CN102421430A - 用于治疗或预防烧伤的药物组合物 - Google Patents
用于治疗或预防烧伤的药物组合物 Download PDFInfo
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- CN102421430A CN102421430A CN2010800211093A CN201080021109A CN102421430A CN 102421430 A CN102421430 A CN 102421430A CN 2010800211093 A CN2010800211093 A CN 2010800211093A CN 201080021109 A CN201080021109 A CN 201080021109A CN 102421430 A CN102421430 A CN 102421430A
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- tetrafluoro
- amino
- benzoic acid
- burn
- trifluoromethyl benzyl
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Abstract
本发明涉及用于治疗或预防烧伤的药物组合物,其中所述组合物包含以特定化学式代表的化合物或其可药用盐或溶剂化物作为活性成分。因此,本发明提供用于治疗或预防烧伤的药物组合物,其中所述组合物包含上述化合物或其可药用盐或溶剂化物作为活性成分,还提供了用于治疗烧伤的方法,其包括对需要治疗烧伤的实体施用上述化合物或其可药用盐或溶剂化物。
Description
技术领域
本发明涉及药物组合物及其用于在有此需要的患者或受试者中治疗或预防烧伤的使用方法。
背景技术
烧伤主要是由事故引起的,可根据原因分为热烧伤、电流烧伤、化学烧伤和辐射烧伤。
根据烧伤面积、烧伤深度、导致烧伤的物体的温度及与之接触的时间,以及皮肤的状况,烧伤的严重程度可分为一度、二度、三度和四度烧伤。二度或更高度烧伤可能会留下疤痕并需要住院治疗。
一度烧伤使皮肤变红,并伴有刺痛。另外,皮肤层的最外层(表皮)受损并常常肿胀,伴随疼痛和红斑。
所述症状在几天内消失,但会原位残留轻微脱皮和色素沉着。恢复后,不会留下疤痕。日光灼伤是最常见的一度烧伤实例。
二度烧伤影响表皮和真皮,并能在事发后24小时内导致发红、疼痛、肿胀和水疱。另外,这种烧伤还影响汗腺和毛孔。主观上,能够感觉到剧烈的灼热感或疼痛。如果水疱破裂,皮肤的受损区域将暴露,大量液体流出。在烧伤面积超过身体表面积约15%的情况下,需要特别注意。伤口在几周内愈合,但许多情况下会原位残留色素沉着或色素脱失。如果发生继发感染,则局部症状将更为严重并持续很长时间。
三级烧伤影响表皮、真皮和皮下组织,使得皮肤呈黑色或半透明白色,并导致皮肤表面下血液凝结。这些烧伤区域可能是无知觉的,但患者可感觉到剧烈疼痛,皮肤组织和结构的坏死需要大量时间来治疗,之后会留下疤痕。事发后2周内,痂脱落,出现溃疡面。产生大量分泌液,且易出血,但是通过表皮再生进行的新组织形成逐渐使烧伤区域愈合,留下疤痕。如果皮肤坏死很深或发生继发感染,则愈合过程会推迟且疤痕表面变得不规则,常常导致产生瘢痕疙瘩并遗留形变或运动障碍。如果烧伤面积约为身体表面积的10%,则要特别注意。
四度烧伤的情况是烧伤组织碳化并变黑,位于皮肤层下的脂肪层、韧带、筋膜、肌肉或骨骼也遭受烧伤。四度烧伤发生于高压电伤害的情况,有时也发生于深二度和三度烧伤中真菌感染的情况。如果烧伤范围超过身体表面积的20%,身体可能引起生理反应,可能发生由于体液流失过多而导致的低血压、休克、急性肾衰竭,随后可能会发生伤口感染、肺炎、败血症或多器官功能障碍症状。
对烧伤的治疗而言,重要的是尽可能快地使早期烧伤创口愈合或减少烧伤面积。在初期烧伤创口敷料中,初期处理着重于防止转变成深度烧伤,这通过以下手段实现:控制感染和炎症、维持湿润环境,以帮助皮肤再生的生长因子或细胞因子进行处理、局部使用肝素等。
如果开发出治疗或预防烧伤的有效治疗化合物,将大大有助于治疗烧伤患者,改善状态,并视烧伤的严重程度而减少疤痕。
发明内容
技术问题
据此,本发明的目的是提供可用于治疗或预防烧伤的药物组合物和使用该组合物的医疗方法。
技术方案
为解决该技术问题,本发明提供了用于治疗或预防烧伤的药物组合物,其包含如下化学式1所示的四氟苄基衍生物或其可药用盐或溶剂化物作为有效成分:
其中,
R1、R2和R3独立地为氢或卤素;
R4为羟基、烷基、烷氧基、卤素、卤素取代的烷氧基、烷酰基氧基(alkanoyloxy)或硝基;
R5为羧酸、带有烷基的羧酸酯、羧酰胺、磺酸、卤素或硝基。
本发明提供了用于治疗或预防烧伤的药物组合物或医疗方法,其包含化学式1所示的四氟苄基衍生物或其可药用盐或溶剂化物。
优选地,在化学式1中,烷基为C1-C5烷基,更优选地为C1-C3烷基。更特别地,优选的烷基包括但不限于:甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基。烷氧基优选地为C1-C5烷氧基,更优选地为C1-C3烷氧基。更特别地,优选的烷氧基包括但不限于:甲氧基、乙氧基和丙氧基。卤素包括但不限于氟、氯、溴和碘。优选地,烷酰基为C2-C10烷酰基,更优选地为C2-C5烷酰基。更特别地,优选的烷酰基包括但不限于:乙酰基、丙酰基和环己基甲酰基(cyclohexanecarbonyl)。优选地,烷酰基氧基为C1-C4烷酰基氧基。
上述化学式1所示四氟苄基衍生物的优选实例包括但不限于如下:
2-羟基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸(下文称为“2-羟基-TTBA”),
2-硝基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-氯-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-溴-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-羟基-5-(2,3,5,6-四氟-4-甲基苄氨基)-苯甲酸,
2-甲基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-甲氧基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-2-三氟甲氧基苯甲酸。
本发明中,烧伤通常指皮肤细胞由于热而损伤或导致坏死的现象。烧伤的实例包括但不限于:火造成的火焰烧伤,热的液体(水、油等)造成的烫伤,与热的物体(如电熨斗、电饭煲等)接触造成的接触灼伤,强酸、强碱造成的化学灼伤,强紫外光造成的晒伤,暴露于放射物和X-射线造成的辐射烧伤。此外,本发明中的烧伤可以是一度、二度、三度和四度烧伤。
上述化学式1所示四氟苄基衍生物或其可药用盐或溶剂化物可用于治疗或预防烧伤,但不限于特定类型或程度(严重性)的烧伤。
本发明的四氟苄基衍生物或其可药用盐可以但不限于通过US6,927,303公开的反应方案来制备。
本发明的某些化合物能够以其可药用盐形式施用。本发明中的术语“可药用盐”意为由无毒或近乎无毒的碱所产生的盐。在本发明化合物为酸性的情况下,本发明化合物的碱加成盐可通过将该化合物的中性形式与足量的目的碱和适当的惰性溶剂进行反应来制备。可药用碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铵盐、镁盐或由有机胺形成的盐。在本发明化合物为碱性的情况下,本发明化合物的酸加成盐可通过将该化合物的中性形式与足量的目的酸和适当的惰性溶剂进行反应来制备。可药用酸加成盐包括但不限于:丙酸、异丁酸、草酸、苹果酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、扁桃酸、酞酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、盐酸、溴酸、硝酸、碳酸、一氢碳酸(monohydrogencarbonic acid)、磷酸、一氢磷酸(monohydrogen-phosphoric acid)、二氢磷酸(dihydrogen-phosphoticacid)、硫酸、一氢硫酸(monohydrogen-sulfuric acid)、碘化氢和亚磷酸。此外,本发明的可药用盐包括但不限于氨基酸(如精氨酸)的盐以及有机酸类似物(如葡萄糖醛酸或半乳糖醛酸)的盐。
一些本发明化合物可以是水化物形式,并可以溶剂化或非溶剂化的形式存在。一部分本发明化合物以结晶形式或无定形形式存在,任何物理形态均包括在本发明范围内。此外,一些本发明化合物可包含一个或多个不对称碳原子或双键,并因此存在两种或更多种立体异构形式如外消旋物、对映异构体、非对映异构体、几何异构体等。本发明包括本发明化合物的这些单个立体异构体。
本发明还提供药物组合物,其包含上述化合物或其可药用盐或溶剂化物以及可药用赋形剂或添加剂。上述化学式1所示本发明四氟苄基衍生物或其可药用盐/溶剂化物可以单独施用或与任何便利的载体、稀释剂等一起施用,所施用的制剂可以是单剂量单位或多剂量单位。
本发明的药物组合物可以固体或液体形式制备。固体制剂包括但不限于:粉剂、颗粒剂、片剂、胶囊剂、栓剂等。另外,固体制剂还可包含稀释剂、调味剂、粘合剂、防腐剂、崩解剂、润滑剂、填充剂等,但不仅限于此。液体制剂包括但不限于溶液剂(如水溶液和丙二醇溶液)、混悬剂、乳剂等,并可通过加入适当添加剂如着色剂、调味剂、稳定剂、增稠剂等来制备。
例如,粉剂可通过简单地将本发明的四氟苄基衍生物与可药用赋形剂如乳糖、淀粉、微晶纤维素等混合来制备。颗粒剂可如下制备:将四氟苄基衍生物或其可药用盐与可药用稀释剂、可药用粘合剂(如聚乙烯吡咯烷酮、羟丙基纤维素等)混合;然后用适当的溶剂如水、乙醇、异丙醇等进行湿法造粒,或是用压片机直接压制。此外,片剂可通过将颗粒与可药用润滑剂如硬脂酸镁混合并利用制片机将混合物压片来制备。
本发明的药物组合物可以以下形式施用:经口制剂、注射剂(例如肌肉注射、腹膜内注射、静脉注射、输注、皮下注射、植入)、吸入、经鼻、经***、经直肠、经舌下、经皮、局部等,但不仅限于此,这取决于要治疗的病症和患者的状况。本发明的组合物可以制备成适当的剂量单位,其根据给药途径而包含本领域常用的可药用且无毒的载体、添加剂和/或载剂。能够在期望的时间内持续释放药物的贮库(depot)类型制剂也包括在本发明范围内。
本发明还提供了使用四氟苄基衍生物或其可药用盐或溶剂化物来治疗和/或预防烧伤的方法,包括以治疗有效量向需要治疗或预防烧伤的受试者进行给药。
就烧伤的治疗而言,本发明化合物或其可药用盐或溶剂化物可以约0.1mg/kg至约1000mg/kg(优选约2.5mg/kg至约500mg/kg)的剂量每天施用。不过,剂量可因患者情况(年龄、性别、体重等)、需要治疗患者的严重程度、使用的有效化合物等而异。本发明化合物可以一天一次给药,或者必要时以拆分剂量一天数次给药。
有益效果
本发明提供用于治疗或预防烧伤的药物组合物,其包含化学式1所示的化合物或其可药用盐或溶剂化物作为活性成分。本发明还提供化学式1所示化合物或其可药用盐或溶剂化物用于治疗或预防烧伤的用途。本发明还提供治疗烧伤的方法,包括对需要治疗或预防烧伤的个体施用治疗有效量的化学式1所示化合物或其可药用盐或溶剂化物。
附图说明
图1利用血液化学测试(即通过减少血清中的乳酸脱氢酶)的结果来显示2-羟基-TTBA对热烧伤的保护效应。
图2是显示热烧伤7天后皮肤形态学观察结果的照片。本图显示了2-羟基-TTBA对烧伤的治疗效果。
图3是显示各个实验组上皮细胞用苏木精-伊红染色后的可比较状态的照片。
图4是显示10倍放大显微镜下以苏木精-伊红染色的烧伤7天后淤滞区(zone of stasis,组织损伤区)全层(full-thickness)皮肤状态的照片。
图5是显示10倍放大显微镜下以甲酚紫染色的淤滞区(组织损伤区)全层皮肤组织活细胞状态的图像。
图6是显示通过Masson三色染色的淤滞区(组织损伤区)全层皮肤组织的胶原蛋白和肌纤维状态的图像。
发明模式
下文中,用大量细节描述本发明以帮助本领域技术人员了解本发明。然而,本发明的多个实例可转变为其他形式,对本发明范围的理解不应当局限于如下实例。提供本发明的实例以对本领域技术人员进行更全面的解释。
<实施例1>对接触烧伤的治疗效果
为证实2-羟基-TTBA对烧伤的治疗效果,用沸水(保持在100℃)预热3分钟的铜梳在大鼠的背上(皮肤两侧)进行接触烧伤诱导30秒。5分钟后,在5分钟中静脉施用10mg/5ml/kg的2-羟基-TTBA。此后,持续7天每天以相同条件注射2次(间隔为10~12小时)。向载体处理组以同样的方式施用相同量的不含化合物的盐水。烧伤实验分组与下表1相同。
【表1】
N/A:不适用
分析结果时,用于比较的正常组的动物数量、各个组的动物数量以及烧伤7天后死亡的动物数量在上述表1中展示。烧伤对照组中两只大鼠分别在烧伤后第5天和第7天死亡,但其他实验组的所有动物均存活。
通过血液化学来测定血清中的乳酸脱氢酶
乳酸脱氢酶(LDH)是几乎分布于所有组织中的一种酶,催化丙酮酸和乳酸之间的可逆反应。
已知当组织和细胞受损时,血清LDH水平升高。因此,除了可能干扰测试结果的溶血样品外,对来自于各个组的血清样品检测LDH的量。结果见图1。
如图1所示,与正常组相比,烧伤对照组的LDH水平升高为约2倍,而与烧伤对照组相比,2-羟基-TTBA处理组的LDH值显著降低。
对烧伤后背部皮肤外观的观察
图2是烧伤7天后观察到的皮肤照片。用有4个10×20mm大小的矩形的经预热铜梳在实验大鼠背部两侧诱导全层皮肤烧伤。诱导2小时后,在背部两侧出现了4个浅色或微暗的凝固区(或组织坏死区)和3个淤滞区(或组织损伤区)。凝固区(或组织坏死区)是不可逆损伤的小区,不可能随时间而恢复;而淤滞区(或组织损伤区)是这样的区域,其在无特殊处理时在24~28小时内继续发生细胞坏死,由于持续的纤维蛋白沉积、血管收缩、血栓形成等引起的局部缺血而导致细胞死亡。
因此,为评估该实验的效力,在淤滞区中,除了朝向头部接近药物防护背心的区域以外,对单个小鼠上出现的6个区域中其余的4个区域(以虚线矩形区表示)进行了分析。
如图2所示,在不采取任何行动的烧伤对照组中可观察到淤滞区中的硬皮形成、转变成创口、创口分离或皮肤丧失。
载体和2-羟基-TTBA处理组中很少发生焦痂形成(如结疤)。特别地,2-羟基-TTBA处理组的皮肤恢复到很好的状态,以致于肉眼可观察到毛发生长。
烧伤后焦痂形成和创口表皮形成的组织学外观
图3是根据分组通过对组织进行苏木精-伊红染色来比较上皮层状态的结果。如图3中所示,与观察到正常上皮层(用箭头表示的部分)以及健康毛囊的正常对照组不同,在烧伤对照组中,由于焦痂的形成,除了炎性细胞外并未观察到正常上皮细胞。发现载体处理组和2-羟基-TTBA处理组中有创口表皮正在形成。在一些情况下也可观察到表皮增生比正常表皮层更厚。
通过分析每个组共计28个组织区域(每组7只大鼠,每只大鼠4个淤滞区)来测定焦痂的形成和创口表皮形成率。结果,烧伤对照组中发生的约为93%的创伤转换率在载体处理组和2-羟基-TTBA处理组中分别降至约18%和4%。并且,创口表皮形成率相对于烧伤对照组分别增加了约32%和71%。结果显示如下表2(组织外观:焦痂的形成和创口表皮形成率)。
【表2】
组别 | 烧伤对照组 | 载体处理组 | 2-羟基-TTBA处理组 |
焦痂形成(%) | 92.857 | 17.857 | 3.571 |
创口表皮形成(%) | 10.714 | 32.143 | 71.429 |
苏木精-伊红染色的全层皮肤组织学
图4是通过10倍放大显微镜以苏木精-伊红染色来观察全层皮肤组织状态的照片。
其显示,在烧伤对照组中贯穿全层皮肤的上皮、真皮、皮下组织和肌肉层均受损。观察到形成了焦痂,其下的炎性细胞浸润,并且皮下组织和肌肉层之间有大量炎性细胞。载体处理组中,没有形成焦痂(如结疤),但观察到遍及皮肤组织和皮下组织的相当大量炎性细胞,在再生上皮组织下也显示许多炎性细胞的浸润。在2-羟基-TTBA处理组中,除了肌细胞和皮下组织区域以外,炎性细胞的浸润被相当程度地抑制,并且不仅出现了创口上皮形成,甚至还在毛囊、皮脂腺和肌肉层中也有保护作用。
甲酚紫染色的全层皮肤组织学
图5是通过10倍放大显微镜以甲酚紫染色来观察淤滞区中活细胞的照片。在烧伤对照组和载体处理组中,极少观察到毛囊,可观察到遍及全层皮肤的大量炎性细胞。另一方面,在2-羟基-TTBA处理组中观察到活的毛囊和上皮,以及相对少的炎性细胞。
Masson三色染色的全层皮肤组织学
图6是通过Masson三色染色来观察淤滞区中的皮肤组织胶原蛋白和肌纤维的照片。在正常组中,染成蓝色的胶原均匀分布在整个真皮层,肌纤维被染成红色。在烧伤对照组中,胶原蛋白不规则地沉积在焦痂下,染色水平弱于正常组。几乎所有的肌纤维均受损,且未被染色。在载体处理组中,观察到的胶原的量相对于其他组最为丰富,即便与正常对照组相比也达到非常高的水平。此外,受损的肌纤维未被染色,并伴随显著量的出血和炎性细胞浸润。不过,与正常组类似,在2-羟基-TTBA处理组中表皮、真皮、皮下脂肪和肌肉层排列良好,显示在活毛囊周围均匀分布的胶原和染成红色的肌纤维。
Claims (6)
2.权利要求1的药物组合物,其中所述四氟苄基衍生物选自以下任何一个:
2-羟基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-硝基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-氯-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-溴-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-羟基-5-(2,3,5,6-四氟-4-甲基苄氨基)-苯甲酸,
2-甲基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-甲氧基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-2-三氟甲氧基苯甲酸。
3.权利要求2的药物组合物,其中所述四氟苄基衍生物为2-羟基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)苯甲酸。
5.权利要求4的药物组合物,其中所述四氟苄基衍生物选自以下的任何一个:
2-羟基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-硝基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-氯-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-溴-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-羟基-5-(2,3,5,6-四氟-4-甲基苄氨基)-苯甲酸,
2-甲基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
2-甲氧基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-苯甲酸,
5-(2,3,5,6-四氟-4-三氟甲基苄氨基)-2-三氟甲氧基苯甲酸。
6.权利要求5的方法,其中所述四氟苄基衍生物为2-羟基-5-(2,3,5,6-四氟-4-三氟甲基苄氨基)苯甲酸。
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