必须足够大。在生理条件(0.15mol/l NaCl)下,此值在白蛋白与硫酸吲哚酚之间,Ks=48,000L/mol[12]。相比之下,溶液中的(天然)环糊精具有仅Ks=12,000L/mol的结合常数。然而,根据Fislage等人的专利,可示出在实验条件下,仍可去除55%的大部分毒素(对甲酚)[15]。在具有1.6m2的有效膜面积的透析器的所有内腔的近似100mL的填充体积的情况下,模型血浆的停留时间在110ml/min下是~55s。此时间明显足以允许在扩散去除第一批“再复合的”毒素之后发生新平衡调整并且因此实现有效去除。相比于白蛋白复合物(近似65,200g/mol),对甲酚和羟丙基β-环糊精的复合物具有~1,500g/mol的分子量并且因此可容易地透析。由于此事实,另外两个方面使得在本发明的上下文中提出的吸附剂远远更有效:1)阳离子聚(三甲基铵-β-环糊精)或其多取代衍生物包含配体,其使吸附剂的结合常数与天然环糊精相比增加多至3,000个因子(Ks=12,000L/mol相对于3,410,000L/mol;两者均在溶液中)-由于季铵残基[18];2)与在溶液中的客体-主体复合物相比,当吸附剂作为固体状态或可溶胀膜存在时,其结合常数通常增加10至15个因子[26]。此原因是固体状态上的另外物理地导致的吸附焓。在患有慢性肾病的人的血液中,除其他物质之外,以下白蛋白毒素主要在所述血液中发现:具有41.0±13.3mg/l血液的对甲酚、具有44.5±15.3mg/l血液的硫酸吲哚酚、具有87.2±61.7mg/l血液的马尿酸以及具有18.3±6.6mg/l血液的对羟基马尿酸[11]。
相比之下,认为健康人的血液仅含有1%至5%浓度的所提及的物质[11],每升待纯化的血液需要仅~1.4g的量的具有吸附效应的所述载体结合的聚合物,涉及使用表氯醇交联的“天然”β-环糊精。
当前没有针对多至~500g/mol的蛋白质结合的血液毒素的选择性吸附剂。根据本发明的吸附剂可固定在具有变化的能力和亲和力的任何底物上。这通过以下事实区别:与其他吸附剂相比,仅需要少量的官能聚合物。无论所述吸附剂在透析器的血液帽中(图2)或在中空纤维膜的整个表面上(图3)使用,需要少量另外的血液体积用于单独的药筒与透析器的串联连接(图1)或不需要另外的血液体积。此外,所述吸附剂在没有扩散抑制保护层的情况下做到这一点,因为所述材料本身适于直接血液接触。
原理上,所述发明性吸附剂可用于任何透析处理,因为难以透析并且对于每位患者产生沉重负担的<500g/mol的毒素可被有效地去除。其可以所需量整合到血液透析系统中而不影响功能,即,理想地在血液帽中的非织造织物上(图2)而没有压力损失。
环糊精是已知的并且在制药工业中被接受,并且在药物制造中用作“赋形剂”(注射剂、片剂和膏剂)以溶解水不可溶药物并且因此使其生物上可用。
由于修饰的聚-(环糊精)的化学特性,与活性碳相比,可在合适的制剂的情况下实现含水系统中疏水性毒素的吸附速率的15至200倍增加[23,27]。
此外,重要矿物质、氨基酸或维生素不从血液去除。
因此,本发明描述一种用于有效去除多至500g/mol的蛋白质结合的血液毒素的作为常规血液透析的支持物的新吸附剂。所述吸附剂可基于修饰的环糊精并且可使用LbL技术整合到血液透析系统的任何部分中。
文献
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Claims (8)
1.一种用于分离患者的血液或血浆中含有的并且关于其载体蛋白具有<500g/mol的分子量的蛋白质结合的尿毒症毒素的血液相容性吸附剂,所述尿毒症毒素为:对甲酚、硫酸吲哚酚、苯酚、苯酚衍生物、同型半胱氨酸、尿呋喃酸、马尿酸以及对羟基马尿酸,所述载体蛋白是人类白蛋白,其特征在于,
所述血液相容性吸附剂包含基于环状低聚糖的以至少一层设置在固态载体组分上的聚合物,和所述基于环状低聚糖的所述聚合物选自由以下组成的组:聚(羧甲基-β-环糊精)、聚(三甲基铵-β-环糊精)以及与表氯醇融合的环糊精,以及
所述固态载体组分为基于:聚醚砜[PES]、聚砜[PSU]、聚醚醚酮[PEEK]、聚苯砜[PPSU]、聚甲醛[POM]、多酚、聚酰胺的多孔材料,聚苯乙烯、聚碳酸酯或包含丙烯腈或甲基烯丙基磺酸盐的聚合物或其共聚物。
2.如权利要求1所述的血液相容性吸附剂,其特征在于所述尿毒症毒素为3-羧基-4-甲基-5-丙基-2-呋喃丙酸。
3.如权利要求1或2所述的血液相容性吸附剂,其特征在于所述固态载体组分为基于尼龙的多孔材料。
4.如权利要求1-3任一项所述的血液相容性吸附剂,其特征在于基于环状低聚糖的所述聚合物通过叠层技术以多层施加到所述固态载体组分。
5.一种可布置在血液透析系统的透析器的上游的单独的药筒,其由如权利要求1-4任一项所述的血液相容性吸附剂形成,其中设置在药筒中的固态载体组分涂覆有所述聚合物。
6.一种血液透析系统的透析器的血液帽,其特征在于如权利要求1-4任一项所述的血液相容性吸附剂作为涂覆有所述聚合物的固态载体组分整合在所述血液帽中。
7.一种血液透析系统的透析器,其特征在于如权利要求1-4任一项所述的血液相容性吸附剂整合到所述透析器的中空纤维膜的孔系统中。
8.一种血液透滤设备,其包括用于接收待纯化的血液的体外回路和可连接到患者的血液循环的血液透析器;
其中提供血液相容性吸附剂用于分离患者的血液或血浆中含有的并且关于其载体蛋白具有<500g/mol的分子量的蛋白质结合的尿毒症毒素;并且其中
在所述血液透析器内的血液侧上以至少一层设置在固态载体组分上的如权利要求1-4任一项所述的血液相容性吸附剂。
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US10625241B2 (en) | 2020-04-21 |
RU2018118955A (ru) | 2019-11-25 |
JP2019005569A (ja) | 2019-01-17 |
DE102017113853A1 (de) | 2018-12-27 |
EP3417937B1 (de) | 2021-04-14 |
RU2018118955A3 (zh) | 2021-09-15 |
JP7048425B2 (ja) | 2022-04-05 |
EP3417937A1 (de) | 2018-12-26 |
US20180369783A1 (en) | 2018-12-27 |
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