CN115666545A - 纤维化疾病的复合治疗剂的开发 - Google Patents
纤维化疾病的复合治疗剂的开发 Download PDFInfo
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- CN115666545A CN115666545A CN202180037540.5A CN202180037540A CN115666545A CN 115666545 A CN115666545 A CN 115666545A CN 202180037540 A CN202180037540 A CN 202180037540A CN 115666545 A CN115666545 A CN 115666545A
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Abstract
本发明涉及一种用于治疗纤维化的二甲双胍和Chir99021的复合组合物。本发明的组合物抑制胶原蛋白沉积、抑制炎症反应、防止血管的纤维化、防止组织损伤,因而具有优异的预防及治疗纤维化的效果。
Description
技术领域
本发明涉及一种用于预防或治疗纤维化的复合组合物。
背景技术
纤维化为一种由成纤维细胞引起细胞外基质的异常生成、积累以及沉积的疾病,是由器官或组织的纤维化引发的。纤维化为导致器官损伤的非常致命的疾病。作为一例,特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)为与成纤维细胞积累以及肌成纤维细胞分化相关的复发性肺泡上皮细胞损伤的结果,是对肺实质(lung parenchyma)组织造成不可逆性破坏且会导致细胞外基质(extracellular matrix;ECM)的过量积累的慢性、进行性以及致命性的疾病。然而,由于到目前为止还没有针对纤维化的有效的治疗方法(Fibrogenesis Tissue Repair,2012,5(1):11;N Engl J Med,2001,345(7):517),因此不断需要开发一种能够有效预防或治疗纤维化的治疗剂。
纤维化是各种基础疾病的结果。慢性炎症或组织损伤/再生为典型的纤维化诱发病例。具体的疾病的例子有特发性肺纤维化(IPF)、酒精性以及非酒精性肝硬化相关肝纤维化、肾纤维化、心脏纤维化以及由伤口异常愈合导致的瘢痕疙瘩的形成[Wynn,T.A.(2004)Nature Reviews Immunology.4:583-594;Friedman,S.L.(2013)Science TranslationMedicine.5(167):1-17]。此外,纤维化为与包括类风湿关节炎、克罗恩病、系统性红斑狼疮以及系统性硬化症在内的慢性自身免疫性疾病相关的关键病理特征。表现严重的未满足医疗需求的疾病的例子有特发性肺纤维化(IPF)、系统性硬化症以及非酒精性脂肪肝炎(NASH)相关肝纤维化。预计NASH相关肝纤维化的增加的发病率与2型糖尿病以及肥胖的发病率直接相似。
尤其,放射性肺纤维化(radiation-induced lung fibrosis:RILF)为在体部立体定向放射治疗(stereotactic body radiotherapy,SBRT)后最常见的并发症,是由于成纤维细胞、肌成纤维细胞以及白细胞的积累所致,并由于胶原蛋白等细胞外基质蛋白增加及呼吸障碍而导致威胁生命的非常严重的并发症。对此,虽然已知在放射线治疗时可能会产生放射性肺纤维化的副作用,但对其治疗的研究尚未充分。
另一方面,肝纤维化(liver cirrhosis或hepatic fibrosis)或肝硬化(或肝硬变,liver cirrhosis)属于一种由于肝组织反复损伤及再生而引起肝炎,从肝炎进展为肝纤维化,再从肝纤维化进展为肝硬化的过程中发生的疾病。肝纤维化为随着肝细胞的持续破坏及反复的肝损伤而出现的纤维化现象(liver fibrogenesis),发生细胞外基质(extracellular matrix,ECM)的生成增加,但对其的分解相对减少的现象,严重时会进展为肝硬化、肝衰竭或肝癌。肝纤维化一旦进行纤维化,很难恢复到正常的肝,随着进展为肝硬化或肝癌,其死亡率持续增加。肝硬化是指由于慢性炎症,正常肝组织变为再生结节(regenerative nodules;形成小肿块的现象)等纤维化组织而导致肝功能下降。到目前为止,还没有针对这些疾病的具体治疗方法。
本发明人为了开发用于预防或治疗纤维化的组合物而锐意努力的结果,通过在放射线诱导肺纤维化小鼠模型、非酒精性肝纤维化小鼠模型等中确认具有纤维化预防及治疗纤维化效果的复合制剂,从而完成本发明。
发明内容
技术问题
本发明的目的在于,提供一种用于预防或治疗纤维化的药物组合物,包含二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐作为有效成分。
本发明的再一目的在于,提供一种预防或治疗纤维化的方法,包括向个体给药二甲双胍(Metformin)或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的步骤。
本发明的另一目的在于,提供一种用于预防或改善纤维化的食品组合物,包含:二甲双胍或其食品学上可接受的盐;以及Chir99021或其食品学上可接受的盐。
解决问题的方案
以下进行详细说明。另一方面,在本发明中公开的各种说明以及实施方式可以分别应用于不同的说明以及实施方式。即,在本发明中公开的各种要素的所有组合均属于本发明的范畴。并且,不能认为本发明的范畴限制于下述的具体描述。
用于实现上述目的的本发明的一实施方式为用于预防或治疗纤维化的药物组合物,包含二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐作为有效成分。
上述二甲双胍可以为如下化学式1所示的化合物。
化学式1
如上述化学式1所示的化合物可以命名为N,N-二甲基亚氨基二碳亚胺二酰胺(N,N-Dimethylimidodicarbonimidic diamide)。
上述化学式1的化合物可以使用有机化学领域已知的常规知识来制备,或者可以通过购买市售的化合物来使用。
上述Chir99021可以为如下化学式2所示的化合物。
化学式2
如上述化学式2所示的化合物可以命名为6-((2-((4-(2,4-二氯苯基)-5-(4-甲基-1H-咪唑-2-基)嘧啶-2-基)氨基)乙基)氨基)烟酸腈(6-((2-((4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)ethyl)amino)nicotinonitrile)。
上述化学式2的化合物可以使用有机化学领域已知的常规知识来制备,或者可以通过购买市售的化合物来使用。
在本发明中,“药学上可接受的盐”是指在医药行业通常使用的盐,例如,用钙、钾、钠以及镁等制备的无机离子盐;用盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸以及硫酸等制备的无机酸盐;用乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等制备的有机酸盐;用甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸以及萘磺酸等制备的磺酸盐;用甘氨酸、精氨酸、赖氨酸等制备的氨基酸盐;以及用三甲胺、三乙胺、氨、吡啶以及甲基吡啶等制备的胺盐等,但本发明中指的盐的种类并不限制于这些所列的盐。
在本发明中,术语“纤维化”是指在器官或组织中形成过量的纤维性结缔组织。这可以与作为器官或组织中的正常部分的纤维性组织区分开来。应理解,纤维化是一种由于成纤维细胞导致的纤连蛋白(fibronectin)、胶原蛋白(collagen)等细胞外基质(extracellular metrix)的过量积累,最终导致器官损伤的致命性疾病。
在本发明中,上述纤维化可以包括在肺、肾、肝、心脏、脑、血管、关节、肠、皮肤、软组织、骨髓、阴茎、腹膜、肌肉、脊柱、睾丸、卵巢、乳房、甲状腺,鼓膜、胰腺、胆囊、膀胱或前列腺等所有组织中出现的纤维化相关疾病。
具体地,在本发明中,纤维化可以为由身体各组织中发生的纤维化而引起的疾病,例如,伤口异常愈合、肺纤维化(放射性肺纤维化、特发性肺纤维化等)、肝纤维化(例如,酒精性肝损伤诱导肝纤维化、非酒精性肝纤维化等)、桥接纤维化、克罗恩病(肠的纤维化)、胰腺以及肺的囊性纤维化、特别是在儿童中能够作为肌内注射的并发症发生的肌肉注射纤维化、心内膜心肌纤维化或心脏纤维化、由移植物抗宿主病(Graft-Versus-Host Disease,GVHD)引起的纤维化、脾脏的纤维化、包括视网膜纤维化的眼的纤维化、手术或注射纤维化的纤维化并发症、肾小球肾炎、间质纤维化、瘢痕疙瘩以及肥厚性瘢痕(皮肤的纤维化)、黄斑变性、纵隔纤维化(纵隔的软组织纤维化)、局灶性硬皮病(morphea)、多灶性纤维硬化症,骨髓纤维化、肾源性系统性纤维化(皮肤的纤维化),结节性表皮下纤维化(例如,良性纤维组织细胞瘤)、胸膜纤维化、作为手术(例如,手术移植)的结果的纤维化、增殖性纤维化、干线型纤维化(pipestem fibrosis)、纤维蛋白形成后纤维化、进行性大块纤维化(肺的纤维化的一种、煤工尘肺的一种并发症)、陈旧心肌梗死(心脏的纤维化)、胰腺纤维化、进行性大块纤维化、放射线纤维化、肾纤维化、与慢性肾病相关的或由慢性肾病引起的肾纤维化、腹膜后纤维化(腹膜后软组织的纤维化)、术后瘢痕、硬皮病/系统性硬化症(皮肤的纤维化)、上皮下纤维化、子宫纤维化,或病毒性肝炎诱导纤维化,但不限于此。
上述纤维化可以具体为肺纤维化或肝纤维化。
在本发明中,肺纤维化可以包括特发性肺纤维化(Idiopathic PulmonaryFibrosis)、非特异性间质性肺炎(Nonspecific Interstitial Pneumonia)、急性间质性肺炎(Acute Interstitial Pneumonia)、隐源性机化性肺炎(Cryptogenic OrganizingPneumonia)、呼吸性细支气管炎相关的间质性肺疾病(RespiratoryBronchiolitisassociated Interstitial Lung)、脱屑性间质性肺炎(DesquamativeInterstitial Pneumonia)、淋巴间质性肺炎(Lymphoid Interstitial Pneumonia)、间质性肺纤维化、以及弥漫性肺纤维化、放射性肺纤维化等,但不限于此。
具体地,上述肺纤维化可以为特发性肺纤维化或放射性肺纤维化。
在本发明中,“放射性肺纤维化(RILF:radiation-induced lung fibrosis)”是指一种由于放射线治疗等原因肺的间质组织(interstitial tissue)像纤维一样变硬的疾病,并会引起严重的呼吸困难。放射性肺纤维化是作为肺癌患者的主要治疗方法之一的三维放射线照射(3DRT)治疗方法的副作用而出现的疾病。这疾病广义上包含在特发性肺纤维化的子概念中,但其发病原因表现出明显的特征。
特发性肺纤维化(idiopathic pulmonary fibrosis)推测是由环境、病毒等各种原因引起的,但其原因尚未明确,但不同的是,放射性肺纤维化是由放射线照射引起的。
在本发明中,“肝纤维化(liver fibrosis)”是指随着由于组织的损伤持续进行炎症反应从活性肝星状细胞(hepatic stellate cell)中大量分泌的胶原蛋白(collagen)与细胞外基质(extracellularmatrix,ECM)结合而出现的伤口愈合的过程。如果肝纤维化持续进展,则在肝组织内大量沉积胶原蛋白,再生结节被胶原蛋白包围,从而可能会发展为具有异常结构的肝硬化。
优选地,上述肝纤维化可以为非酒精性肝纤维化。
非酒精性肝纤维化可能是由非酒精性脂肪肝炎(Nonalcholic steatohepatitis;NASH或Non-alcoholic fatty liver disease;NAFLD)以及肝硬化(liver cirrhosis)引起的。
在本发明中所使用的术语“治疗”是指通过给药上述药物组合物来改善或有益地改变纤维化的症状,“预防”是指通过给药上述药物组合物来抑制或延迟纤维化发病的所有行为。
在本发明中,首次确认到二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐在放射性肺纤维化以及非酒精性肝纤维化中具有抑制纤维化的治疗功效,尤其它们的组合具有显著的协同效应,因此鉴定可以将二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐用作预防及治疗纤维化的用途。
具体地,在本发明实施例中,通过被放射线诱导肺纤维化的小鼠来进行动物实验的结果,可以确认在给药二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的情况下,体内(in vivo)的组织损伤及胶原蛋白沉积显著减少,这无论给药途径如何均表现出相同的协同效应并表现出优异的治疗效果。
不仅如此,通过被诱导非酒精性肝纤维化的小鼠来进行动物实验的结果,可以确认在给药二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的情况下,体内(in vivo)的组织损伤及胶原蛋白沉积显著减少。
因此,本发明的组合物在预防及治疗纤维化的方面具有优异的效果,因此可以非常有用地用作预防或治疗纤维化的用途。
并且,本发明的药物组合物还可以包含在药物组合物的制备中通常使用的适合的载体、赋形剂或稀释剂。包含药学上可接受的载体的组合物可以为用于口服给药或肠胃外给药的各种剂型。在制剂化的情况下,可以使用常用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂来配制。用于口服给药的固体制剂可以包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固体制剂可以通过将一种以上的化合物与一种以上的赋形剂,例如,淀粉、碳酸钙、蔗糖(sucrose)或乳糖(lactose)、明胶等混合来配制。并且,除了简单的赋形剂以外,还可以使用硬脂酸镁、滑石等润滑剂。用于口服给药的液体制剂可以包括悬浮液、内用液剂、乳剂、糖浆剂等,除了作为常用的作为简单稀释剂的水、液体石蜡以外还可以包括各种赋形剂,例如,润湿剂、甜味剂、香料、防腐剂等。用于肠胃外给药的制剂可以包括灭菌的水溶液、非水溶剂、悬浮剂、乳剂、冻干制剂、栓剂。可以使用丙二醇(propylene glycol)、聚乙二醇、橄榄油等植物油、油酸乙酯等可注射的酯类等作为非水溶剂、悬浮溶剂。可以使用半合成脂肪酸酯(Witepsol)、聚乙二醇、吐温(tween)61,可可脂,月桂酯,甘油明胶等作为栓剂的基质。
并且,本发明的药物组合物可以为选自由片剂、丸剂、散剂、颗粒剂、胶囊剂、悬浮剂、内用液剂、乳剂、糖浆剂、灭菌的水溶液、非水溶剂、悬浮剂、油剂、冻干制剂以及栓剂组成的组中的一种剂型,但不限于此。
上述组合物可以通过包含剂量为10μg/kg至100mg/kg的上述化学式1的化合物以及剂量为10μg/kg至100mg/kg的上述化学式2的化合物来进行给药,但不限于此。本发明的组合物可以与公知的纤维化治疗剂在不同时间或同时联合给药,或可以并用公知的纤维化治疗方法。并且,上述组合物也可以单次或多次给药。考虑到所有上述因素,重要的是要在没有副作用的情况下,能够以最小的量获得最大效果的量来给药,这可以很容易地由本领域的技术人员确定。
用于复合疗法的各种活性成分在治疗上有效的给药量可以取决于所用的特定化合物或药物组合物、给药方式、要治疗的症状的严重程度、温血动物的种类、体重、性别、饮食状况以及年龄。因此,使用本发明的化合物的给药方案根据包括给药途径以及患者的肾和肝功能等各种因素来选择。本领域的外科医生、临床医生或兽医可以容易地确定并开出预防、抵抗或阻止症状进展所需要的有效量的药物。在产生效率而无毒性的范围内实现药物浓度的最佳准确度需要以部位靶向的药物可用性的流行病学为基础的方案。这包括考虑药物的分布、平衡以及清除。因此可以调整给药量方案,即下述记载的本发明的组合物的任何单个组分的给药水平以及给药频率,以提供最佳的治疗反应。
“共同给药”是指将本发明的组合物的组分一起或实际上同时给药,例如在15分钟之内从相同的运载体中或从额外的运载体中给药,例如,根据给药方式的不同,两种化合物可以同时存在于胃肠道中。化合物可以作为固定组合物给药或以单独给药的形式给药。应当理解,在每个给药形式中以单独的给药量包含的活性成分或成分的单位含量本身无需构成有效量,可以通过多个给药单位的给药来实现所需要的有效量。
并且,本发明的化合物还可以依次给药。
在本发明中,术语“给药”是指通过任何适合的方法向对象注入本发明的药物组合物,给药途径只要能够到达目标组织,可以通过口服或肠胃外等各种途径来给药。
根据目的或需要,上述药物组合物可以通过本领域使用的常规方法、给药途径、给药量来向个体适当地给药。作为给药途径的例子,可以有口服、肠胃外、皮下、腹腔内、肺内以及鼻腔内给药,肠胃外注入包括肌肉内、静脉内、动脉内、腹腔内或皮下给药。并且可以根据本领域公知的方法选择适合的给药量以及给药次数,实际上给药的本发明的药物组合物的量以及给药次数可以适当地取决于要治疗的症状的种类、给药途径、性别、健康状况、饮食、个体的年龄及体重、以及疾病的严重程度等各种因素。
本发明的药物组合物还可以与激素治疗、药物治疗等各种方法联合使用,以预防或治疗纤维化。
本发明提供一种用于治疗纤维化的组合物,包含:二甲双胍或其药学上可接受的盐;以及Chir99021或其药学上可接受的盐。
本发明提供一种二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐在制备用于治疗纤维化的药剂中的用途。
本发明中的术语“药学上有效的量”是指以可应用于医疗用途的合理的受益/风险比例充分抑制或缓解血管通透性增加的量,有效剂量水平可以取决于包括个体种类及严重程度、年龄、性别、药物的活性、对药物的敏感度、给药时间、给药途径及排泄率、治疗期间、同时使用的药物等要素以及其他医学领域已知的要素。
在本发明中,术语“个体”是指患有本发明的纤维化疾病或引发疾病的包括人类在内的所有动物。本发明的药物组合物可以通过向个体给药来预防或治疗纤维化。
本发明的另一实施方式为预防或治疗纤维化的方法,包括向个体给药二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的步骤。
用于预防或治疗纤维化的二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的用途如上所述。
本发明提供一种用于预防或改善纤维化的食品组合物,包含二甲双胍或其食品学上可接受的盐以及Chir99021或其食品学上可接受的盐作为有效成分。
在本发明中所用的术语“食品学上可接受的盐”是指在作为阳离子与阴离子通过静电引力结合的物质的盐中可以以食品学上使用的形式的盐,其种类具体例子包括上述“药学上可接受的盐”的例子。
本发明的食品组合物可以用作保健功能食品。上述“保健功能食品”是指根据保健功能食品相关法律第6727号的使用对人体有用的功能性原料或成分来制备以及加工的食品,“功能性”是指以获得调节人体结构和功能的营养素或生理作用等对保健用途有用的效果为目的而摄入。
本发明的食品组合物可以包含常用于改善气味、味道、观感等的附加成分。例如,可以包含维生素A、维生素C、维生素D、维生素E、维生素B1、维生素B2、维生素B6、维生素B12、烟酸(niacin)、生物素(biotin)、叶酸(folate)、泛酸(panthotenic acid)等。并且,可以包含锌(Zn)、铁(Fe)、钙(Ca)、铬(Cr)、镁(Mg)、锰(Mn)、铜(Cu)等矿物质。并且,可以包含赖氨酸、色氨酸、半胱氨酸、缬氨酸等氨基酸。并且,可以添加防腐剂(山梨酸钾、苯甲酸钠、水杨酸、脱氢乙酸钠等)、杀菌剂(漂白粉及高漂白粉、次氯酸钠等)、抗氧化剂(丁基羟基茴香醚(BHA)、丁化羟基甲苯(BHT)等)、着色剂(焦油色素等)、显色剂(亚硝酸钠等)、漂白剂(亚硫酸钠)、调味料(谷氨酸钠(MSG)等)、甜味剂(对乙氧基苯脲、环磺酸盐、糖精、钠等)、香料(香草醛、内酯类等)、膨胀剂(明矾、D-酒石酸氢钾等)、强化剂、乳化剂、增稠剂(浆糊)、成膜剂、胶基剂、消泡剂、溶剂、改良剂等食品添加剂(food additives)。上述添加剂可以根据食品的种类选择且适量使用。
在将本发明的食品组合物作为食品添加剂使用的情况下,可以将其直接添加或与其他食品或食品成分一起使用,可以根据常规方法适当使用。
本发明的食品组合物以预防和/或改善纤维化为目的,相对于组合物总重量,分别可以包含0.01%至95%的上述二甲双胍或其食品学上可接受的盐;以及Chir99021或其食品学上可接受的盐,优选地可以包含1重量百分比至80重量百分比。并且,以预防和/或改善纤维化为目的,可以以片剂、胶囊、粉末、颗粒、液体、丸、饮料等形态来制备及加工。
并且,本发明提供一种二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐在制备用于治疗纤维化的药剂中的用途。其中,“纤维化”以及“药学上可接受的盐”的定义如上所述。
并且,本发明提供一种预防或治疗纤维化的方法,包括以药学上有效的量向有需要的对象给药二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的步骤。其中,“纤维化”、“药学上可接受的盐”以及“对象”的定义如上所述。
并且,本发明提供一种用于治疗纤维化的组合物,包含二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐作为有效成分。其中,“纤维化”以及“药学上可接受的盐”的定义如上所述。
发明的效果
对于纤维化来说,二甲双胍或其药学上可接受的盐;以及Chir99021或其药学上可接受的盐恢复组织损伤、抑制胶原蛋白沉积、防止血管纤维化、抑制炎症,因为对预防及治疗纤维化具有非常优异的效果。
附图说明
图1为关于通过用4mm、强度为90Gy的放射线照射小鼠的胸部来制备的放射线诱导肺纤维化小鼠模型的制备以及药物给药(腹腔给药)时机及剂量的示意图。
图2为示出通过苏木精-伊红染色法在放射线诱导肺纤维化小鼠模型中确认不同药物给药(腹腔给药)的组织损伤部位的炎症反应以及纤维化程度的结果的。
图3为从统计学上示出在放射线诱导肺纤维化小鼠模型中不同药物给药(腹腔给药)的纤维化程度的图。
图4为关于通过用4mm、强度为90Gy的放射线照射小鼠的胸部来制备的放射线诱导肺纤维化小鼠模型的制备以及药物给药(口服给药)时机及剂量的示意图。
图5为示出通过苏木精-伊红染色法在放射线诱导肺纤维化小鼠模型中确认不同药物给药(口服给药)的组织损伤部位的炎症反应以及纤维化程度的结果的图。
图6为从统计学上示出在放射线诱导肺纤维化小鼠模型中不同药物给药(口服给药)的纤维化程度的图。
图7为关于通过每周2次向小鼠的肝腹腔内注射CCl4(1.5%CCl4:1mg/kg)来诱导非酒精性肝纤维化小鼠模型的制备以及药物给药时机及剂量的示意图。
图8为示出通过苏木精-伊红染色法以及三色染色法在非酒精性肝纤维化小鼠模型中确认不同药物给药的组织损伤部位的炎症反应以及纤维化程度变化的结果的图。
图9为从统计学上示出在非酒精性肝纤维化小鼠模型中不同药物给药的胶原蛋白沉积程度的图。
具体实施方式
以下,通过实施例更详细地说明本发明。然而这些实施例仅用于示例性地说明本发明,本发明的范围并不限制于这些实施例。
实施例1:根据二甲双胍以及Chir99021的复合腹腔内给药的放射线诱导肺纤维化抑制试验
通过用4mm、强度为90Gy的放射线照射小鼠的胸部来诱导由放射线引起的肺纤维化。自放射线照射日起,共6次,每次腹腔内给药或未给药。在药物给药的情况下,向实验动物给药二甲双胍(Met)(35mg/kg)、Chir99021(CHIR)(30mg/kg)、Met+CHIR(35mg/kg+30mg/kg)或对照组(Vehicle)(未给药)。用于药物给药的溶剂的组成中二甲双胍为PBS条件,对于Chir99021使用5%的DMSO以及30%的PEG的组成。
在照射放射线后的第14天牺牲实验动物并进行尸检来具体确认肺纤维化是否缓解。上述实验过程的示意图如图1所示。
通过苏木精-伊红染色法(H&E染色)来确认在放射线诱导肺纤维化小鼠模型中的组织损伤部位的炎症反应以及纤维化。用10%的福尔马林固定肺组织后,制备石蜡切片并进行苏木精(hematoxylin)-伊红(eosin)染色。具体地,首先,将切薄的小鼠组织与二甲苯(Xylene)反应3次,每次5分钟,并与100%的乙醇反应两次后,分别与95%、70%、50%的乙醇溶液反应3分钟,在与50%的乙醇反应的过程结束后,用流动的水清洗10分钟。与苏木精溶液反应2分钟来对细胞核进行染色后用流动的水清洗10分钟,以作为去除渗透到组织内的石蜡的过程。之后,与伊红溶液反应30秒钟来对细胞质进行染色,并分别与50%、70%、95%、100%的乙醇反应1分钟,最后,与二甲苯溶液反应后,加一滴封片液后盖上盖玻片并在显微镜下进行观察。
并且,以下述条件为标准通过三色染色法来测定活体组织的纤维化等级。
如果进行苏木精(hematoxylin)-伊红(eosin)染色,则可以观察到细胞核呈蓝色,细胞质呈粉红色。
上述各自的分析结果如图2以及图3所示。
如图2所示,通过苏木精-伊红染色可以知道在照射放射线后未给药组(Vehicle)中出现组织的损伤。相反,Met+CHIR的处理显著改善组织损伤程度,这比分别单独的二甲双胍、Chir99021表现更优异的效果。
并且,如图3所示,从统计学上确认纤维化程度及胶原蛋白沉积程度的结果,考虑到纤维化程度的等级及胶原蛋白沉积程度,通过根据其组合的协同效应,Met+CHIR的处理显著改善肺的纤维化。
实施例2:根据二甲双胍以及Chir99021的复合口服给药的放射线诱导肺纤维化的抑制试验
通过用4mm、强度为90Gy的放射线照射小鼠的胸部来诱导由放射线引起的肺纤维化。自放射线照射日起,共6次,每次口服给药或未给药。在药物给药的情况下,向实验动物给药二甲双胍(Met)(65mg/kg)、Chir99021(CHIR)(30mg/kg)、Met+CHIR(65mg/kg+30mg/kg)或对照组(Vehicle)(未给药)。用于药物给药的溶剂的组成中二甲双胍为PBS条件,对于Chir99021使用5%的DMSO以及30%的PEG的组成。
在照射放射线后的第14天牺牲实验动物并进行尸检来具体确认肺纤维化是否缓解。上述实验过程的示意图如图4所示。
通过苏木精-伊红染色法(H&E染色)来确认在放射线诱导肺纤维化小鼠模型中的组织损伤部位的炎症反应以及纤维化。用10%的福尔马林固定肺组织后,制备石蜡切片并进行苏木精(hematoxylin)-伊红(eosin)染色。具体地,首先,将切薄的小鼠组织与二甲苯(Xylene)反应3次,每次5分钟,以作为去除渗透到组织内的石蜡的过程,并与100%的乙醇反应两次后,分别与95%、70%、50%的乙醇溶液反应3分钟,在与50%的乙醇反应的过程结束后,用流动的水清洗10分钟。与苏木精溶液反应2分钟来对细胞核进行染色后用流动的水清洗10分钟。之后,与伊红溶液反应30秒钟来对细胞质进行染色,并分别与50%、70%、95%、100%的乙醇反应1分钟,最后,与二甲苯溶液反应后,加一滴封片液后盖上盖玻片并在显微镜下进行观察。
并且,通过三色染色法来测定活体组织的纤维化等级。
如果进行苏木精(hematoxylin)-伊红(eosin)染色,则可以观察到细胞核呈蓝色,细胞质呈粉红色。
上述各自的分析结果如图5以及图6所示。
如图5所示,通过苏木精-伊红染色可以知道在照射放射线后未给药组(Vehicle)中出现组织的损伤。相反,Met+CHIR的处理显著改善组织损伤程度,这比分别单独的二甲双胍、Chir99021表现更优异的效果。
并且,如图6所示,从统计学上确认纤维化程度及胶原蛋白沉积程度的结果,考虑到纤维化程度的等级及胶原蛋白沉积程度,通过根据其组合的协同效应,Met+CHIR的处理显著改善肺的纤维化。
实施例3:根据二甲双胍以及Chir99021的复合给药的非酒精性肝纤维化的抑制试验
通过每周2次向小鼠的肝腹腔内注射CCl4(1.5%CCl4:1mg/kg)来诱导非酒精性肝纤维化。从给药CCl4的4.5周后开始给药二甲双胍(Met)以及Chir99021(CHIR)(65mg/kg+30mg/kg)或对照组(vehicle)(未给药),6.5周后观察肝组织的损伤及纤维化。对此的示意图如图7所示。
与上述实施例1类似地,通过苏木精-伊红染色法以及三色染色法来确认在非酒精性肝纤维化小鼠模型中的组织损伤部位的炎症反应以及纤维化。用10%的福尔马林固定肝组织后制备石蜡切片来进行苏木精(hematoxylin)-伊红(eosin)染色以及三色染色。如果进行苏木精(hematoxylin)-伊红(eosin)染色,则可以观察到细胞核呈蓝色,细胞质呈粉色,通过三色染色可以观察到蓝色的胶原蛋白沉积。
在三色染色的情况下,将小鼠组织用10%的福尔马林(Formalin)固定5天并制备石蜡块。为了去除组织内的石蜡,与二甲苯(xylene)反应3次,每次5分钟,并分别与100%、95%、75%、50%的乙醇溶液反应3分钟,并在最后的反应结束后用流动的水清洗10分钟。首先,在60℃的水浴中与波恩氏溶液(Bouin's Solution)反应1小时。反应结束后,用流动的水清洗10分钟,并以1:1的比例混合魏格特氏苏木精(Weigert's hematoxylin)A与B后反应10分钟,并用流动的水清洗10分钟。之后,与红色染剂(Red staining)反应3分钟,并用三次蒸馏水冲洗一次,与磷光性/磷钼酸(Phosphotunstic/phosphomolydic acid)反应20分钟,与苯胺蓝(aniline blue)反应30分钟后用三次蒸馏水冲洗3次,并依次与1%的醋酸反应1分钟。最后,经过脱水过程并用二甲苯溶液收尾后,加一滴封片液后盖上盖玻片并在显微镜下进行观察。
其结果如图8以及图9所示。
如图8所示,通过苏木精-伊红染色以及三色染色可以知道在照射放射线后的未给药组(Vehicle)中出现组织的损伤及胶原蛋白沉积。
相反,二甲双胍(Met)以及Chir99021(CHIR)的给药显著改善这种组织损伤以及胶原蛋白沉积。
尤其,如图9所示,二甲双胍(Met)以及Chir99021(CHIR)的给药显著改善胶原蛋白沉积。进一步地,二甲双胍(Met)以及Chir99021(CHIR)的复合给药通过协同效果显著抑制组织的损伤及胶原蛋白沉积来显著改善肝组织的纤维化。
综合上述结果,可以知道二甲双胍以及Chir99021的复合给药在纤维化中抑制胶原蛋白沉积、抑制炎症反应、防止血管的纤维化、防止组织损伤,因而对纤维化具有优异的效果。尤其,这两种化合物的组合通过协同效应显著改善纤维化的症状,并且无论给药途径如何均表现出优异的协同效应。
并且,通过动物实验确认到二甲双胍以及Chir99021的给药在体内具有抑制放射性肺纤维化、非酒精性肝纤维化等优异的预防以及治疗纤维化的效果。
因此,二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐可以非常有用地用作预防或治疗纤维化的用途。
通过以上的说明,本发明所属的技术领域的技术人员应理解,本发明可以在不改变其技术思想或必要特征的情况下以其他具体形式实施。与此相关,应理解以上描述的实施例在所有方面都是示例性的而不是限制性的。本发明的范围应被解释为所述的发明要求保护范围的含义及范围以及从其等同概念中导出的所有修饰或变形都包含在本发明的范围,而不是上述详细说明。
Claims (12)
1.一种用于预防或治疗纤维化的药物组合物,其特征在于,包含二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐作为有效成分。
2.根据权利要求1所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述纤维化发病于选自由肺、肾、肝、心脏、脑、血管、关节、肠、皮肤、软组织、骨髓、阴茎、腹膜、肌肉、脊柱、睾丸、卵巢、乳房、甲状腺、鼓膜、胰腺、胆囊、膀胱以及前列腺组成的组中的一种以上。
3.根据权利要求1所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述纤维化为放射性肺纤维化。
4.根据权利要求1所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述纤维化为特发性肺纤维化。
5.根据权利要求1所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述纤维化为肝纤维化。
6.根据权利要求3所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述放射性肺纤维化伴随由放射线暴露引起的血管损伤、组织炎症或组织纤维化。
7.根据权利要求5所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述肝纤维化为非酒精性肝纤维化。
8.根据权利要求1所述的用于预防或治疗纤维化的药物组合物,其特征在于,上述用于预防或治疗纤维化的药物组合物配制为口服给药制剂或注射剂。
9.一种用于预防或改善纤维化的食品组合物,其特征在于,包含二甲双胍或其食品学上可接受的盐以及Chir99021或其食品学上可接受的盐作为有效成分。
10.一种二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐在制备用于治疗纤维化的药剂中的用途。
11.一种预防或治疗纤维化的方法,其特征在于,包括向有需要的对象给药药学上有效剂量的二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐的步骤。
12.一种用于治疗纤维化的组合物,其特征在于,包含二甲双胍或其药学上可接受的盐以及Chir99021或其药学上可接受的盐作为有效成分。
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