CN110662546A - 寡糖化合物在治疗动脉型糖尿病患者的伤口中的用途 - Google Patents
寡糖化合物在治疗动脉型糖尿病患者的伤口中的用途 Download PDFInfo
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Abstract
本发明的主题是具有1‑4个单糖单元的合成多硫酸化寡糖、其盐或其复合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
Description
技术领域
本发明的主题是具有1-4个单糖单元的合成多硫酸化寡糖,其盐或其复合物在用于治疗动脉病患者的糖尿病足溃疡中的用途,特别是在用于激活动脉病患者的糖尿病足溃疡的愈合中的用途。
背景技术
伤口愈合是一种自然的生物学现象,哺乳动物组织能够通过其特有的修复和再生过程来修复局部病灶。
伤口愈合的速度和质量取决于受影响生物体的总体状况、伤口的病因、伤口的状况和位置、和是否发作感染、以及易患伤口愈合障碍的遗传因素。
伤口的自然愈合主要按照三个连续阶段进行,每个阶段的特征在于特定的细胞活性,其根据精确的时间顺序推进修复过程:炎症阶段、肉芽形成阶段(或增殖阶段)和成熟阶段。
第一阶段,即炎症阶段,从血管破裂开始,其触发主要由纤维蛋白和纤连蛋白组成的血块(血液凝集)的形成,且其将形成临时基质。这种基质部分填补了病灶,并能够使募集的炎症细胞在受损区域内迁移,以清洁伤口。存在的血小板还会释放能够募集愈合细胞(诸如炎症细胞(多核嗜中性粒细胞和巨噬细胞)、成纤维细胞和内皮细胞)的因子(例如,细胞因子、生长因子)。
第二阶段对应于肉芽组织的发育。首先,观察到伤口通过增殖成纤维细胞定植。然后,来自健康血管的血管内皮细胞迁移将能够使受损组织形成新的血细胞(新血管形成)或血管生成。该血管生成步骤是启动伤口愈合的基础。在肉芽组织中,成纤维细胞被激活并且分化为由肌动蛋白微丝产生的具有明显收缩性能的肌成纤维细胞,从而使伤口收缩。
修复过程的第三阶段,成熟阶段,伴随着肉芽组织的重塑。一部分细胞外基质由蛋白酶(主要是基质金属蛋白酶(MMPs)和弹性蛋白酶)消化,并且观察到细胞外基质的逐渐重组。逐渐地,在肉芽组织中占优势的III型胶原蛋白被I型胶原蛋白(真皮的主要基质组分)替代。在成熟阶段结束时,成纤维细胞、肌成纤维细胞和血管细胞开始增殖和/或它们的活性降低。然后,剩余细胞通过细胞凋亡死亡。随着细胞外基质的重塑和剩余细胞的凋亡,炎症状态逐渐降低。这是最长的阶段:在约一年后,疤痕被重塑,它不再是红色,不再僵硬,不再导致疼痛并且变平。
但是,尽管建立了最佳的物理化学条件和生物学条件,某些类型的伤口仍无法正确愈合,该过程的三个关键阶段均发生异常。实际上,伤口愈合的速度和质量取决于内在和外在因素。因而,此修复过程可能会异常延长,这取决于:
-伤口的病因;
-由此的状况及其位置;
-由某些感染性剂(诸如金黄色葡萄球菌或铜绿假单胞菌)的存在引起的感染发作;
-曾患病症(诸如糖尿病、免疫缺陷、静脉功能不全等)的存在;
-外部环境;或
-易患伤口愈合障碍的遗传因素。
在这些伤口中发现了慢性伤口,诸如静脉溃疡、褥疮或糖尿病受试者的特征性伤口。慢性伤口的定义是,从出现伤口开始的六周间隔后,无论使用何种治疗方法,均无法愈合。为了治疗此类伤口,加速愈合过程可能至关重要。
糖尿病伤口的特征是具有自己专有的非常特定的慢性伤口类型。
糖尿病是一种越来越普遍的疾病。根据最近的估计,全世界约有2.85亿人患有该病,这一数字到2030年会达到4.39亿人。糖尿病患者面临与其疾病相关的各种并发症。其中包括心血管突发(诸如心肌梗塞)、中风和微血管并发症(诸如视网膜病灶(可能导致失明)和肾病(可能导致肾衰竭))的发生率增加。糖尿病的最严重的并发症之一是截肢。据估计,在世界范围内,每30秒就有一个人的下肢因糖尿病而被截肢,并且这些截肢者中有85%的人患有足溃疡(International Diabetes Federation,IDF 2005)。约15%的糖尿病患者一生中会患上足部溃疡。
糖尿病足溃疡(DFU)的定义是“糖尿病患者脚踝下方的全层伤口,与持续时间无关”(IDF,2005年)。实际上,这些糖尿病伤口无法愈合的主要原因与葡萄糖的生物利用度恶化有关。这引起许多生理和代谢改变,诸如皮肤增厚、可能导致神经病或动脉病的明显的氧化应激。因而,动脉病和神经病是糖尿病伤口愈合,特别是糖尿病足伤口愈合延迟的两个不同的风险因素。
糖尿病足溃疡分为不同类别。一方面,神经病患者的糖尿病足溃疡,和另一方面,通过存在缺血性损伤而明显区别于神经病患者的糖尿病足溃疡的动脉病患者的糖尿病足溃疡(特别地,其特征在于减少器官的动脉血液供应)。因此,神经病患者的糖尿病足通常特征在于温暖、充分灌注的足和可感知的足动脉脉冲。此外,神经病患者在其病灶水平上表现出非常明显的,甚至完全的敏感性丧失。溃疡经常位于脚底,在受到强大的足底压力的被忽视的愈伤组织之下。相反,动脉病患者的糖尿病足则由于无法感知的足动脉脉冲而感到寒冷。通常,这是痛苦的,因为在这种情况下患者的敏感度几乎没有或没有受到损伤。然而,这种类型的患者在伤口血管的水平上或多或少地表现出明显的损伤,范围从仅仅血液供应的减少到有可能导致在受损区域或甚至更大范围水平上的截肢的不同血管组织的不可逆的坏死。对于这种类型的患者,溃疡部分位于脚底的水平,但也经常位于脚趾的尖端或脚后跟的区域。因此,糖尿病足溃疡形式之间的主要临床差异需要完全不同的治疗方法。对于神经病溃疡的治疗,要求尽可能多地去除坏死组织和老茧,以便重新开始伤口愈合过程。相反,在恢复常规伤口愈合过程之前,不应在有损伤新血管生成阶段的风险的情况下清除缺血性溃疡。此外,患有神经病溃疡的患者的平均康复速度比患有缺血性溃疡的患者快两至四倍,缺血严重阻碍了伤口的愈合过程并增加了感染的风险,例如从研究“Comparison ofcharacteristics and healing course of diabetic foot ulcers by etiologicalclassification:neuropathic,ischemic and neuroischemic",Totsu RR et al.,JDiabetes Complications,2014Jul_Aug;28(4):528-35”中发现的。因此,目前提出的针对神经病患者的糖尿病足溃疡的治疗是不合适的,并且不能被转用于动脉病患者。迄今为止,对于缺血性伤口,尚无治疗方法(皮肤替代物、生长因子、敷料或医疗器械)证明其功效。
因此,仍然需要寻找一种有效的治疗动脉病患者(其中缺血使愈合明显复杂化)的糖尿病足溃疡的方法。
发明内容
根据第一方面,本发明涉及具有1-4个单糖单元的合成多硫酸化寡糖,其盐或其复合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
根据第二方面,本发明还涉及包含具有1-4个单糖单元的合成多硫酸化寡糖,其盐或其复合物的药物组合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
动脉病患者
根据本申请,“动脉病患者”应理解为呈现缺血的糖尿病患者。
以下出版物中描述的Texas分类体系明确定义了呈现缺血的神经病患者和动脉病患者之间的区别:“A comparison of two diabetic foot ulcer classificationsystems:the Wagner and the University of Texas wound classification systems".Oyibo SO et al.,Diabetes Care.2001Jan;24(1):84-8”和“A new classification ofdiabetic foot complications:a simple and effective teaching tool",Dr AmitKumar C Jain et al.,The Journal of Diabetic Foot Complications,2012;Volume 4,Issue 1,No.1,Pages 1-5”,其执行二维分类,如下表所示:
阶段 | 临床观察 |
A | 无感染或缺血 |
B | 感染但无缺血 |
C | 缺血但无感染 |
D | 感染并缺血 |
根据本申请的动脉病患者属于IC和IIC类,而神经病患者属于IA类。
首先,可以通过踝肱压力测量值小于或等于0.9,优选小于0.8和/或大脚趾肱压力指数测量值小于或等于0.7来确认缺血。
可以通过踝收缩压力大于或等于70mmHg和/或大脚趾收缩压力大于或等于50mmHg来进一步确认缺血。
测量这些参数中的一个或多个使得可以鉴别根据本发明的动脉病患者群。
根据一个具体实施方案,根据本申请的动脉病患者表现为:
-踝肱压力指数大于或等于0.9,优选小于0.8或大脚趾肱压力指数测量值小于或等于0.7,
和
-踝收缩压力大于或等于70mmHg和/或大脚趾收缩压力大于或等于50mmHg。
根据一个优选实施方案,根据本申请的动脉病患者表现为:
-踝肱压力指数≤0.9,优选小于0.8,结合大脚趾收缩压力≥50mmHg,或者,如果无法进行大脚趾测量(截肢),则踝收缩压力≥70mmHg;
-或踝肱压力指数>0.9,结合大脚趾收缩压力≥50mmHg和大脚趾肱压力指数≤0.7。
糖尿病足溃疡
本发明提供了具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
如上所述,糖尿病足溃疡(DFU)被定义为“糖尿病患者脚踝下方的全层伤口,与持续时间无关”。
根据一个具体实施方案,在本申请范围内治疗的糖尿病足溃疡的尺寸小于5cm2,即伤口在面积为5cm2的圆内。
根据另一个优选实施方案,在本申请范围内治疗的糖尿病足溃疡不是顽固的,即其在小于6个月之前形成。
具有1-4个单糖单元的合成多硫酸化寡糖
在本发明范围内使用的寡糖是由1-4个单糖单元,优选地1-3个单糖单元,并且更优选地1-2个单糖单元形成的合成低聚物,其通常通过α或β糖苷键彼此连接。换句话说,它由单糖、二糖、三糖或四糖组成,优选由单糖或二糖组成。
关于这些多糖的单糖单元的性质没有特别限制。优选地,它们将由戊糖或己糖组成。作为单糖的实例,可以提及葡萄糖、半乳糖或甘露糖。作为二糖的实例,可以提及麦芽糖、乳糖、蔗糖或海藻糖。作为三糖的实例,可以提及松三糖。作为四糖的实例,可以提及水苏糖。
优选地,寡糖是二糖,更优选是蔗糖。
根据本申请,“多硫酸化寡糖”应理解为其中每个单糖的至少两个羟基,并且优选所有羟基已被硫酸基团取代的寡糖。
优选地,在本申请范围内使用的多硫酸化寡糖是蔗糖八硫酸盐。
在本发明范围内使用的多硫酸化寡糖可以盐或复合物形式存在。
作为盐的实例,可以提及碱金属盐,诸如钠盐、钙盐或钾盐;银盐;或实际是氨基酸盐。
作为复合物的实例,可以提及羟基铝复合物。
在本发明的范围内,特别优选如下化合物:
-蔗糖八硫酸钾盐;
-蔗糖八硫酸银盐;和
-蔗糖八硫酸的羟基铝复合物,通常称为硫糖铝。
特别地,在本发明的范围内,所用的多硫酸化寡糖优选是蔗糖八硫酸的钾盐而不是铝盐。
在本发明范围内使用的多硫酸化寡糖可以以微粉化粉末形式或以溶解形式存在。
根据一个具体实施方案,根据本发明的合成多硫酸化寡糖以大于或等于70mg/mL,优选大于或等于100mg/mL的浓度使用。根据一个优选实施方案,根据本发明的合成多硫酸化寡糖以100mg/mL-1000mg/mL的浓度使用。
组合物
本发明还涉及包含上述合成多硫酸化寡糖的药物组合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
其它活性物质
通常,根据本发明的寡糖化合物可以单独使用或以其两种或两种以上的混合物使用,或者实际上与一种(或多种)其他活性物质组合使用。
通常,活性物质选自抗菌剂、防腐剂、止痛药、抗炎药、促进伤口愈合的活性物质、脱色剂、止痒剂、紫外线过滤剂、润肤剂、保湿剂、抗氧化剂及它们的混合物。
通常,活性物质选自:
-抗菌剂,诸如多粘菌素B、青霉素(阿莫西林)、克拉维酸、四环素、米诺环素、氯四环素、氨基糖苷、阿米卡星、庆大霉素、新霉素、银及其盐(磺胺嘧啶银)、益生菌、银盐;
-防腐剂,诸如硫柳汞、曙红、双氯苯双胍己烷、硼酸苯汞、过氧化氢、达金氏溶液、三氯生、双胍、己脒定、百里酚、Lugol、聚维酮碘、汞溴红、苯扎氯铵和苄索氯铵、乙醇、异丙醇;
-止痛药,诸如扑热息痛、可待因、右丙氧芬、曲马多、吗啡及其衍生物、皮质类固醇及其衍生物;
-抗炎药,诸如糖皮质激素、非甾体类抗炎药、阿司匹林、布洛芬、酮洛芬、氟比洛芬、双氯芬酸、醋氯芬酸、酮咯酸、美洛昔康、吡罗昔康、替诺昔康、萘普生、吲哚美辛、萘普西诺、尼美舒利、塞来昔布、依托昔布、帕瑞昔布、罗非昔布、伐地昔布、保泰松、尼氟酸、甲芬那酸;
-促进伤口愈合的活性物质,诸如视黄醇;维生素A;维生素E;N-乙酰基-羟脯氨酸;积雪草提取物;木瓜蛋白酶;硅酮;百里香,绿花白千层(niaouli),迷迭香和鼠尾草的精油;透明质酸;尿囊素;(Gattefossé);维生素C;TEGO Pep 4-17(Evonik);Toniskin(Silab);Collageneer(Expanscience);Timecode(Seppic);Gatuline skinrepair(Gattefossé);泛醇;PhytoCellTec Alp Rose(Mibelle Biochemistry);Erasyal(Libragen),Serilesine(Lipotec);Heterosides of Talapetraka(Beyer);Stoechiol(Codif);macarose(Sensient);Dermaveil(Ichimaru Pharcos);Phycosaccaride AI(Codif);
-脱色剂,诸如曲酸(Kojic Acid-Quimasso(Sino Lion))、熊果苷(-Quimasso(Sino Lion))、棕榈酰丙基钠和白睡莲提取物的混合物(-Seppic)、十一碳烯酰基苯丙氨酸(-Seppic);
-止痒剂:氢化可的松、依诺洛酮、苯海拉明、局部H1拮抗剂抗组胺药;
-保湿活性物质,诸如xpermoist(Lipotec)、透明质酸、尿素、脂肪酸、甘油、蜡、Exossine(Unipex);
-紫外线过滤剂,诸如Parsol MCX、Parsol 1789;
-润肤剂,诸如洋甘菊、红没药醇、xanthalene、甘草次酸(glycyrrhebenic acid)、tanactine(CPN)、Calmiskin(Silab);
-抗氧化剂,诸如维生素E。
根据一个优选实施方案,根据本发明的寡糖化合物可以与抗氧化剂组合使用。
盖伦制剂
在本发明范围内使用的合成多硫酸化寡糖可以局部施用,特别是以盖伦制剂施用,例如胶凝剂、溶液、乳剂、膏剂、颗粒剂、从纳米级或微米级到毫米级范围内的各种尺寸的胶囊,这使得能够将其施加至伤口上。或者,在本发明范围内使用的化合物可以在用于皮下注射的溶液中使用。
如果它们以两种或多种混合物使用,或者实际上与一种或多种其他活性物质组合使用,则可以将这些化合物掺入相同的盖仑制剂或分开的盖仑制剂中。
显然,在盖伦制剂中使用的根据本发明的合成多硫酸化寡糖的量根据所寻求的动力学以及与其性质、溶解性、耐热性等相关的具体限制条件进行调整。
敷料
优选地,将在本发明范围内使用的合成多硫酸化寡糖或含有其的盖伦制剂掺入敷料中。
可以将合成多硫酸化寡糖化合物,特别是蔗糖八硫酸钾盐或盖伦制剂掺入敷料结构的任何元件中,条件是该化合物可以直接或间接与伤口表面接触。
优选地并且为了促进快速作用,将这种化合物(或含有其的盖仑制剂)掺入与伤口接触的敷料层中或沉积在与伤口接触的敷料的表面上。
有利地,可以将蔗糖八硫酸钾盐(或含有其的盖仑制剂)连续或不连续地沉积在意欲与伤口接触的表面上:
-以液体形式,例如通过喷雾溶液或含有其的悬浮液;
-或以固体形式,例如通过筛选含有其的粉末。
例如,与伤口接触的层或表面可以由吸收性材料(诸如聚氨酯亲水吸收性泡沫);纺织材料(诸如敷布);诸如非织造材料;膜;纤维薄纱;任选的吸收性粘合剂材料;任选的粘附界面结构组成。
或者,例如,与伤口接触的层或表面可以由织物纬纱组成,优选由如专利申请WO01/70285或专利申请WO2013/093298中所述的其上将被覆盖或涂覆弹性体基质的聚酯制成,该弹性体基质包含如专利申请WO2008/149035或申请WO2014/009488中所述的具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物,特别是蔗糖八硫酸钾盐。
因此,本发明涉及包含用弹性体基质涂覆的织物纬纱的敷料在用于治疗动脉病患者的糖尿病足溃疡中的用途,该弹性体基质包含具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物,特别是蔗糖八硫酸钾盐。
通常,可以根据需要调整盖伦制剂或敷料的结构,以获得特定的、快速的或延迟的蔗糖八硫酸钾盐释放谱。
显然,根据所寻求的动力学以及与其性质、溶解性、耐热性等相关的具体限制条件,可以调整在盖伦制剂或敷料中使用的蔗糖八硫酸钾盐的量。
根据本申请,敷料意指用于伤口处理的所有类型的敷料。
典型地,敷料包含至少一个任选的粘合剂层或基质。
可以将根据本发明的合成多硫酸化寡糖化合物或包含其的盖伦制剂掺入敷料结构的任何元件中,例如基质中。
优选地,为了促进快速作用,可以将该化合物(或含有其的盖仑制剂)掺入与伤口接触的敷料的层中或沉积在与伤口接触的敷料的层表面上。
该沉积技术是本领域技术人员众所周知的。例如,在专利申请WO 2006/007814中已有所描述。
通常,当放置这些敷料时,护理人员使用束带将后者保持在适当位置,或者用第二元件(诸如第二吸收性敷料或压迫带)覆盖后者。因此,使敷料保持固定在伤口上是有用的,以便护理人员将其双手放开以放置这些第二元件。通常,为此目的,可以使用任何类型的粘合剂。
为了不损害健康的组织或伤口边缘,特别是在去除敷料时,将优选具有粘附到皮肤而不粘附到伤口的性能的粘合剂。
作为这种粘合剂的实例,可以提及基于硅或聚氨酯弹性体的粘合剂,诸如硅酮或聚氨酯胶凝剂,以及水胶体粘合剂。
特别地,该水胶体粘合剂是由基于选自聚(苯乙烯-烯烃-苯乙烯)序列聚合物的一种或多种弹性体的弹性体基质与选自增塑剂(诸如矿物油、增粘树脂)的一种或多种化合物,以及抗氧化剂(如果需要)组成,其中掺有一定量的,优选少量的亲水胶体(3重量%-20重量%),例如羧甲基纤维素钠或超吸水性聚合物,诸如BASF以商标名销售的产品。
根据一个优选实施方案,在本发明范围内使用的合成多硫化物寡糖化合物或含有该化合物的盖伦制剂将被集成在包含亲水性胶体粘合剂的敷料中,优选地,相对于粘合剂的重量,所述多硫化物寡糖以1重量%-15重量%,更优选5重量%-10重量%的量掺入所述粘合剂中。
本领域技术人员熟知这种亲水性粘合剂的配方,例如,在专利申请FR 2 783 412,FR 2 392 076和FR 2 495 473中已描述的那些。
特别有利的是,在非织造物上使用粘合剂网可以减少或防止细小的纺织材料纤维与伤口接触并粘在组织上,从而触发移除时的痛感,甚至阻碍伤口的愈合过程的风险。
根据本发明的一个优选替代实施方案,将根据本发明的合成多硫酸化寡糖化合物以与其溶解性及其耐热性相容的浓度掺入到这种粘合剂中。
基于这些标准,相对于粘合剂的总重量,本发明的合成多硫酸化寡糖化合物优选以1-15重量%,更优选以5-10重量%的量使用。
如果试图增加这种非织造敷料的吸收性,则可以将其与其它吸收层联合,优选非胶凝吸收层,特别是诸如敷布(诸如在产品Duo或Trio中使用的)、吸收性亲水性泡沫(优选亲水性聚氨酯泡沫,其吸附能力大于非织造物(诸如产品中使用的))。
根据一个优选的实施方案,将根据本发明的合成多硫酸化寡糖化合物掺入非织造敷料中,所述非织造敷料与其它吸收层,以及优选地非胶凝吸收层(特别是诸如敷料)联合。
根据另一个优选实施方案,将根据本发明的合成多硫酸化寡糖化合物掺入非织造敷料中,所述非织造敷料与其它吸收层,以及优选地非胶凝吸收层(特别是诸如吸收性亲水性泡沫,优选具有比无纺布更大的吸收能力的亲水性聚氨酯泡沫)联合。
非织造物和泡沫可以与本领域技术人员众所周知的技术相关,例如通过使用基于TPU/聚己内酯聚合物的热熔粉末进行热轧获得。
该技术通常用于将用于医疗市场的非织造物彼此粘合。
最后,该泡沫和非织造物(当单独使用后者时)可以用基材覆盖,以保护伤口免受外界伤害。
该基材的尺寸可以大于其他层的尺寸,并且在其与伤口接触的表面上连续或不连续地提供粘合剂,从而在敷料使用期间,特别是在伤口位于非平面身体区域的情况下,优化敷料的固定。
优选地,该基材及其粘合剂是流体不可渗透的,但水蒸气非常容易渗透,从而能够最佳地处理敷料吸收的渗出物并防止浸渍问题。
这种基材是本领域技术人员众所周知的,例如由透气且不可渗透的膜组成,诸如聚氨酯膜、泡沫/膜或非织造物/膜复合物。
添加剂
除了活性剂之外,根据本发明的寡糖化合物可以与在敷料的制备中常规使用的一种(或多种)添加剂组合使用。特别地,这些添加剂可以选自香料、防腐剂、维生素、甘油,柠檬酸等。
在以下非限制性实施例中证明了根据本发明的合成多硫酸化寡糖的活性。
具体实施方式
实施例:证实蔗糖八硫酸钾盐(KSOS)在用于治疗动脉病患者的糖尿病足溃疡中的
作用。
基于将240位动脉病糖尿病患者分为两个平行组,进行了一项双盲随机对照试验:对照组114例患者,治疗组126例患者。根据伤口的尺寸及其顽固性将这些组分为亚组。因此,将溃疡尺寸小于5cm2(即伤口在面积为5cm2的圆内)的患者与溃疡尺寸为5-30cm2的那些患者区分开。在本申请范围内治疗的患者之间也有区分,即溃疡在小于6个月之前形成的非顽固性溃疡患者,以及溃疡在大于6个月之前形成的顽固性溃疡患者。
动脉病患者是指患有1型或2型糖尿病且糖化血红蛋白(HbA1c)≤10%,且表现出表面积为1-30cm2的糖尿病足溃疡的患者。
这些患者属于Texas分类的IC和IIC类,并且表现为以下特征的局部缺血:
-踝肱压力指数≤0.9,并结合大脚趾收缩压力≥50mmHg,或者,如果无法进行大脚趾测量(截肢),则踝收缩压力≥70mmHg;
-或踝肱压力指数>0.9,并结合大脚趾收缩压力≥50mmHg和大脚趾肱压力指数≤0.7。
用盐溶液清洗伤口后,将包含蔗糖八硫酸钾盐的敷料或具有相同结构但不含多硫酸化寡糖的敷料施用于患者。
敷料由涂覆有弹性体基质的聚酯镂空织物纬纱组成;该基质特别描述于专利申请WO 201009488中。
根据伤口渗出的程度,每两到四天更换敷料,并且对患者进行不超过20周的治疗。
每个月,都会根据以下标准进行临床伤口愈合评估:
-治疗耐受性
-病灶周围皮肤状况
-伤口疼痛
-伤口的临床检查(坏死组织、肉芽组织、褥疮等)
-伤口特征(追踪随时间变化的伤口尺寸、总体外观、边缘分析、病灶周围皮肤、伤口周长轮廓)。
结论
根据本实施例,术语“伤口闭合”应理解为任何愈合的伤口,即直至真皮的完全上皮化,后者由专业医生在第20周的后两周确认。
如图1所示,本研究证实,用本发明的包含蔗糖八硫酸钾盐的敷料处理的伤口表现出明显增强的溃疡愈合,特征尤其在于伤口闭合率为47.6%,而用具有相同结构但不含多硫酸化寡糖的对比敷料处理的对照组仅为29.8%。。
从图2和图3进一步清楚地看出,当用根据本发明的包含蔗糖八硫酸钾盐的敷料处理的溃疡的尺寸小于5cm2(即伤口在面积为5cm2的圆内)时,它们表现出明显增强的愈合,特征尤其在于伤口闭合百分比为51.5%,而对照组为31.3%。
图4和5还显示,当用根据本发明的包含蔗糖八硫酸钾盐的敷料处理的溃疡不是顽固的(即它们在小于6个月之前形成)时,它们表现出明显增强的愈合,特征尤其在于伤口闭合百分比为64.8%,而对照组为39.7%。
以下表1交叉引用了图2-5中的数据:
从该表中清楚地看出,患有尺寸小于5cm2的非顽固性溃疡(在小于6个月之前形成)的患者,当用根据本发明的包含蔗糖八硫酸钾盐的敷料进行治疗时,表现出特别增强的愈合。
从下面的表2中清楚地看出,用本发明的敷料治疗的患者的经治疗伤口的表面积显著减少(以%减少或以表面积cm2减少表示),对于施用本发明敷料的患者而言,所述经治疗伤口的表面积实际显示出1.76cm2的中值减少,而对于施用对照敷料的患者而言,显示出1.23cm2的中值减少。
表2
最后,从下面的表3中清楚地看出,用本发明敷料治疗的患者之间的平均伤口闭合间隔(平均119.7+/-4.7天)比用对照敷料治疗的患者组明显更快(平均180.5+/-8.7天):
表3
因此,本研究有助于证明,无论所治疗患者的性别如何,无论他们是否表现出顽固性溃疡,且无论所治疗溃疡的尺寸如何,与用具有相同结构但不含多硫酸化寡糖的对比敷料治疗的患者相比,明显更多数量的用根据本发明的包含蔗糖八硫酸钾盐的敷料治疗的患者显示出溃疡的完全愈合。此外,用根据本发明的敷料处理的伤口的愈合比用不含多硫酸化寡糖的对比敷料处理的伤口的愈合更快,这通过进行的伤口闭合百分比测量得以证明。本研究的所有结果将作为参考文献“Explorer study”的主题。
结论是,多硫酸化寡糖,特别是蔗糖八硫酸钾盐,能够快速且有效地治疗动脉病患者的糖尿病足溃疡,特别是缺血性动脉病患者的糖尿病足溃疡。
Claims (10)
1.具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
2.根据权利要求1所述的寡糖在用于激活动脉病患者的糖尿病足溃疡的愈合中的用途。
3.根据权利要求1或2所述的寡糖,其特征在于,其浓度大于或等于70mg/mL,优选大于或等于100mg/mL,更优选为1000-1000mg/mL。
4.根据前述权利要求中任一项所述的寡糖,其特征在于,它包含1-3个单糖单元,1或2个优选选自戊糖和己糖的单糖单元,以及这些化合物的盐和复合物。
5.根据前述权利要求中任一项所述的寡糖,其特征在于,它选自:
-蔗糖八硫酸钾盐;
-蔗糖八硫酸银盐;和
-蔗糖八硫酸的羟基铝复合物。
6.根据前述权利要求中任一项所述的寡糖,其特征在于,它是蔗糖八硫酸钾盐。
7.根据前述权利要求中任一项所述的寡糖,其特征在于,它以诸如胶凝剂、溶液、乳剂、膏剂、颗粒剂或胶囊的组合物的形式使用,从而能够直接施用于伤口上。
8.包含具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物的药物组合物在用于治疗动脉病患者的糖尿病足溃疡中的用途。
9.包含具有1-4个单糖单元的合成多硫酸化寡糖、其盐或其复合物,特别是蔗糖八硫酸钾盐的敷料在用于治疗动脉病患者的糖尿病足溃疡中的用途。
10.根据权利要求9所述的敷料,其包含涂覆有包含所述合成多硫酸化寡糖的弹性体基质的织物纬纱。
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FR1754363A FR3066390B1 (fr) | 2017-05-17 | 2017-05-17 | Utilisation de composes oligosaccharidiques pour traiter les plaies des patients diabetiques arteriopatiques |
FR1754363 | 2017-05-17 | ||
FR1755620 | 2017-06-20 | ||
FR1755620A FR3066391B1 (fr) | 2017-05-17 | 2017-06-20 | Utilisation de composes oligosaccharidiques pour traiter les plaies des patients diabetiques arteriopatiques |
PCT/EP2018/062811 WO2018210969A1 (fr) | 2017-05-17 | 2018-05-16 | Utilisation de composes oligosaccharidiques pour traiter les plaies des patients diabetiques arteriopatiques |
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JP (1) | JP2020519578A (zh) |
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2017
- 2017-05-17 FR FR1754363A patent/FR3066390B1/fr not_active Expired - Fee Related
- 2017-06-20 FR FR1755620A patent/FR3066391B1/fr active Active
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- 2018-05-16 JP JP2019560357A patent/JP2020519578A/ja active Pending
- 2018-05-16 CA CA3063237A patent/CA3063237A1/fr active Pending
- 2018-05-16 ES ES18723038T patent/ES2887410T3/es active Active
- 2018-05-16 EP EP18723038.8A patent/EP3624807B1/fr active Active
- 2018-05-16 WO PCT/EP2018/062811 patent/WO2018210969A1/fr unknown
- 2018-05-16 CN CN201880031433.XA patent/CN110662546A/zh active Pending
- 2018-05-16 US US16/613,474 patent/US20210085702A1/en not_active Abandoned
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ES2887410T3 (es) | 2021-12-22 |
FR3066390A1 (fr) | 2018-11-23 |
US20210085702A1 (en) | 2021-03-25 |
CA3063237A1 (fr) | 2018-11-22 |
FR3066390B1 (fr) | 2019-07-12 |
FR3066391B1 (fr) | 2019-07-12 |
EP3624807A1 (fr) | 2020-03-25 |
JP2020519578A (ja) | 2020-07-02 |
WO2018210969A1 (fr) | 2018-11-22 |
EP3624807B1 (fr) | 2021-07-07 |
FR3066391A1 (fr) | 2018-11-23 |
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