CN118252832A - Vofopitant用于治疗硬皮病的用途 - Google Patents
Vofopitant用于治疗硬皮病的用途 Download PDFInfo
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- CN118252832A CN118252832A CN202211685438.9A CN202211685438A CN118252832A CN 118252832 A CN118252832 A CN 118252832A CN 202211685438 A CN202211685438 A CN 202211685438A CN 118252832 A CN118252832 A CN 118252832A
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- Prior art keywords
- vofopitant
- scleroderma
- treatment
- present disclosure
- skin
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Abstract
本公开涉及Vofopitant用于治疗硬皮病的用途。通过博莱霉素诱导皮肤纤维化小鼠模型进行的实验结果表明,Vofopitant能够明显减少皮肤胶原沉积和皮肤增厚,由此治疗硬皮病。
Description
技术领域
本公开属于Vofopitant和硬皮病治疗技术领域,具体涉及Vofopitant用于制备治疗硬皮病的药物的用途。
背景技术
硬皮病的发病率为(2.3~22.8)例/(100万人·年),患病率为(50~300)例/100万人,是一种系统性的自身免疫性疾病。硬皮病患者除皮肤增厚硬化外,还可出现雷诺现象、指端溃疡、毛细血管扩张、甲翳毛细血管异常等,内脏受累则表现为间质性肺病变、肺动脉高压和胃食管反流等,常伴特异性自身抗体的出现。系统性硬化病发病机制复杂,目前认为在遗传及环境因素促发下,血管微循环被破坏,血管内皮细胞损伤,免疫系统紊乱,效应细胞释放多种细胞因子,成纤维细胞激活增殖,胶原等细胞外基质过度沉积,导致组织纤维化。
硬皮病是一种复杂的异质性疾病,其发病基础尚不明确,近期的报道显示,环磷酰胺、吗替麦考酚酯、利妥昔单抗、自体干细胞移植和IL-6单抗可能延缓硬皮病合并间质性肺病的进展。
然而目前尚无能改变硬皮病病程的治疗方式,需要进一步开发硬皮病的治疗药物。
Vofopitant,IUPAC名称为(2S,3S)-N-{2-甲氧基-5-[5-(三氟甲基)-1H-四唑-1-基]苄基}-2-苯基-3-哌啶胺((2S,3S)-N-{2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}-2-phenyl-3-piperidinamine),也称为沃氟匹坦或沃伏吡坦,是一种有效、选择性的,口服有效的速激肽NK1受体拮抗剂,用作镇吐药,其结构式如下:
目前,尚无Vofopitant治疗硬皮病的报道。
发明内容
本公开一方面提供Vofopitant用于制备治疗硬皮病的药物的用途。
本公开另一方面提供Vofopitant,其用于治疗硬皮病。
本公开另一方面提供一种用于治疗硬皮病的药物组合物,其包含治疗有效量的Vofopitant。
本公开又一方面提供一种治疗硬皮病的方法,包括向受试者给予治疗有效量的Vofopitant。
在实施方式中,Vofopitant包括其药学上可接受的盐、溶剂化物、N-氧化物、多晶型物、前体药物、立体异构体、外消旋体。
在实施方式中,Vofopitant为其盐酸盐。
在实施方式中,所述药物包含Vofopitant作为唯一的用于治疗硬皮病的活性成分。
在实施方式中,所述硬皮病为局限性硬皮病或弥漫性硬皮病。
在实施方式中,Vofopitant通过减少胶原沉积来治疗硬皮病。
在实施方式中,Vofopitant通过注射或局部给药。
附图说明
图1是显示皮肤纤维化模型小鼠的肺组织病理学染色的图。
具体实施方式
本公开一方面提供Vofopitant用于制备治疗硬皮病的药物的用途。
本公开另一方面提供Vofopitant,其用于治疗硬皮病。
本公开另一方面提供一种用于治疗硬皮病的药物组合物,其包含治疗有效量的Vofopitant。
本公开又一方面提供一种治疗硬皮病的方法,包括向受试者给予治疗有效量的Vofopitant。
通过博莱霉素诱导皮肤纤维化小鼠模型进行的实验结果表明,Vofopitant能够明显减少胶原沉积和皮肤增厚,由此治疗硬皮病,特别是局限性硬皮病。
硬皮病(Scleroderma),也称全身性硬化症(Systemic sclerosis),根据皮肤受侵犯的程度,硬皮病可以分为局限性硬皮病和弥漫性硬皮病。局限性硬皮病的患者仅远端肢体皮肤增厚,躯干不受侵犯。CREST综合征包括:钙质沉积、雷诺现象、食管功能障碍、指端硬化和毛细血管扩张,归属于局限性硬皮病范畴。弥漫性硬皮病患者表现为肢体远端及近端和/或躯干皮肤增厚。
在本公开中使用的短语“治疗有效量”指的是足够在患者体内激发治疗生理性和药理性反应的活性物质的量。优选所述活性物质的有效量激发所需的生理性和药理性反应而不产生副作用。
在本公开中,受试者被定义为需要Vofopitant的任何人或者非人类的动物,或者对其而言用Vofopitant进行治疗可能是有益的任何对象,包括人或者非人类的动物。这些将被治疗的非人类动物包括所有驯化的和野生的脊椎动物。要治疗的非人类的动物包括所有驯养的或野生的脊椎动物,包括,但不限于,小鼠、大鼠、兔子、鱼、鸟、仓鼠、狗、猫、猪、羊、马、牛和非人类的灵长类动物。在进行治疗的时候,所述受试者可以具有任何一种本公开活性物质的稳态血浆水平。
本公开中使用的术语“治疗”包括预防性治疗模式和根据病症的治疗模式两者,指的是减轻或缓解受试者的硬皮病的症状,和/或预防硬皮病的复发和/或进展。
对受试者的治疗包括给予治疗有效量的Vofopitant。本领域的普通技术人员可以凭经验来确定施用Vofopitant的最佳剂量和疗程剂量。然而,治疗有效量是能减轻或缓解受试者的硬皮病的症状,和/或预防硬皮病的复发和/或进展的量。
在整个疗程中可以用一次剂量或多次剂量来施用治疗有效量。本公开的Vofopitant可通过本领域技术人员所熟悉的任何方式施用,例如,Vofopitant可以通过静脉、腹膜内(IP)、体内、关节内、心室内、鞘内、肌内、皮下、局部、扁桃体、粘膜、鼻内、经皮、阴道内、口服或吸入施用。
在本公开中使用的Vofopitant包括其药学上可接受的盐、溶剂化物(包括水合物)、N-氧化物、多晶型物、前体药物、立体异构体、外消旋体或者其它任何形式。这些形式在体内能提供Vofopitant活性形式。
所述药学上可接受的盐,与活性化合物的游离形式相比,可能赋予活性化合物改善的药物动力学特性。所述药学上可接受的盐也可能赋予活性化合物之前不具备的所期望的药物动力学特性,并且相对于其在体内的治疗活性甚至可以正面影响该活性化合物的药效。
所述药学上可接受的盐可以通过用足够量的药学上可接受的有机或无机酸处理活性化合物的游离碱形式来形成。无机酸盐的实例非限制性地包括:氢卤化物,例如盐酸盐、氢溴酸盐、氢碘酸盐;其它无机酸及其相应的盐,例如硫酸盐、硝酸盐、硫酸氢盐、亚硫酸氢盐、磷酸一氢盐、磷酸二氢盐、磷酸盐、偏磷酸盐等。有机酸盐的实例非限制性地包括:烷基-和单芳基磺酸盐,例如甲烷磺酸盐、乙烷磺酸盐、氢磺酸盐、2-羟基乙烷磺酸盐、羟乙基磺酸盐、甲苯磺酸盐、2-萘磺酸盐和苯磺酸盐;和其它有机酸盐,例如乙酸盐、己二酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、樟脑柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、二硝基苯甲酸盐、十二烷基硫酸盐、富马酸盐、半乳糖二酸盐、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、丙二酸盐、扁桃酸盐、甲基苯甲酸盐、烟酸盐、硝酸盐、乙二酸盐、油酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、膦酸盐和邻苯二甲酸盐等。
在一些实施方式中,所述药学上可接受的盐是盐酸盐。
Vofopitant及其药学上可接受的盐、N-氧化物、前体药物、立体异构体、外消旋体、轭合物、络合物等可以吸收溶剂(例如水)而形成溶剂合物(例如水合物)。因此,本公开的Vofopitant也包括这些溶剂合物。
Vofopitant中的胺基也可能形成N-氧化物。本公开的Vofopitant也包括这些N-氧化物。
Vofopitant及其药学上可接受的盐、N-氧化物、前体药物、立体异构体、外消旋体、轭合物、络合物等可以与溶剂(例如水)形成多晶型物。在某些实施方式中,这些多晶型物可能提供额外的益处,例如更高的溶解度、更快的溶解速度、更高的生物利用度、更低的毒副作用等。因此,本公开的Vofopitant也包括这些多晶型物。
Vofopitant也存在一些前体药物,能够在体内通过酶解等转化为Vofopitant活性形式。例如所述前体药物可能是酰胺化合物,在体内被酶解而转化为Vofopitant活性形式。因此,本公开的Vofopitant也包括这些前体药物。
Vofopitant结构中存在手型分子,因此存在立体异构体。这些立体异构体通常也具有Vofopitant活性成分的部分活性。因此,本公开的Vofopitant也包括这些立体异构体。“立体异构体”指的是具有相同分子式并且其原子以相同的顺序结合在一起但是其原子在空间上的配置不同的化合物。立体异构体包括对映异构体(也称为旋光异构体,其为镜象和具有相等但是相反旋光率的立体异构体)和非对映异构体(没有镜象的立体异构体)。本公开所述的Vofopitant可以是单独的对映异构体、非对映异构体、阻转异构体或几何异构体的形式,或者可以是立体异构体混合物的形式,包括外消旋混合物和富含一种或多种立体异构体的混合物。
本公开中的药物或药物组合物可以包含药学上可接受的载体。
本公开中使用的术语“载体”包括可接受的稀释剂、赋形剂、佐剂、介质、增溶助剂、粘度调节剂、防腐剂和用于在给予受试者的最终药物或药物组合物中提供有利性质的其它已知试剂。
更具体而言,本公开药物或药物组合物中可以包含的载体包括:用于得到所需或者预先确定的pH值的酸化剂或者碱化剂;抗微生物剂(包括抗细菌剂、抗真菌剂和抗原虫剂);用于保护药物组合物的组分免于破坏或者降解的抗氧化剂;用于保持所需pH值的缓冲剂;用于保持离子强度的螯合剂;分散剂和悬浮剂;乳化剂;赋形剂;防腐剂;稳定剂;糖;填料;稀释剂;溶剂;甜味剂;气味剂;香味剂;润滑剂和表面活性剂。这些各种类型的载体的实例对于本领域中的技术人员而言是已知的。
根据所需的给药途径,本公开的药物或药物组合物可以制备成任何适合的剂型。例如,本公开的药物或药物组合物可以是口服剂型,例如糖浆剂、片剂、胶囊剂或锭剂等;适合吸入给药的剂型,例如干粉、溶液、分散液、气雾剂等;注射剂型,例如用于胃肠外注射、真皮内注射、皮下注射、肌肉注射或者静脉注射的剂型。本公开的药物或药物组合物可以是控释制剂或速释制剂。
药物制剂可以用在药物领域内的任何已知方法制备。通常,可以将活性化合物与液体载体或者固体载体或者两者均匀和精细地混合,然后,如果需要,将所述产物成型或者包装为所需制剂。
本公开的药物或药物组合物可以是用于胃肠外、真皮内或者皮下施用的制剂,其可以包括:无菌稀释剂比如水、盐溶液、非挥发性油、聚乙二醇、甘油、丙二醇或者其它的合成溶剂;抗菌剂例如苯甲醇或者对羟基苯甲酸甲酯;抗氧化剂比如抗坏血酸或者亚硫酸氢钠;螯合剂比如乙二胺四乙酸;缓冲剂例如乙酸盐、柠檬酸盐或者磷酸盐;用于调节渗透压的试剂例如氯化钠或者葡萄糖;用于调节pH值的试剂包括酸例如盐酸和碱例如氢氧化钠。该制剂可以被封装在由玻璃或者塑料制成的安瓿、一次性注射器或者多剂量瓶中。
适于可注射应用的本公开的药物或药物组合物包括无菌水溶液或者分散液和用于即时制备无菌可注射溶液或者分散液的无菌粉末。除了活性成分以外,本公开的药物或药物组合物可以包含载体、表面活性剂、抗菌剂、抗真菌剂、等渗剂、延迟吸收的试剂等。载体可以是溶剂或者分散介质,例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)及其适合的混合物,特别是生理盐水、抑菌水或者磷酸盐缓冲盐水。抗菌剂和抗真菌剂例如对羟基苯甲酸酯类、三氯叔丁醇、苯酚、抗坏血酸、硫柳汞等。等渗剂例如糖,例如甘露糖醇、山梨糖醇的多元醇,或氯化钠。延迟吸收的试剂例如单硬脂酸铝和明胶。
本公开的药物或药物组合物也可以是用于局部给药的制剂,例如局部给药于皮肤的制剂。所述制剂可以是凝胶、乳膏、软膏、乳剂、洗剂、糊剂、泡沫、悬浮液或喷雾贴剂。或者可以是含药的膏药、贴剂或者膜片的形式。
用于局部给药的本公开的药物或药物组合物可以包含适于局部给药于受试者皮肤的载体。载体可以包含例如,增溶剂、缓冲剂或两者。载体也可以是包含亲水相成分和疏水相成分的混合物。如以下所描述的,载体还可以包含一种或多种附加的组分以便产生局部形式,如增稠剂或胶凝剂、防腐剂、抗氧化剂、渗透促进剂、乳化剂、润肤剂或湿润剂,但不限于此。
增溶剂例如选自醇,如糖醇、二醇、多元醇、聚醚醇、脂肪酸、有机溶剂、蜡、油、泊洛沙姆、环糊精或其任何组合,但不限于此。例如,增溶剂可以是甘油、聚乙二醇、丙二醇、泊洛沙姆124、泊洛沙姆407、羟丙基环糊精(HPB)、磺丁基β-环糊精或其任何组合,但不限于此。
亲水相成分例如选自水、甘油、聚丙二醇、聚乙二醇、乙醇、苯甲醇、1,3-丙二醇、1,2-戊二醇、碳酸丙烯酯、2-(2-乙氧基)乙醇、二甲基异山梨醇、四甘醇、吡咯烷酮、二甲基乙酰胺、辛酰己酰聚氧甘油酯-8、己二醇、丁二醇或其任何组合,但不限于此。亲水相成分也可以包括水性缓冲溶液。例如,亲水相成分可以包括0.01M至1.0M柠檬酸盐、磷酸盐、Tris、碳酸盐、琥珀酸盐、酒石酸盐、硼酸盐、咪唑、马来酸盐或pH为4.5至9.0的邻苯二甲酸盐缓冲液,但不限于此。
疏水相成分例如选自芳族烃、烷烃、环烷烃、炔烃、萜烯、有机油、矿物油或其任何组合,但不限于此。示例性疏水相成分选自矿物油、异硬脂酸异丙酯、异硬脂酸异硬脂、烃基安息香酸盐、硬脂酸丁酯、己二酸二异丙酯、己二酸二乙基己酯、辛酸/癸酸甘油三酯、异鲸蜡醇硬脂酸酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、月桂醇乳酸酯、肉豆蔻酸肉豆蔻酯、椰油酸辛酯、棕榈酸乙基己酯、壬酸乙基己酯、硬脂酸辛酯、琥珀酸二乙基己酯、丙二醇二辛酸酯/二癸酸酯、PPG-2肉豆蔻醚丙酸酯、季戊四醇四辛酸酯/癸酸酯、季戊四醇四异硬脂酸酯、PEG二硬脂醇醚、硬脂醇聚醚-21、以及异十三烷醇异壬酸醇,但不限于此。
增稠剂或胶凝剂例如选自羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、黄原胶、卡波姆、聚维酮、泊洛沙姆、聚酰胺-3,以及其它适当的试剂,但不限于此。
防腐剂例如选自苯扎氯铵、对羟基苯甲酸酯、山梨酸及其盐、苯甲酸及其盐、西曲溴铵和氯盐、苯氧乙醇和其它试剂,但不限于此。
抗氧化剂例如选自焦亚硫酸钠、抗坏血酸、生育酚乙酸酯、2,6-二叔丁基对甲酚(BHT)或丁基羟基茴香醚(BHA),但不限于此。
渗透增强剂例如选自二甘醇单乙醚或二甲基异山梨醇,但不限于此。
乳化剂例如选自Tween、Span、泊洛沙姆、聚氧乙烯硬脂醇醚(例如Brij S2和Brij721)、Crodex M、Crodafos CES、聚乙二醇脂肪酸酯DPHS或聚乙二醇羟基硬脂酸酯,但不限于此。
润肤剂例如选自辛酸-癸酸甘油三酯、异硬脂酸异丙酯、异硬脂酸异硬脂(Crodamol ISIS)、PPG-11硬脂醇醚(Arlamol PS HE)、聚乙二醇6甘油癸酸酯(Glycerox767HC)或(辛酰己酰聚氧甘油酯-8),但不限于此。
湿润剂例如选自甘油、丙二醇、1,3-丙二醇或1,2-戊二醇,但不限于此。
用于局部给药的本公开的药物或药物组合物还可以包含挥发性溶剂,该挥发性溶剂在涂敷后至少部分从皮肤表面蒸发。该挥发性溶剂例如是水。
用于局部给药的本公开的药物或药物组合物可以使用常规技术进行局部给药。例如,可以通过将药物组合物的等分试样递送至医生或受试者的手上来进行给药,这用于将药物或药物组合物涂抹并且然后摩擦至身体部位上期望治疗的皮肤区域上。在喷雾贴剂的情况下,药物组合物可以使用任何适合的机制进行喷涂,如气溶胶、雾、喷雾瓶等。
本公开的药物或药物组合物也可以是适于口服的制剂。所述口服制剂可以以含有预先确定量的活性化合物的离散单元的形式例如胶囊、扁胶囊或药片存在。所述制剂可以是粉末或者颗粒;在水或者非水液体中的溶液或者悬浮液;或者水包油液体乳液或者油包水液体乳液;或者丸剂或者糊剂。
本公开的口服药物或药物组合物一般包括惰性稀释剂、可食用载体、赋形剂、粘合剂、崩解剂、滑爽剂、助流剂、增香剂等。粘合剂可包括,例如,微晶纤维素、黄蓍树胶或明胶。赋形剂可包括,例如,淀粉或乳糖。崩解剂可包括,例如,藻酸或玉米淀粉。滑爽剂可包括,例如,硬脂酸镁。助流剂可包括,例如,胶体二氧化硅。增香剂可包括,例如,薄荷、水杨酸甲酯或柑橘香料。
当口服组合物为糖浆剂的形式时,该制剂一般由在液体载体中的所述化合物或盐的悬浮液或溶液组成。液体载体的实例为:乙醇、花生油、橄榄油、甘油或者水。
当所述组合物为片剂的形式时,可以使用常规用于制备固态剂型的任何药物载体,包括:硬脂酸镁、石膏粉、滑石粉、明胶、阿拉伯胶、硬脂酸、淀粉、乳糖和蔗糖。药片可以通过非必须地与一种或多种辅助成分一起压缩或者模压来制备。
当所述组合物为胶囊剂的形式时,任何常规胶囊化方法都是适合的,例如硬或软明胶胶囊壳。
在控释制剂中,可以使用可生物降解的和/或生物相容的聚合物,例如聚维酮、共聚维酮、羟丙纤维素、乙烯-乙酸乙烯酯共聚物、聚酐、聚乙醇酸、胶原、聚原酸酯和聚丙烯酸。
本公开的药物或药物组合物可以为单位剂型,例如药片、胶囊或者计量的气雾剂剂量,以便可以将单一剂量给予受试者。
本公开的药物或药物组合物可以以单一方式给药,也可以以多种方式联合给药,这取决于需要的是局部还是系统治疗以及待治疗的区域。在以不同的剂型给药联合给药时,可以同时给药,或者可以时间相隔很近给药或者相隔很远给药,例如一种剂型在上午给药而另一种剂型在晚上给药。
获得治疗效果所需的本公开的药物或药物组合物的准确量将随着对象而变,取决于对象的物种、年龄、体重和总体状况、被治疗病状的严重性、所使用的具体活性药剂、其给药方式等。用于本公开的药物或药物组合物给药的剂量范围大的足以产生治疗效果。可以对剂量进行调整以避免或减轻不利副作用、例如不想要的交叉反应、过敏反应等的发生。剂量可以随着患者的年龄、状况、性别和疾病程度、给药途径或治疗方案中是否包含其他药物而变化。在发生任何相反指征的情况下,剂量可以由单独的医师调整。剂量可以改变,并可以每天给药一剂或多剂,给药一天或几天。对于给定类型的药物产品来说,适合剂量的指导方针可以在文献中发现。
例如,本公开的药物或药物组合物的给药可以是每月一次、每两周一次、每周一次、每三天一次、每天1~6次等,但不限于此。在一个实施方式中,本公开的药物或药物组合物每天给药一次。
本公开的药物或药物组合物中,Vofopitant可以是唯一的用于治疗硬皮病的活性成分,或者本公开的药物或药物组合物还可以含有用于治疗硬皮病的其他活性成分。所述其他活性成分可以是任何已知的用于治疗硬皮病的药物。所述其他活性成分可以是用于治疗硬皮病的一个或多个症状的药物。例如所述其他活性成分可以选自:用于治疗硬皮症肾危机的药物,例如血管紧张肽I转化酶抑制剂、钙离子通道阻滞剂、血管紧张素II受体拮抗剂等;用于治疗肺动脉高压的药物,例如内皮素受体激动剂、第五型磷酸二酯酶抑制剂或前列腺素;用于治疗雷诺氏综合征的药物,例如血管扩张剂、钙离子通道阻滞剂、第五型磷酸二酯酶抑制剂、血管紧张素II受体拮抗剂、前列腺素等;用于治疗间质性肺病的药物,例如环磷酰胺、霉酚酸酯、anti CD20 Rituximab、尼达尼布等,但不限于此。
此外,所述其他活性成分可以是用于治疗瘙痒的药物,例如选自:皮质类固醇、地托咪定、多塞平、他克莫司、吡美莫司、普莫卡因、利多卡因、丙胺卡因、氯胺酮、阿米替林、辣椒素、薄荷醇、樟脑、托法替尼、克瑞沙泊、N-棕榈酰乙醇胺、抗组胺药、5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)、选择性血清素再摄取抑制剂(SSRI)、纳曲酮、布托啡诺、纳呋拉啡、加巴喷丁、普瑞巴林、阿瑞匹坦、沙利度胺、来那度胺、熊去氧胆酸、利福平、消胆胺、苯巴比妥、A型肉毒毒素、纳洛酮、ASN008、SNA-125、TS-022、KPL-716和奥维匹坦。
皮质类固醇例如选自阿氯米松、安西奈德、倍氯米松、倍他米松、布地奈德、环索奈德、氯倍他索、氯倍他松、氯可托龙、可的松、地奈德、去羟米松、地塞米松、二氟拉松、氟轻松、氟可龙、氟泼尼定、氟氢缩松、氟替卡松、哈西奈德、卤倍他索、卤米松、氢化可的松、莫米松、甲基强的松龙、泼尼卡酯、泼尼松龙、强的松、替可的松、去炎松。
抗组胺药例如选自阿伐斯汀、氮卓斯汀、比拉斯汀、溴苯海拉明、溴苯那敏、安其敏、卡比沙明、西替利嗪、氯苯海拉明、扑尔敏、氯马斯汀、赛克利嗪、赛庚啶、地氯雷他定、右溴苯那敏、右扑尔敏、茶苯海明、二甲茚定、苯海拉明、抗敏安、依巴斯汀、恩布拉敏、非索非那定、羟嗪、左卡巴斯汀、左西替利嗪、氯雷他定、氯苯甲嗪、米氮平、奥洛他定、奥芬那君、苯茚胺、苯吡胺、苯托沙敏、异丙嗪、新安特甘、卢帕他定、曲吡那敏以及曲普利啶。
SNRI例如选自文拉法辛、度洛西汀、米那普仑、米氮平和左米那普仑。
SSRI例如选自氟西汀、氟伏沙明、帕罗西汀、舍曲林、西酞普兰和依他普仑。
在受试者同时还具有其他疾病、紊乱、病症时,本公开的药物或药物组合物可以与用于治疗这些疾病、紊乱、病症的药物同时给药,或者可以时间相隔很近给药或者相隔很远给药。
在上文中已经详细地描述了本发明,但是上述实施方式本质上仅是例示性,且并不欲限制本发明。此外,本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。
实施例
以下实施例将结合附图对本发明作进一步说明。
下述实施例所使用的实验方法如无特殊说明,均为常规方法。
下述实施例所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
试剂和仪器
博莱霉素购买自MCE(HY-17565A),vofopitant dihydrochloride购买自MCE(HY-12143),福沙匹坦购买自MCE(HY-14407A)。C57BL/6小鼠购自维通利华。
磷酸盐缓冲生理盐水(PBS)购自MCE,含有8.01g/L的NaCl,0.20g/L的KCl,1.78g/L的Na2HPO4·2H2O,0.27g/L的KH2PO4,pH 7.4。
Vofopitant注射溶液如下配制:称取30mg的vofopitant溶解于5ml生理盐水中,涡旋震荡,使其充分溶解,用1.5mlEP管进行分装用于后续实验。
福沙匹坦注射溶液如下配制:称取30mg的福沙匹坦溶解于5ml生理盐水中,涡旋震荡,使其充分溶解,用1.5mlEP管进行分装用于后续实验。
福沙匹坦(Fosaprepitant),IUPAC名称为([3-[[(2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)-4-吗啉基]甲基]-2,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]膦酸((2S,3S)-N-{2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}-2-phenyl-3-piperidinamine),也称为福沙吡坦,是阿瑞匹坦(Aprepitant)的前药,是一种神经激肽-1受体(neurokinin-1 receptor)拮抗剂,被开发用于预防化疗引起的恶心呕吐(CINV),结构式如下:
动物实验方法:
1.动物分组及给药
8周大的C57BL/6小鼠(体重18g左右)购自维通利华。所有小鼠均在中国科学院上海高等研究所无特异性病原体室饲养,以7只为一笼饲养。小鼠可随意获得标准实验室食物和水。实验人员在无病原体条件下进行了实验,照料小鼠的人员定期检查它们的健康状况。未观察到不良事件。所有动物实验均得到中国科学院上海高等研究所动物护理和使用委员会批准。小鼠被随机分成对照组、博莱霉素模型组、vofopitant组、福沙匹坦组,每组7只小鼠。
小鼠硬皮病模型的构建
隔天在小鼠背部皮下注射100ul博来霉素(1mg/ml,以PBS为溶剂),注射6周。注射区域为小鼠背部1cm*1cm正方形区域,事先剃毛,每次注射从正方形四角向区域中心进针,四角轮换进针。
从第4周开始,每组小鼠分别接受PBS 5ml/Kg(博莱霉素模型组)、vofopitantdihydr ochloride 30mg/kg(vofopitant组)、福沙匹坦30mg/kg(福沙匹坦组)腹腔注射。第42天牺牲所有小鼠,收取皮肤组织。
2.皮肤组织病理学染色
取各组小鼠皮肤组织,于4%甲醛溶液中固定24h、脱水、石蜡包埋、切片(厚度4μm),行苏木精-伊红(HE)染色和Masson三色染色。使用光学显微镜(200×)观察皮肤组织病理形态并采集图像,
3.动物实验结果分析:
HE染色结果见图1的上图,如图所示,对照组小鼠皮肤组织具有完整的毛囊结构及正常的的皮下脂肪层,皮肤厚度均一;博莱霉素模型组小鼠皮肤组织与对照小鼠相比皮肤厚度增加,皮下脂肪层减少,但是毛囊结构并未遭到破坏;福沙匹坦组皮肤小鼠组织与博莱霉素组小鼠相比皮肤厚度并未得到显著改善。与博莱霉素模型组比较,vofopitant组小鼠的皮肤厚度得到显著挽救,与福沙匹坦组比较,vofopitant组小鼠的皮肤厚度显著降低,皮下脂肪层也得到一定程度的恢复。
Masson染色结果见图1的下图,如图所示,胶原纤维被苯胺蓝染成蓝色,对照组小鼠皮肤组织颜色呈现浅蓝色;博莱霉素模型组小鼠皮肤组织呈现深蓝色,说明经过博来霉素诱导之后小鼠皮肤有丰富的胶原纤维的产生;福沙匹坦组小鼠皮肤组织与博莱霉素组的小鼠相比胶原产生并未出现减少,说明福沙匹坦并不能抑制博来霉素诱导皮肤胶原产生;与博莱霉素模型组比较,vofopitant组小鼠组织着色呈浅蓝色,说明沃氟吡坦可以显著抑制皮肤胶原的产生,从而治疗博来霉素诱导的皮肤纤维化;与福沙匹坦组比较,vofopitant对于博莱霉霉素诱导的皮肤胶原纤维的产生抑制效果优于福沙匹坦。
上述结果表明,与对照组相比,博莱霉素模型组小鼠masson染色中胶原沉积明显增多。Vofopitant可显著减少博莱霉素诱导的皮肤纤维化模型小鼠皮肤中的胶原沉积。而福沙匹坦对此无显著改善。(图1)
表1显示各组小鼠皮肤组织的厚度。
表1.博莱霉素诱导皮肤纤维化小鼠皮肤厚度(um)
由表1数据可知,与对照组相比,博莱霉素模型组小鼠皮肤厚度明显增厚。Vofopitant可减少博莱霉素诱导的皮肤纤维化模型小鼠皮肤厚度。而福沙匹坦对皮肤厚度的改善无统计学差异,因此不能认为具有明显改善。
以上结果说明,vofopitant可以有效改善博莱霉素诱导皮肤纤维化小鼠模型的皮肤纤维化,而同为NK-1R抑制剂的福沙匹坦对博莱霉素诱导皮肤纤维化小鼠模型的皮肤纤维化并没有明显改善。
上述实施例仅为本发明的较佳实施例,不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等,均应仍归属于本发明专利涵盖范围之内。
Claims (7)
1.Vofopitant用于制备治疗硬皮病的药物的用途。
2.权利要求1所述的用途,其中,Vofopitant包括其药学上可接受的盐、溶剂化物、N-氧化物、多晶型物、前体药物、立体异构体、外消旋体。
3.权利要求1所述的用途,其中,Vofopitant为其盐酸盐。
4.权利要求1所述的用途,其中,所述药物包含Vofopitant作为唯一的用于治疗硬皮病的活性成分。
5.权利要求1所述的用途,其中,所述硬皮病为局限性硬皮病或弥漫性硬皮病。
6.权利要求1所述的用途,其中,Vofopitant减少胶原沉积来治疗硬皮病。
7.权利要求1所述的用途,其中,Vofopitant通过注射或局部给药。
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