CN111194216B - 用于伤口治疗的组合物和方法 - Google Patents
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Abstract
本发明公开了用于治疗伤口的组合物包括共价连接的氧化石墨烯(GO)和透明质酸(HA),XAV939,和水。该组合物还可包含表面活性剂,例如PEG。可以将组合物局部施用于对象以治疗对象的伤口。还提供了使用该组合物治疗伤口的方法。
Description
相关申请的交叉引用
本申请要求2017年10月6日提交的美国临时申请号62/569,025和2018年6月13日提交的美国临时申请号62/684,439的优先权,其各自的全部公开内容通过引用包括在本申请之中。
背景技术
在此描述的发明涉及用于伤口治疗的组合物和方法,尤其涉及在伤口愈合期间预防和/或减少疤痕形成。
伤口愈合是一个复杂的过程,涉及炎症阶段,肉芽组织形成阶段和组织重塑阶段。这些事件是由损伤部位释放的细胞因子和生长因子触发的。许多因素可能会使正常的伤口愈合变得复杂或干扰正常的伤口愈合。慢性伤口,例如糖尿病性足溃疡,下肢静脉溃疡和压疮,特别麻烦且难以治疗。
疤痕是新的结缔组织在皮肤上留下的痕迹,该结缔组织取代了受伤的组织。创伤,手术,烧伤或运动损伤后皮肤上的疤痕可造成医疗问题,导致功能丧失,组织运动受限和不良的心理影响。皮肤纤维化是导致皮肤正常组织结构和器官功能丧失的不可逆病理过程,与瘢痕形成有关。尽管近年来已经更好地了解了形成疤痕的途径和过程,但尚无有效的疤痕治疗方法,也没有用于预防或治疗皮肤疤痕的处方药。
目前可用的治疗疤痕的技术(例如,硅胶片(压力疗法),局部软膏,表面重修,剥离,磨皮,激光,冷冻手术,博来霉素和5-氟尿嘧啶注射,切除(翻修手术,放射疗法,通过皮肤或皮瓣移植重建等)集中于改善现有疤痕的美观性,并有与疤痕复发和副作用有关的问题,例如皮肤萎缩和色素沉着不足。
最近显示,Wnt通路在皮肤纤维化和瘢痕形成中起关键作用。Wnt通路是一种进化保守的通路,在胚胎发育过程中调节细胞命运决定,细胞极性,细胞迁移,神经模式和器官生成等关键方面。该通路有助于确保胚胎中适当的组织发育和成人的组织维持。Wnt信号传导参与皮肤发育的开始阶段。原肠胚形成后,外胚层和中胚层的胚胎细胞分化形成表皮和真皮。
尽管在信号转导过程中至少涉及三个不同的Wnt信号通路,但最常被理解的是经典的(或依赖于β-连环蛋白的)Wnt通路。β-连环蛋白是由经典Wnt信号通路产生的关键效应分子,其蛋白质水平通过“破坏复合物”调控。在没有Wnt信号的情况下,转录激活因子β-连环蛋白通过蛋白质复合物(称为“破坏复合物”)的作用在细胞中被主动降解。在这种复合物中,Axin-1和-2与腺瘤性多虫病形成支架,通过酪蛋白激酶19α和糖原合酶激酶3β促进β-连环蛋白磷酸化。磷酸化的β-连环蛋白被识别并泛素化,导致其蛋白体降解。端锚聚合酶(Tankryase)I和II(TNK1和2)是聚(ADP-核糖)聚合酶(PARP),其作用是使Axin-1和-2蛋白核糖基化并使其不稳定,从而使β-连环蛋白破坏复合物不稳定。一旦破坏复合物不稳定,这将使β-连环蛋白去磷酸化,然后稳定下来并使其积聚在细胞质中并进入细胞核,并在其中与Tcf/Lef家族成员相互作用。β-连环蛋白通过募集辅助激活蛋白将Tcf蛋白转化为有效的转录激活蛋白,从而确保Wnt目标基因的有效激活。Wnt通路一旦被Wnt天然配体家族激活,就会上调TNK1和2来帮助破坏破坏复合物的稳定性。研究表明,TNK1和2是经典Wnt信号的关键调节因子。
经典Wnt信号传递在多种肿瘤中被过度激活,在细胞生长和转移中起着核心作用。另外,已经显示出Wnt通路调节成年表皮中的细胞增殖,间接影响皮肤伤口愈合和纤维化或瘢痕形成的速率和程度。此外,已经显示Wnt/β-连环蛋白通路引起皮肤成纤维细胞的过度刺激,这可以形成肌成纤维细胞。肌成纤维细胞具有收缩功能,这使其能够在细胞外基质(ECM)纤维中发挥作用,以闭合开放性伤口。肌成纤维细胞的过度表达会导致胶原蛋白和ECM蛋白分泌过多,进而导致纤维化和瘢痕形成。皮肤成纤维细胞中持续的β-连环蛋白活性通过上调ECM蛋白编码基因的表达来促进纤维化。已经证明β-连环蛋白水平可调节伤口大小并介导TGF-β在皮肤愈合中的作用。Wnt/β-连环蛋白通路在肥厚性瘢痕和瘢痕疙瘩成纤维细胞中被上调。因此,Wnt/β-连环蛋白通路在皮肤间充质细胞中诱导β-连环蛋白信号传导,从而导致它们的活化和持续纤维化反应的诱导。
已显示TNK1和2是可调节Wnt/β-连环蛋白通路的药物靶标。然而,最近已经证明,由于抑制肠隐窝细胞更新,TNK1和2的全身性抑制可引起肠毒性,该过程主要由Wnt/β-连环蛋白通路驱动。
XAV939是一种小分子,可在无细胞试验中通过TNK 1和2抑制选择性抑制Wnt/β-连环蛋白介导的转录,IC50为11nM/4nM,调节毒素水平,并且不影响CRE,NF-κB或TGF-β。近来,XAV939在小鼠耳穿孔试验中的局部应用表明XAV939可以显着提高伤口闭合的速率,同时减少纤维化(疤痕)。但是,由于XAV939的水溶性极低(<1mg/mL),因此溶解在DMSO中,仅用作“研究工具”化合物。这种方法的问题是人不能容忍DMSO的使用。实用和医学用途需要适用于人的XAV939可溶性形式。
发明内容
在本发明的一个方面,提供了一种用于治疗伤口的组合物。该组合物包含:包含氧化石墨烯(GO)和透明质酸(HA)的基质组分,其中GO和HA通过连接体共价连接;和XAV939;和水。共价连接的GO和HA在本文中也称为GO-HA或GO-HA缀合物。该组合物可以是悬浮液的形式,其中GO-HA可以以悬浮在水中的分散微粒的形式存在。
在一些实施方案中,组合物还包含表面活性剂,其可以是聚乙二醇(PEG)。PEG可具有约200至约400道尔顿的分子量。PEG的量可以为总组合物的约0.1重量%至约20重量%。
在一些实施方案中,组合物还包含增稠剂,例如可以是羟丙基纤维素(HPC)。
在一些实施方案中,连接GO和HA的连接体包含2-25个碳。在一些实施方案中,连接体可以是直链的(或线性的)。在其他实施方案中,连接体可以是分支的。在一些实施方案中,连接体包含线性亚烷基-CmH2m-单元,其中m可以为1至20。在一些其他实施方案中,连接体可以包含一个或多个杂原子。例如,连接体可包含一个或多个-CH2CH2O-单元。在某些实施方案中,连接体包含-Rx-RS-Ry-,其中Rx和Ry各自独立地选自-CO-,-COO-,-NH-,-NH-NH-,-NH-NH-CO-,-CS-,-S-,-O-,其中RS是具有1-40或2-20个主链碳原子的未取代或取代的线性亚烷基。在特定的实施方案中,Rx和Ry均为-NH-NH-CO-。
在一些实施方案中,XAV939与GO-HA的重量比可为约1:100至约100:1,例如约1:2至约2:1。在一些实施方案中,XAV939占总组合物的约0.001重量%至约5重量%。在某些实施方案中,GO-HA占总组合物的0.001重量%至约5重量%。
在另一方面,提供了一种医疗设备。该医疗设备包括基底和以及在基底上施加的本文所述的组合物。基底可以是贴,垫,缝线,纱布,带或绷带。
在另一方面,提供了通过使伤口与有效量的本文所述的组合物接触来治疗对象(人类或非人类动物,例如哺乳动物)的皮肤伤口的方法。伤口可以是外科伤口或烧伤。在一些实施方案中,伤口可以是慢性伤口,例如溃疡。在一些实施方案中,该方法进一步包括将第二伤口药物施用给对象,该第二伤口药物包含以下中的一种或多种:皮质类固醇,细胞毒性药物,抗生素,防腐剂,尼古丁,抗血小板药物,NSAID,秋水仙碱,抗凝剂,血管收缩药或免疫抑制剂,生长因子,抗体,蛋白酶,蛋白酶抑制剂,抗菌肽,粘附肽,止血剂,活细胞,蜂蜜或一氧化氮。
在另一方面,提供了一种制备GO-HA缀合物的方法。该方法包括:通过将GO的至少一些苯氧基酸基团转化为末端脂族羧酸基团来改性GO;通过使HA与具有对末端脂族羧酸基具有反应性的双官能团的试剂反应,使HA衍生化,所述双官能团之间有间隔基;使改性的GO和衍生的HA反应形成GO-HA缀合物。在一些实施方案中,间隔基可包含具有2-20个主链碳的直链亚烷基。在一些实施方案中,用于衍生化HA的试剂是二酰肼。在一些实施方案中,在GO-HA缀合物中,GO:HA的重量比为约1:1至约1:20,或约1:6至约1:10。
详细描述
在本发明的一个方面,提供了一种用于治疗伤口的组合物,其包括:基质组分,其包含氧化石墨烯(GO)和透明质酸(HA)的缀合物,其中GO和HA通过连接体共价连接;XAV939;和水。共价连接的GO和HA在本文中也称为GO-HA缀合物或简称为GO-HA。
XAV939是一种有效的端锚聚合酶抑制剂,化学名称为3,5,7,8-四氢-2-[4-(三氟甲基)苯基]-4H-硫代吡喃并[4,3-d]嘧啶-4-酮。XAV939的结构如下所示:
本文所指的氧化石墨烯(GO)是指以石墨单层形式存在的石墨烯的氧化形式。GO可以通过用强氧化剂处理石墨来获得。GO包含多少碳,氧和氢,具体取决于其制备方式。它的平面方向可以具有数百纳米,最高可达数微米,厚度约为0.7-1.2nm。当使用硫酸(例如,Hummers方法)制备时,GO可以包含各种含氧部分,例如环氧基,羧酸(-COOH),苯酚等。下面显示了一个示例GO结构。
透明质酸(HA)是一种阴离子,高度亲水的非硫酸化糖胺聚糖,天然存在于人体各处。它可以是数千个碳水化合物单位长,并且可以与水结合,形成有坚硬粘性的水凝胶。HA的示例结构如下:
在本发明的组合物中,GO和HA共价连接以形成基质组分(或载体),其可以用于溶解XAV939以及为伤口愈合提供其他同时的益处。共价连接可以通过使用连接体(或连接体部分)来完成。在一些实施方案中,连接体可包含2-25个碳。在一些实施方案中,连接体是线性的。在其他实施方案中,连接体是带分支的。连接体可以是饱和的或不饱和的。
在一些实施方案中,连接基可以包含C2-C25亚烷基,其中亚烷基中的碳和氢可以被氧或其他原子或基团例如羟基,羧基,氨基,烷基,烷氧基,烯基,炔基,硝基等取代。在一些实施方案中,连接体可包含一个或多个-CH2CH2O-单元。
在一些实施方案中,连接体包含-Rx-RS-Ry-,其中Rx和Ry各自独立地选自-CO-,-COO-,-NH-,-NH-NH-,-NH-NH-CO-,-CS-,-S-,-O-,其中RS(在本申请中也称为间隔基)可以是未取代或取代的具有2-20的饱和或不饱和线性亚烷基碳骨架。在特定的实施方案中,Rx和Ry均为*-NH-NH-CO-(*表示远离RS的连接体的末端)。
在组合物的一些实施方案中,XAV939与GO-HA的重量比可以为约1:100至100:1,例如约1:2至约2:1。在一些实施方案中,在GO-HA缀合物中,GO:HA的重量比可以为约1:1至约1:20,或约1:6至约1:10。
通常,该组合物总体上可以表现为略暗或黑色粘性液体。XAV939均匀地分散在粘稠的悬浮液中,该悬浮液在室温下稳定数月。在一些实施方案中,该组合物还包含增强疏水性物质在水中的混合性或溶解性的表面活性剂。在一些实例中,表面活性剂可以是非离子亲水材料,例如聚乙二醇(PEG)。PEG的数均分子量可为约100至约10,000道尔顿,或约200至约4000道尔顿,例如约200至约1000,约200至约800,约200至约500,从约200到约400,从约300到约400,从约350到约450,约200,约250,约300,约350,约400,约450,约500,约550,约600,约650,约700,约750,约800,约850,约900,约950,约1000道尔顿等。在一些实施方案中,PEG可以以约0.1至约20wt%的占总组合物的比例量存在于组合物中。例如,PEG可以占总组合物的约0.2重量%至约10重量%,或约0.5重量%至约10重量%,或约1重量%至约10重量%。
也可以使用其他非离子亲水材料,例如PEG和PPG(聚丙二醇)的共聚物,例如泊洛沙姆。在一实例中,可使用泊洛沙姆-188(平均分子量为约8400道尔顿)。
在一些实施方案中,组合物还包含药物载体或赋形剂化合物或材料,其使组合物能够以可局部施用的半固体水性凝胶形式存在。例如,羧甲基纤维素可以用作凝胶形成剂。但是,其他纤维素衍生物如微晶纤维素以及多糖如藻酸盐和琼脂糖,黄芪胶,瓜尔豆胶,黄原胶也适合作为凝胶形成剂。如果需要,可以通过添加相对有弹性的凝胶形成材料,例如交联的纤维蛋白,例如聚丙烯酰胺,明胶或甲醛交联的胶原蛋白,使凝胶更粘稠和/或更硬。
在一些实施方案中,组合物可以是乳膏的形式,其可以包括适合乳膏制剂的那些赋形剂,例如石蜡油,凡士林,蜡,有机酯例如棕榈酸十六烷基酯等。
在一些实施方案中,本发明的组合物还包含用于通过皮肤施用的组合物所需粘度的增稠剂。例如,增稠剂可包括羟丙基纤维素(HPC)。HPC可以将组合物制成光滑的膜,易于使用。它还可以减少蒸发,并使伤口保持更长的湿润时间,这已被证明可以改善愈合并减少疤痕。根据特定浓度的HPC水溶液的分子量或粘度,可以使用不同等级的HPC。
在组合物的一些实施方案中,XAV939可占全部组合物(包括水)的约0.001重量%至约5重量%。在一些实施方案中,XAV939可占总组合物的约0.01重量%至约2重量%,约0.02重量%至约1重量%,或约0.05重量%至约0.5重量%。在一些实施方案中,GO-HA占总组合物的约0.001重量%至约5重量%。在一些实施方案中,GO-HA可占总组合物的约0.01重量%至约2重量%,约0.02重量%至约1重量%,或约0.05重量%至约0.5重量%。
在本文所述的组合物中,除XAV939之外或作为XAV的替代,可以包括其他药物或治疗性化合物。换句话说,含XAV939或去除XAV939的组合物还可以用作基础分散介质,其中可以分散其他药物或治疗剂,尤其是疏水的,例如用于局部给药以治疗伤口。这些药物可包括抗纤维化化合物例如吡非尼酮,氟丁酮,任尼达尼,托珠单抗,利罗那普等,抗癌药,抗炎药,镇痛药,抗生素等。
在本发明的另一方面,提供了一种医疗设备,其包括如本文所述的组合物和在其上施加了该组合物的基底。该医疗设备可以是促进局部施用该组合物的形式,其中该基底可以被构造成具有适当的强度和柔性以覆盖,固定和/或保护伤口。例如,基底可以是贴、垫、带、绷带、纱布、缝合线等。
在本发明的又一方面,提供了一种治疗对象(例如人或非人动物)的皮肤伤口的方法。该方法包括使伤口与有效量的本文所述的组合物接触。伤口可以是其正常愈合伴有疤痕形成的类型。伤口可能是外科伤口。外科伤口是由破坏皮肤的结构和功能的物理冲击造成的(例如由刀、手术刀、子弹或其他尖锐或钝物造成的刺伤、擦伤、割伤、划伤或刺破)。伤口也可因为过度的温度(低温或高温)造成,例如烧伤。伤口也可以是慢性伤口,由于缺乏一种或多种主要的治愈所需的条件,包括良好的血液,氧气和营养供应以及清洁和无感染的环境,因此无法在预期的时间内愈合的伤口。慢性伤口的例子包括伤口区域没有获得足够的血液供应的缺血性伤口。糖尿病性溃疡是缺血性伤口的常见类型。
本文所述的本发明的组合物可以通过在伤口部位局部施用组合物来施用。如果该组合物包含在本文所述的医疗设备中,该医疗设备包括诸如贴或垫的基底,则该医疗设备可以固定至伤口部位,使得该组合物接触伤口。
在一些实施方案中,治疗方法可包括向治疗对像施用第二伤口药物或治疗剂,其包含以下中的一种或多种:皮质类固醇,细胞毒性药物,抗生素,防腐剂,尼古丁,抗血小板药物,NSAID,秋水仙碱,抗凝剂,血管收缩药或免疫抑制剂,生长因子,抗体,蛋白酶,蛋白酶抑制剂,抗菌肽,粘附肽,止血剂,活细胞,蜂蜜或一氧化氮。这些治疗剂可以作为与本文所述的组合物分开的剂型施用,或者可以作为本文所述的组合物的其他组分而与XAV939同时施用。
在另一方面,本发明提供了制备本文所述的组合物和中间体化合物的方法。在一个实施方案中,提供了一种制备GO-HA缀合物的方法,该方法包括:(a)通过将石墨烯氧化物的至少一些苯氧基酸基团转化为末端脂族羧酸基团来改性GO;(b)通过使HA与具有对末端脂族羧酸基团具有反应性的双官能团的试剂反应而使HA衍生化,所述双官能团之间有间隔基;(c)使(a)中获得的改性GO与(b)中获得的衍生化HA反应,从而形成GO-HA缀合物。
在上述制备方法中,间隔基可以是具有2-20个主链碳的未取代或取代的,饱和或不饱和的直链亚烷基。为了说明而非限制,用于HA衍生化的试剂可以选自以下化合物:
其中R1和R2可以独立地是-CONHNH2,-SH,-NH2,-OH或其他亲核试剂,并且n是整数,可以是例如1-20,如1、2、3、4、5、6、7、8、9、10等。在一些实施方案中,用于HA衍生化的试剂可以是二酰肼,例如己二酸二酰肼。
在一些实施方案中,用于制备本发明的组合物的方法包括:获得GO-HA(例如,通过上述方法);将GO-HA缀合物溶解在水中以获得GO-HA水溶液;以及将XAV939添加至GO-HA水溶液形成混合物。在一些示例中,这是通过首先将XAV939溶解在非离子亲水聚合物(例如PEG-400(或PEG 400,平均摩尔质量约为400))中,然后将XAV939溶液添加到GO-HA缀合物水溶液。
本发明提供了一种结合了在多功能支架(GO)上偶联传统上有利于伤口愈合的高吸湿性材料(HA),以及可改善皮肤伤口的愈合并减少疤痕的有效Wnt通路抑制剂(XAV939)的水性增溶的伤口治疗策略而同时解决了伤口治疗中多方面的问题。不希望受任何特定理论的束缚,据信本发明的组合物和方法可通过经由靶向Wnt/β-连环蛋白的XAV939抑制TNK1和2来预防、减少或抑制伤口愈合中的皮肤纤维化和瘢痕形成,从而使伤口愈合朝着再生过程而非纤维化过程发展。据信,XAV939被涂覆在作为纳米载体的GO上,因为GO具有复合(通过π-π相互作用)疏水化合物的能力,并且具有与GO连接的亲水性HA,从而使疏水化合物具有了“水溶性”。而且,GO由于其良好的生物相容性和影响细胞-细胞通讯,细胞分裂和细胞命运以及可能抑制微生物的特性,可以用作细胞生长和通讯的支架。
本发明的实施方案的局部组合物和局部施用的其他益处是有益组分对损伤/伤口部位的低毒性和高生物利用度。
具体实施方式
提供以下实施例是为了说明本文描述的某些方面,并且不应被认为以任何方式限制本发明。
实施例中使用的仪器:FT-IR:带SmartOrbi Diamond ATR附件的Thermo Nicolet380FT-IR;1H NMR:500MHz Bruker(布鲁克)DRX500或AV-500NMR;UV-Vis:ShimadazuPharma Spec UV1700(岛津紫外可见分光光度计UV-1700PharmaSpec型)。溶剂:99%纯度,由Sigma-Aldrich(西格玛奥德里奇)提供;在浴超声仪中以42kHz进行超声。
实施例1:GO的改性
尽管GO在其边缘包括许多羧酸基团,但是这些芳族羧酸基团的反应性不高。为了提高其与HA的连接效率,将GO上的某些芳香族羧酸基团转化为脂肪族芳香族羧基基团。参见方案1。在该步骤中,GO的一些羟基也被转化为羧基(如上所述)。
将氧化石墨烯(1.25g,在去离子水中的250mL的5mg/mL GO分散液;供应商:Goographene Inc.)添加到250mL的超纯去离子水中,并搅拌5分钟。在30分钟内将氢氧化钠颗粒(3g(0.075摩尔);供应商:Sigma-Aldrich(西格玛奥德里奇))以少量固体加入到混合物中。添加完成后,在室温下搅拌1小时,然后将溶液超声处理30分钟在20分钟内加入氯乙酸(3.54g(0.0375摩尔);供应商:Alfa Aesar(阿法埃莎)),在20分钟内以小部分固体分批加入,然后将反应混合物在室温下搅拌18小时,将反应混合物用盐酸酸化(7mL,12N),然后将溶液转移到离心管中,以5000rpm离心15分钟,然后倒出水层,并在离心前将更多的超纯去离子水(约30mL)加入管中。重复该过程3次,将甲醇(约30mL)加入到沉淀的改性石墨烯中,并保留在离心管中,并以5000rpm离心15分钟,重复此过程3次。倒出后,将试管在室温下真空放置48小时以干燥。获得总计0.926g的改性氧化石墨烯。1H NMR(500MHz,D2O)δ:4.173(-CH2CO2H)ppm(诊断峰)。FT-IR:1593cm-1,(C=C),UV-Visλ:268纳米。
实施例2:制备HA衍生物
方案2中显示了HA衍生化的一般步骤。将透明质酸(100mg,MW=10,000(方案中n=13.5),0.00001摩尔;供应商:Creativepegworks)在超纯去离子水(20mL)中搅拌5分钟。在室温下。将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)(52mg,0.00027摩尔,供应商:Alfa Aesar)加入到混合物中,并在室温下搅拌3小时。在此期间,通过少量添加0.1N盐酸将溶液的pH保持在约5至6。将该混合物在室温下逐滴加入到含有己二酸二酰肼(ADH)(17mg,0.00027摩尔;供应商:Alfa Aesar)在5mL超纯去离子水中的单独的混合物中。一旦添加完成,将其在室温搅拌18小时。然后将溶液进行透析(MWC=3500)24小时。然后将混合物冻干以获得白色粉末(100mg)。1H NMR(500MHz,D2O):2.4(2H),2.26(2H),1.66(4H)ppm(诊断峰)。取代/负载度由己二酰肼的亚甲基氢与透明质酸部分的乙酰甲基质子的比率确定。积分表明有30%的偶联,导致大约8个取代。耦合范围通常为6-30%。6%的偶联导致约1.6个羧基单元被取代。
实施例3:改性的GO和衍生的HA之间的反应以制备GO-HA缀合物
下文方案3概述了制备GO-HA的一般程序。将实施例1中获得的改性GO(0.90g)添加至超纯去离子水(100mL)中,并搅拌5分钟,随后超声处理15分钟。在室温下向混合物中加入2-琥珀酸亚氨基-1,1,1,3-四甲基溴化四氟硼酸酯(TSTU)(0.32g,0.001摩尔;供应商:AlfaAesar),2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铀六氟磷酸盐(HBTU)(0.41g,0.001摩尔;供应商:Aldrich)和二异丙基乙胺(DIEA)(0.15mL,0.001摩尔;供应商:Sigma-Aldrich)并搅拌5分钟。然后在室温下将透明质酸-己二酰肼溶液(从实施例2中获得)(0.90g,在150mL超纯去离子水中)滴加到活化的氧化石墨烯溶液中。将反应混合物搅拌18小时,然后进行渗析(MWC=20,000)2天。然后将溶液冻干,得到黑色粉末(1.13g)。1H NMR(500MHz,D20)δ:1.94(2H),1.90(2H),1.21(4H)ppm(诊断峰)。
实施例4:伤口处理组合物的制备
方案4中示意性地示出了制备该组合物的过程。将11mg实施例3中获得的GO-HA溶解在11mL的超纯水中,以产生1mg/mL的有效浓度。将该溶液超声处理10分钟。将XAV939(11mg;供应商:APEBIO)加入到PEG-400(0.5mL)中,并进行超声处理30分钟。将XAV939PEG-400溶液滴加到GO-HA中,并剧烈搅拌5分钟。然后将合并的溶液超声处理1小时,然后在室温下搅拌18小时。在室温下在剧烈搅拌下分批加入羟丙基纤维素(0.2g;供应商:Sigma-Aldrich)。一旦添加完成,将溶液在室温搅拌24小时以形成GO-HA/XAV939复合物的粘稠溶液。该复合物被原样使用。
实施例5:动物试验1
该研究的目的是在局部施用本发明的组合物(STM42)在皮肤全层损伤大鼠模型后观察其对伤口愈合作用。
5-1测试品
STM42:根据实施例4中所述的程序制备的组合物。
载体:96体积%的水和4体积%的PEG-400。
5-2动物饲养
使用了约6-8周龄的16只Sprague-Dawley大鼠。设置动物室以保持23±2℃的温度,40-70%的湿度和12小时的光照/12小时的黑暗周期。在研究的整个过程中,SPF大鼠生长繁殖饲料提供任意足量。动物可获得任意足量反渗透水。在整个研究过程中,动物可以自由获取食物和水。
5-3动物分组和试验程序
每个笼子圈养5只大鼠,并适应5-7天。然后将它们分别用戊巴比妥钠(45mg/kg,腹腔注射,生理盐水中2%)麻醉,并用电动推剪在背部的两侧剃毛,先用甜菜碱消毒,再用70%乙醇擦拭消毒。通过使用带齿的镊子(12毫米,Acuderm Inc,美国)和剪刀,从下面的肌肉上去除皮肤,创建一个(3至4cm2)全层的椭圆形切除伤口。
根据伤口面积和体重将动物分为两组。每组由8只动物组成。载体组:G1(G1-1,G1-2,G1-3,G1-4,G1-5,G1-6,G1-7,G1-8);STM42组:G2(G2-1,G2-2,G2-3,G2-4,G2-5,G2-6,G2-7,G2-8)。分组总结如下。
分别通过注射器将STM42和载体局部施用于动物,以将制剂直接滴入伤口床中,以在伤口上形成均匀且一致的层以覆盖所有伤口区域。伤口形成后每天治疗,持续2周(14天)。
每周两次测量动物体重。在第1天,第5天,第10天和第15天,在具有永久性标记的透明纸上绘制伤口区域边界,并使用测量该区域。在第1、5、10和15天拍摄每只大鼠伤口的照片。
HE染色:每个伤口用H&E和Masson的Trichrome对两个5微米切片进行染色,并进行数字扫描以进行病理分析。病理分析包括:(1)对所有测试品,评估愈合皮肤中的疤痕消解和表皮突的形成(真皮-表皮交界处):从全层切除伤口上创建Massons三色染色的皮肤切片,并评估“线性”细胞外基质(像瘢痕的)。(2)对每个测试品,通过用圆偏振光成像的Massons三色染色切片评估愈合皮肤的纤维厚度。(3)对每个测试品,通过H&E染色评估表皮突。
5-4病理学测试:
材料:皮肤样本,10%福尔马林,苏木精,曙红染色液,酸性品红,苯胺蓝,二甲苯,70%酒精,95%酒精,100%酒精等
仪器:组织脱水器(Shandon Excelsior ESTM组织处理机Fisher/ThermoA78400006);组织包埋器(Shandon HistocentreTM3组织包埋中心Fisher/ThermoB64100010);徕卡自动切片机(Leica RM2255);自动染色机(自动切片染色器Fisher/Thermo A74200010,24-4)
组织处理和切片:(1)用组织脱水器进行组织处理:梯度乙醇脱水,二甲苯苯透明化,石蜡渗透,包埋。(2)将样品通过徕卡自动切片机切成5μm厚的片(3)H&E染色,Masson染色。
评价参数:再上皮化,新血管形成,表皮突,结痂,肉芽形成。评分标准汇总在下表中:
5-5观察与分析
临床体征:治疗开始前和研究期间每天一次,记录动物的所有体征;每天在相同的时间间隔进行观察。
试验终结:绝境动物或出于人道原因处置的动物以及已完成计划测试时间的动物将通过二氧化碳安乐死。
统计分析:使用学生未配对t检验分析结果(单个和小组)。数据以平均值±SD或平均值±SEM给出。P<0.05被认为是显著的。
5-6结果
临床体征:在实验治疗期间未发现死亡、发病或行为异常。在试验过程中,没有出现以下症状:痛苦(恶病质、虚弱、行动或进食困难、疼痛、哭);毒性(弯背、抽搐);连续三天体重减轻25%,或者每天体重减轻20%。在实验过程中,伤口区域的各组之间无显着差异(p>0.05)。
在第15天,每组3只大鼠(载体组:G1-4,G1-5,G1-8;STM42组:G2-3,G2-4,G2-6)用二氧化碳安乐死。伤口组织切开并用中性福尔马林缓冲液固定,然后将其包埋在石蜡中进行组织学检查。
STM42组和载体组的得分如图1所示。从图1中可以看出,STM42对以下有有显著影响:再上皮化(伤口愈合的基本组成部分,成功闭合伤口的决定性参数),新血管形成的改善(新血管的自然形成,通常以功能性能够被红细胞灌注的微血管网络的形式出现,形成以响应局部不良灌注或局部缺血的侧支循环),表皮突的形成的改善(投射到皮肤和粘膜下层结缔组织中的上皮延伸-改善的表皮突形成是组织再生的表现,而不是纤维化/疤痕形成(表皮突形成减少)的表现),结痂减少(有结痂的伤口愈合时间更长,而且是纤维化/疤痕的迹象),和肉芽的减少(肉芽组织由通过最初募集的成纤维细胞大量涌入伤口部位而迅速沉积下来的如纤维蛋白和III型胶原蛋白等细胞外基质蛋白组成,而引起疤痕)。
可以用以下公式评估STM42对伤口愈合中减小疤痕的总体效果:总得分=(再上皮化+新血管形成+表皮突形成)-(结痂+肉芽形成)。使用每个组的平均测量值:STM42=4.66。载体组=-1.33。在该指标下,与对照组相比,使用STM42进行的疤痕减少增加了5.99倍。
实施例6:动物试验2
此研究的目的是在局部给药的情况下,观察STM-52在真皮全层损伤STZ诱导的糖尿病大鼠模型中的伤口愈合效果。
6-1化合物及制备
STM-52(或者STM52):和STM42相同,根据实施例4中的程序制备的组合物。
载体:96体积%水和4体积%PEG-400。
6-2试验品制备程序
通过超声处理10分钟将STM-52充分混合,然后通过注射器将100微升样品注入伤口。
6-3动物饲养
使用了14只雄性Sprague-Dawley大鼠,其SPF等级为约6-8周龄。大鼠的血糖>16.7mM。
开始治疗时的体重:200到300g。
适应期:7天。
动物房的环境控制设置为保持温度23±2,℃湿度40%至70%,以及12小时光照/12小时黑暗周期。为了适应研究程序,可暂时中断12小时的黑暗周期。
食物和水:在研究的整个生命阶段中,SPF大鼠生长繁殖饲料(北京科澳协力饲料有限公司)随意充足提供。可随意使用反渗透水。
动物的选择和禁食:根据总体健康状况和对笼养的适应程度选择本研究中使用的动物。在整个研究过程中,动物可以自由获取食物和水。
6-4试验设计
到达动物设施后,将每个笼子中的动物圈养5只大鼠,并使其适应7天。在实验之前,停止供应食物约16小时。腹膜内麻醉,注射溶解在pH 4.5柠檬酸钠缓冲液中的STZ(65mg/kg)使大鼠患有糖尿病。最终血糖水平>16.7mM(300mg/dL)的大鼠纳入研究。所有选择的大鼠均用戊巴比妥钠(45mg/kg,在生理盐水中i.p.2%)麻醉,并用电动推剪在背部的两侧剃毛,用碘伏消毒,然后用75%乙醇擦拭消毒。使用(12毫米,Acuderm Inc,美国)创建一个(3至4cm2)全层椭圆形切除伤口。用剪刀和带齿的镊子将皮肤从下面的肌肉中去除。
根据伤口面积和体重将动物分为两组。
用STM-52或载体(100μL/大鼠)局部施用于伤口(通过注射器将制剂直接滴入伤口床中,以在伤口上形成均匀且一致的层,确保覆盖所有伤口区域)。伤口形成后每天治疗,持续21天。
图2是显示在21天的治疗过程中,载体组和STM-52组伤口的平均面积大小的图。结果表明,与载体相比,局部施用STM-52增加了糖尿病大鼠受损的愈合动物模型的愈合速率。主要地,在21天试验中的第10-18天观察到了速率增加。同样在这段时间内,如体重测量所表明,没有任何明显的毒性迹象。
如本文中所使用的,与数值或数值范围相关联的词“约”意指“大约”,并且是指可以在一定误差范围内获得的结果,并且本领域技术人员知道如何获得误差,例如,相对给定值或范围的±10%。
如本文所用,术语“有效量”是指当施用于对象以治疗对象的不良或疾病状态(例如,治疗伤口)时足以改进或改善这种状态的组合物的量。“有效量”可以根据组合物、疾病状况和其严重程度,以及年龄、身体状况和待治疗对象的反应性而变化。
尽管已经在本文中描述和示出了各种发明实施例,但是本领域普通技术人员将容易想到用于执行功能和/或获得结果和/或所描述的一个或多个优点的多种其他手段和/或结构。在本文中,这些改变和/或修改中的每一个都被认为在本文所述的发明实施例的范围内。更一般地,本领域技术人员将容易地理解,本文描述的所有参数,尺寸,材料和构造均是示例性的,并且实际参数,尺寸,材料和/或构造将取决于一个或多个特定应用。使用本发明的教导。仅通过常规实验,本领域技术人员将认识到或能够确定本文所述的具体发明实施方案的许多等同方案。因此,应理解,前述实施方案仅以举例的方式给出,并且在所附权利要求及其等同物的范围内,可以以不同于具体描述和要求保护的方式实践本发明的实施方案。本公开的发明实施例涉及本文所述的单独的特征、组合物、装置、系统、制品、材料、组件和/或方法。另外,如果这样的特征、组合物、装置、系统、制品、材料、组件和/或方法不互相矛盾,本公开的发明范围内包括的这些特征、组合物、装置、系统、制品、材料、组件和/或方法中任何两个或多个的组合。
而且,各种发明构思可以体现为一种或多种方法,已经提供了示例。作为该方法的一部分执行的动作可以以任何合适的方式排序。因此,可以构造这样的实施例,其中以与所示出的顺序不同的顺序执行动作,即使在说明性实施例中被示为顺序动作,也可包括同时执行一些动作。
Claims (22)
1.一种用于治疗伤口的局部用药组合物,其包含:
基质组分,包含氧化石墨烯GO和透明质酸HA的缀合物GO-HA,其中GO和HA通过连接体共价连接;
XAV939;和
水;所述连接体包含-Rx-RS-Ry-,其中Rx和Ry各自独立地选自-CO-,-COO-,-NH-,-NH-NH-,-NH-NH-CO-,-CS-,-S-和-O-,其中RS是未取代或取代的具有2-20个主链碳原子的饱和或不饱和线性亚烷基。
2.根据权利要求1所述的局部用药组合物,其还含聚乙二醇PEG。
3.根据权利要求2所述的局部用药组合物,其中所述PEG具有约200至约400道尔顿的分子量。
4.根据权利要求2所述的局部用药组合物,其中所述PEG的量为所述全部组合物的约0.1重量%至约20重量%。
5.根据权利要求1所述的局部用药组合物,其还包含增稠剂。
6.根据权利要求5所述的局部用药组合物,其中所述增稠剂包含羟丙基纤维素HPC。
7.根据权利要求1所述的局部用药组合物,其中所述连接体包含2-25个碳。
8.根据权利要求1所述的局部用药组合物,其中,所述连接体是直链或支链的。
9.根据权利要求1所述的局部用药组合物,其中Rx和Ry均为-NH-NH-CO-。
10.根据权利要求1所述的局部用药组合物,其中XAV939与GO-HA的重量比为约1:2至约2:1。
11.根据权利要求1所述的局部用药组合物,其中XAV939占总组合物的约0.001重量%至约5重量%。
12.根据权利要求1所述的局部用药组合物,其中GO-HA占总组合物的约0.001重量%至约5重量%。
13.一种医疗设备,包括:
基底;以及
权利要求1-12中任一项的局部用药组合物,其施加在基底上。
14.根据权利要求13所述的医疗设备,其中,所述基底是贴,垫,缝线,纱布,带或绷带。
15.权利要求1-12任一项所述的局部用药组合物或权利要求13或14所述的医疗设备在用于制备治疗皮肤伤口的药物产品中的应用。
16.根据权利要求15所述的应用,其中,所述伤口是外科伤口。
17.根据权利要求15所述的应用,其中所述伤口是烧伤。
18.根据权利要求15所述的应用,其中所述伤口是慢性伤口。
19.根据权利要求15-18任一项所述的应用,其进一步包括将第二伤口药物施用至对象,所述第二伤口药物包含以下中的一种或多种:皮质类固醇,细胞毒性药物,抗生素,防腐剂,尼古丁,抗血小板药物,NSAID,秋水仙碱,抗凝剂,血管收缩药或免疫抑制剂,生长因子,抗体,蛋白酶,蛋白酶抑制剂,抗菌肽,粘附肽,止血剂,活细胞,蜂蜜或一氧化氮。
20.根据权利要求15-18任一项所述的应用,其中对象是人。
21.根据权利要求15-18任一项所述的应用,其中对象是非人的哺乳动物。
22.权利要求1-12任一项所述的局部用药组合物或权利要求13或14所述的医疗设备在用于制备减少对象皮肤伤口愈合中的皮肤纤维化或疤痕的产品中的应用。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102727901A (zh) * | 2012-07-12 | 2012-10-17 | 上海师范大学 | 一种氧化石墨烯/透明质酸纳米药物载体材料及其制备方法和应用 |
CN103030140A (zh) * | 2012-12-21 | 2013-04-10 | 郑州大学 | 透明质酸修饰的氧化石墨烯及其药物组合物的制备方法与应用 |
CN103980505A (zh) * | 2014-05-27 | 2014-08-13 | 武汉大学 | 透明质酸/氧化石墨烯纳米复合水凝胶的制备方法及医药组合物 |
CN106893012A (zh) * | 2017-04-17 | 2017-06-27 | 山东本源晶体科技有限公司 | 一种纳米银改性石墨烯晶体复合材料及其制备方法 |
CN106916313A (zh) * | 2017-03-22 | 2017-07-04 | 中国科学院宁波材料技术与工程研究所 | 透明质酸修饰的聚(n‑异丙基丙烯酰胺‑丙烯酸)水凝胶及应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4649075A (en) * | 1984-08-09 | 1987-03-10 | Leonora Jost | Transdermal and transmucosal vortexed foam devices and the method of making |
US4568343A (en) * | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
US5340586A (en) * | 1991-04-12 | 1994-08-23 | University Of Southern California | Methods and formulations for use in treating oophorectomized women |
GB0202874D0 (en) * | 2002-02-07 | 2002-03-27 | Novartis Ag | Organic compounds |
US20040202665A1 (en) * | 2002-07-01 | 2004-10-14 | Janette Lazarovits | Compositions and methods for therapeutic treatment |
US20060051384A1 (en) * | 2004-09-07 | 2006-03-09 | 3M Innovative Properties Company | Antiseptic compositions and methods of use |
US7652043B2 (en) | 2004-09-29 | 2010-01-26 | The Johns Hopkins University | WNT pathway antagonists |
GT200600396A (es) * | 2005-09-07 | 2007-04-23 | Dispositivos para la aplicacion de medicamentos transdermicos conteniendo o-desmetil venlafaxina (odv) o sus sales | |
JP2011504461A (ja) | 2007-11-05 | 2011-02-10 | ノバルティス アーゲー | Wnt活性を測定するためのおよびwnt関連がんを処置するための方法および組成物 |
US20120318262A1 (en) * | 2011-03-21 | 2012-12-20 | Ethan Lee | Pyrvinium Wound Treatment Methods and Devices |
EP2887954B1 (en) | 2012-08-23 | 2020-05-06 | Susan Marie Metcalfe | Neurotherapeutic nanoparticle compositions |
WO2015190995A1 (en) | 2014-06-13 | 2015-12-17 | Advanced First Aid Research Pte. Ltd. | Thermally conductive material-infused hydrogel bandages |
CN105288695B (zh) * | 2015-11-17 | 2018-06-15 | 张建刚 | 含氧化石墨烯成分的创可贴及其制备方法 |
US20190307904A1 (en) * | 2016-03-30 | 2019-10-10 | Convatec Technologies Inc. | Modified wound dressings |
-
2018
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- 2018-10-06 ES ES18864379T patent/ES2930254T3/es active Active
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- 2018-10-06 DK DK18864379.5T patent/DK3691649T3/da active
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-
2020
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-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102727901A (zh) * | 2012-07-12 | 2012-10-17 | 上海师范大学 | 一种氧化石墨烯/透明质酸纳米药物载体材料及其制备方法和应用 |
CN103030140A (zh) * | 2012-12-21 | 2013-04-10 | 郑州大学 | 透明质酸修饰的氧化石墨烯及其药物组合物的制备方法与应用 |
CN103980505A (zh) * | 2014-05-27 | 2014-08-13 | 武汉大学 | 透明质酸/氧化石墨烯纳米复合水凝胶的制备方法及医药组合物 |
CN106916313A (zh) * | 2017-03-22 | 2017-07-04 | 中国科学院宁波材料技术与工程研究所 | 透明质酸修饰的聚(n‑异丙基丙烯酰胺‑丙烯酸)水凝胶及应用 |
CN106893012A (zh) * | 2017-04-17 | 2017-06-27 | 山东本源晶体科技有限公司 | 一种纳米银改性石墨烯晶体复合材料及其制备方法 |
Non-Patent Citations (5)
Title |
---|
Hyaluronic acid-conjugated graphene oxide/ photosensitizer nanohybrids for cancer targeted photodynamic therapy;Fangyuan Li;《journal of materials chemistry B》;第1卷;1678-1686 * |
Inhibition of Wnt/b-catenin pathway promotes regenerative repair of cutaneous and cartilage injury;Dikshya Bastakoty et al.,;《The faseb journal》;20150812;第29卷(第12期);摘要,第4884页右栏 * |
Nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/collagen/ graphene oxide scaffolds for wound coverage;Rashtrapal Zine et al.,;《Materials Science and Engineering C》;20170525;第80卷;全文 * |
Nanographene OxideHyaluronic Acid Conjugate for Photothermal Ablation Therapy of Skin Cancer;Ho Sang Jung et al.,;《ASC NANO》;第8卷(第1期);260-268 * |
余元勋著.Wnt信号通路与乳腺癌.《中国分子乳腺癌学》.安徽科学技术出版社,2017,第29-32页. * |
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