CN1283115A - 用于治疗呼吸道和皮肤病的含有至少一种白三烯拮抗剂和至少一种抗组胺药的组合物 - Google Patents
用于治疗呼吸道和皮肤病的含有至少一种白三烯拮抗剂和至少一种抗组胺药的组合物 Download PDFInfo
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Abstract
一种用于治疗哺乳动物喷嚏、瘙痒、流涕、鼻充血、眼充血、流泪、耳或腭瘙痒、呼吸短促、支气管粘膜炎症、每秒强力呼气容量(FEV1)减少、咳嗽、疹、皮肤瘙痒、头痛,以及与季节性过敏性鼻炎相关的疼痛、非过敏性变应性鼻炎、普通感冒、耳炎、窦炎、过敏反应、哮喘、过敏性哮喘和/或炎症的药物组合物。组合物包括:i)有效量的至少一种白三烯拮抗剂,选自a)montelukast,b)1-((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸;c)1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸;d)pranlukast;或f)[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃]氧代甲基]苯基]乙酸;或它们的药物可接受的盐;与ii)有效量的至少一种抗组胺药,包括descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们的药物可接受盐混合。
Description
发明背景
本发明涉及治疗过敏性鼻炎和其它过敏性疾病的组合物。二十碳四烯酸代谢的5-脂肪氧合酶途径产物,特别是白三烯,可以导致支气管狭窄,粘液分泌作用,气管粘膜水肿,细胞的趋化性和迁移进入哮喘发生炎症的气管。尽管白三烯拮抗剂本身有效,但对与呼吸道疾病相关的多种症状的治疗并不是很有效,如季节性过敏性鼻炎、非季节性过敏性鼻炎、普通感冒、鼻窦炎以及过敏性哮喘的并发症。这些疾病的症状包括喷嚏、瘙痒、流涕、鼻充血、眼充血、流泪、耳或腭瘙痒、和后鼻滴注有关的咳嗽。它对增强白三烯拮抗剂的效果很理想,可以增进它们的全面功效。
发明概述
在实施方案中,本发明的目的在于药物组合物,包括:
ⅰ)有效量的至少一种白三烯拮抗剂,包括
a)montelukast,
b)1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸;
c)1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸;
d)pranlukast;
e)zafirlukast;或
f)[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃]氧代甲基]苯基]乙酸;它们药物可接受的盐;与
ⅱ)有效量的至少一种抗组胺药,包括descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们药物可接受盐混合。
药物组合物优选设计为口服给药方式。白三烯拮抗剂优选montelukast和monoleukast的药物可接受盐如montelukast钠。以及monoleukast的药物可接受盐优选约10毫克(mg)。抗组胺药更优选是descarboethoxyloratidine。西替利嗪或fexofenadine的药物可接受盐优选是盐酸盐。以及优选descarboethoxyloratidine或西替利嗪约2.5-约20mg,更优选约5,7.5或10mg。优选,fexofenadine约60-180mg。更优选,montelukast药物可接受盐约10mg和descarboethoxyloratidine是约5或7.5mg。
任选地,药物组合物可以进一步包含第三种活性成分,它可以是:ⅲ)减充血剂(decongestant)(如伪麻黄碱),镇咳剂(如右美沙芬),去痰药/粘液溶解的(如愈创木酚甘油醚),NSAIDs或止痛药(如阿司匹林,对乙酰氨基酚和非那西丁)。
本发明可用于治疗哺乳动物的皮肤,呼吸道疾病和/或与此有关的并发症,其包括将上述的药物组合物给以需要此种治疗的哺乳动物。皮肤病包括变应性皮炎,牛皮癣和慢性自发性荨麻疹,以及其它已知的皮肤瘙痒和/或荨麻疹。呼吸道疾病包括季节性过敏性鼻炎、非季节性过敏性鼻炎、普通感冒、耳炎、窦炎、过敏反应、哮喘、过敏性哮喘和/或是症。与呼吸道疾病相关的症状包括打喷嚏、瘙痒和/或流涕、鼻充血;眼充血、流泪或瘙痒;耳或腭瘙痒、呼吸短促、支气管粘膜炎症、每秒强力呼气容量(FEV1)减少、咳嗽、疹、荨麻疹、皮肤瘙痒;头痛,以及各种疼痛。根据上述药物组合物,可以将descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们的药物可接受盐与白三烯拮抗剂或其药物可接受盐以分开剂型同时给药或结合成单位剂型方式给药。哺乳动物优选是人类。优选,上述药物组合物的分开剂型以及单位剂型设计成口服给药方式。分开剂型以及单位剂型优选包括5或7.5mg的descarboethoxyloratidine和10mg的montelukast钠。
实施方案详述
抗组胺药
Descarboethoxyloratidine(DCL)是没有镇静作用的抗组胺药,它的化学名称是8-氯-6,11-二氢-11-(4-亚哌啶基)-5H-苯并[5,6]环庚三烯并[1,2]吡啶。此化合物在Quercia,et al.,Hosp.Formul.,28:137-53(1993),U.S.专利4,659,716以及WO96/20708中有描述。DCL是H-1组胺受体蛋白的拮抗剂。H-1受体是那些通过常用抗组胺药对抗诱导反应。H-1受体存在,例如,人和其它哺乳动物的肠,皮肤以及支气管平滑肌中。在本发明组合物的单位(即单一)剂型中DCL的使用量可以是约2.5-约20mg,以及约5-约10mg,优选约5或7.5mg。
在本发明组合物的单位剂型中西替利嗪的使用量可以是约2.5-约20mg,以及约5-约10mg,优选约10mg。
Fexofenadine(MDL 16,455A)是没有镇静作用的抗组胺药,它的化学名称是4-[1-羟基-4-(4-羟基-二苯基甲基)-1-哌啶基)丁基]-α,α-二甲基-苯乙酸。药物可接受盐优选是盐酸盐,如已知的fexofenadine盐酸盐.在本发明组合物的单位剂型中fexofenadine的使用量可以是约40-约200mg,以及约60-约180mg,优选约120mg。
依巴斯汀是-种抗组胺药,它的化学名称是1-[4-(1,1-二甲基乙基)苯基]-4-[4-(二苯基甲氧基)-1-哌啶基-1-丁酮。CAS 90729-43-4。EP 134124公开了该化合物。此化合物的化学结构式如下:在单位剂型中依巴斯汀的使用量可以是约5-约20mg,优选约10mg。
阿司咪唑是一种抗组胺药,它的化学名称是1-[(4-氟苯基)甲基]-N-[1-[2-(甲氧基苯基)乙基]-4-哌啶基]-1H-苯并咪唑-2-胺。CAS68844-77-9。US 4,219,559公开了该化合物。此化合物的化学结构式如下:
在单位剂型中阿司咪唑的使用量可以是约5-约20mg,优选约10mg。
Norastemizole是一种抗组胺药,其化学名称是1-((4-氟苯基)甲基)-N-4-哌啶基-1H-苯并咪唑-2-胺。CAS 75970-99-9。此化合物是阿司咪唑的活性代谢产物。此化合物的化学结构式如下:
在单位剂型中norastemizole的使用量可以是约5-约40mg,优选约10-约20mg。
依匹斯汀是一种抗组胺药,其化学名称是9,13b-二氢-1H-二苯基[c,f]咪唑并[1,5-a]氮杂-3-胺。CAS 80012-43-7。该化合物公开于DE3008944或Jpn.J.Clin.Pharmocol Ther,1991,22,617页。此化合物的化学结构式如下:
单位剂型中依匹斯汀的使用量可以是约1-约20mg,优选约2-约18mg。
单位剂型中Efletirizine的使用量可以是约4-约60mg。
白三烯拮抗剂
除上述任意化合物以外和/或作为替代其使用量,单位剂型中白三烯拮抗剂的使用量可以是约5-约500mg,以及约50-约300mg,并约100-约200mg。
Montelukast是拮抗半胱氨酰白三烯受体的白三烯D4拮抗剂。化学名称是[R-(E)]-1-[[[1-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫代]甲基]环丙烷乙酸。EP480,717公开了该化合物。Montelukast的药物可接受盐优选是一钠盐,如已知的Montelukast钠盐。在本发明组合物的单位剂型中Montelukast的使用量可以是约1-约100mg,以及约5-约20mg,优选约10mg。
化合物1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸是白三烯拮抗剂,公开于WO 97/28797和US专利5,270,324中。该化合物的药物可接受盐是钠盐,如已知的1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸钠。
化合物1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸是白三烯拮抗剂,公开于WO 97/28797和US专利5,472,964中。该化合物的药物可接受盐是钠盐,如已知的1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸钠。
Pranlukast是白三烯拮抗剂,公开于WO 97/28797和EP173,516中。化学名称是N-[4-氧代-2-(1H-四唑-5-基)-4H-1-苯并吡喃-8-基]-p-(4-苯基丁氧基)苯甲酰胺。单位剂型中Pranlukast的使用量可以是约100-约700mg,优选约112-约675mg;并约225mg-约450mg;以及约225-约300mg。
Zafirlukast是一种白三烯拮抗剂,其公开于WO 97/28797和EP199,543中。化学名称是环戊基-3-[2-甲氧基-4-[(o-甲苯磺酰基)氨基甲酰基]苄基]-1-甲基吲哚-5-氨基甲酸酯。
化合物[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃]氧代甲基]苯基]乙酸是一种白三烯拮抗剂和/或抑制剂,它的制备方法公开在U.S.专利5,296,495和日本专利JP08325265A中。此化合物的另-个名称是2-[[[2-[4-(1,1-二甲基乙基)-2-噻唑基]-5-苯并呋喃]氧代甲基]苯乙酸。该化合物的代号是FK011或FR150011。分子结构式是C24H23NO4S和分子量为421.52。该化合物的化学结构式如下:
本发明药物组合物可以根据病人的年龄,性别,体重和需要治疗的严重程度给药。一般,含有descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们药物可接受盐和白三烯拮抗剂的人的口服剂型每天给药1或2次。
下面提供一种优选的白三烯拮抗剂和抗组胺药结合的片剂。
白三烯拮抗剂+抗组胺药
Montelukast+Descarboethoxyloratidine
Pranlukast+Descarboethoxyloratidine
Montelukast+西替利嗪
Pranlukast+西替利嗪
Montelukast+Fexofenadine
Pranlukast+Fexofenadine
Montelukast+依巴斯汀
Pranlukast+依巴斯汀
Montelukast+Norastemizole
Pranlukast+Norastemizole
Montelukast+Efletirizine
Pranlukast+Efletirizine
此处使用的名词“NSAID”是指任意没有麻醉作用的止痛的非甾族消炎化合物,包括它们的药物可接受盐,属于以下5种结构类型之一,但不包括阿司匹林,对乙酰氨基酚和非那西丁,如下:
1)丙酸衍生物如布洛芬,萘普生,氟比洛芬,非诺洛芬,酮洛芬,芬布芬和氟洛芬;
2)乙酸衍生物如托美丁,舒林酸钠和吲哚美锌;
3)fenamic酸衍生物如mefanamic酸和甲氯灭酸钠;
4)二苯基羧酸衍生物如二氟尼柳和氟苯柳;和
5)Oxicams如吡罗昔康,舒多昔康和伊索昔康。
止痛药是缓解疼痛的药物或化舍物,包括阿司匹林,对乙酰氨基酚和非那西丁。
在本发明的药物组合物和方法中,前述的活性成分可以特别与合适的药物稀释剂,赋形剂或载体(此处总起来作为载体材料)混合在一起给药。根据不同的给药方式选择,即口服片剂、胶囊(固体填充,半固体填充或液体填充的)、构成粉剂(powders for constitution)、口服凝胶、酏剂、糖浆、悬浮液、溶液、滴鼻剂、opthalmic drops、口滴剂、特定的霜剂等,并按照常规的药物制备方法制备。例如,对于片剂或胶囊剂型口服给药方式,活性药物成分可以与任意口服无毒的药物可接受的惰性载体混合,如乳糖、淀粉、蔗糖、纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露糖醇、乙醇(液体形式)等。而且,如需要,也可以在混合物中加入合适的粘合剂、润滑剂、崩解剂和着色剂。合适的粘合剂包括淀粉、明胶、天然蔗糖、玉米增甜剂、天然和合成胶如***树胶、藻酸钠、羧甲基纤维素、聚乙二醇和蜡。在这些剂型中可以使用的润滑剂是硼酸、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括淀粉,甲基纤维素,瓜耳树胶等。如需要也可以加入甜味剂和调味剂以及防腐剂。
此外,本发明组合物可以制成持续释放剂型以控制任一或几种组分或活性成分的释放速率达到最佳治疗效果,即白三烯拮抗剂和抗组胺药等。合适的持续释放剂型包括层状片剂,其含有可变化崩解率层或浸渍有活性成分的可控制释放的聚合基质以及含有这些浸渍过或包有胶囊的多孔聚合基质的片剂或胶囊。
剂型-将含有descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们的药物可接受盐与白三烯拮抗剂的组合物送入生产设备中,即与非活性成分一起制成片剂,胶囊,口服凝胶,组成粉剂或悬浮液。
胶囊-指用于装填或含有descarboethoxyloratidine、西替利嗪或fexofenadine与白三烯拮抗剂的组合物的由甲基纤维素,聚乙烯醇或改性明胶或淀粉制成的特定的容器或包装物。硬胶囊特别是由相对高凝胶强度的骨骼和猪皮凝胶的混合物制成。胶囊本身可以含有少量的染料,不透明剂,增塑剂和防腐剂。
片剂-指含有活性成分(descarboethoxyloratidine、西替利嗪或fexofenadine与白三烯拮抗剂)和合适的稀释剂的压缩或模塑固体剂型。片剂可以通过混合物的压缩制成或通过湿造粒,干造粒或压制获得颗粒。
口服凝胶剂-是指将descarboethoxyloratidine、西替利嗪或fexofenadine与白三烯拮抗剂分散或溶解在亲水的半固体基质中。
构成粉剂是指含有descarboethoxyloratidine、西替利嗪或fexofenadine与白三烯拮抗剂以及合适的稀释剂的粉状混合物,其可以悬浮在水中或糖汁中。
稀释剂-是指通常占组合物或制剂的主要部分的物质。合适的稀释剂包括糖类如乳糖,蔗糖,甘露糖醇和山梨糖醇;来自小麦,玉米稻和马铃薯的淀粉;以及纤维素如微晶纤维素。在组合物中稀释剂的量占组合物总量的约10-约90%重量,优选约25-约75%,更优选约30-约60%重量,甚至更优选约12-约60%。
崩解剂-是指加入组合物中的材料以帮助破碎(崩解)和释放药物成分。合适的崩解剂包括淀粉;“冷水可溶的”改性淀粉如羧甲基淀粉钠;天然和合成胶如刺槐豆胶,梧桐胶,瓜耳树胶,黄蓍胶和琼脂;纤维素衍生物如甲基纤维素和羧甲基纤维素钠;微晶纤维素和交联微晶纤维素如sodium croscarmellose;藻酸盐如藻酸和藻酸钠;粘土如皂土;以及泡腾混合物。在组合物中崩解剂的量占组合物的约2-约15%重量,优选约4-约10%重量。
粘结剂-是指粘性物质或“胶性”粉末,并使它们粘结形成颗粒,由此用作制剂中的“粘结物”。粘结剂增强了粘结强度,可用于稀释剂或填充剂中。合适的粘结剂包括糖类如蔗糖;来自小麦,玉米稻和马铃薯的淀粉;天然胶如***树胶,明胶和黄蓍胶;海藻衍生物如藻酸,藻酸钠和藻酸铵钙?;纤维素物质如甲基纤维素和羧甲基纤维素钠以及羟丙基甲基纤维素;聚乙烯吡咯烷酮;以及无机物如硅酸镁铝。在组合物中粘结剂的量占组合物总量的约2-约20%重量,更优选约3-约10%重量,甚至更优选约3-约6%重量。
润滑剂-是指在压缩后加入制剂中的物质以使片剂,颗粒剂等在减小摩擦或磨损的情况下从塑模或模具中释放。合适的润滑剂包括硬脂酸金属盐如硬脂酸镁,硬脂酸钙或硬脂酸钾;硬脂酸;高熔点蜡;以及水溶性润滑剂如氯化钠,苯甲酸钠,乙酸钠,油酸钠,聚乙二醇和d’1-亮氨酸。既然它们必须存在颗粒的表面以及它们与压缩片剂各部分之间,因此润滑剂通常是在压缩前的最后一部加入。在组合物中润滑剂的量占组合物总量的约0.2-约5%重量,优选约0.5-约2%重量,更优选约0.3-约1.5%重量。
Glidents-防止结块的物质并提高造粒过程的流动性,以使均匀一致地流动。合适的glidents包括二氧化硅和滑石。在组合物中glident量占组合物总量的约0.1-约5%重量,优选约0.5-约2%重量。
着色剂-赋形剂提供组合物或制剂着色。这些赋形剂可以包括食品级的染料和吸附在合适的吸附剂如粘土或氧化铝上的食品级的染料。在组合物中着色剂的量占组合物总量的约0.1-约5%重量,优选约0.1-约1%重量。
生物药效率-是指与标准或对照相比给药剂型的活性药物成分或治疗组分被体循环吸收的速率和程度。
制备片剂的常规方法是已知的。这些方法包括干法如直接压缩和由压制成的颗粒压缩,或湿法或其它特殊方法。
Claims (12)
1.一种药物组合物,包括:
ⅰ)有效量的至少一种白三烯拮抗剂,选自
a)montelukast,
b)1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫代)甲基环丙烷乙酸;
c)1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫代)甲基)环丙烷乙酸;
d)pranlukast;或
e)zafirlukast;或
f)[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃]氧代甲基]苯基]乙酸;
或它们的药物可接受的盐;与
ⅱ)有效量的至少一种抗组胺药,包括
descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、阿司咪唑、norastemizole、依匹斯汀、efletirizine或它们的药物可接受盐混合。
2.根据权利要求1的药物组合物,其中白三烯拮抗剂是a)montelukast以及抗组胺药是descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、norastemizole或efletirizine。
3.根据权利要求2的药物组合物,其中的抗组胺药是descarboethoxyloratidine。
4.根据权利要求2的药物组合物,其中所述的montelukast是约10mg以及所述的descarboethoxyloratidine约5或7.5mg。
5.根据权利要求1的药物组合物,其中白三烯拮抗剂是d)pranlukast以及抗组胺药是descarboethoxyloratidine、西替利嗪、fexofenadine、依巴斯汀、norastemizole或efletirizine。
6.根据权利要求5的药物组合物,其中的抗组胺药是descarboethoxyloratidine。
7.根据权利要求1或5的药物组合物,进一步包含第三种活性成分,其可以是:
ⅲ)减充血剂,镇咳剂,去痰药/粘液溶解的或止痛药。
8.根据权利要求7的药物组合物,其中减充血剂是伪麻黄碱。
9.根据权利要求7的药物组合物,其中镇咳剂是右美沙芬。
10.根据权利要求7的药物组合物,其中去痰药/粘液溶解的物质是愈创木酚甘油醚。
11.一种治疗哺乳动物皮肤病、呼吸道疾病和/或与此相关的并发症的方法,包括将权利要求1的药物组合物给以上述的哺乳动物。
12.权利要求1-10中任一项的组合物在制备治疗哺乳动物皮肤病、呼吸道疾病和/或与此相关的并发症的药物中的用途。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103687591A (zh) * | 2011-07-15 | 2014-03-26 | 韩美药品株式会社 | 包含蒙特鲁卡斯特及左旋西替利的胶囊调配物 |
CN103889424A (zh) * | 2011-10-18 | 2014-06-25 | 株式会社那笔制药 | 白三烯拮抗剂和依匹斯汀的复合制剂 |
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