CN114340612A - 包含n-酰基氨基酸作为有效成分的用于预防或治疗哮喘、鼻炎或结膜炎的组合物 - Google Patents
包含n-酰基氨基酸作为有效成分的用于预防或治疗哮喘、鼻炎或结膜炎的组合物 Download PDFInfo
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- CN114340612A CN114340612A CN202080053136.2A CN202080053136A CN114340612A CN 114340612 A CN114340612 A CN 114340612A CN 202080053136 A CN202080053136 A CN 202080053136A CN 114340612 A CN114340612 A CN 114340612A
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- oleoyl
- tryptophan
- alanine
- rhinitis
- acid
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Abstract
本发明涉及利用对人体几乎没有副作用的N‑酰基氨基酸的用于预防、改善或治疗哮喘、鼻炎和/或结膜炎的组合物。本发明的组合物对作为哮喘主要临床症状的气管内炎症反应及气管纤维化均表现出改善效果,改善哮喘症状的效果优秀,因此,可以有效用作用于改善哮喘的药品或食品。并且,可以显著改善鼻炎及结膜炎的临床症状,从而可以有效用作用于改善鼻炎及结膜炎的药品或食品。
Description
技术领域
本发明涉及包含N-酰基氨基酸作为有效成分的用于预防或治疗哮
喘、鼻炎或结膜炎的组合物。
背景技术
哮喘为因遗传及环境因素诱发的呼吸系统的炎症疾病,是肺内的支气管处于非常敏感的状态,即,表现出支气管时常变狭窄而使呼吸困难并伴有呼噜呼噜的喘息声和严重的咳嗽的症状的疾病。近来,随着环境污染的加剧和化学物质排放的增加,哮喘的发生呈增加的趋势。哮喘虽发生在各年龄段,但30%左右为儿童,会发展为慢性呼吸系统炎症疾病,是频繁住院治疗并降低生活质量的主要疾病之一(Eur Res pir J 2001;17(5):881-6)。
鼻炎为表现出鼻腔粘膜炎症反应的疾病,大体可分为过敏性鼻炎和非过敏性鼻炎。过敏性鼻炎根据细节类型有多种表现,主要因特定免疫球蛋白(IgE、IgM等)的异常反应而出现喷嚏、流涕、鼻塞、黏膜细胞扩张之类的症状。非过敏性鼻炎除病毒感染引起的感冒外,还有细菌及真菌感染引起的感染性鼻炎、可能因分布于鼻粘膜的自主神经系统的异常引起的血管运动性鼻炎、因用药不当、寒冷气温等物理原因、食物引起的鼻炎、因鼻腔结构异常引起的鼻炎等。
在全世界范围内,过敏性鼻炎的发病率呈稳步增加的态势。二十世纪美国的有关过敏性鼻炎的直接医疗费用(门诊费、处方费和急诊费)已超过19亿美元,因并发症引起的额外损失达40亿美元。根据2011年的健康保险统计年鉴,在韩国因多发性疾病前往门诊的患者中过敏性鼻炎患者人数从2000年的200万人激增到2011年的560万人(第14位→第5位),因此,在500多种疾病中,该疾病在健康保险的赔付中居第4位。可以预想未来过敏性鼻炎所消耗的社会成本将持续增加,因此,有关治疗或者改善过敏性鼻炎的需求也将呈增加的趋势。
结膜炎为结膜发生过敏反应的疾病,是发生作为由过敏引起的疾病的花粉过敏或者过敏性鼻炎时经常伴发的疾病。作为代表性的季节性疾病,春季的症状较重,而到秋季和冬季则好转。主要多发于过敏体质的人群中,通常从青春期之前开始发作,在之后的5年至10年内复发,这之后发作次数减少,症状减轻。然而,近来随着持续的异常高温来袭,出现无论男女老少都与季节和体质无关地发病的现象,其主要原因是动物的毛、灰尘、花粉、房屋灰尘及螨虫等,近来已知汽车尾气或化学粉尘之类的公害物质也有很大的影响。通常的症状常见眼部非常瘙痒、严重的充血、眼睑浮肿及眼泪增加,当揉眼时症状可能加剧。并且,有被划伤或是灼烧的疼痛,还会出现异物感、眼屎及结膜下出血等症状。
哮喘的治疗主要依靠药物疗法,通常在进行抗炎治疗(口服给药及吸入类固醇)的同时使用支气管扩张剂(茶碱(theophylline))及作为抗炎剂之一的白三烯(leukotriens)抑制剂等(Clin Exp Allergy.2012 42:650-8)。
过敏性鼻炎的情况下,虽然推荐服用抗组胺剂来缓解症状,但大量服用抗组胺剂可能引起嗜睡或眩晕等,长期服用反倒会出现引起组氨过度分泌而导致症状加剧的情况。
作为结膜炎的代表性治疗剂的糖皮质激素家族中的类固醇类抗炎药通常用作抗炎药物,在类风湿关节炎等疾病中显出优秀的疗效,抑制或者预防包括放射性、机械性、化学性、感染性及免疫刺激在内的多种炎症反应。
现在,类固醇是在包括哮喘、鼻炎及结膜炎在内的过敏性炎症疾病中广泛使用的药剂。在哮喘的情况下,已知类固醇比较好地调节急性哮喘。但在哮喘发展为慢性或者症状非常严重的哮喘(severe asthm a)的情况下,对类固醇没有反应,具有这种症状的许多患者因没有治疗方法而受到长期的痛苦,生活质量显著降低,严重的甚至会导致死亡(ClinExp Allergy.2012 42:650-8)。
类固醇在使用上具有引起严重副作用的问题。类固醇包括因降低免疫反应而导致微生物感染或者增加癌症发病的致命的副作用,会引起皮肤、肌肉、骨、眼、神经系统、内分泌系统、免疫系统、消化器官等的功能异常及其他疾病,因此其使用受到极大限制(N EnglJ Med.2005,353:1711-23)。
因此,能够代替类固醇的安全的过敏性炎症抑制剂的开发是现代医学应该解决的至为重要且紧迫的问题之一。为了克服类固醇的副作用,该方面的研究者开发出了非甾体抗炎药(Non-steroidal antiinflammatory drugs;NSAID)。代表性的药物为阿司匹林,阿司匹林为环氧合酶(cyclooxygenase,COX)抑制剂,是一种参与从通过细胞质磷脂酶A2(cytosolic phospholipase A2,cPLA2)的作用形成的花生四希酸(arachidonic acid)合成前列腺素的酶,除阿司匹林之外,还有许多非甾体抗炎药(NSAID)(吲哚美辛(Indomethacin)、布洛芬(Ibuprofen)、西乐葆(Celecoxib)、罗非昔布(Rofecoxib)等)都是环氧合酶(CO X)抑制剂。但是,这些非甾体抗炎药与类固醇相比,炎症抑制效果弱,因此不在过敏性炎症疾病中使用。并且,虽然科学家在很早以前就已开发了作为诱发炎症的酶的p38丝裂原活化蛋白激酶(p38 mitogen-ac tivated protein kinase)及细胞质磷脂酶A2的抑制剂,但由于副作用,现在临床上处于无药可用的状态(Bioorg Med Chem 2008;16:1345-58)。
因此,急需开发“类固醇辅助药物”及“类固醇替代药物”,这些药物的开发必将给包括哮喘在内的多种过敏性炎症疾病的治疗带来划时代的贡献。
发明内容
对此,本发明人为了开发没有副作用且对哮喘、鼻炎及结膜炎的改善效果优秀的药物,经多次努力研究的结果,确认给药N-酰基氨基酸时具有卓越的抑制哮喘、鼻炎及结膜炎的效果,从而完成本发明。
因此,本发明的目的在于,提供包含N-酰基氨基酸作为有效成分的用于预防、改善或治疗哮喘的组合物。
本发明的再一目的在于,提供包含N-酰基氨基酸作为有效成分的用于预防、改善或治疗过敏性鼻炎的组合物。
本发明的另一目的在于,提供包含N-酰基氨基酸作为有效成分的用于预防、改善或治疗结膜炎的组合物。
本发明的其他目的及优点将通过下述本发明的详细说明、发明要求保护范围及附图得到进一步明确。
解决问题的方案
根据本发明的一方面,本发明提供包含N-酰基氨基酸作为有效成分的用于预防、改善或治疗哮喘、鼻炎或结膜炎的组合物。
根据本发明的再一方面,本发明提供预防、改善或治疗哮喘、鼻炎或结膜炎的方法,包括向对象(subject)给药有效量的N-酰基氨基酸的步骤。
根据本发明的另一方面,本发明提供N-酰基氨基酸在预防、改善或治疗哮喘、鼻炎或结膜炎中的用途。
本发明的上述哮喘作为肺内的支气管处于非常敏感的状态,即,表现出支气管时常变狭窄而使呼吸困难并伴有呼噜呼噜的喘息声和严重的咳嗽的症状的疾病,是指因支气管的过敏性炎症引起的过敏性疾病。
本发明的上述鼻炎作为以鼻腔粘膜的炎症反应为表现的疾病,大体可分为过敏性鼻炎和非过敏性鼻炎。过敏性鼻炎为鼻粘膜对特定物质表现出过敏反应,是指鼻粘膜暴露于引起过敏的病原物质(抗原)后,包括肥大细胞、嗜酸性粒细胞在内的多种以免疫球蛋白E(IgE)抗体为媒介的炎症细胞聚集于刺激部位,通过它们分泌的多种媒介物质引起炎症反应的疾病。非过敏性鼻炎除病毒感染引起的感冒外,还有细菌及真菌感染引起的感染性鼻炎、可能因分布于鼻粘膜的自主神经系统的异常引起的血管运动性鼻炎、因用药不当、寒冷气温等物理原因、食物引起的鼻炎、因鼻腔结构异常引起的鼻炎等。
本发明的上述结膜炎是指因局部感觉引起的结膜炎,从结膜的轻微充血到伴有眼睑肿胀、结膜浮肿等的症状,尤其将与遗传因素相关的表现为速发型过敏的疾病称为过敏性结膜炎。
优选地,本发明N-酰基氨基酸为N-酰基丙氨酸或N-酰基色氨酸,更优选地,为N-酰基-L-丙氨酸或N-酰基-L-色氨酸。
上述N-酰基-L-丙氨酸或N-酰基-L-色氨酸为丙氨酸或色氨酸的α氨基被酰化的形态,可以通过有机合成方法合成,也可以通过购买市面上出售的试剂来使用。
本说明书中的术语“酰基(acyl)”或“酰基(acyl group)”没有特别限制,是指去除羧酸的羧基OH后剩下原子团,通常以RCO来表示。R是指一个或一个以上的取代基,只要是能够与上述CO结合的取代基就不受限制。在上述R为芳香族原子团的情况下,尤其还有称为“芳酰基”的情况,但这也是酰基的一种。上述酰基的例包括甲酰基(HCO-)、乙酰基(CH3CO-)、丙酰基(C2H5CO-)、丁酰基(C3H7CO-)、戊酰基(C4H9CO-)、戊酰基(CH3(CH2)3CO-)、棕榈酰基(C15H31CO-)、硬脂酰基(C17H33CO-)、油酰基(C17H31CO-)、草酰基(-CO-CO-)、丙二酰基(-COCH2CO-)、琥珀酰基(-CO(CH2)2CO-)、苯甲酰基(C6H5CO-)、甲苯甲酰基(CH3-C6H4-CO-)、羟基苯甲酰基(HO-C6H4-CO-)、肉桂酰基(C6H5CH=CHCO-)、萘甲酰基(C10H7CO-)、邻苯二甲酰基(CO-C6H4-CO-)、呋喃甲酰基(C5H3O2-)、十一酰基(CH3(CH2)9CO-)、从二十二碳烯酸(docosenoic acid)中去除OH基而获得的二十二碳烯酰基,但不限定于此。
优选地,上述N-酰基丙氨酸(N-acyl-alanine)为N-乙酰丙氨酸(N-acetyl-alanine)或N-油酰基丙氨酸(N-oleoyl-alanine),但不限定于此。
优选地,上述N-酰基色氨酸(N-acyl-tryptophan)为N-乙酰色氨酸(N-acetyl-tryptophan)或N-油酰基色氨酸(N-oleoyl-tryptophan),但不限定于此。
优选地,上述N-酰基-L-丙氨酸(N-acyl-L-alanine)为N-乙酰-L-丙氨酸(N-acetyl-L-alanine)或N-油酰基-L-丙氨酸(N-oleoyl-L-alani ne),但不限定于此。
优选地,上述N-酰基-L-色氨酸(N-acyl-L-tryptophan)为N-乙酰-L-色氨酸(N-acetyl-L-tryptophan)或N-油酰-L-色氨酸(N-oleoyl-L-tr yptophan),但不限定于此。
另一方面,本说明书中的术语“包含……作为有效成分”或者“有效量”是指包含能够实现N-酰基氨基酸的功效或活性的充分的量。在本发明的一具体例中,本发明的组合物中包含例如10μg/kg以上的N-酰基氨基酸,优选地,包含0.1mg/kg以上的N-酰基氨基酸,更优选地,包含1mg/kg以上的N-酰基氨基酸,更加优选地,包含10mg/kg以上的N-酰基氨基酸。即使过量给药N-酰基氨基酸也几乎不会给人体带来副作用,因此,本发明的组合物中所包含的N-酰基氨基酸的量的上限可以通过本发明所属技术领域的普通技术人员在适当的范围内选择并实施。
本发明的组合物中被用作有效成分的上述N-酰基氨基酸不仅包括该化合物本身,还应解释为包括其在药剂学、食品学或化妆品学上可接受的盐、水合物、溶剂化物或前体药物。
本说明书中的术语“药剂学上可接受的盐”、“食品学上可接受的盐”或“化妆品学上可接受的盐”是指在给药该化合物的有机体中不诱发严重的刺激并且不损伤化合物的生物学活性及物性的化合物的剂型。上述药剂学、食品学或化妆品学上可接受的盐可以通过将本发明的化合物与盐酸、溴酸、硫酸、硝酸、磷酸等无机酸、甲磺酸、乙磺酸、对甲苯磺酸等磺酸、酒石酸、甲酸、柠檬酸、醋酸、三氯乙酸、三氟乙酸、癸酸、异丁酸、丙二酸、琥珀酸、邻苯二甲酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、水杨酸等之类的有机碳酸反应来获得。并且,本发明的化合物可以通过与碱反应来获得铵盐、钠盐或钾盐等碱金属盐、钙盐或镁盐等碱土金属盐,与二环己胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺等有机碱反应获得有机碱盐,也可以与精氨酸、赖氨酸等氨基酸反应形成盐来获得,但不限定于此。
本说明书中的术语“药剂学上可接受的水合物”、“食品学上可接受的水合物”或“化妆品学上可接受的水合物”表示具有所期望的药理学效果的上述N-酰基氨基酸的水合物。术语“药剂学上可接受的溶剂化物”、“食品学上可接受的溶剂化物”或“化妆品学上可接受的溶剂化物”表示具有所期望的药理学效果的上述N-酰基氨基酸化合物的溶剂化物。上述水合物及溶剂化物也可以利用上述的酸来制备,可以在广义上包括在上述药剂学、食品学或化妆品学上可接受的盐中。
本说明书中的术语“药剂学上可接受的前体药物”、“食品学上可接受的前体药物”或“化妆品学上可接受的前体药物”表示在发挥上述N-酰基氨基酸的药理学效果之前需经生物转化的上述N-酰基氨基酸的衍生物。上述前体药物是为改善化学稳定性、患者依从性、生物学利用度、器官选择性或制备的便利性、作用时间的长期化以及减少副作用而制备的。本发明前体药物的制备可以利用上述N-酰基氨基酸根据本发明所属技术领域通常使用的方法(例如Burger's Medicinal Che mistry and Drug Chemistry,5th ed.,1:172-178and 949-982(1995))来轻易地制备。
根据本发明的优选实例,本发明的组合物为药剂学组合物。
根据本发明的优选实例,本发明的药剂学组合物包含药剂学上可接受的载体。
本发明的药剂学组合物所包含的药剂学上可接受的载体为制剂时通常使用的载体,包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等,但不限定于此。除上述成分外,本发明的药剂学组合物还可以包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂、保存剂等。适当的药剂学上可接受的载体及制剂详细记录在Remington's Pharmaceutical Sciences(19th ed.,1995)中。
本发明的药剂学组合物可以口服或胃肠外给药,胃肠外给药的情况下可以通过鼻腔给药、滴眼给药、静脉内注射、皮下注射、肌肉注射、腹腔注射、经皮给药、直肠给药、子宫内膜给药、脑血管内注射等方式给药。
本发明药剂学组合物的适当给药量可以根据配制方法、给药方式、患者的年龄、体重、性别、疾病状态、饮食、给药期间、给药途径、代谢速度及反应敏感度之类的因素而多种多样,具有普通熟练度的医生可以轻易决定及处方所期望治疗或预防的有效给药量。根据本发明的优选实例,本发明的药剂学组合物的一天给药量为10μg/kg~1000mg/kg。
本发明的药剂学组合物可以根据本发明所属技术领域的普通技术人员能够轻易实施的方法,利用药剂学上可接受的载体和/或赋形剂来配制,可以制备为单位剂量形态或者装入多剂量容器内来制备。在此情况下,可以为油剂或水性介质中的溶液、悬浮液或乳化液形态,也可以为萃取剂、粉末剂、颗粒剂、片剂或胶囊剂形态,还可以包含分散剂或稳定剂。
本发明的药剂学组合物可以制备为皮肤外用剂、气雾剂、喷剂、滴眼剂、口服剂以及注射剂形态的剂型。
本发明的药剂学组合物可以为预防及治疗哮喘、鼻炎或结膜炎而单独使用,或者与手术、放射线治疗、激素治疗、化学治疗及使用生物学反应调节剂的方法联合使用。
本发明的药剂学组合物可以用于人类或动物。
本说明书中的术语“对象”或“subject”是指需要给药上述N-酰基氨基酸的人类或动物。
本说明书中的术语“预防”是指通过给药本发明组合物来抑制哮喘、鼻炎或结膜炎或者延迟其病程的所有行为。
本说明书中使用的术语“治疗”是指通过给药本发明组合物来使哮喘、鼻炎或结膜炎好转或者变为治愈所有行为。
根据本发明的优选实例,本发明的组合物为食品组合物。
本发明的食品组合物可以用作功能食品,或者添加于各种食品中。可以添加本发明组合物的食品有例如饮料类、酒精饮料类、饼干类、减肥棒、乳制品、肉类、巧克力、披萨、面包类、拉面、其他面类、口香糖类、冰淇淋类、综合维生素、健康辅助食品类等。
除包含N-酰基氨基酸作为有效成分外,本发明的食品组合物还可以包含制备食品时通常添加的成分,包含例如蛋白质、碳水化合物、脂肪、营养素、调味剂及香味剂。上述碳水化合物的例有单糖,例如葡萄糖、果糖等;二糖、例如麦芽糖、蔗糖、寡糖等;以及多糖,例如糊精、环糊精等之类的通常的糖以及如木糖醇、山梨糖醇、赤藓糖醇等糖醇。香味剂可以使用天然香味剂(索马甜、甜菊叶萃取物(例如莱鲍迪甙A、甘草酸等))以及合成香味剂(糖精、阿巴斯甜等)。例如,在将本发明的食品组合物制备为饮剂或饮料的情况下,除N-酰基氨基酸以外,还可以包含柠檬酸、液体果糖、砂糖、葡萄糖、醋酸、苹果酸、果汁及各种食物萃取液。
除上述成分以外,本发明的食品组合物还可以包含多种营养剂、维生素、电解质、风味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料所使用的碳酸化剂等。此外,本发明的组合物还可以包含用于制备天然果汁、果汁饮料及蔬菜饮料的果肉。这些成分可以单独或者组合来使用。这些添加剂的比例不是很重要,但通常在每100重量份的本发明的组合物添加0.01重量份至10重量份的范围内选择。
本发明提供包含N-酰基氨基酸或其在食品学上可接受的盐作为有效成分的食品组合物的保健功能食品。所谓健康功能食品是指具有预防及改善疾病、活体防御、免疫、疾病后的恢复、抑制老化等活体调节功能的食品,长期服用时应对人体无害。上述保健功能食品为通过将N-酰基氨基酸添加到饮料、茶类、香辛料、口香糖、饼干类食品等的食品材料而制成的食品或者制成胶囊、粉末、悬浮液等的食品,在服用的情况下能够对健康具有特定效果,与通常的药品不同,由于以食品为原料,具有不发生长期服用药品时可能发生的副作用的优点。以上述方式获得的本发明的保健功能食品由于可以日常服用,因此非常有用。在如上所述的保健功能食品中,N-酰基氨基酸的添加量因作为添加对象的保健功能食品的种类的不同而不同,因此无法固定下来,但可以在不损及食品本味的范围内添加,通常相对于对象食品,添加的范围为0.01重量百分比至50重量百分比的范围,优选地,为0.1重量百分比至20重量百分比的范围。并且,在丸剂、颗粒剂、片剂或胶囊剂形态的保健功能食品的情况下,通常在0.1重量百分比至100重量百分比的范围内添加,优选地,在0.5重量百分比至80重量百分比的范围内添加。在一具体例中,本发明的保健功能食品可以为丸剂、片剂、胶囊剂或饮料的形态。
本说明书中使用的术语“改善”是指通过摄取或给药本发明的组合物来使与哮喘、鼻炎或结膜炎相关的症状不再恶化或者好转的所有行为。
本发明的食品组合物可以用做人类用食品或者动物用饲料或饲料添加剂等。
根据本发明的优选实例,本发明的组合物为化妆品组合物。
在将本发明的组合物制备为化妆品组合物的情况下,除上述N-酰基氨基酸外,本发明的组合物还包含化妆品组合物中通常使用的成分,例如抗氧化剂、稳定剂、增溶剂、维生素、颜料及香料之类的通常的辅助剂,还包含载体。并且,除上述N-酰基氨基酸外,本发明的组合物还可以在不损及其作用的情况下混合现有的哮喘、鼻炎或结膜炎的改善剂或镇静剂来使用。
作为上述载体,可以使用纯化水、一元醇(乙醇或丙醇)、二元醇(乙二醇、1,3-丁二醇或丙二醇)、高级脂肪酸(棕榈酸或亚油酸)、油脂(小麦胚芽油、山茶油、荷荷巴油、橄榄油、角鲨烯、葵花籽油、澳洲坚果油、鳄梨油、氢化大豆卵磷脂或脂肪酸甘油酯)等,但不限定于此。并且,可以根据需要添加表面活性剂、杀菌剂、抗氧化剂、紫外线吸收剂、消炎剂及凉味剂。
表面活性剂可以选择性地包含选自由聚氧乙烯、氢化蓖麻油、聚氧乙烯、油醚、聚氧乙烯单油酸酯、聚氧乙烯、单硬脂酸甘油酯、山梨糖醇单硬脂酸酯、聚氧乙烯单油酸酯、山梨糖醇酐、蔗糖脂肪酸酯、六甘油单月桂酸酯、聚氧乙烯还原羊毛脂、POE、甘油焦谷氨酸、异硬脂酸、二酯、N-乙酰谷氨酰胺以及异硬脂酸酯组成的组中的表面活性剂。
杀菌剂可以选择性地包含选自由日柏醇、三氯生、葡萄糖酸氯己定、苯氧乙醇、间苯二酚、异丙基甲基苯酚、薁(azulene)、水杨酸及吡啶硫酮锌组成的组中的杀菌剂。
抗氧化剂可以在丁基羟基茴香醚、没食子酸、没食子酸丙酯及异抗坏血酸中任意使用。
紫外线吸收剂可以在二羟基二苯甲酮等二苯甲酮、黑色素、对氨基苯甲酸乙酯、对二甲氨基苯甲酸2-乙基己酯、西诺沙酯、对甲氧基肉桂酸2-乙基己酯、2-(2-羟基-5-甲基苯基)苯并三唑、尿刊酸及金属氧化物微粒子中任意使用。
消炎剂可以使用甘草酸二甲或尿囊素,凉味剂可以使用辣椒酊或1-薄荷醇。
上述组合物的剂型可以制备为能够以N-酰基氨基酸为有效成分配制的任意的剂型,可以制备为滋补剂、洗发液、护发素、护发精、发胶、粉末、凝胶、霜剂、精华液、润肤乳、溶胶、乳液、油剂、发蜡、啫喱水、喷剂等多种形态,但不限定与此。
发明的效果
本发明的特征及优点概括如下。
(i)本发明提供利用N-酰基氨基酸的用于预防、改善或治疗哮喘、鼻炎或结膜炎的组合物。
(ii)本发明的组合物可以无副作用地安全有效地用在多种病因引起的过敏性疾病及哮喘的改善或治疗中。
附图说明
图1为口服给药N-酰基-L-丙氨酸、N-油酰基-L-丙氨酸、N-酰基-L-色氨酸、N-油酰-L-色氨酸时通过肺组织的苏木精伊红(H&E)染色来示出炎症抑制的照片(OVA=卵清蛋白(ovalbumin),NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
图2为口服给药N-酰基-L-丙氨酸、N-油酰基-L-丙氨酸、N-酰基-L-色氨酸、N-油酰-L-色氨酸时通过肺组织的马松三色(masson's trichr ome)染色来示出支气管纤维化抑制的照片(OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
图3为示出N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制源自气管内细胞的Th2细胞因子(IL4)分泌的效果的图(*p<0.05vs卵清蛋白组;OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
图4为示出N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制源自气管内细胞的Th2细胞因子(IL5)分泌的效果的图(*p<0.05vs卵清蛋白组;OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
图5为示出N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制源自气管内细胞的Th2细胞因子(IL13)分泌的效果的图(*p<0.05vs卵清蛋白组;OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
图6为示出N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制鼻炎反应的效果的图(图6a:揉鼻动作,图6b:打喷嚏)(*p<0.05vs卵清蛋白组;OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NO T=N-油酰-L-色氨酸)。
图7a、图7b为示出N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制过敏性结膜炎的效果的图。(图7a:眼球照片,图7b:临床等级(Clinicalgrade))(*p<0.05vs卵清蛋白组;OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸)。
具体实施方式
以下,通过实施例更详细地说明本发明。这些实施例仅用于更加具体地说明本发明,对于本发明所属技术领域的普通技术人员而言显而易显的是,根据本发明的要旨,本发明的范围不受这些实施例的限制。
实施例
制备例1.准备实验动物
小鼠是从DooYeolBiotech公司(乌山市,韩国)购入的没有特定病原体的BALB/c小鼠(6周,雄性)。在实验开始时使用7周龄-10周龄的小鼠,在层流箱(laminar flowcabinet)中饲育,无限制地供应水和饲料。
制备例2.制备使用的药物
Sigma公司(密苏里州,美国)购入本发明所使用的药物N-乙酰-L-丙氨酸、N-乙酰-L-色氨酸等,从Cayman公司(密歇根州,美国)购入N-油酰基-L-丙氨酸。N-油酰基色氨酸(N-oleoyl-tryptophan)是通过如下方法合成:首先,为了制备甲基油酰-L-色氨酸(methyloleoyl-L-tryptophanate),将油酸(oleoic acid)(2.36mmol)、L-色氨酸甲酯盐酸盐(L-tryptophan methyl ester hydrochloride)(2.60mmol)、1-乙基-3-(3-二甲氨丙基)碳酰二亚胺盐酸盐(1-Ethyl-3-(3-dimethylamino propyl)carbodiimide,EDCI))(2.60mmol)、羟基苯丙三唑(Hydro xybenzotriazole,HOBt)(2.60mmol)、三乙胺(triethylamine)(11.8mmol)溶于二氯甲烷(dichloromethan)的混合物在室温下搅拌12小时。将反应物浓缩后,使用饱和NaHCO3溶液稀释后使用乙酸乙酯(ethyl acetate)萃取3次。收集萃取的有机溶剂层并使用盐水(brine)洗涤后,使用1N的HCl洗涤后,再次用盐水洗涤。用无水MgSO4干燥有机溶剂层,浓缩后在中低压制备色谱仪(Medium pressure liquid chromatography,MPLC)上利用正己烷和乙酸乙酯(n-hexane and et hyl acetate)纯化。收率为73%,甲基油酰-L-色氨酸的性质如下:1HNMR(500MHz,Chloroform-d)δ8.18(s,1H),7.56(dd,J=7.9,1.0Hz,1H),7.39(dt,J=8.1,0.9Hz,1H),7.29(s,1H),7.22(ddd,J=8.2,7.1,1.2Hz,1H),7.14(ddd,J=8.0,7.0,1.0Hz,1H),7.00(d,J=2.4Hz,1H),5.99(d,J=7.9Hz,1H),5.37(qd,J=4.1,2.1Hz,2H),5.00(dt,J=8.0,5.3Hz,1H),3.72(s,3H),3.39-3.28(m,2H),2.20-2.13(m,2H),2.08-1.99(m,5H),1.60(t,J=7.4Hz,2H),1.34-1.28(m,24H),0.92-0.89(m,3H).LC-MS(ESI),calcd for C30H46N2O3 482.4,found m/z 483.4(M+H+)。为了从甲基油酰-L-色氨酸制备N-油酰基色氨酸(N-oleoyl trypto phan),向溶解有甲基油酰-L-色氨酸(0.37mmol)的四氢呋喃(tetrah ydrofuran)溶液中加入NaOH(1.48mmol)溶液后,在室温下搅拌12小时。向反应物加入水后使用二氯甲烷萃取。向水层中加入1N的HCl将pH调节为1后,使用乙酸乙酯萃取3次。用MgSO4干燥萃取的有机溶剂层并浓缩。收率为86%,N-油酰基色氨酸的性质如下:1H NM R(500MHz,Chloroform-d)δ8.22(s,1H),7.61(d,J=7.9Hz,1H),7.40(dt,J=8.1,0.9Hz,1H),7.23(ddd,J=8.1,6.9,1.2Hz,1H),7.15(ddd,J=8.0,7.1,1.0Hz,1H),7.08(d,J=2.4Hz,1H),5.37(qd,J=5.3,4.6,2.3Hz,2H),4.95(dt,J=7.3,5.6Hz,1H),3.45-3.33(m,2H),2.17-2.10(m,2H),1.59-1.51(m,2H),1.38-1.26(m,26H),0.91(d,J=6.8Hz,3H).C29H44N2O2 468.3,found m/z 469.3(M+H+)。
制备例3.诱发小鼠哮喘
分别在第0天和第14天,向小鼠的腹腔注射0.02mg的卵清蛋白和作为免疫辅助剂的明矾(alum)(1mg)(Sigma-Aldrich公司)2次来使小鼠致敏。从第28天开始在4天内每天将小鼠放入规定大小的塑料喷雾器(nebulizer)桶中分别使用5%的卵清蛋白以氧气喷雾的方式喷射30分钟以使小鼠吸入气喷形式的卵清蛋白。将其命名为气管挑战(airwaychallenge)。
制备例4.诱发小鼠鼻炎
分别在第0天和第14天,向小鼠的腹腔注射0.02mg的卵清蛋白和作为免疫辅助剂的明矾(1mg)(Sigma-Aldrich公司)2次来使小鼠致敏。从第21天开始,在7天内每天一次将100μg的OVA溶于20μl的磷酸盐缓冲溶液(phosphate buffered saline)中后分别在两侧鼻腔内各注射10μl来进行局部刺激。最后一次在鼻腔内点滴卵清蛋白后(实验第27天),将小鼠做出的揉鼻动作(nasal rubbing)和打喷嚏(sne ezing)的次数的和定义为症状分数(symptom score)。记录症状分数15分钟后比较各实验组的结果,其结果如图6所示。
制备例5.诱发小鼠结膜炎
分别在第0天和第7天,向小鼠的腹腔注射0.5mg的卵清蛋白和作为免疫辅助剂的明矾(1.5mg)(Sigma-Aldrich公司)2次来使小鼠致敏。从第14天开始,在12天内每天一次将100μg的卵清蛋白溶于10μl的磷酸盐缓冲溶液(phosphate buffered saline)中后分别向一只眼内各注射10μl来进行局部刺激来诱导结膜炎。
制备例6.测定支气管内的炎症细胞
将小鼠麻醉后,向支气管内插入导管(tube)并使用缓冲液清洗支气管来获得细胞。将其离心分离来以1×104cells/100μl的浓度悬浮,利用细胞离心涂片机(cytospin)将细胞离心分离于载玻片(slide)来固定后通过迪夫快速(Diff-Quik)染色测定嗜酸性粒细胞、单核细胞、中性粒细胞及巨噬细胞的数量。
制备例7.肺组织染色
通过组织学分析方法摘出肺并使用福尔马林溶液固定之后包埋于石蜡中。将包埋的组织切为4μm厚度的切片后,1)为获知炎症程度进行苏木精伊红(Hematoxylin andEosin,H/E)染色,2)为获知肺纤维化程度进行马松三色染色。
制备例8.测定结膜的浮肿及发红的临床分级
最后一次卵清蛋白滴眼(实验第25天)24小时后,使用便携式裂隙灯(portableslit lamp,Cail Zeiss公司,奥博科亨,德国)进行结膜的浮肿及发红(redness)的临床分级(clinical grading)。评价是在注入卵清蛋白2小时后以盲检的方式(blinded fashion)进行的。各临床参数按照Merayo-Lloves,J.,Calonge,M,and Foster,C.S.1995.Experimental model of allergic conjunctivitis to ragweed in guineapig.Curr.Eye Res.14:487-494中说明的方式在0至4+(0无(absent)、1+最低、2+轻微、3+普通、4+严重)的范围内记录。将一个组用作阴性对照组,未进行任何处置。
实施例1.N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色
氨酸抑制哮喘的效果
实施例1-1.在哮喘诱导小鼠中通过给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、
N-乙酰-L-色氨酸、N-油酰-L-色氨酸抑制炎症细胞流入气管内的效果
作为气管内炎症细胞观察了中性粒细胞(neutrophils)、巨噬细胞(macrophages)、单核细胞(monocytes)及嗜酸性粒细胞(eosinophi ls)。按照3.5μmole/kg的量分别将N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸溶于10ml的磷酸盐缓冲溶液中,从第25天开始以一天一次的方式口服给药7天。如表1所示,鼻腔内给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸均显著抑制了嗜酸性粒细胞流入气管内。
表1
支气管肺泡灌洗液参数(Bronchoalveolar lavage fluid parameters)
OVA=卵清蛋白,NAA=N-乙酰-L-丙氨酸,NOA=N-油酰基-L-丙氨酸,NAT=N-乙酰-L-色氨酸,NOT=N-油酰-L-色氨酸,MAC=巨噬细胞,NEU=中性粒细胞,MONO=单核细胞,EOS=嗜酸性粒细胞,N=小鼠的数量(the number of mice),S.D.=标准差(standarddeviati on),Min=最小值(minimum value),Max=最大值(maximum valu e)。
实施例1-2.肺组织的苏木精伊红染色的炎症程度
在口服给药药物一周后实施肺组织的苏木精伊红染色。在正常组中,气管周围几乎没有炎症细胞,使用卵清蛋白挑战(challenge)的组(OVA)中在气管周围大范围地聚集很多炎症细胞,支气管也变窄,可以在支气管周围观察到血管形成(图1),相反,在口服给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸的组(OVA+NAA、OVA+NOA、OVA+NAT、OVA+NOT)中,上述炎症程度被显著抑制,尤其在N-油酰基-L-丙氨酸的作用下,抑制程度最高(图1)。
实施例1-3.测定支气管洗涤液内的细胞因子(cytokine)
使用酶联免疫吸附测定试剂盒(ELISA Kit)(R&D Systems公司,明尼阿波利斯,明尼苏达州,美国)测定支气管洗涤液内的多种细胞因子(肿瘤坏死因子α(TNF-α)、白细胞介素4(IL-4)、白细胞介素5(IL-5)、白细胞介素13(IL-13))的浓度。
实施例2.N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色
氨酸抑制支气管闭塞的效果
在口服给药药物一周后实施肺组织的马松三色染色。在正常组中,气管周围几乎没有纤维化,使用卵清蛋白挑战(challenge)的组(OV A)中可以在气管周围观察到高度纤维化(图2),相反,在口服给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸的组(OVA+NAA、OVA+NOA、OVA+NAT、OVA+NOT)中,上述纤维化程度被抑制,尤其在N-油酰基-L-丙氨酸的作用下,抑制程度最高(图2)。
实施例3.N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色
氨酸抑制源自气管内细胞的Th2细胞因子(白细胞介素4、白细胞介素5及白细胞介素13)分
泌的效果
已知作为Th2细胞因子(Th2 cytokines)的白细胞介素4、白细胞介素5及白细胞介素13与由嗜酸性粒细胞引起的气管炎症、支气管过敏反应及IgE抗体的生成有关。按照3.5μmole/kg的量分别将N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸溶于10ml的磷酸盐缓冲溶液中,从第25天开始以一天一次的方式口服给药7天后测定细胞因子。通过口服给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸均显著抑制了白细胞介素4、白细胞介素5及白细胞介素13(图3、图4及图5)。
实施例4.N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色
氨酸(N-oleoyl-L-tryptophan)抑制鼻炎的效果
将制备例3的卵清蛋白用作诱发过敏性鼻炎的抗原,从试验的第21天到第26天,在卵清蛋白挑战(OVA challenge)12小时后,分别将N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸溶于磷酸盐缓冲溶液中使浓度达到10μM并以10μl的量分别向鼻腔给药。在最后一次向鼻腔内点滴卵清蛋白后(实验第27天),将小鼠作出的揉鼻动作和打喷嚏的次数的和定义为症状分数。记录症状分数15分钟后比较各实验组的结果,其结果如图6所示。在正常组中几乎没有柔比动作或者喷嚏,在使用卵清蛋白挑战的组中,柔比动作或喷嚏显著增加(图6a及图6b),相反,在鼻腔给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸的组中,柔比动作及喷嚏的次数均显著降低(图6a及图6b)。
实施例5.N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色
氨酸抑制结膜炎的效果
将制备例4的卵清蛋白用作诱发结膜炎的抗原,从试验的第15天到第26天,在使用100μg的卵清蛋白挑战眼睛30分钟和12小时后,分别将N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-乙酰-L-色氨酸、N-油酰-L-色氨酸溶于磷酸盐缓冲溶液中使浓度达到100μM并以10μl的量分别向眼睛给药。第26天,在注入卵清蛋白24小时后,使用便携式裂隙灯(Cail Zeiss公司,奥博科亨,德国)进行结膜的浮肿及发红(redness)的临床分级(clinical grading)。比较各实验组临床等级的结果如图7a、图7b所示。在正常组中,几乎没有结膜炎的症状,在仅使用卵清蛋白挑战的组中,结膜炎的临床等级增加(图7a和图7b),相反,在滴眼给药N-乙酰-L-丙氨酸、N-油酰基-L-丙氨酸、N-油酰-L-色氨酸的组中,临床等级均显著降低(图7a和图7b)。
以上,详细描述了本发明特定的部分,但本发明所属技术领域的普通技术人员应该明白的是,这些具体的描述只不过是优选的实例,而不是要限制本发明的范围。因此,本发明的实质范围应由随附的发明要求保护范围及其等价物来定义。
Claims (8)
1.一种用于预防或治疗哮喘、鼻炎或结膜炎的药剂学组合物,其特征在于,包含N-酰基氨基酸或其药剂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哮喘、鼻炎或结膜炎的药剂学组合物,其特征在于,上述N-酰基氨基酸为N-酰基丙氨酸或N-酰基色氨酸。
3.根据权利要求2所述的用于预防或治疗哮喘、鼻炎或结膜炎的药剂学组合物,其特征在于,上述N-酰基丙氨酸为N-乙酰丙氨酸或N-油酰基丙氨酸。
4.根据权利要求2所述的用于预防或治疗哮喘、鼻炎或结膜炎的药剂学组合物,其特征在于,上述N-酰基色氨酸为N-乙酰色氨酸或N-油酰基色氨酸。
5.一种用于预防或改善哮喘、鼻炎或结膜炎的食品组合物,其特征在于,包含N-酰基氨基酸或其药剂学上可接受的盐作为有效成分。
6.根据权利要求5所述的用于预防或改善哮喘、鼻炎或结膜炎的食品组合物,其特征在于,上述N-酰基氨基酸为N-酰基丙氨酸或N-酰基色氨酸。
7.根据权利要求6所述的用于预防或改善哮喘、鼻炎或结膜炎的食品组合物,其特征在于,上述N-酰基丙氨酸为N-乙酰丙氨酸或N-油酰基丙氨酸。
8.根据权利要求6所述的用于预防或改善哮喘、鼻炎或结膜炎的食品组合物,其特征在于,上述N-酰基色氨酸为N-乙酰色氨酸或N-油酰基色氨酸。
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CN101243053A (zh) * | 2005-06-15 | 2008-08-13 | 本国药品上市股份公司 | N-酰基氨基酸衍生物、其制备方法、药物组合物及其作为抗变应性、抗炎和降血脂药物的用途 |
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KR102376756B1 (ko) | 2022-03-21 |
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