CN104320971A - 用于预防和治疗创伤的组合物和方法 - Google Patents
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- CN104320971A CN104320971A CN201180015602.9A CN201180015602A CN104320971A CN 104320971 A CN104320971 A CN 104320971A CN 201180015602 A CN201180015602 A CN 201180015602A CN 104320971 A CN104320971 A CN 104320971A
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Abstract
本发明提供了组合物和方法,其用于促进创伤造成的损伤组织的快速治愈和/或再生,该方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括(E)-羧基苯乙烯基-4-氯苄基砜的化合物、或其官能化衍生物;和药学上可接受的赋形剂。
Description
本申请要求2010年3月24日提交的,申请号为61/316,932的美国临时申请的优先权,其内容以全文引入并入本文中。
技术领域
一般地,本发明涉及通过施用药物组合物,以治疗和/或预防恒温(warm-blooded)动物,例如哺乳动物尤其是人类的皮肤创伤,从而获得有益的效果。
发明背景
α,β-不饱和芳基砜化合物为小分子激酶调节化合物,其被研究用于改变接受放射治疗的癌细胞的细胞周期的分布格局,且已经确定α,β-不饱和芳基砜化合物是辐射保护研究的潜在候补物质。这些化合物在美国专利6,656,973和6,667,346中公开了,特别地,这两篇专利通过引入它们的全文并入本文中。
先前,在PCT申请WO 2007/016201和PCT申请WO 2008/105808公开了一些α,β-不饱和芳基砜化合物,以及关于悬浮液和/或这些化合物的含水组合物的具体制剂,特别地,其内容通过引入它们的全文并入本文中。
对动物来说,已经证实了α,β-不饱和芳基砜,尤其是,α,β不饱和苄基苯乙烯基砜,可以有效地以及选择性全身保护了在辐射致损伤中的正常细胞。还证明了α,β-不饱和芳基砜化合物显示出保护DNA、骨髓、干细胞、肠胃的陷窝细胞和改善由于辐射引起的血球减少。这类化合物还显示了抗增殖活性和在杀死增殖细胞例如肿瘤细胞,而不是正常细胞的选择性。
α,β-不饱和芳基砜化合物可提供辐射防护,该辐射防护通过调节促凋亡蛋白质例如p53以及p53下游调节物p21、Bax、c-Abl和p73的水平来实现,表明这些化合物能够将细胞从电离辐射所诱导且依赖于p53的细胞凋亡中解救出来。请见anchita P.Ghosh等人于2009年发表的Radiation Protection by a New Chemical Entity,Ex-Rad:Efficacy andMechanisms,Radiation Research 171,000–000(2009)的文章。
虽然以前公开了细胞凋亡的许多生理过程,皮肤创伤愈合是一个只在最近才被研究的领域。细胞凋亡对正常创伤治愈是至关重要的,特别地在炎症细胞和疤痕形成的消除上。因为在组织重组过程中,细胞群快速地增殖,细胞增长由细胞凋亡来平衡。例如,为了开始下阶段的创伤治愈,炎症细胞必须被消除。否则,持久的炎症能导致无法治愈的创伤。相似地,肉芽组织在细胞结构中必须减小,以逐步形成疤痕。最近的研究阐明了在创伤治愈过程中细胞凋亡的一些关键作用。
先前,Michelle Olive等人在“p21modulats arterial wound repair”,J Clin Invest.;118(6):2050-2061 2008,中证实了,促凋亡蛋白质P21在调整和修复创伤上的作用。它证明了p21为血管增殖的关键调节物,该血管增殖是由于伤害造成的,以及p21调整动脉创伤修护,且它的活性在局部血管细胞的动脉损伤后,对于细胞增殖和炎症的调节是必要的。
美国专利号6,484,210公开了α,β-不饱和芳基砜化合物,其证明了该化合物通过绑定靶受体络氨酸激酶,例如丝裂原活化蛋白激酶(MAPK),具有细胞凋亡和抗癌化疗活性,引起调节激酶级联(例如,Ras/Raf/MEK/ERK激酶级联)。最好的理解MAPK路径涉及细胞外信号调节激酶,其构成了Ras/Raf/MEK/ERK激酶级联(Boudewijin等,Trends Biochem.Sci.20,18(1995))。一旦这信号路径由不同的刺激物激活,MAPK使包括若干转录因子的各种蛋白质磷酸化,该转录因子移位至细胞核中并激活基因转录。此路径的负调节可阻止这些事件的级联。
Masayuki Towatari等在The Journal of Biological Chemistry,270,4101-4107(1995),中表明MAPK在造血祖细胞的增殖和控制上起着决定性的作用。Rama K.Jaiswal等在TheAmerican Society for Biochemistry and Molecular Biology,Inc.Vol.275,No.13,pp.9645–9652(2000)中还表明MAPK与成体干细胞的成骨分化的激活有关,并表明由丝裂原活化蛋白激酶的族成员的激活或抑制来支配细胞成为成骨系或脂肪系。
包括造血干细胞在内的干细胞,在机体中的若干不同过程中起着非常重要的作用。例如,白细胞造血细胞对于维持机体对疾病的防御是很重要的;单核细胞、巨噬细胞和淋巴球涉及增强机体对感染和肿瘤的反应,而粒细胞涉及克服感染、寄生虫和肿瘤。血小板、另一种造血细胞,通过启动血栓的形成,产生了止血机理中重要的元素,该止血机理通过相互粘结或者与损坏的表面粘结,以及释放促进纤维蛋白凝块形成的因素来实现。红血球主要涉及氧气的传输。
干细胞和/或祖细胞的补充在与炎症和创伤治愈相关的各种应用中很重要。血管生成(vasculogenesis)涉及源于内皮祖细胞的血管的生长,这是这种过程的例子。血管生成、以及血管新生(angiogenesis),其过程中新血管由现存的毛细血管形成,且调节这些过程的因素,在炎症和创伤治愈中很重要,还有助于病理情况例如肿瘤生长、糖尿病视网膜病变、风湿性关节炎、和慢性炎症疾病(参见,例如,美国专利号5,318,957;Yancopoulos等.Cell 93:661-4(1998);Folkman等.Cell 87;1153-5(1996);and Hanahan等.Cell 86:353-64(1996))。
血管新生和血管生成都涉及内皮细胞的增殖。内皮细胞排列为血管的壁;毛细血管包括几乎全部的内皮细胞。生成血管的过程不仅涉及增加内皮细胞增殖,还包括级联附加事件,该级联附加事件包括内皮细胞的蛋白酶分泌、基膜的降解、通过环境基质的迁移、增殖、队列、分化为管状结构、和新基膜的合成。血管生成涉及间叶细胞补充和分化为成血管细胞,然后其分化为内皮细胞,然后形成新血管(de novo vessels)(例如,参见,Folkman等.Cell 87:1153-5,(1996))
人们对于病患耐受良好的治疗方案有强烈的兴趣,但其在影响干细胞的刺激和/或补充祖细胞以治疗炎症且影响创伤治愈方面具有高效力。本发明的方法和组合物满足这些和其它长期需要满足的需求。
发明内容
本发明公开并提供了一种用于促进创伤造成的损伤的组织的快速治愈和/或再生的方法和组合物,所述方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括(E)-羧基苯乙烯基-4-氯苄基砜化合物,或其官能化衍生物;和药学上可接受的赋形剂,其中该药物组合物促进损伤的组织的快速治愈和/或再生,同时保留组织的原组成且最大限度地减少并发症和疤痕。
在一实施方式中,在创伤发生之前、创伤的形成或发生的同时、或创伤形成之后、或他们的组合,向病患施用药。在一优选实施方式中,在创伤发生之前,向病患施用药。
在另一实施方式中,在创伤发生前4小时,和/或在创伤发生前约24小时,向病患施用药。
在一实施方式中,本发明的组合物包括(E)-4-羧基苯乙烯基-4-氯苄基砜的化合物,例如,ON 01210.Na。在另一实施方式中,ON 01210.Na以水性溶液组合物形成,该组合物包括在约20mg/ml至约100mg/ml之间的ON O121O.Na,和助溶剂,该助溶剂包括水溶聚合物,以此为例但不限于,聚乙二醇(PEG)、聚丙二醇、聚甘油、DMA、丙二醇、丙三醇、乙醇、山梨糖醇、和异丙醇、或他们的组合,所述助溶剂的含量在约25%和约90%w/v之间,其中所述组合物的pH值在约7.0至约9.5的范围内。
组合物通过多种途径施用,以此为例但不限于,包括非口服途径、局部途径、口服途径、或他们的组合。
在另一方面,本发明提供了一种通过减少与创伤或损伤组织相关的炎症的严重度,来控制或减轻疼痛的方法,该方法包括向病患施用其所需的治疗有效量的药物组合物,该药物组合物包括(E)-羧基苯乙烯基-4-氯苄基砜化合物、或其官能化衍生物;其中与对照组未治疗过的病患相比,用组合物治疗的病患证实了,,加速的治愈过程。
在一实施方式中,当创伤发生三天后测量时,与对照组未治疗过的病患相比,用所述组合物治疗的病患的所述治愈过程至少快4倍。
在另一方面,本发明提供了一种方法,该方法减轻或改善与组织破坏或功能紊乱相关的病症的症状,和与哺乳动物的创伤相关的疼痛或症状;该方法包括向病患施用其所需的治疗有效量的药物组合物,该药物组合物包括(E)-4-羧基苯乙烯基-4-氯苄基砜化合物、或其官能化衍生物、该(E)-4-羧基苯乙烯基-4-氯苄基砜化合物或其官能化衍生物与一种或多种抗炎化合物结合;和药学上可接受的载体或稀释剂,其中该药物组合物抑制炎症路径的一种或多种成分,并且减轻了哺乳动物中该症状的严重度。
在一实施方式中,创伤为刀伤、撕裂伤、穿透伤、穿孔伤、穿刺伤、开放伤、或皮下创伤、或他们的结合。
在另一实施方式中,创伤为疾病或病症、手术、事故、或他们的结合的结果。
在又一实施方式中,创伤为外伤、内伤、或他们的结合。
根据本领域中已知的,根据下列的说明书附图和本发明的说明书、以及根据权利要求,本发明的其它优选实施方式对于本领域的普通技术人员是显而易见的。
附图说明
图1图示了用含有ON 01210.Na的组合物预处理的患者的伤口愈合的显著改善。创伤愈合百分数显示患者的三种分类,即,在创伤前24小时用ON 01210.Na预处理的患者、在创伤前4小时用ON 01210.Na预处理的患者、用空白对照剂预处理的患者(阴性对照)。
具体实施方式
定义:
本文所用术语“细胞激素”为由细胞群释放的蛋白质的通用术语,该细胞群如细胞间介质一样作用于另一细胞。这种细胞激素的实施例为肿瘤坏死因子(TNFα或TNFβ);菌落刺激因子(CSFs),例如巨噬细胞集落刺激因子(巨噬细胞-CSF,M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);和粒细胞-CSF(G-CSF);白介素(ILs),例如IL-1、IL-2、IL-8、IL-12或IL-18;和其他多肽因子,包括白血病抑制因子(LIF)和kit配合基(KL)。本文所用的术语细胞激素,包括来自天然源或来自重组细胞培养的蛋白质,且生物活性与天然顺序细胞因子相等。
本文所用的“约”指的是所述数值的10%以上或10%以下的范围内的数值。
本文所用的数值范围包括所有整数数值。本申请试图列举任意具体的范围,所列举的范围还包括列举的范围之间的所有具体的整数数值。例如,在约75%和100%的范围内,包括76%至99%、77%至98%等等的数值,因此实际上并没有列举每个具体的范围。
本文所用的“治疗”一般用于包括所有的临床应用,该临床应用包括创伤和疾病和与创伤相关的疾病的症状的诊断、预防、治疗和改善。
本文所用的“α,β不饱和芳砜”意为含有一个或多个α,β不饱和芳砜基团的化合物,其中芳基可以是取代的或未取代的,且可选择地,连接至α碳和β碳的氢原子可被其他化学基团取代。
本文所用的“取代”意为原子或原子基团取代氢作为连接至环原子的取代基。环系的取代度可为单取代、二取代、三取代、或更高取代。
本文所用的,单独使用的或与其他术语结合使用的“芳基”,除非另作说明,指的是含有一个或多个环(通常为一个环、两个环、或三个环)的碳环芳香体系,其中,这些环可以悬垂方式连接在一起或可为稠环。实施例包括苯基;蒽基(anthracyl);和萘基,尤其是,1-萘基和2-萘基。上述列举的芳基部分为代表性的,非限制性的。应理解术语“芳基”不限于六元环体系。
本文所用的,单独的或作为另一取代基的一部分的“杂芳基(heteroaryl)”,除非另作说明,意为未取代的或取代的、稳定的、单环或多环的杂环的芳香环体系,该体系由碳原子和由一到四个杂原子组成,该杂原子选自由N、O和S组成的群组,且可选择地,其中氮杂原子和硫杂原子可被氧化,且可选择地,该氮原子可季胺化。除非另作说明,该杂环体系可连接至提供稳定结构的任意杂原子或碳原子上。
此种杂芳基的实施例包括苯并咪唑基(benzimidazolyl);尤其是,2-苯并咪唑基;苯并呋喃基,尤其是,3-苯并呋喃基、4-苯并呋喃基、5-苯并呋喃基、6-苯并呋喃基和7-苯并呋喃基(benzofuryl);2-苯并噻唑基(benzothiazolyl)和5-苯并噻唑基(benzothiazolyl);苯并噻吩基(benzothienyl),尤其是,3-苯并噻吩基、4-苯并噻吩基、5-苯并噻吩基、6-苯并噻吩基、和7-苯并噻吩基;4-(2-苄基恶唑基);呋喃基,尤其是,2-呋喃基和3-呋喃基;异喹啉基,尤其是,1-异喹啉基和5-异喹啉基;异恶唑基,尤其是,3-异恶唑基、4-异恶唑基和5-异恶唑基;咪唑基,尤其是,2-、4-和5-咪唑基;吲哚基,尤其是,3-、4-、5-、6-和7-吲哚基;氧氮茂基,尤其是,2-恶唑基、4-恶唑基、和5-恶唑基;嘌呤基;吡咯基,尤其是,2-吡咯基、3-吡咯基;吡唑基,尤其是,3-吡唑基和5-吡唑基;吡嗪基,尤其是,2-吡嗪基;哒嗪基,尤其是,3-和4-哒嗪基;吡啶基,尤其是,2-吡唑基、3-吡唑基和4-吡啶基;嘧啶基,尤其是,2-嘧啶基和4-嘧啶基;喹喔啉基(quinoxalinyl),尤其是,2-喹喔啉基和5-喹喔啉基;喹啉基,尤其是,2-喹啉基和3-喹啉基;5-四唑基(tetrazolyl);2-噻唑基,尤其是,2-噻唑基、4-噻唑基和5-噻唑基;噻吩基,尤其是2-和3-噻吩基;和3-(1,2,4-三唑基)。上述列举的杂芳基部分为代表性的,非限制性的。
本文所用的“苯乙烯基砜”或“苯乙烯基砜化合物”或“苯乙烯基砜治疗剂”指含有一个或多个苯乙烯基砜基团的化合物。
本文所用的“二甲氨基(C2-C6烷氧基)”指(CH3)2N(CH2)nO-,其中n为从2到6。优选地,n为2或3。最优选地,n为2,即为,该基团为二甲胺基乙氧基基团,即为(CH3)2N(CH2)2O-。
本文所用的“膦酸基”指-PO(OH)2基团。
本文所用的“氨磺酰基”指-SO2NH2基团。
本文所用的“卤”或“卤素”包括氟、氯、溴和碘。
本文所用的“磷酸盐”和“膦酸盐”和“膦酸基”(phosphonato)指具有以下结构的部分:
本文所用的“芳基”、“芳香基团”或“芳香环”包括取代的或未取代的单环芳香基团(例如,苯基、吡啶基、吡唑基等),和多环的环体系(萘基、喹啉基等)。该多环的环可有两个或更多环,其中两个邻近的环(该环为“稠环”)共用两个原子,其中至少一个环是芳香族的,例如,其他环可为环烷基、环烯基、芳基、杂环和/或杂芳基。可选择地,该芳基基团可被一个或多个取代基团取代,该取代基团选自卤、烷基、CN、NO2、CO2R、C(O)R、-O-R、-N(R′R″)、-N(R)C(O)R、N(R)SO2R、-SR、-C(O)N(R′)(R″)、-OC(O)R、-OC(O)N(R′)(R″)、SO2、-SOR、-SO3R、-SO2N(R′)(R″)、磷酸盐、膦酸盐、取代的和未取代的烷基、取代的和未取代的烯基、取代的和未取代的环烷基、取代的和未取代的环烯基、取代的和未取代的芳基和取代的和未取代的杂环基团,其中取代的烷基、取代的烯基、取代的环烷基、取代的环烯基、取代的芳基和取代的杂环基团可被一个或多个卤、CN、CF3、CO2R、C(O)R、C(O)NR2、NR2、NO2、和OR取代。
关于上述定义,每个R独立地选自H、取代的和未取代的烷基、取代的和未取代的环烷基、取代的和未取代的环烯基、取代的和未取代的烯基、取代的和未取代的炔基、取代的和未取代的芳烷基、取代的和未取代的芳基和取代的和未取代的杂环基团。每个R′和R″独立地选自H、取代的和未取代的烷基、取代的和未取代的环烷基、取代的和未取代的环烯基、取代的和未取代的烯基、取代的和未取代的炔基、取代的饿和未取代的芳烷基、取代的和未取代的芳基、和取代的和未取代的杂环基团;或R′和R″可以和氮原子连接在一起,形成5元环至7元环,可选择地,该环含有另外的杂原子。该取代烷基、取代环烷基、取代环烯基、取代烯基、取代炔基、取代芳烷基、取代芳基和取代杂环基团可被一个或多个卤、CN、CF3、OH、CO2H、NO2、C1-6烷基、-O-(C1-6烷基)、-NH2、-NH(C1-6烷基)和-N(C1-6烷基)2取代。
本文所用的“杂原子”,尤其是环杂原子,指的是N、O、和S。
在本文中术语“创伤”指身体的伤害,该伤害为正常组织结构的完整性的破坏。该术语还包含术语“疮”、“损害”、“坏死”和“溃疡”。通常地,术语“疮”为皮肤或粘膜的几乎任何损害的通用术语,且术语“溃疡”为器官或组织的表面的局部缺陷,或凹陷,其由坏死组织的脱落产生。损害通常指任何组织缺陷。坏死与死亡组织相关,该死亡组织由感染、伤害、炎症或梗塞造成。
在术语“创伤”和“溃疡”与“创伤”和“疮”的使用之间,通常有一定的重叠,此外,该术语通常任意使用。所以如上所述,在本文中术语“创伤”包含术语“溃疡”、“损害”、“疮”和“梗塞”,除非另作说明,这些术语可任意使用。
在本文中使用的术语“创伤”还指任意创伤(参见下列创伤的分类)和在治愈过程的任意特定阶段,该任意特定阶段包括任意治愈开始前的阶段。
本发明涉及创伤和与炎症相关的组织损伤的预防和/或治疗。特别地,本发明指治疗方法,该方法用于治疗与创伤相关的局部的和全身的炎症,以及治疗与创伤相关和/或由创伤产生的各种疾病。
在一般实施方式中,本发明涉及一种用于促进由创伤造成的损伤的组织的快速治愈和/或再生的方法,该方法包括向病患施用其需要的治疗上有效量的药物组合物,该药物组合物包含α、β不饱和苄基苯乙烯基砜或其官能化衍生物;和药学上可接受的赋形剂。
不束缚于任意特定的作用机理,本发明的组合物的一个可能机理为将干细胞和/或祖细胞调动、增强其运输和/或补充至创伤或损伤部位。
同样,不束缚于任何具体的作用机理,本发明的组合物另一个可能的作用机理为通过调节(抑制和/或刺激)炎症分子的表达和合成,该炎症分子包括细胞激素(例如IL-1、IL-2、IL-6、IL-8、IL-12、IL-18、TNFα或TNFβ)、一氧化氮、活性的氧中间体(ROI)、白三烯(leukotrenes)、和/或前列腺素、或有关于炎症信号转导途径的任意一种或多种已知生物分子等。
因为抗-细胞激素剂或消炎剂,例如α、β不饱和苯甲基苯乙烯基砜及其官能化衍生物,能将干细胞和/或祖细胞调动、增强其运输和/或补充至损伤部位,这些化合物有能力抑制水肿和发炎反应,从而治疗或预防疾病,其中疾病过程由炎症促成。
相应地,本发明的一个实施方式提供了一种方法,该方法用于促进由创伤造成的损伤组织的快速治疗和/或再生,该方法包括向病患施用其需要的治疗上有效量的药物组合物,该药物组合物包括α、β不饱和苯基苯乙烯基砜、或其官能化衍生物和药学上可接受的赋形剂;其中该药物组合物抑制细胞激素、或任意一种或多种已知生物分子的合成,该生物分子与炎症信号转导途径的活化有关,引起了炎症的阻滞或免疫反应的减少、或者炎症的阻滞和免疫反应的减少。
使用本发明的方法和组合物治疗的创伤可为急性的和/或慢性的创伤。急性的创伤是那些在30天内(或对于糖尿病患者为60天)迅速地治愈的创伤。慢性的创伤包括,但不限于,压疮(pressure sores)、手术创伤、脊髓损伤创伤、灼伤、化学诱发的创伤和由于血管病症导致的创伤。依照本发明可预防和/或治疗的创伤的实施例为,例如,无菌创伤、撞伤、刀伤(incised wounds)、磨伤、撕脱伤、挤压伤、切伤、抛掷的创伤、刺伤、撕裂伤、非穿透伤(例如没有皮肤的破裂但有深层结构损伤的创伤)、开放性创伤、穿透伤、穿孔伤、化脓性创伤(septic wounds)、皮下创伤等等。疮的实施例为褥疮(bed sores)、口疮、糖尿病性皮肤疮、铬毒性溃疡(chrome sores)、唇疱疹、压疮等。溃疡的实施例,例如,消化性溃疡、十二指肠溃疡、胃溃疡、痛风性溃疡、糖尿病性溃疡、高血压缺血性溃疡、淤积性溃疡、小腿溃疡(静脉性溃疡)、舌下溃疡、粘膜下溃疡、症状性溃疡、营养不良性溃疡、热带溃疡、软下疳(veneral ulcer)等等,该软下疳例如,由淋病(包括尿道炎、子宫颈内膜炎和直肠炎)引起的软下疳。
根据本发明治疗的创伤类型包括,以此为例但不限于,i)普遍的创伤,例如,手术伤、外伤、脊柱损伤创伤、和由于血管病症造成创伤、传染伤、缺血伤、烫伤、化学伤和大疱创伤;ii)特别的口腔的创伤,例如,拔牙后创伤、牙髓创伤,尤其是与囊肿和脓疮的治疗有关的外伤、细菌的溃疡和损害、病毒的或自身免疫的病原、物理伤、化学伤、烫伤(thermal wound)、传染性创伤和苔藓样的创伤;具体实施例为疱疹溃疡、口疮性口炎、急性坏死性溃疡性牙龈炎和灼口综合征;iii)皮肤的创伤,例如,瘤、灼伤(例如化学伤、烫伤)、损害(细菌的、毒菌的、自身免疫的)、咬伤和手术刀伤。另一种创伤的分类方式为i)由于手术刀伤、轻微的擦伤和轻微的咬伤引起的少量组织缺失,或ii)重大组织缺失。重大组织缺失包括缺血性的溃疡、压疮、瘘管、撕裂伤、严重的咬伤、烫烧和供体部位创伤(软组织和硬组织)和梗塞。
创伤治愈和疤痕形成
如上述列举的,很明显,创伤的发生可由许多来源。例如,由手术造成的刀伤、钝力引起外伤、或各种疾病造成的组织坏死,但是,不管它们的性质,所有的创伤都经历相似的创伤治愈过程。创伤治愈有三个不同的阶段。第一阶段是炎症期,其特征为外伤处的炎症。这个阶段对于治愈是决定性的,且涉及大量的细胞迁移。创伤治愈第二阶段为增殖期,其标志为上皮形成、血管新生、颗粒组织形成和胶原沉积。血管新生涉及新的毛细管形成,其用于传递营养物和供养肉芽。在创伤中没有形成新的毛细管,所需的营养物不能到达创伤,导致创伤长期不能治愈。创伤治愈的最后阶段为成熟期,其中纤维母细胞分化为胶原蛋白。结缔组织基质和胶原蛋白的分布发生紧缩、由此产生疤痕组织。虽然疤痕形成自身对于创伤治愈至关重要的,但不幸的是,过多的疤痕形成会有附加的美容和/或病理的影响。本发明的组合物在创伤的一个或多个不同阶段是有效的。
在一实施方式中,本发明的组合物和方法引发了适当的治愈顺序,该治愈顺序是所有形式的创伤都需要的,因此防止了通常由创伤引起的破坏性的生化反应。
疤痕形成发生在所有的组织,疤痕形成的副作用包括,例如,但不限于,皮肤的瘢痕疙瘩、肥厚性疤痕、灼伤挛缩和硬皮病;胃肠道的狭窄、粘连和慢性胰腺炎;肝的硬化和胆道闭锁;肺的间质性纤维化和支气管肺发育不良;心脏的风湿性疾病和心室动脉瘤;眼睛的晶状体后纤维组织形成和糖尿病视网膜病变;神经的传输丢失;骨骼的关节僵硬和骨关节炎以及肾的血管球性肾炎等。事实上,能够治愈创伤且具有最小化的疤痕形成,对于病患和内科或外科实践上具有深远的影响。
在一实施方式中,本发明的组合物对抗灼伤是有效的。有各种类型的灼伤,例如热感灼伤、热感控制灼伤、化学灼伤、辐射灼伤、电灼伤、冰灼伤或由暴露于光(lightening)引起的灼伤,该灼伤可用本发明的组合物和方法预防和/或治疗。有各种等级的灼伤,包括那些的为第一级、第二级、第三级或第四级灼伤或其任意组合。
通过预防和/或治疗和/或改善炎症,可能抑制复杂的化学变化,该化学反应对于病患的结果通常为决定性因素。本发明的组合物减少了这些化学变化,使机体以较小的创伤的方式反应,例如轻微的创伤或切口,而不是更严重的创伤。在轻微的切口或创伤后,机体开始用血小板阻塞创伤,治愈阶段就开始了。这是促进受伤部位的修复的正常反应。
在又一实施方式中,通过促进创伤治愈,本发明的组合物和方法直接地或间接地阻止微生物侵入创伤处。因此,病患也会承受的更少,因为他们保持免于各种感染,该感染通常地与典型的创伤有关。所以,该组合物防止创伤伤害发展至更严重。使用本发明的组合物和方法预防、治疗和/或改善组织损伤,该组织损伤在多数创伤中为微生物的繁殖地。干扰感染的周期的能力能够中止疾病过程。减轻感染率转变为减轻疾病、病症和畸形的严重度,该疾病、病症和畸形为创伤的正常结果。革兰氏阳性和革兰氏阴性细菌感染通常在创伤后生长。这些病理生理学阶段的消极结果与早期的MOD有关(多重器官功能障碍)。如果血浆泄露的区域能被阻塞,就能防止微生物的迁移。
在一实施方式中,通过限制炎症,本发明的组合物物阻止中性粒白细胞(neutrophils)的聚集,和它们的氧自由基和各种蛋白酶的释放,从而阻止了进一步的组织损伤。
在另一实施方式中,本发明的组合物用于直接或间接地预防和/或治疗若干创伤关联疾病响应(ADR’s)。一列典型的ADRs包括,但不限于,间室症候群、酸毒症、急性肾功能衰竭、急性肾小管坏死、蜂窝组织炎、继发癫痫、挛缩、减少的末梢器官灌注(reducedend-organ perfusion)、内毒素血症、外毒素血症(exotoxemia)、坏疽、医院获得性肺炎(50%具有燃烧/烟雾吸入性损伤的病患产生此种类型)、ARDs(急性呼吸窘迫综合征)、呼吸机相关肺炎、败血症、感染性休克、血栓栓塞并发症、和那些具有炎症部分的与其他创伤相关的疾病,例如但不限于,贫血、癌症、充血性心力衰竭、减少的末梢器官灌注(reducedend-organ perfusion)、皮肌炎(DM)、皮炎、肺泡蛋白质沉积肺炎(alveolar proteinosispneumonia)、闭塞性细支气管机化性肺炎(BOOP)、慢性吸入性类酯性肺炎、社区获得性肺炎(CAP)、冠状毒肺炎、隐球菌肺炎、衣原体肺炎、脱屑性间质性肺炎、嗜酸性粒细胞肺炎、流感嗜血杆菌性肺炎、流感嗜血杆菌性肺炎、副流感嗜血杆菌性肺炎、特发性肺炎、流感相关性肺炎、特发性间质性肺炎、克雷白杆菌肺炎、支原体肺炎、非特异性间质性肺炎(与皮肌炎-DM相关)、多杀巴斯德菌肺炎、卡氏肺囊虫肺炎(PCP)、绿脓杆菌感染肺炎、呼吸道合胞病毒感染、葡萄球菌性坏死性肺炎、肺结核性肺炎、普通型间质性肺炎(UIP)、水痘带状疱疹病毒性肺炎、中毒性休克综合征、和中毒性表皮坏死松解症(TEN)。
根据本发明可成功治疗或预防的创伤或疮的其他状况为,以此为例但不限于,炭疽创伤、破伤风、气性坏疽、猩红热、丹毒、须疮、毛囊炎、接触传染性脓疱疮、或大疱性脓疱病等。
在另一实施方式中,本发明的组合物和方法包括α,β不饱和苯甲基苯乙烯基砜及它们的官能化衍生物,该组合物和方法对于治疗相关的疼痛是有用的,和/或预防通常伴随有创伤或损伤组织的疾病或病症,其中该疾病或病症选自由下列组成的组:心肌缺血、组织和肌肉相关的缺血、四肢相关的缺血(extremity-associated ischemia)、中风、败血症、肌萎缩性脊髓侧索硬化症(ALS)、癫痫、最初组织损伤后中风的蔓延(extensionof strokes after initial tissue damage)、原发性和继发性脑瘤致功能化脑损伤、脑膜炎或脑脓肿致局部脑损伤、病毒性脑膜炎、病毒性脑炎、和/或外伤致局部脑损伤、器官或组织的移植、由移植引起的移植物抗宿主病、包括风湿性关节炎的自身免疫性综合征、全身性红斑狼疮、桥本氏甲状腺炎、多发性硬化、重症肌无力、I型糖尿病、小儿糖尿病或新发型糖尿病、后葡萄膜炎、变应性脑脊髓炎、肾小球肾炎、包括风湿热和感染后肾小球肾炎的感染后自身免疫性疾病、炎症性皮肤病和过度增生性皮肤病疾病、牛皮癣、过敏性皮炎、接触性皮炎、湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、红疹、皮肤性嗜伊红血球过多、红斑狼疮、痤疮、斑秃、角膜结膜炎、春季结膜炎、与白塞病有关的葡萄膜炎、角膜炎、疱疹性角膜炎、角膜上皮营养不良、眼天胞疮、蚕蚀性角膜溃疡、巩膜炎、葛列夫氏(Graves')眼病变、Vogt-小柳-原田综合征、类肉状瘤病、胃溃疡、由缺血性疾病和血栓症引起的血管损伤、缺血性肠道疾病、炎性肠疾病、坏死性小肠结肠炎、与热烧伤有关的肠损伤、乳糜病、直肠炎、嗜伊红性肠胃炎、肥大细胞增多症、克罗恩病、溃疡性结肠炎、鼻炎、湿疹、间质性肾炎、肺出血肾炎综合征、溶血性尿毒综合征、糖尿病性肾病、肌炎、格林-巴利综合征、多神经炎、单神经炎、神经根病、骨质疏松症、类肉状瘤病、纤维化肺、特发性间质性肺炎、皮肌炎、光过敏、皮肤T细胞淋巴瘤、动脉粥样硬化、主动脉炎综合征、结节性多动脉炎、心肌病、硬皮病、韦格内氏肉芽肿病(Wegener's granulomatosis)、干燥综合征(斯耶格伦氏综合征,Sjogren's syndrome)、嗜伊红性筋膜炎、齿龈损伤、器官的局部缺血再灌注损伤、内毒素休克、假膜性结肠炎、由药物或辐射引起的结肠炎、缺血性急性肾功能不全、慢性肾功能不全、肺癌、肺气肿、皮炎多形性红斑、线状IGA大疱皮病、致癌作用、癌转移、原发性胆汁性肝硬化、硬化性胆管炎(sclerosing cholangitis)、局部肝切除、急性肝坏死、由毒素引起的坏死、病毒性肝炎、肝硬化、酒精性肝硬化、化学疗法效果的增大、巨细胞病毒感染、癌症、外伤、和慢性细菌感染。
α,β不饱和苯甲基苯乙烯基砜或其官能化衍生物可以用于预防和治疗方法中,以治疗与创伤相关的局部和全身炎症,其典型的实施例包括,例如但不限于,包括一种或多种下列化合物的药物组合物,该化合物可单独使用或与辅助活性药物或辅助非活性药物(例如,抗菌药、止痛片、抗病毒物质、及上述的任意组合等)组合使用。
因此,本发明的一方面提供了用于治疗创伤或损伤组织的方法,该方法包括向病患施用其所需要的治疗上有效量的药物组合物,该组合物包括α,β不饱和芳基砜化合物或其官能化衍生物,和药学上可接受的载体或稀释剂。
根据一实施方式,α,β不饱和芳基砜基团为苯乙烯基砜基团,其中,连接至α碳和β碳的氢原子可选择地被其他化学基团取代,且苯环可选择地被取代。该α,β不饱和芳基砜创伤治愈化合物的特征为由双键的存在引起的顺式反式异构现象。在双键周围的空间关系称为“Z型”或“E型”。两种构型都包含在“α,β不饱和芳基砜”的范围内。
根据一实施方式,α,β不饱和芳基砜化合物为化学式I的化合物:
其中:n为1或0;
Q1和Q2可以是相同的或不同的,他们为取代的或未取代的芳基、或取代的或未取代的杂芳基。
优选地,在化学式I中n为1,即,该化合物包括α,β不饱和苄基砜,例如,苯乙烯基苄基砜。
在根据化学式I的一优选实施方式中,Q1和Q2选自取代的和未取代的杂芳基;例如,(E)-3-呋喃乙烯基-2,4-二氯苄基砜。在根据化学式I的另一优选实施方式中,Q1和Q2选自取代的和未取代的苯基。
在优选化合物中,Q1和Q2选自取代的和未取代苯基,其包括化学式Ⅱ的化合物:
其中:
Q1a和Q2a独立地选自下列组成的组:苯基和单取代、二取代、三取代、四取代和五取代苯基,其中取代基可以是相同的或不同的,其独立地选自下列组成的组:氢、卤素、C1-C8烷基、C1-C8烷氧基、硝基、氰基、羧基、羟基、膦酸基、氨基、氨磺酰基、乙酸基、二甲氨基(C2-C6烷氧基)、C1-C6三氟烷氧基和三氟甲基。
在一实施方式中,化学式Ⅱ的化合物为至少一环上有至少二取代,即,在至少一环上有至少两个取代基,而非氢。在另一实施方式中,化学式Ⅱ的化合物在至少一环上有至少三取代,即,在至少一环上有至少三个取代基,而非氢。
在另一实施方式中,创伤治愈化合物具有化学式Ⅲ:
其中R1、R2、R3和R4独立地选自下列组成的组:氢、卤素、C1~C8烷基、C1~C8烷氧基、硝基、氰基、羧基、羟基、膦酸基、氨基、氨磺酰基、乙酸基、二甲氨基(C2~C6烷氧基)、C1~C6三氟烷氧基和三氟甲基。
根据本发明特别的优选实施方式,创伤愈合化合物为化学式Ⅲ,且R1和R2独立地选自由氢、卤素、氰基和三氟甲基组成的组;且R3和R4独立地选自由氢和卤素组成的组。根据化学式Ⅲ的子实施方式,创伤治愈α,β不饱和芳基砜化合物为化学式Ⅲa的化合物,其中R2和R4非氢:
根据化学式Ⅲa的优选化合物具有E-构型,其包括但不限于,(E)-4-氟苯乙烯基-4-氯苄基砜;(E)-4-氯苯乙烯基-4-氯苄基砜;(E)-2-氯-4-氟苯乙烯基-4-氯苄基砜;(E)-4-羧基苯乙烯基-4-氯苄基砜;(E)-4-氟苯乙烯基-2,4-二氯苄基砜;(E)-4-氟苯乙烯基-4-溴苄基砜;(E)-4-氯苯乙烯基-4-溴苄基砜;(E)-4-溴苯乙烯基-4-氯苄基砜;(E)-4-氟苯乙烯基-4-三氟甲基苄基砜;(E)-4-氟苯乙烯基-3,4-二氯苄基砜;(E)-4-氟苯乙烯基-4-氰基苄基砜;(E)-2,4-二氯-4-氯苄基砜;(E)-4-氟苯乙烯基-4-氯苯砜以及(E)-4-氯苯乙烯基-2,4-二氯苄基砜。
根据另一实施方式,化学式Ⅲa的化合物具有Z构型,其中R1和R3为氢,且R2和R4选自由4-卤代基组成的组。这种化合物包括,例如,(Z)-4-氯苯乙烯基-4-氯苄基砜;(Z)-4-氯苯乙烯基-4-氟苄基砜;(Z)-4-氟苯乙烯基-4-氯苄基砜;(Z)-4-溴苯乙烯基-4-氯苄基砜;以及(Z)-4-溴苯乙烯基-4-氟苄基砜。
化学式Ⅲ的优选化合物为化学式ⅢB
ⅢB
其中R1和R3为氢,R2为卤素且R4为羧基且双键的空间构型为E。
在本发明的另一优选实施方式中,R1和R3为氢,R2为氯且R4为羧基,且双键的空间构型为E,例如,(E)-4-羧基苯乙烯基-4-氯苄基砜(ON 1210)。
根据另一实施方式,创伤治愈α,β不饱和芳基砜化合物为化学式Ⅳ的化合物:
其中
R1、R2、R3和R4独立地选由氢、卤素、C1-8烷基、C1-8烷氧基、硝基、氰基、羧基、羟基和三氟甲基组成的组。
在一实施方式中,化学式Ⅳ中的R1选自由氢、氯、氟和溴组成的组;且R2、R3和R4为氢。化学式Ⅳ中的优选化合物为(Z)-苯乙烯基-(E)-2-甲氧基-4-乙氧基苯乙烯基砜。
根据又一实施方式,创伤治愈α,β不饱和芳基砜化合物为化学式Ⅴ的化合物:
其中
Q3、Q4和Q5独立地选自由下列组成的组:苯基、单取代、二取代、三取代、四取代、五取代的苯基,其中取代基可以相同或不同,该取代基独立地选自下列组成的组:卤素、C1-C8烷基、C1-C8烷氧基、硝基、氰基、羧基、羟基、氨基、氨磺酰基、乙酸基、二甲氨基(C2-C6烷氧基)、C1-C6三氟烷氧基和三氟甲基。
根据化学式V的一个子实施方式,创伤治愈α,β不饱和芳基砜化合物为化学式Ⅴa的化合物:
其中
R1和R2独立地选自由下列组成的组:氢、卤素、C1-C8烷基、C1-8烷氧基、硝基、氰基、羧基、羟基和三氟甲基;且R3选自由未取代苯基、单取代苯基和二取代苯基组成的组,苯环上的取代基独立地选自由卤素和C1-8烷基组成的组。
优选地,化学式Ⅴ中的R1选自由氟和溴组成的组;R2为氢;且R3选自由2-氯苯基、4-氯苯基、4-氟苯基和2-硝基苯基组成的组。
根据化学式Ⅴ的另一创伤治愈苯乙烯基砜为化合物,其中R1为氟、R2为氢且R3为苯基,即,化合物2-(苯磺酰基)-1-苯基-3-(4-氟苯基)-2-丙烯-1-酮。其中芳基核上的取代基为烷氧基基团,碳链可为支链的或直链的,优选直链。优选地,该烷氧基基团包括C1-C6烷氧基,更优选地,C1-C4烷氧基,最优选地,甲氧基。
该α,β-不饱和芳基砜可表现为药学上可接受的盐的形式。术语“药学上可接受的盐”包括盐,该盐通常用于形成碱金属盐和形成自由酸或自由碱的加成盐。制剂中有效的优选盐为钠盐(ON 1210Na)。
化学式(Ⅰ-Ⅴ)的化合物的某些衍生物,其本身可有少量药理学活性或无药理学活性,当施用于机体中或机体上时,其可以转换成的具有理想活性化学式(Ⅰ-Ⅴ)的化合物,例如通过水解分裂。该衍生物被称为“前体药物”。在Pro-drugs as Novel DeliverySystems,Vol.14,ACS Symposium Series(T Higuchi和W Stella))和`Bioreversible Carriers inDrug Design`,Pergamon Press,1987(E B Roche,American Pharmaceutical Association))中,可找到关于前体药物使用的更多信息。
在一实施方式中,该前体药物为这样一个化合物,其在活的有机物中转化成化学式(Ⅰ-Ⅴ)的化合物或药学上可接受的盐或化合物溶剂化物。该转化可由各种机理发生,例如通过血液中的水解作用。在T.Higuchi和W.Stella,"Pro-drugs as Novel DeliverySystems,"Vol.14 of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design,Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987中对前体药物的使用作了讨论。
根据本发明的前体药物,例如,可以通过某些部分替代化学式(Ⅰ-Ⅴ)的化合物中合适的功能而产生,该某些部分为本领域技术人员公知的“前体部分”,如在HBundgaard的"Design of Prodrugs"(Elsevier,1985)中所描述的。
此外,化学式(Ⅰ-Ⅴ)的某些化合物本身可作为化学式(Ⅰ-Ⅴ)的其他化合物的前体药物来起作用。
化学式(Ⅰ-Ⅴ)的化合物的前体药物可以以常规的方式形成,该前体药物具有化合物的官能团,例如具有氨基、羟基或羧基。
例如,如果本发明的化合物包含氨基官能团,前体药物可通过用例如R-羰基,RO-羰基,NRR'-羰基这些基团来替代氨基中的氢原子来形成,其中R和R'各自独立的为(C1-C10)烷基;(C3-C7)环烷基;苄基;或R-羰基,该R-羰基为天然α-氨酰基或天然的α-氨酰基-天然α-氨酰基;--C(OH)C(O)OY',其中Y'为H、(C1-C6)烷基或苄基;--C(OYd)Y1其中Yd为(C1-C4)烷基,且Y1为(C1-C6)烷基、羧基(C1-C6)烷基,氨基(C1-C4)烷基或N-(C1-C6)烷基氨基烷基-或N,N-二(C1-C6)烷基氨基烷基;--C(Y2)Y3其中Y2为H或甲基、且Y3为N-(C1-C6)烷基氨基或N,N-二(C1-C6)烷基氨基、吗啉基、哌啶-1-基或吡咯烷基-1-基。
同样地,如果本发明的化合物包括醇官能团,前体药物可以通过用基团取代醇基的氢原子来形成,该基团例如(C1-C6)烷酰氧基甲基、1-((C1-C6)烷酰氧基)乙基、1-甲基-1-((C1-C6)烷酰氧基)乙基、(C1-C6)烷氧羰基氧甲基、N--(C1-C6)烷氧羰基氨甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳酰基和α-氨基酰基、或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基基团独立地选自天然生成L-氨基酸、P(O)(OH)2,--P(O)(O(C1-C6)烷基)2或糖基(由碳水化合物的半缩醛形式的羟基去除后产生的自由基)。
如果本发明的化合物含有羧酸官能基团,前体药物可以包括用基团取代羧酸基团的氢原子形成的酯,该基团例如(C1-C8)烷基、(C2-C12)烷酰基氧甲基、具有4至9个碳原子的1-(烷酰氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰氧基)-乙基、具有3至6个碳原子的烷氧基羰基氧基甲基、具有4至7个碳原子的1-(烷氧基羰基氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧基羰基氧基)乙基、具有3至9个碳原子的N-(烷氧基羰基)氨基甲基、具有4-10个碳原子的1-(N-(烷氧基羰基)氨基)乙基、3-酞基、4-巴豆酰内酯基、γ-丁内酯-4-基、N,N-(C1-C2)烷基氨基(C2-C3)烷基(例如β-二甲基氨基乙基)、氨基甲酰基-(C1-C2)烷基,N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基和哌啶子基、吡咯基或吗啉基(C2-C3)烷基。
本发明的范围内还包括化学式(Ⅰ-Ⅴ)的化合物的代谢物,该代谢物为基于施用药物在活体内形成的化合物。依照本发明的代谢物的一些实施例包括:(i)化学式(Ⅰ-Ⅴ)的化合物含有甲基、甲基的衍生物羟甲基(-CH3→-CH2OH);(ii)化学式(Ⅰ-Ⅴ)的化合物含有叔胺基、叔胺基的衍生物仲胺基(-NR1R2→-NHR1或-NHR2);(iii)化学式(Ⅰ)的化合物含有仲胺基、仲胺基的衍生物一级胺(-NHR1→-NH2);(iv)化学式(Ⅰ-Ⅴ)的化合物含有苯基部分、苯基的衍生物苯酚(-Ph→-PhOH);和(v)化学式(Ⅰ-Ⅴ)的化合物含有酰胺基、酰胺基的衍生物羧酸(-CONH2→-COOH)。
根据前述的实施例中的取代基团的进一步实施例和根据本发明的其他前体药物类型的实施例,可在上述参考文献中找到。
本发明的化合物可以各种水合物形式存在。例如,本发明的化合物可以以非溶剂化形式,以及药学上可接受的溶剂的溶剂化形式存在,该药学上可接受的溶剂例如水、乙醇等等,且本发明包括溶剂化形式及非溶剂化形式。
本发明的化合物能够以多于一种晶型的形式结晶,,该特性成为多晶型现象,所有这些多晶形物(“同质多形体”)都包括在本发明的范围内。
或者,本发明的化合物可为无定形状态。
一般地,多晶型现象在温度或压力发生变化或温度和压力同时发生变化时发生,也可由结晶过程的变化产生。同质多形体能够通过各种物理性质区分,典型地,用X-射线衍射图形、溶解度行为、和化合物的熔点来区分同质多形体。
本发明还包括本发明的同位素标记化合物,其与这里所述的化合物相同,但事实上一个或多个原子被原子量或质量数与自然界中通常发现的原子量或质量数不同的原子取代。能够并入本发明的化合物的同位素的实施例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素,例如,分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31p、32P、35S、18F、123I、125I和36Cl。
本发明的某些同位素标记的化合物(例如那些标记为3H和14C的)在化合物和/或基底组织分布试验中为有用的。氚同位素(即3H)和碳-14同位素(即为14C)是特别优选的,因为它们容易制备且具有可检测性。进一步地,用较重的同位素取代,例如氘(即2H)具有由更好的代谢稳定性产生的某些治疗优势(例如,在活体内的半衰期的增加或减少剂量需求),所以在一些情况下是优选的。正电子发射同位素,例如15O、13N、11C和18F对于用正电子放射断层扫描(PET)研究来检验底物受体占有率是有用的。一般地,本发明同位素标记的化合物可以由以下过程制备,该过程类似于下文方案和/或实施例所公开的,通过用同位素标记的试剂取代非同位素标记的试剂。
当本发明的化合物中存在一个或多个手性中心,本文描述的化学式包括单个同分异构体及这些同分异构体的混合物(例如,外消旋物、外消旋混合物、单一非对映异构体或对映异构体等)。因此,例如,本文公开的例证的化合物作为具体的立体异构体进行描述。应该理解,本发明包括这些化合物,但在一个或多个手性中心具有交替的立体化学。
此外,本发明包括所有的几何异构体和位置异构体。例如,如果本发明的化合物包含双键或稠环,顺式和反式、以及顺式和反式的混合物都属于本发明的范围。
根据非对映异构体混合物的物理化学性质差异,通过本领域技术人员已知的方法,可以将非对映异构体混合物分离成单个的非对映异构体。例如通过色谱分析法和/或分布结晶作用。对映异构体可以通过与合适的光学活性化合物(例如,手性助剂,例如手性乙醇或Mosher's酰氯)反应,将对映异构体混合物转变成非对映异构体混合物而分离;分离非对映异构体;将单个非对映异构体转变成相应的纯的对映异构体。并且,本发明的一些化合物可为阻转异构体(例如,取代联芳基),认为其是本发明的一部分。对映异构体还可通过使用手性的高效液相色谱柱分离。
在某些实施方式中,本发明的化合物以几种互变异构的形式存在。因此,本文中描述的化学结构包括所阐的化合物的所有可能的互变异构的形式。术语“互变异构体”或“互变异构的形式”指的是不同能量的结构异构体,其可经由低的能垒相互转换。例如,质子互变异构体(也被称为质子异变互变异构体)包括通过质子迁移相互转换,例如酮-烯醇和亚胺-烯胺的异构化。质子互变异构体的具体实施例为咪唑部分,其中质子可在环上的两个氮之间迁移。价键互变异构体包括由一些成键电子的重整的互变现象。
使用方法
因此,在最简单的方面,本发明提供了一种方法,该方法通过施用α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,用于治疗创伤,以及用于预防或治疗因创伤而产生的疾病和/或情况的症状。
在一方面,本发明涉及通过减小与创伤或损伤的组织相关的炎症的严重程度,来控制或减轻疼痛的方法,该方法包括向病患施用其所需的治疗上有效量的药物组合物,该药物组合物包括α,β-不饱和芳基砜的化合物,尤其是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的载体或稀释剂。
本申请还涉及一种促进由创伤或疾病造成的损伤的组织的快速治愈和/或再生的方法,该方法包括向病患施用其所需的治疗上有效量的药物组合物,该药物组合物包括α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的赋形剂,其中所述的药物组合物促进损伤的组织的快速治愈和/或再生,同时保留组织的原组成和将并发症和疤痕最小化。
在本发明的一方面,提供了一种用于改善与炎症介质相关的疾病和创伤或组织伤害对全身的影响的方法。初期的炎症和伴随创伤或组织伤害的水肿包含氧化剂和花生四烯酸代谢物,其引发中性粒白细胞和巨噬细胞释放细胞激素,包括但不限于,肿瘤坏死因子、IL-1、IL-2、IL-8、IL-12、IL-18、以及一氧化氮。来自创伤和/或胃肠道病原体的内毒素发起并增强炎症,且能导致微生物移位、穿过肠且在远处的位点产生病理,否则,该远处的位点不会被外伤影响。败血反应是由来源于宿主的过多的炎症介质和它的并发症造成的,该炎症介质特别是IL-1、IL-2、TNF、IL-8、NO、活性氧中介物(ROI)。这些并发症或“疾病相关的反应”(ADRs)由水肿、炎症和微生物菌丛的易位造成。
在又一方面,本发明涉及一种预防或改善有害的炎症反应的方法,该炎症反应与受控的治疗的热引起的皮肤损伤有关,应用于用于身体状况治疗所使用的激光,及在各种美容整形中的引发的热伤害中的使用,该方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的载体或稀释剂,其中所述的药物组合物预防或改善有害的炎症反应和/或与受控的治疗的热引起的皮肤损伤有关的副作用。
在另一方面,本发明还涉及一种用于预防或改善与受控的热引起的皮肤损伤有关的副作用的方法,该方法用于疤痕和纹身去除、癌症切除、息肉的烧灼切除、溃疡、褥疮性溃疡(褥疮)的治疗、痤疮、皮肤的真菌感染,该方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的赋形剂,其中所述的药物组合物促进损坏的组织的快速再生,同时保留组织的原组成且将与一种或多种上述情况中的热致灼伤相关的并发症和疤痕最小化。
在又一方面,本发明涉及一种预防或改善与在阳光下过度曝晒有关的起疱或疼痛的方法,该方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的载体或稀释剂。
在本发明的又一方面,提供了一种限制分子内的亲核反应的方法,该亲核反应发生在影响分子内基团和分子间基团的反应性的大部分途径中,该方法包括向病患施用其所需的治疗上有效量的药物组合物,该药物组合物包括α,β-不饱和芳基砜的化合物,特别是α,β-不饱和苄基苯乙烯基砜的化合物,或其官能化衍生物;和药学上可接受的载体或稀释剂。有些含氧基团或ROI在创伤损伤中是不稳定的,使用本发明的组合物治疗将会抑制这些氧自由基或氧化剂。
在本发明的每个上述的方面和实施方式中,本发明还可以将治疗与其他活性药物结合。特别地,本发明的组合物可与一种或多种大环内酯类抗菌素或非大环内酯类抗菌素、抗菌剂、抗真菌剂、抗病毒剂、抗寄生虫剂和/或抗炎的或免疫调节的药物或药剂一起施用。
可与本发明的组合物结合使用的大环内酯类抗生素实施例尤其包括,下列合成物、半合成物或天然生成微晶抗生素化合物:酒霉素、新酒霉素、YC-17、雨滨蛙肽、红霉素A至红霉素F、竹桃霉素、罗红霉素、地红霉素、氟红霉素、克拉霉素、环酯红霉素、阿奇霉素、交沙霉素、北里霉素、螺旋霉素、麦迪霉素、罗他霉素、米奥卡霉素、兰卡杀菌素、及这些化合物的衍生物。因此,红霉素和红霉素衍生的化合物属于抗生素的普通种类,称为“大环内酯类”。优选地,红霉素和红霉素类化合物的实施例包括:红霉素、克拉霉素、阿奇霉素和醋竹桃霉素。
除了上述的大环内酯类抗生素,另外的适合于在本发明的方法中使用的抗生素包括,例如,倾向于预防、抑制或毁灭生命的任意分子,就这一点而论,如本文所使用的,包括抗菌剂、抗真菌剂、抗病毒剂、和抗寄生虫剂。这些药剂可以与有机体分离,这些有机体可以产生药剂或由商业来源获得。
抗菌抗生剂包括,但不限于,青霉素、头孢菌素、碳头孢烯类、头霉素类、碳青霉烯类、单环β-内酰胺类、氨基糖苷类、糖肽类、喹诺酮类、四环素类、大环内酯类、噁唑烷酮类、链霉杀阳菌素类、和氟喹诺酮类。抗生素的例子包括,但不限于,利奈唑胺(Zyvax)、达福普丁、奎奴普丁、青霉素G(CAS注册号:61-33-6);甲氧西林(CAS注册号:61-32-5);萘夫西林(CAS注册号:147-52-4);苯甲异噁唑青霉素(CAS注册号:66-79-5);邻氯青霉素(CAS注册号:61-72-3);双氯青霉素(CAS注册号:3116-76-5);氨苄青霉素(CAS注册号:69-53-4);阿莫西林(CAS注册号:26787-78-0);羟基噻吩青霉素(CAS注册号:34787-01-4);羧苄青霉素(CAS注册号:4697-36-3);美洛西林(CAS注册号:51481-65-3);阿洛西林(CAS注册号:37091-66-0);哌拉西林(CAS注册号:61477-96-1);亚胺培南(CAS注册号:74431-23-5);氨曲南(CAS注册号:78110-38-0);头孢菌素(CAS注册号:153-61-7);头孢唑林(CAS注册号:25953-19-9);头孢克洛(CAS注册号:70356-03-5);头孢羟唑甲酸钠(CAS注册号:42540-40-9);头孢西丁(CAS注册号:35607-66-0);头孢呋辛(CAS注册号:55268-75-2);头孢尼西(CAS注册号:61270-58-4);头孢美唑(CAS注册号:56796-20-4);头孢替坦(CAS注册号:69712-56-7);头孢丙烯(CAS注册号:92665-29-7);氯碳头孢(CAS注册号:121961-22-6);头孢他美(CAS注册号:65052-63-3);头孢哌酮(CAS注册号:62893-19-0);头孢噻肟(CAS注册号:63527-52-6);头孢唑肟(CAS注册号:68401-81-0);头孢曲松钠(CAS注册号:73384-59-5);头孢他啶(CAS注册号:72558-82-8);头孢吡肟(CAS注册号:88040-23-7);头孢克肟(CAS注册号:79350-37-1);头孢泊肟(CAS注册号:80210-62-4);头孢磺啶(CAS注册号:62587-73-9);氟罗沙星(CAS注册号:79660-72-3);萘啶酸(CAS注册号:389-08-2);诺氟沙星(CAS注册号:70458-96-7);环丙沙星(CAS注册号:85721-33-1);氧氟沙星(CAS注册号:82419-36-1);依诺沙星(CAS注册号:74011-58-8);洛美沙星(CAS注册号:98079-51-7);西诺沙星(CAS注册号:28657-80-9);强力霉素(CAS注册号:564-25-0);二甲胺四环素(CAS注册号:10118-90-8);四环素(CAS注册号:60-54-8);阿米卡星(CAS注册号:37517-28-5);庆大霉素(CAS注册号:1403-66-3);卡那霉素(CAS注册号:8063-07-8);乙基西梭霉素(CAS注册号:56391-56-1);妥布霉素(CAS注册号:32986-56-4);链霉素(CAS注册号:57-92-1);阿奇霉素(CAS注册号:83905-01-5);克拉霉素(CAS注册号:81103-11-9);红霉素(CAS注册号:114-07-8);依托红霉素(CAS注册号:3521-62-8);红霉素琥珀酸乙酯(CAS注册号:41342-53-4);葡庚糖酸红霉素(CAS注册号:23067-13-2);乳糖酸红霉素(CAS注册号:3847-29-8);硬酯酸红霉素(CAS注册号:643-22-1);万古霉素(CAS注册号:1404-90-6);替考拉宁(CAS注册号:61036-64-4);氯霉素(CAS注册号:56-75-7);克林霉素(CAS注册号:18323-44-9);甲氧苄氨嘧啶(CAS注册号:738-70-5);磺胺甲噁唑(CAS注册号:723-46-6);呋喃咀啶(CAS注册号:67-20-9);利福平(CAS注册号:13292-46-1);莫匹罗星(CAS注册号:12650-69-0);甲硝哒唑(CAS注册号:443-48-1);头孢氨卡(CAS注册号:15686-71-2);罗红霉素(CAS注册号:80214-83-1);Co-amoxiclavuanate;哌拉西林和他唑巴坦的结合;和它们的各种的盐、酸、碱和其他衍生物。
抗真菌剂包括,但不限于,盐酸特比萘芬、制霉菌素、两性霉素B、灰黄霉素、酮康唑、硝酸咪康唑、氟胞嘧啶、氟康唑、伊曲康唑、克霉唑、苯甲酸、水杨酸、伏立康唑、卡泊芬净、和硫化晒。
抗病毒剂包括,但不限于,盐酸金刚烷胺、金刚烷乙胺(rimantadin)、阿昔洛韦、泛昔洛韦、膦甲酸、更昔洛韦钠、疱疹净、病毒唑、索利夫定、三氟尿苷、伐昔洛韦、缬更昔洛韦(vangancyclovir)、喷昔洛韦(pencyclovir),阿糖腺苷(vidarabin),地达诺新、司他夫定、扎西他滨、齐多夫定、干扰素、和依度尿苷。
抗寄生虫剂包括,但不限于,除虫菊酯/增效醚、苄氯菊酯、双碘喹啉、甲硝哒唑、枸橼酸二乙碳酰嗪、哌嗪、双羟萘酸噻嘧啶、甲苯咪唑、噻苯咪唑、吡喹酮、阿苯达唑、氯胍、葡萄糖酸奎尼丁注射剂、硫酸奎宁、磷酸氯喹、盐酸甲氟喹、磷酸伯氨喹、阿托伐醌、复方磺胺甲噁唑(磺胺甲噁唑/甲氧苄氨嘧啶)、和羟乙基磺酸戊烷脒。
在另一方面,在本发明的方法中,例如,可通过施用治疗上有效量的一种或多种抗炎的或免疫调节的药物或药剂,补充组合物。通过“免疫调节药物或药剂”指的是,例如,直接地或间接地作用于免疫系统的药剂,例如,通过刺激或抑制免疫系统中细胞的细胞活性,这些细胞例如T-细胞、B-细胞、巨噬细胞、或其他抗原提呈细胞(APC);或通过作用于免疫系统外部的组分,依次刺激、抑制、或调解免疫系统,例如激素、受体激动剂或反协同试剂、和神经传导物质;免疫调节剂可以是免疫抑制剂或免疫刺激剂。
适用于本发明的抗炎的或免疫调节药物或药剂包括,但不限于,干扰素衍生物,例如倍泰龙、β-干扰素;前列腺素衍生物、伊洛前列素、西卡前列素;糖皮质激素,例如皮质醇、氢化波尼松、甲基强的松龙、地塞米松;免疫抑制剂,例如环孢霉素A、FK-506、甲氧补骨脂素(methoxsalene)、萨力多胺、柳氮磺胺吡啶、咪唑硫嘌呤、甲氨蝶呤;脂氧合酶抑制剂,例如齐留通(zileutone)、白三烯拮抗药、前列腺素、肽衍生物例如促肾上腺皮质激素(ACTH)和类似物;IL-1受体拮抗剂、IL-18结合蛋白质、活性蛋白质C(Xigris)、可溶解的TNF-受体;TNF-抗体;白介素的可溶解受体、其它细胞激素、T-细胞-蛋白质;抗白介素受体的抗体、其它细胞激素、和T-细胞-蛋白质(每个前述参考的原文,通过引用清楚地并入本文中)。
其他应用
本发明还应用于应急包全套装备中,其含有药物组合物,该药物组合物包括α,β不饱和苄基苯乙烯基砜或其官能化衍生物,能在所有应急急救药箱中使用。在一个实施方式中,本发明的组合物的外用制剂可以在事故或者受伤后直接用于皮肤。例如,这种应急包应用于紧急家庭事故和车辆中,其对于每个家庭是无价的,这些车辆包括住宅车辆、商用车辆、和大多数应急车辆和警车。
本发明还应用于各种类型的晒伤,还将应用于日照前防护和/或日照后防护以防止皮肤癌,防止起泡,舒缓、冷却和减少/消除晒伤的疼痛。本发明还应用于人造日光浴沙龙中。
本发明还应用于所有领域的专业使用中,包括例如,医院、紧急和灼伤处理、医生办公室、普通医师办公室、救护车和救急车辆、高风险行业、消防、军事、海军、法律执行、机械车间、自动修理、焊接、餐厅等。
本发明的药物组合物对于人类、鼠类和其他哺乳类动物是有效的,例如兽类(veterinary animals),包括但不限于,狗、猫、其他家庭宠物、马、农场动物等等。
药物组合物制剂、剂量和施用方式
本发明还提供药物组合物,该药物组合物包括治疗上有效量的α,β-不饱和芳基砜化合物和药学上可接受的载体。该药物组合物还指另外包含一种或多种活性或非活性试剂的组合物。
根据一个实施方式,本发明的组合物具有所述的创伤治愈活性,在其药学上可接受的制剂中,具有分离的、基本上纯的化合物。这些制剂可由标准的途径施用。
在一个具体实施方式中,术语“药学上可接受的”意为由联邦的管理机构或国家政府批准或在美国药典或其他普遍公认的药典中列举的,用于动物体,更尤其是用于人体的。
术语“载体”指与治疗剂一起给药的稀释剂、辅助剂、赋形剂、或媒介物。此种药物载体可以是无菌液体,例如水和油,包括石油、动物油、植物油或人工合成的油,例如花生油、豆油、矿物油、芝麻油等等。当药物组合物通过静脉注射施用时,水为优选载体。盐溶液和葡萄糖水溶液(aqueous dextrose)和甘油溶液也可以作为液体载体使用,尤其是用于可注射溶液。
合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、干燥的脱脂牛奶、甘油、丙烯、乙二醇、水、乙醇等等。在一实施方式中,本文所述的组合物为水性基,尽管乙醇也是本文所述的制剂的优选基底组分。
若有需要,该组合物也可以含有少量的润湿剂或乳化剂、或pH缓冲剂。这些组合物的形式可为溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉末、缓释制剂等等。在一实施方式中,该组合物与传统的粘合剂和载体例如甘油三酯一起制成栓剂。
本发明的组合物可制成中性制剂形式或盐的形式。如本文所用,“药学上可接受的盐”,它意为这样一些盐,其在合理的医学判定范围内适合与人类和低等动物的组织接触,而没有异常毒性、刺激、过敏反应等等,且与合理的收益/风险比相称。
药学上可接受的盐包括那些与阴离子一起形成的盐,例如那些氯化氢、磷酸、乙酸、草酸、酒石酸等衍生的盐;和那些与阳离子一起形成的盐,例如那些由钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等衍生的盐。这些盐可以在本发明的化合物的最后分离和纯化过程中原位制备,或通过游离碱的官能团与合适的有机酸反应而分离。典型的酸加成盐包括醋酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸钠(camphersulfonate)、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐(hemisulfate)、庚糖酸盐(heptonate)、己酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂烷硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐(2-naphthalenesulfonate)、占替诺烟酸盐、硝酸盐、油酸盐、草酸、棕榈酸酯、双羟萘酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐(3-phenylpropionate)、磷酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)、十一烷酸盐、戊酸盐等等。典型的碱金属盐或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等,以及无毒的铵盐、季铵盐(quaternaryas ammonium)、和矿物阳离子,包括但不限于铵盐、四甲基铵、四乙胺、甲胺、二甲胺、三甲胺、三乙胺、乙胺等等。
在一实施方式中,本发明的组合物局部地且直接应用于创伤。在本实施方式中,该组合物为油膏、药膏或乳膏的形式,其直接抹在创伤上,然后用标准的无菌敷垫或其他合适的包扎材料覆盖。或者,本发明组合物的油膏、乳膏或药膏直接应用在敷垫或其他合适的包扎材料上。
本文描述的组合物的优选给药途径包括,例如,非口服给药、鼻内投药、局部施药(包括含服和舌下给药)和口服。非口服给药包括静脉内的、肌肉的、动脉内的、腹膜内的、阴道内的、膀胱内的(例如,在膀胱内)、皮肤内的、颅内的、气管内的和硬脑膜外的)施药。本发明的化合物包括α,β-不饱和苄基砜的化合物(例如ON01210.Na)以及至少一种稳定剂和药学上可接受的载体。在这种制剂中的ON 01210.Na的重量百分数为0.1%至99.99%。“药学上可接受的载体”是指任意载体,稀释剂或赋形剂,例如水溶性的聚合物/助溶剂,其与制剂的其他成分相容,且对于患者是无害的。
口服制剂可包括标准的载体,例如药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。E.W.Martin在“Remington’s Pharmaceutical Sciences”中描述了合适的药物载体的例子。这些组合物会含有治疗上有效量的化合物,优选以纯化合物的形式,和适当量的载体,以便给患者病患提供合适的用药形式。该制剂应该适合该用药方式。
在又一实施方式中,该组合物制成可对人类进行静脉内用药。通常地,用于静脉内给药的组合物为无菌的等渗的缓冲水溶液。一般地,这些成分分别或混合在一起以单位剂量的形式供给,例如,为干燥冻干的粉末或无水浓缩物处于密闭容器中,该密闭容器例如安瓿瓶或标有活性剂的量的瓶。该组合物通过输注给药,其可在输液瓶分散,该输液瓶含有无菌药用级的水或生理盐水。通过注射施用该组合物,可提供有用于注射的无菌水或生理盐水的安瓿瓶,以便在用药前可将成分混合。
此外,本发明的该组合物可包在生物可降解的聚合物里,使该化合物可以缓慢释放。该聚合物被注入需要药物传递的周围,例如,在创伤处,以便该组合物可缓慢地释放至全身。通过在有问题处插管,还可以使用渗透性的微型-泵,以提供高浓度的本发明组合物的的受控输送,通过插管输送至重要部位,例如直接输送至损伤的组织内。例如,在Brem等,J.Neurosurg.74:441-446(1991)中,详细地描述了可生物降解的聚合物和它们的应用,通过引用将其全文并入本发明。
适合于非口服给药的制剂包括无菌注射水溶液和非水相无菌注射溶液,其可含有抗氧化剂、缓冲剂、抗菌剂和溶质,这使的该制剂与接受者的血液等渗;以及水相的无菌悬浮液和非水相的无菌悬浮液,其可包括悬浮剂和增稠剂。
药学上可接受的无菌水溶液或无菌非水溶液包括,以此为例但不限于,分散液、悬浮液、或乳液、以及无菌粉末,该无菌粉末在使用前才冲调成无菌可注射的溶液或分散液。合适的水相的和非水相载体、稀释剂、溶剂或媒介物的实施例包括:水、乙醇、多元醇(例如丙三醇、丙二醇、聚乙二醇等等)、及其适当的混合物、植物油(例如橄榄油)、和可注射的有机酯例如油酸乙酯。例如,通过使用涂层材料,例如卵磷脂;通过在分散液中保持所需要的颗粒尺寸;以及通过使用表面活性剂,本发明的溶液可以维持适当的流动性。
制剂可存在于单位剂量或多剂量容器中,例如,密封的安瓿和小瓶;且可储存于冰冻干燥的(冻干的)条件下,在使用前只需要直接加入无菌液体载体,例如,注射用水。即用的注射溶液和悬浮液可由前述种类的无菌粉末、颗粒和片剂制备。
药物组合物制剂可以单位剂量形式存在,且可由常规的制药技术制备。这些技术包括加入有效成分和药物载体或赋形剂的步骤。一般来说,该制剂通过均匀地且紧密地加入有效成分和液体载体、或细小的固体载体、或液体载体和细小的固体载体,接着如果必要的话,将产品成形。
当然,达到创伤治愈成效的化合物的具体剂量和进程,由各个的病患的具体情况决定,该具体情况包括,病患的体型、体重、年龄和性别、创伤或与正在治疗的创伤相关的原发疾病的性质和阶段、疾病的侵略性、和施药途径。例如,使用每日剂量从约0.01/mg/kg/天至约150/mg/kg/天,更优选地,为从约0.05/mg/kg/天至约100mg/kg/天。尤其优选的剂量为从约1.0/mg/kg/天至约50./mg/kg/天,例如剂量为约10.0/mg/kg/天。该剂量可超过多次给药,例如,两次施用5mg/kg。也可以考虑更高或更低的剂量。
本发明的药物组合物的局部给药的剂型包括粉末、喷雾、油膏、和吸收药。该活性的化合物在无菌条件下,与药学上可接受的载体和任意所需要的防腐剂、缓冲剂或可能需要的推进剂混合。本发明的范围还包括眼科制剂、眼膏、粉末和溶液。
本发明的药物组合物中的有效成分的实际剂量水平可变化,以便获得有效化合物的量,这对于获得对特定病患、组合物、和施药方式的理想的治疗反应,是有效的。选择的剂量水平依赖于本发明特定的药物化合物或它的类似物的活性,服药的途径、治疗的病情的严重程度、和情况和被治疗的病患身体状况和之前的病史。然而,药物化合物的开始剂量比达到理想的治疗效果所需要的水平低,逐渐地增加用量直到达到理想的效果,这也属于本领域的技术范围。
已知的各种输送系统可以用于施用本发明的组合物,即脂质体的包囊、微粒、微胶囊等。本发明的化合物或组合物可与其它生物活性剂一起给药。给药可以是全身的或局部的。此外,理想的是,通过任何合适的途径,将本发明的药物化合物或组合物引入到中枢神经系统中,该合适的途径包括鞘内注射和心室内的注射,该鞘内注射和心室内的注射可通过将心室内的导管例如连接至贮器来促进,例如Ommaya贮器。也可使用肺部施药,即,通过使用吸入器或喷雾器、和具有雾化剂的制剂。
在本发明的一实施方式中,药物组合物可制备成盐溶液的形式用于局部给药(与任意防腐剂和抗菌剂结合,通常应用于眼用制剂中)、以及以滴眼液的形式给药。溶液或悬浮液可以纯的形式制备,在辐射前或辐射后每天向病患施用数次。或者,上述制备的药物组合物也可以直接给药至角膜。在优选实施方式中,本发明的组合物与粘膜粘附性聚合物一起制备,其可以粘合至眼角膜。局部的治疗对角膜损伤的预防性也是有效的,已知该角膜损伤引起血管生成反应,例如化学灼伤的概率很高。在这种情况下,应该立即研究该治疗与类固醇结合的可能性,以帮助预防随后的并发症。
缓释形式的注射每年可能只需要2-3次。也可将类固醇加入至注射溶液,以减轻由注射本身造成的炎症。在其他实施方式中,本发明的组合物可置于任意位置,使它持续释放至水状液中。
在一具体实施方式中,理想的是,将本发明的药物化合物或组合物局部施用至需要创伤预防和/或治疗的区域;这可由下列实现:例如但并不限于,通过局部输注、局部应用,即与手术后与创伤敷裹结合;通过注射;通过导管;通过栓剂;或通过植入物,该植入物为多孔的、无孔的、或凝胶状的材料,该植入物包括膜,该膜例如硅橡胶膜或纤维。
在一实施方式中,本发明的化合物或组合物可用控释系统输送。在一实施方式中,可以使用泵(参见,Sefton,Biomed.Eng.14:201(1987))。在另一实施方式中,可使用聚合物材料(参见,Langer and Peppas,J.,Macromol.Sci.Rev.Macromol.Chem.23:61(1983);和Levy et等,Science 228:190(1985))。在又一实施方式中,控释系统可置于目标即大脑附近,因此仅需要全身剂量的一小部分。在Langer,Science 249:1527-1533(1990)的背景技术中介绍了其他控释系统。
在创伤的治疗、抑制和预防中有效的本发明的化合物的量,可由标准的临床技术确定。此外,可选择性地使用体外测定以帮助确定最佳的剂量范围。
特别地,本发明的组合物的剂量取决于临床因素,例如人类或动物的体重和身体状况、和化合物施用的途径。因此,在制剂中使用的精确的剂量,应该根据医师的判断和每位病患的情况来决定。有效的剂量可由剂量-反应曲线外推得到,该曲线来源于体外或动物模型试验体系。
对于治疗人类或动物,施用本发明的药物化合物的典型的宽范围为大约0.5到500mg/千克之间。本发明的方法包括一次以及多次给药,该同时给药或超过延长期给药。应该理解,本发明应用于人类和兽类使用。
本文所用术语化合物的“有效量”指在稀释后的量,其对缓和、减轻或消除病患的创伤或与创伤有关的原发疾病是有效的。例如,该化合物以约0.25微摩尔至100微摩尔的浓度施用;优选地,从约1.0微摩尔至50微摩尔;更优选地,从约2.0微摩尔至25微摩尔。特别优选的施用浓度为,例如,约0.5、1.0和2.5微摩尔以及约5、10和20微摩尔。根据本领域公知的因素,也可使用更高或更低的浓度。
根据优选实施方式,本发明的化合物以药物化合物的形式施用,该药物化合物包括ON 01210.Na,以及至少一种稳定剂和药学上可接受的载体结合。在此种制剂中的ON01210.Na可包括从0.1到99.99的重量百分数。“药学上可接受的载体”意为任意载体、稀释剂或赋形剂,例如水溶性聚合物/助溶剂,其与该制剂中的其他组分是相容的,且对病患是无毒的。
优选的单位剂量制剂是,如本文上述,含有每日剂量或每日单位、每日分次剂量、或其合适的分数的施用组分的制剂。通常地,单一剂量的范围为,约1ml至约5ml的本文描述的任意组合物。例如,包括本文描述的单个3ml剂量的组合物。例如,该剂量可包装在5ml的小瓶中。
应当理解,除组分外,特别是上述的组分外,考虑到制剂的类型问题,本发明的制剂可包括本领域常规的其他试剂。必要时,该组合物也可包括增溶剂和局部麻醉剂,该局部麻醉剂例如利诺卡因,以减轻注射处的疼痛。
贮藏稳定的制剂也可装入自-注射装置中,以易于个人使用,以减少创伤愈合或的尺寸。此设备可传递预定单剂量(或多剂量)的化合物。
对非口服给药,在非口服给药前,可用适当的稀释剂将稀释化合物,该稀释剂选自水、盐溶液、葡萄糖水溶液(葡萄糖)和相关的糖溶液、丙二醇或聚乙二醇,。例如,也可添加稳定剂、抗氧化剂、螯合剂、和防腐剂。稳定剂为优选,水溶性维他命E衍生物是最优选的。合适的抗氧化剂包括亚硫酸盐、抗坏血酸、柠檬酸及其盐,以及作为螯合剂的乙二胺四乙酸的钠盐(EDTA钠)。合适的防腐剂包括氯化苯甲烃铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、和氯丁醇。
在另一实施方式中,本发明的化合物与有效成分例如ON01210.Na、稳定剂、和PH值在7.0与8.7之间缓冲的助溶剂一起制剂。本发明的优选组合物包括在水溶液有约5mg/ml至约200mg/ml的ON 01210.Na。在一实施方式中,在施用前稀释的,本发明的贮藏稳定的组合物,包括在约10mg/ml至约150mg/ml的ON 01210.Na。这些贮藏稳定的制剂对口服和非口服给药是有用的。在另一实施方式中,非口服给药是通过皮下途径给药、肌肉途径给药或皮下途径和肌肉途径一起给药。对静脉内施药,若需要,这些组合物可在输注前用适当的非口服稀释剂稀释。例如,本发明的组合物可在静脉内施药前用7倍的稀释剂(7:1)稀释。然而,使用的稀释系数和稀释剂取决于制剂中药物的浓度。然而,在静脉内注射前,本发明的组合物可在任何地方稀释,例如,在输注前,用约2倍量的适当的非口服稀释剂至约12倍量的适当的非口服稀释剂稀释。
在一实施方式中,本发明用于静脉内施药的组合物具有从约7.0至约9.5的范围内的pH。稀释的产品的pH优选为约7.0至约8.0。用于非口服用药的稀释制剂的渗透压,应该大约在约200mOsm/kg至约400mOsm/kg的范围内。用于给药的稀释的制剂的优选渗透压,应该大约在约270mOsm/kg至约330mOsm/kg的范围内。用于施用的稀释制剂的优选渗透压,应该为大约300mOsm/kg。
本发明的组合物的例子包括在约20mg/ml至约150mg/ml之间(例如,约25mg/ml、50mg/ml、75mg/ml、100mg/ml、125mg/ml、150mg/ml)的至少一种α,β-不饱和芳基砜(例如,(E)-4-羧酸苯乙烯基-4-氯苄基砜的钠盐(ON 01210.Na));其中组合物具有在约7到约10的范围内的pH值。优选的pH,例如,在约8到约9之间。例如,在约8.3和约8.7之间的pH值为优选。pH至约为8.5是优选实施例(在约8.4和约8.6之间)。例如,最优选的缓冲液为三羟甲基氨基甲烷-乙二胺四乙酸(Tris-EDTA),其对于施药的pH值具有良好的生理缓冲能力。本文描述的本发明典范的组合物具有最终浓度约0.2M的三羟甲基氨基甲烷和最终浓度为0.02M的乙二胺四乙酸。然而,该三羟甲基氨基甲烷浓度可在约0.005M至约0.5M的范围内(例如,或约0.005M至约0.5M“三羟甲基氨基甲烷-乙二胺四乙酸”)以适应施药的条件。本领域已知的适用于可注射的制剂的任何缓冲液,可在本发明的组合物中使用。适当的缓冲剂,例如,包括磷酸盐缓冲液例如正磷酸三钠、磷酸氢二钠,碳酸氢钠,以及柠檬酸钠,柠檬酸钾,N-甲葡糖胺,L(+)赖氨酸,甘氨酸和L(+)精氨酸,例如,这些缓冲剂在pH值约7-9.5之间具有良好的缓冲能力。
本发明的组合物的溶液例子包括在制剂中有效量的ON 01210.Na,该制剂中包括约10mg/ml至约100mg/ml之间的化合物(例如,ON 01210.Na);至少一种选自组的缓冲液,该组的组成为:三羟甲基氨基甲烷-乙二胺四乙酸、碳酸氢钠、柠檬酸钠、N-甲葡糖胺、L(+)赖氨酸、甘氨酸、L(+)精氨酸、和磷酸盐;在约20%w/v至约60%w/v的范围内的水溶性的助溶剂;在约0.1%w/v至约10%w/v的范围内的稳定剂,其中,该组合物的pH值在约8至9的范围内。这种类型的本发明的组合物的例子包括在约0.005M-0.5M的范围内的三羟甲基氨基甲烷-乙二胺四乙酸缓冲液;在约40%w/v至约60%w/v的范围内的PEG;其中组合物的pH值在约8.3至约8.7之间的范围内。此类型的优选实施例包括在约0.1M至约0.3M(例如0.2M)范围内的三羟甲基氨基甲烷-乙二胺四乙酸缓冲液;在约40%w/v至约60%w/v(例如,50%w/v)的范围内的PEG 400,其中,组合物的pH值在约8.3至约8.7之间的范围内(例如,在约8.4至约8.6之间)。
本发明的组合物的另一例子包括约20mg/ml至约60mg/ml的化合物(ON 01210.Na);在约0.15M至约0.25M的范围内的三羟甲基氨基甲烷-乙二胺四乙酸缓冲液;在约45%w/v至约55%w/v范围内的PEG 400,其中组合物的pH在约8.4至8.6的范围内,且在约25°C至约40°C,在至少约120天,化合物在组合物中是基本上稳定的。
本文描述的制剂优选具有在约7.5至约9.2范围内的pH值。优选高pH值,例如,约8.5。组合物优选为包括在约0.5%和约90%之间的至少一种助溶剂,例如,至少约10%、至少约20%、至少约25%、至少约30%、至少约35%、至少约40%、至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、和至少约90%。本文所用的术语“助溶剂”,包括但不限于本领域已知的水溶性赋形剂,该赋形剂包括水溶聚合物,例如聚乙二醇(PEG)(例如,PEG 400),聚丙二醇、聚甘油、二甲基乙酰胺(DMA),丙二醇,丙三醇,乙醇,山梨醇,和异丙醇。
例如,制剂的粘度可使用适当的粘度改性剂来调节,例如羧基甲基纤维素或本领域已知的任意类似的赋形剂。例如,参见药用辅料手册。该粘度改性剂为生物相容的且适用于非口服给药。悬浮剂的浓度可从0.1%至5%变化。优选的量在约1%的范围内。
本发明的药物组合物可口服地、直肠地、非口服、脑池内地(intracisternally)、阴道内地、腹膜内地、局部地(如通过粉末、油膏或液滴)、口地(bucally)、或作为口腔喷雾或鼻腔喷雾,施用于人类和其它动物。
在一些情况,为了延长药物的作用,期望减缓来自皮下注射或肌肉注射的药物的吸收。这可通过使用水溶性差的、结晶材料的或无定形材料的液体悬浮液来实现。药物的吸收率取决于它的溶解速率,反过来其可取决于晶体大小和晶形。或者,由将药物溶解或悬浮在油介质中,完成非口服给药形式的药物的延迟吸收。
通过形成可生物降解高分子药物微胶囊质,可得到可注射的储存形式,该可生物降解高分子例如聚乳酸-聚乙交酯。根据药物与聚合物的比值和使用的特定的聚合物的性质,可控制药物释放的速率。其它可生物降解高分子的实施例包括聚(原酸酯)和聚(酸酐)。储存可注射的制剂也可通过将药物包埋在与身体组织相容的脂质体或微乳液中来制备。
可注射的制剂可以通过,例如细菌保留过滤器(bacteria-retaining filter)进行过滤杀菌,或通过加入无菌固体组合物形式的灭菌剂进行杀菌,在使用前,将该无菌固体组合物溶解于或分散于无菌水或其他无菌可注射的介质中。
用于口服的固体剂量形式包括胶囊、片剂、丸剂、粉末、和颗粒。在此固体剂量形式中,活性化合物与至少一种惰性的药学上可接受的赋形剂或载体混合,该药学上可接受的赋形剂或载体例如柠檬酸钠或磷酸氢钙和/或(a)填料或填充剂例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇、和硅酸;(b)粘结剂,例如,羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖、和阿拉伯胶;(c)湿润剂例如丙三醇;(d)分裂剂例如琼脂、碳酸钙、土豆或木薯淀粉、藻酸、某些硅酸盐、和碳酸钠;(e)溶液阻滞剂例如石蜡;(f)吸收促进剂例如季铵类化合物;(g)润湿剂,例如,十六醇和单硬脂酸甘油酯;(h)吸收剂例如高岭土和膨润土;和(i)润滑剂例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠、及其混合物。在胶囊、片剂和丸剂中,剂型也可包括缓冲剂。
相似类型的固体组合物也可在软填充和硬填充胶囊中作为填料使用,该胶囊使用此种赋形剂例如乳糖或奶糖以及高分子量聚乙二醇等等。
固体剂型的片剂、胶囊、烷基、和颗粒可制备为具有涂层和壳体,例如肠溶衣和在药物制剂领域已知的其他涂层。可选择地,这些剂型可含有遮光剂,也可以为只释放活性成分的组合物,或优选地,在肠道的某部分,可选择地,以延迟的方式释放。可以使用的包埋组合物的实施例包括聚合物和蜡。
用于口服的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆剂、和万能药(elixirs)。除活性化合物以外,液体剂型可含有本领域常用的惰性稀释剂,例如,水或其他溶剂、增溶剂和乳化剂,这些稀释剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁烯二醇、二甲基甲酰胺、油(特别地,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、和芝麻油)、丙三醇、四氢糠醇、聚乙二醇和山梨聚糖的脂肪酸酯、及他们的混合物。
除了惰性稀释剂,口服组合物还可包括辅助药,例如润湿剂、乳化剂、和悬浮剂、增甜剂、调味剂、和芳香剂。
除了活性化合物,悬浮液可含有悬浮剂,例如,乙氧基化异硬脂醇、聚氧乙烯山梨醇和山梨醇酐酯、微晶纤维素、氢氧化铝氧化物(aluminium metahydroxide)、膨润土、琼脂和黄芪胶、及他们的混合物。用于直肠用药或阴道用药的组合物,优选为栓剂,其可由将本发明的化合物与合适的无刺激性的赋形剂或载体混合来制备,该赋形剂或载体例如可可油、聚乙二醇、或栓剂蜡;该栓剂蜡在室温为固体,但是在人体温度下为液体,因此在直肠腔或阴道腔中融化并释放活性化合物。
本发明由下列的实施例说明,然而,应该理解,本发明不限于这些实施例的具体细节。
实施例
实施例1.(E)-4-羧基苯乙烯基-4-氯苄基砜(ON 1210Na)在创伤治愈中的影响
评估测试物质ON 01210.Na溶液对于皮肤伤害的小鼠创伤治愈的可能影响。测试物质以两种给药方式进行皮下施药:第一种为在皮肤冲击前24小时15分钟给药,第二种为在皮肤冲击前4小时15分钟。在第1、3、5、7、9、11、13、15、17、19、21和22天测定创伤愈合的百分数(%),然后获得半愈合时间(CT50)。根据Dunnett测试来进行单因素方差分析,通过使用该测试来测定,在各个时间点的介质对照组和治疗组之间的显著差异,。在P<0.05的水平被认为是显著差异。结果总结在下面的表格中:
表1.(E)-4-羧基苯乙烯基-4-氯苄基砜(ON 1210Na)在创伤治愈的影响
测定了创伤愈合百分数(%)和创伤半愈合时间(CT50)。根据Dunnett测试的单因素方差分析被用于介质对照组和治疗组之间的比较。与介质对照组相比,*P<0.05。
对皮肤伤害的小鼠,以第一种给药方式(在皮肤冲击前24小时15分钟),进行皮下给药500mg/kg的ON 01210.Na溶液,促进了在第3天、第5天、第7天、第13天、第15天和第17天的创伤愈合的显著提高,显著减小CT50值(为7.2±0.3天,而介质对照组为9.4±0.6天)。然而,当在皮肤冲击前4小时15分钟,使用两次500mg/kg剂量的ON01210.Na溶液,有八分之二的动物在第二天死亡。在第一给药方式中,两次剂量间的间隔为3小时45分钟对23小时45分钟。死亡的原因未知。相似地,存活的动物在第13天和15天的创伤愈合百分数显著提高了;产生的CT50值(8.2±0.5天)比介质对照组稍低,但差别在统计上并不显著。
对皮肤伤害的小鼠,当500mg/kg的ON 01210.Na溶液,以两剂,在间隔23小时45分钟进行皮下(SC)给药时,促进了小鼠的创伤治愈,且CT50值显著地降低。
实施例2测试物质和配量方式
Onconova Therapeutics公司提供了预配置形式的ON 01210.Na。测试物质以两种配量方式进行皮下用药(SC),第一种为皮肤冲击前24小时15分钟,且第二种为皮肤冲击前4小时15分钟。按照第二种方式提供介质(ON 01210.Na空白溶液)的配量时间。配量的量为10mg/kg。
制剂的类型总结如下:
(a)根据目测
S:可溶的;SS:微溶 I:不溶解的(悬浮液或沉淀)
(b)Y:制剂保持在棕色的管或小瓶,或以铝箔覆盖。
N:没有光的保护
(c)RT:新鲜配制并在20-25°C保存。4°C:新鲜配制并在冰箱中保存或保持在冰中。
动物:BioLasco台湾公司(具有Charles River实验室技术执照)提供重量为24±2g的雄性ICR鼠。通过实验的皮肤伤害后,测试动物单独地居住在笼子(29x18x13cm)中。在MDS药物服务公司-台湾实验室,所有动物在使用之前,都供养在温度(21-23°C)和湿度(50%-70%)可控的环境中,有至少三天每天处于12小时的光/暗循环。使鼠类可以自由通往标准实验室的食物MF-18(Oriental Yeast股份有限公司,日本)]和反渗透(RO)水。一般根据实验室动物的照料和使用的指南(国家科学院,华盛顿,1996),来执行此工作的所有方面,包括住处、动物的实验和处理。
化学品:环己烯巴比妥(Sigma,美国),磷酸盐缓冲盐水(Sigma,美国)和氯化钠(Wako,日本)。
设备:动物笼(艾伦镇,美国),Image–ProPlus(Media Cybernetics,版本4.5.0.29),自动移液器(吉尔森,法国)和强烈冲击,内径12mm(Sinter,R.O.C.)。
方法:皮肤的创伤治愈
使用8只重量为24±2g的ICR雄性鼠的组。在研究中,被测试的动物居住于单独的笼子里。用环己烯巴比妥(90mg/kg,IP)麻醉后,每只动物的肩部和背部被剃干净。使用强烈冲击(内径12mm)来去除皮肤,包括肉膜和附着的组织。测试物质以两种配量方式皮下施药,第一种为在皮肤冲击前24小时15分钟,且第二种为在皮肤冲击前4小时15分钟,介质(ON 01210.Na空白溶液)以第二种配量方式使用。通过使用Image–ProPlus(Media Cybernetics,版本4.5.0.29),在第1天、第3天、第5天、第7天、第9天、第11天、第13天、第15天、第17天、第19天、第21天和第22天,将创伤区域描绘在透明的塑料板上。计算创伤的愈合百分数(%),且使用Graph-Prism(美国图表软件)由线性回归分析创伤半愈合时间(CT50)。Dunnett测试进行的单因素方差分析被应用于在每个测试时间点治疗组和介质组之间的比较。在P<0.05时,认为这些差异有统计学意义。
表2在鼠的皮肤的创伤治愈(第1天至第11天)
表3鼠的皮肤的创伤治愈(第13天至第22天)
测试物质以两种配量方式进行皮下施药(SC),第一种为在皮肤冲击前24小时15分钟,第二种为在皮肤冲击前4小时15分钟;介质的配量时间(ON 01210.Na空白溶液)为第二种方式。可确定创伤愈合百分数(%)和创伤半愈合时间(CT50)。通过Dunnett测试进行的单因素方差分析被应用于治疗组和介质组之间的比较。与介质对照组相比,*P<0.05。
等同实施例
以上对实施例的描述仅用于举例,并不是对本发明实施方式的范围的限制。其他没有具体描述的实施方式对于本领域的技术人员也应该是明显的。然而,认为那些实施方式也属于本发明的范围和精神内。因此,本发明仅由本发明的权利要求进行适当地限定。
Claims (20)
1.一种促进创伤造成的损伤组织的快速治愈和/或再生方法,所述方法包括向病患施用其所需的治疗有效量的药物组合物,该组合物包括(E)-羧基苯乙烯基-4-氯苄基砜的化合物,或其官能化衍生物;和药学上可接受的赋形剂,其中所述的药物组合物促进损伤组织的快速治愈和/或再生,同时保留组织的原组成,且最大限度的减少并发症和疤痕。
2.根据权利要求1所述的方法,其特征在于,创伤产生之前,向病患用药。
3.根据权利要求2所述的方法,其特征在于,创伤产生之前4小时,向病患用药。
4.根据权利要求2所述的方法,其特征在于,创伤产生之前24小时,向病患用药。
5.根据权利要求1所述的方法,其特征在于,所述(E)-羧酸苯乙烯基-4-氯苄基砜化合物为ON 01210.Na。
6.根据权利要求5所述的方法,其特征在于,将ON 01210.Na制成水溶液组合物,所述水溶液组合物包括在约20mg/ml至约100mg/ml之间的ON01210.Na;至少一种助溶剂,所述助溶剂包括聚乙二醇(PEG)、聚丙二醇、聚甘油、二甲基乙酰胺(DMA)、丙二醇、丙三醇、乙醇、山梨醇、和异丙醇、或他们的结合,所述助溶剂的量在约25%和约90%w/v之间,其中,所述组合物的pH在约7.0至约9.5的范围内。
7.根据权利要求1所述的方法,其特征在于,所述组合物由非口服途径施用。
8.根据权利要求1所述的方法,其特征在于,所述组合物由局部途径施用。
9.根据权利要求1所述的方法,其特征在于,所述组合物由口服途径施用。
10.一种控制或减轻与创伤或损伤的组织相关的疼痛的方法,该方法包括向病患施用其所需的治疗有效量的药物组合物,所述药物组合物包括(E)-4-羧基苯乙烯基-4-氯苄基砜、或其官能化衍生物;其中与对照组未治疗过的病患相比,用所述组合物治疗的病患证实了,加速的治愈过程,并且减轻了与创伤或损伤的组织相关的炎症的严重度。
11.根据权利要求10所述的方法,其特征在于,当创伤发生三天后测量时,与对照组未治疗过的病患相比,用所述组合物治疗的病患的所述治愈过程至少快4倍。
12.根据权利要求10所述的方法,其特征在于,创伤产生之前,向病患用药。
13.根据权利要求10所述的方法,其特征在于,创伤产生之前4小时,向病患用药。
14.根据权利要求10所述的方法,其特征在于,创伤产生之前24小时,向病患用药。
15.根据权利要求10所述的方法,其特征在于,所述(E)-4-羧基苯乙烯基-4-氯苄基砜化合物为ON01210.Na。
16.一种减轻或改善与哺乳动物的组织破坏或功能紊乱相关的病症的症状方法,所述方法包括向病患施用其所需的治疗有效量的药物组合物,该药物组合物包括与一种或多种抗炎症化合物结合的(E)-4-羧基苯乙烯基-4-氯苄基砜、或其官能化衍生物;药学上可接受的载体或稀释剂,其中所述药物组合物抑制炎症路径的一种或多种组分,并且减轻了哺乳动物中所述症状的严重程度。
17.根据权利要求16所述的方法,其特征在于,所述组织破坏或功能紊乱包括热致皮肤损伤、癌症切除、息肉、溃疡、褥疮、痤疮、皮肤真菌感染、或他们的组合。
18.根据权利要求10所述的方法,其特征在于,所述创伤为刀伤、撕裂伤、穿透伤、穿孔伤、刺穿伤、开放伤、或皮下伤、或他们的结合。
19.根据权利要求15所述的方法,其特征在于,所述创伤为疾病或病症、手术、意外、或他们的结合的结果。
20.根据权利要求15所述的方法,其特征在于,所述创伤为外伤、内伤、或他们的结合。
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PCT/US2011/029817 WO2011119848A1 (en) | 2010-03-24 | 2011-03-24 | Compositions and methods for prevention and treatment of wounds |
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RU2634576C1 (ru) * | 2016-10-24 | 2017-10-31 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Способ стимуляции регенерации тканей |
WO2018151838A1 (en) * | 2017-02-17 | 2018-08-23 | Mayo Foundation For Medical Education And Research | Methods and materials for reducing scar formation during wound healing |
PL3691620T3 (pl) | 2017-10-05 | 2022-11-21 | Fulcrum Therapeutics, Inc. | Inhibitory kinazy p38 zmniejszają poziom ekspresji genu dux4 i dalszych genów do leczenia fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
CN117599033A (zh) * | 2023-10-25 | 2024-02-27 | 华南师范大学 | 一种抗皮肤老化制剂及其应用 |
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US20030060505A1 (en) * | 2001-02-28 | 2003-03-27 | Reddy E. Premkumar | Method for protecting cells and tissues from ionizing radiation toxicity with alpha, beta unsaturated aryl sulfones |
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US20110250184A1 (en) * | 2008-12-16 | 2011-10-13 | Onconova Therapeutics ,Inc. | Methods for determining efficacy of a therapeutic regimen against deleterious effects of cytotoxic agents in human |
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US20030060505A1 (en) * | 2001-02-28 | 2003-03-27 | Reddy E. Premkumar | Method for protecting cells and tissues from ionizing radiation toxicity with alpha, beta unsaturated aryl sulfones |
CN1718212A (zh) * | 2005-04-25 | 2006-01-11 | 王本明 | 一种治疗筋骨病的骨病贴膏及其制备方法 |
WO2007016201A2 (en) * | 2005-07-29 | 2007-02-08 | Onconova Therapeutics, Inc. | FORMULATION OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES |
WO2008105808A2 (en) * | 2006-07-28 | 2008-09-04 | Onconova Therapeutics, Inc. | FORMULATIONS OF RADIOPROTECTIVE α, β UNSATURATED ARYL SULFONES |
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KR20130008593A (ko) | 2013-01-22 |
US20130012588A1 (en) | 2013-01-10 |
EP2549867A4 (en) | 2013-08-14 |
JP2013522374A (ja) | 2013-06-13 |
EA022360B1 (ru) | 2015-12-30 |
US9044427B2 (en) | 2015-06-02 |
JP5882296B2 (ja) | 2016-03-09 |
WO2011119848A1 (en) | 2011-09-29 |
MX336278B (es) | 2016-01-13 |
EP2549867A1 (en) | 2013-01-30 |
EA201270747A1 (ru) | 2013-02-28 |
AU2011232326A1 (en) | 2012-10-04 |
MX2012010845A (es) | 2012-10-15 |
CA2792883A1 (en) | 2011-09-29 |
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