CN111212639B - 包含芝麻酚和肽的缀合物作为活性成分的缓解宿醉的组合物 - Google Patents
包含芝麻酚和肽的缀合物作为活性成分的缓解宿醉的组合物 Download PDFInfo
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- CN111212639B CN111212639B CN201880066935.6A CN201880066935A CN111212639B CN 111212639 B CN111212639 B CN 111212639B CN 201880066935 A CN201880066935 A CN 201880066935A CN 111212639 B CN111212639 B CN 111212639B
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Abstract
本发明涉及一种缓解宿醉的组合物,该组合物包含芝麻酚和肽的缀合物作为活性成分。具体而言,根据本发明的芝麻酚和肽的缀合物显著提高了酒精代谢过程中涉及的乙醇脱氢酶(ADH)或醛脱氢酶(ALDH)的活性,快速降低体内酒精的浓度,并且改善酒精诱发的运动障碍,因此具有能够有效地用作缓解宿醉的组合物中的活性成分的优点。
Description
技术领域
本发明涉及芝麻酚和肽的缀合物,以及包含该缀合物作为活性成分的缓解宿醉的组合物。
背景技术
韩国的酒精消费是世界的最高水平,并且由饮酒引起的对社会经济和健康的危害正在迅速增加。据报道,过量饮酒会影响身体的几乎所有部分,从而引起许多疾病,例如肝病、胃炎、胰腺炎、高血压、中风、糖尿病和心脏病。
根据由保健福利部下属的韩国保健和社会事务研究所进行的全民健康与营养调查的最新结果表明,在韩国,超过20岁的成年人的饮酒天数平均为每月约8天,男性为约11天并且女性为约4天。在这种情况下,已经研究发现,醉酒次数为每周至少一次的约有4.7%,每月1次至3次的约有10.7%,并且每3个月1次至3次的约有13.2%,因此,这在全民健康方面备受关注。
因此,现代人过多饮用了人体无法应付的过量的酒精,并对能够消除宿醉的药品或饮品的兴趣逐步增加,并且由于这些因素,目前缓解宿醉的饮品市场的规模已经增长到销售额超过1000亿,并且甚至在海外市场也已经引起了关注。
宿醉是指饮酒后出现的诸如头痛、腹泻、厌食、恶心、呕吐、寒颤和冷汗之类的症状,并且客观症状包括认知、运动能力降低、血液学变化和激素变化。已知宿醉的原因是脱水、酒精和酒精代谢物(乙醛、甲醛、丙酮等)的毒性以及由吸收障碍引起的营养素的缺乏(血糖、维生素和矿物质的缺乏)。宿醉的程度有很大的差异,这取决于根据遗传和环境条件(营养状态、运动状态、脱水程度和健康状况)的个体差异。
在饮酒后,酒精通过三种途径进行代谢,其中当乙醇的浓度低时,酒精通过存在于胃肠道或肝脏中的乙醇脱氢酶和乙醛脱氢酶的作用代谢为乙醛和乙酸,当乙醇的浓度高时,酒精通过存在于内质网中的微粒体乙醇氧化体系(MEOS)代谢为乙醛和乙酸,然后最终通过存在于过氧化物酶体中的过氧化氢酶的作用分解为二氧化碳(CO2)和水(H2O)。当引入适量的酒精时,上述代谢系统平稳地起作用,因而不会发生由酒精引起的症状,但是当引入大量的酒精时,破坏了代谢系统的平衡并且不能维持生物体内平衡,因而结果是,短期内可能引起头痛或头部沉重的感觉、注意力不集中、胃灼热和消化不良,并且长期内可能发生肝功能障碍。
同时,目前,包含黄芪、莲子、稻米胚芽和枳椇子提取物的缓解宿醉的饮品、包含发酵的米-大豆提取物和奶蓟提取物粉末作为主要成分的缓解宿醉的饮品以及包含赤杨树和花楸提取物作为活性成分的缓解宿醉的饮品是市售可得的,但是因为这些饮品中的大部分包含提取物作为活性成分,所以原料的固定是易变的,并且构建用于大规模生产的提取所需的工艺或设备是昂贵的。此外,由于提取物的性质而存在许多问题,缓解宿醉的程度根据个体而显著不同,并且需要长时间来缓解宿醉。因此,仍然需要开发一种产品,该产品在确保原料或大规模生产方面是容易且有效的,并且可以在短时间内同时解决酒精分解和宿醉缓解。
发明内容
[技术问题]
本发明的目的是提供一种用于缓解宿醉的芝麻酚和肽的缀合物。
本发明的另一目的是提供包含缀合物作为活性成分的缓解宿醉的组合物。
本发明的又一目的是提供一种缓解宿醉的方法,该方法包括对有此需要的受试者施用缀合物或包含该缀合物作为活性成分的组合物。
[技术方案]
为了实现上述目的,本发明的一个方面提供了一种用于预防或缓解宿醉的药物组合物,该药物组合物包含芝麻酚和肽的缀合物作为活性成分。
本发明的另一方面提供了一种用于预防或缓解宿醉的组合物,该组合物包含芝麻酚和肽的缀合物作为活性成分。
本发明的又一方面提供了一种预防或缓解宿醉的方法,该方法包括对有此需要的受试者施用芝麻酚和肽的缀合物或包含该缀合物作为活性成分的组合物。
[有利效果]
根据本发明,芝麻酚和肽的缀合物具有显著改善酒精分解过程中涉及的乙醇脱氢酶(ADH)和醛脱氢酶(ALDH)的活性、在体内快速分解酒精以及改善酒精诱发的运动障碍的优点,因此能够有效地用作缓解宿醉的组合物中的活性成分。
然而,本发明的效果不限于上述效果,并且本领域技术人员将从以下描述中清楚地理解未提及的其他效果。
附图说明
图1为示出了证实芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物提高了醛脱氢酶(ALDH)的活性的效果的结果的图。
图2为示出了证实芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物提高了醛脱氢酶(ALDH)的活性的效果的结果的图。
图3为示出了证实芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物以及芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物提高了乙醇脱氢酶(ADH)和ALDH的mRNA表达的效果的结果的图示。
图4为示出了证实通过与根据本发明的芝麻酚和肽的缀合物混合的缀合物复合物改善了小鼠模型的运动能力的效果的结果的图。
图5为示出了证实通过与根据本发明的芝麻酚和肽的缀合物混合的缀合物复合物降低了小鼠模型的血清中的醛浓度的效果的结果的图。
图6为示出了证实与根据本发明的芝麻酚和肽的缀合物混合的缀合物复合物对缓解宿醉的效果的结果的图。
在图1至图3中,“SEQ ID NO:1”是用芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物处理的组,并且“SEQ ID NO:2”是用芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物处理的组。在图4至图6中,“缀合物复合物”是用混合有重量比为1:1的芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物以及芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物的复合物处理的组。
具体实施方式
在下文中,将详细描述本发明。
1.用于预防或缓解宿醉的药物组合物
本发明的一个方面提供了一种用于预防或缓解宿醉的药物组合物,该药物组合物包含芝麻酚和肽的缀合物作为活性成分。
芝麻酚代表化学式为C7H6O3的化合物,并且具有以下化学式1的化学结构。
[化学式1]
肽是指由通过肽键连接的两个或更多个氨基酸组成的聚合物,并且肽的缺点在于,由于肽本身的尺寸太大,因此不能将肽有效地引入到靶组织或靶细胞中,或者由于半衰期短,因此肽在短时间内会在体内消失。因此,本发明的肽包含20个以下、优选15个以下、更优选10个以下的氨基酸。
本发明的新的肽可以包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列,并且可为在不影响本发明的宿醉缓解的范围内,通过氨基酸残基的缺失、插入、置换或它们的组合而得到的具有不同序列的氨基酸的变体或片段。不改变肽整体的缓解宿醉活性的在肽水平上的氨基酸交换在本领域中是已知的。在一些情况下,可以通过磷酸化、硫酸化、丙烯酸酯化、糖基化、甲基化、法尼基化等修饰氨基酸交换。因此,本发明包括具有与氨基酸序列为SEQ IDNO:1或SEQ ID NO:2的肽基本上相同的氨基酸序列的肽及其变体或活性片段。基本上相同的肽是指分别与SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的序列同源性为75%以上,优选为80%以上,更优选为90%以上,并且最优选为95%以上的氨基酸序列。此外,肽还可包括为了特定目的制备的氨基酸序列,从而增加靶向序列、标签、标记的残基、半衰期或肽稳定性。
进一步地,可以通过本领域公知的各种方法获得本发明的肽。例如,可以通过使用多核苷酸重组和蛋白表达系统制备肽,或者由通过诸如肽合成、无细胞蛋白合成法等的化学合成在体外合成制备肽。
此外,为了获得更好的化学稳定性、增强的药理学性质(半衰期、吸收性、效价、功效等)、修饰的特异性(例如,宽的生物活性谱)和降低的抗原性,使肽的N端键合至选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂基或聚乙二醇(PEG)组成的组中的基团的保护基,以改善稳定性。同时“稳定性”是指储存稳定性(例如,室温储存稳定性)以及保护本发明的肽在体内免受蛋白裂解酶的攻击的体内稳定性。
芝麻酚和肽可以通过接头彼此连接。接头可为脂肪族、脂环族或芳香族二羧酸,优选为脂肪族或脂环族二羧酸,并且更优选为脂肪族二羧酸。更具体而言,脂肪族二羧酸可为具有以下化学式2的化学结构的二羧酸。
[化学式2]
在化学式2中,R可为:亚烷基,该亚烷基具有1个至12个碳原子,优选1个至10个碳原子,并且更优选1个至6个碳原子;亚烯基,该亚烯基具有2个至12个碳原子,优选2个至10个碳原子,并且更优选2个至6个碳原子;或者亚炔基,该亚炔基具有2个至12个碳原子,优选2个至10个碳原子,并且更优选2个至6个碳原子。
特别地,接头可为具有以下化学式3的化学结构的脂肪族饱和二羧酸。
[化学式3]
在化学式3中,n为1至12的整数,优选为1至10,更优选为1至6,并且最优选为1至4。
二羧酸的一侧的羧基与芝麻酚的羟基(-OH)形成酯键,并且二羧酸的另一侧的羧基与暴露于肽的N端的氨基(-NH2)形成肽键,从而使得芝麻酚和肽彼此连接以形成本发明的缀合物。
进一步地,可以通过i)制备肽,ii)通过使接头与肽反应从而将接头与肽键合,以及iii)通过使芝麻酚与键合至肽的接头反应从而将芝麻酚与接头键合来制备本发明的芝麻酚和肽的缀合物。
此外,芝麻酚和肽的缀合物可为芝麻酚和包含SEQ ID NO:1的氨基酸序列的肽的缀合物、芝麻酚和包含SEQ ID NO::2的氨基酸序列的肽的缀合物或它们的混合物。
为了证实通过本发明的芝麻酚和肽的缀合物提高醛脱氢酶(ALDH)的活性的效果,在本发明的一个具体实施方案中,分别用芝麻酚和具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽的缀合物处理肝癌细胞,然后进行ALDH活性分析。作为结果,证实了在用本发明的芝麻酚和肽的缀合物处理的细胞中,ALDH活性以浓度依赖性方式提高(参见图1和图2)。
此外,为了证实本发明的芝麻酚和肽的缀合物的提高酒精分解过程中涉及的乙醇脱氢酶(ADH)和ALDH表达的效果,在本发明的具体实施方案中,分别用芝麻酚和具有SEQ IDNO:1或SEQ ID NO:2的氨基酸序列的肽的缀合物处理肝癌细胞,然后通过RT-PCR证实ADH和ALDH的表达水平。作为结果,证实了与未处理的对照组相比,在用本发明的芝麻酚和肽的缀合物处理的细胞中,ADH4、ALDH1和ALDH2的mRNA表达显著提高(参见图3)。
此外,为了证实本发明的芝麻酚和肽的缀合物的改善运动能力的效果,在本发明的具体实施方案中,将芝麻酚和具有SEQ ID NO:1氨基酸序列的肽的缀合物以及芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物以1:1的重量比混合,然后对酒精小鼠模型施用,随后进行行为测试。作为结果,证实了施用缀合物复合物的组显著改善了因酒精摄入而降低的运动能力(参见图4)。
此外,为了证实本发明的芝麻酚和肽的缀合物的酒精分解效果,在本发明的一个具体实施方案中,对酒精小鼠模型施用缀合物复合物,然后在小鼠血清中进行醛分析。作为结果,证实了施用缀合物复合物的组显著降低了血清中的醛浓度(参见图5)。
此外,为了证实本发明的芝麻酚和肽的缀合物缓解宿醉的效果,在本发明的具体实施方案中,使临床试验受试者摄入缀合物复合物与酒精,然后在1小时和2小时后测定血液酒精浓度。作为结果,证实了施用缀合物复合物的组显著降低了血液酒精浓度(参见图6)。
因此,本发明的芝麻酚和肽的缀合物显著提高了酒精分解过程中涉及的乙醇脱氢酶或醛脱氢酶的活性,迅速降低了体内的酒精浓度,并且改善了酒精诱发的运动障碍,从而能够有效地用作缓解宿醉的组合物中的活性成分。
同时,可以在药学可接受的载体中携带本发明的芝麻酚和肽的缀合物,药学可接受的载体例如为胶体悬浮液、粉末、生理盐水、脂质、脂质体、微球或球形纳米颗粒。这些缀合物可以与载体形成复合物或与复合物相关,并且可以通过使用本领域已知的携带体系在体内携带,所述本领域已知的携带体系例如为脂质、脂质体、微粒、金、纳米颗粒、聚合物、缩合试剂、多糖、聚氨基酸、树状聚合物、皂苷、吸附增强物质或脂肪酸。
此外,药学可接受的载体可以包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、金合欢胶、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、滑石粉、硬脂酸镁和矿物油,以上通常用于制备,但不限于此。此外,除上述成分以外,药物组合物还可以包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
本发明的药物组合物可以根据所需方法口服施用或肠胃外施用(例如,肌内给药、静脉内给药、腹腔内给药、皮下给药、皮内给药或局部给药),并且剂量根据患者的状况和体重、疾病的程度、药物形式以及施用的途径和时间而变化,但是可以由本领域技术人员适当地选择。
以药学有效量施用本发明的药物组合物。在本发明中,“药学有效量”是指以适用于医学治疗的合理的效益/风险比治疗疾病的足够的量,并且可以根据包括患者的疾病的类型和严重程度、药品的活性、对药品的敏感性、施用的时间、施用的途径、排放速率、治疗的持续时间和同时使用的药物在内的因素以及医学领域中公知的其他因素确定有效量水平。根据本发明的药物组合物可以作为单独的治疗剂施用或与其他缓解宿醉的制剂联合施用,并且可以与常规缓解宿醉的制剂同时施用、单独施用或依次施用,并且可以单次或多次施用。重要的是通过考虑所有因素,从而施用能够获得最大效果而没有副作用的最小量,并且这可以由本领域技术人员容易地确定。
具体而言,本发明的药物组合物的有效剂量可以根据患者的年龄、性别、状况和体重,活性成分在体内的吸收,失活速率,排泄速率,疾病类型和组合使用的药品而变化,并且可以根据施用的途径、肥胖的严重程度、性别、体重、年龄等而增加或减少。例如,可以以每天每kg患者体重约0.0001μg至500mg,优选0.01μg至100mg施用本发明的肽。
2.用于预防或缓解宿醉的组合物
本发明的另一方面提供了用于预防或缓解宿醉的组合物,该组合物包含芝麻酚和肽的缀合物作为活性成分。
芝麻酚和肽的缀合物与“1.用于预防或缓解宿醉的药物组合物”部分中描述的芝麻酚和肽的缀合物相同,因此,使用“1.用于预防或缓解宿醉的药物组合物”部分以进行详细描述,并且在下文中,将仅描述组合物的具体结构。
与药物组合物一样,本发明的芝麻酚和肽的缀合物显著提高了酒精分解过程中涉及的乙醇脱氢酶或醛脱氢酶的活性,迅速降低了体内的酒精浓度,并且改善了酒精诱发的运动障碍,从而能够有效地用作用于缓解宿醉的组合物中的活性成分。
活性成分的混合量可以根据其使用目的(用于预防或改善)适当地确定,通常优选为原料的15重量%以下,更优选为10重量%以下。然而,在为了健康和卫生或健康调节的目的而长期摄取的情况下,该添加量可以等于或低于上述范围。
除活性成分以外,本发明的组合物还可以包含其他成分作为所需成分,没有特别的限制。例如,与一般饮品一样,可以包含各种调味剂或天然碳水化合物作为附加成分。上述天然碳水化合物的实例可以包括一般的糖,例如:单糖,如葡萄糖、果糖等;二糖,如麦芽糖、蔗糖等;以及多糖,如糊精、环糊精等;和糖醇,如木糖醇、山梨糖醇、赤藓糖醇等。作为上述以外的调味剂,可以优选使用天然调味剂(索马甜、甜叶菊提取物(例如,甜叶菊甙A、甘草甜素等))和合成调味剂(糖精、天冬甜素等)。天然碳水化合物的比例可以通过本领域技术人员的选择适当地确定。
此外,本发明的组合物可以包含各种营养素、维生素、矿物质(电解质)、诸如合成调味剂和天然调味剂之类的调味剂、着色剂和增味剂(奶酪、巧克力等)、果胶酸及其盐、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、醇、用于碳酸饮料的碳酸化剂等。这些成分可以单独使用或组合使用,并且这些添加剂的比例也可以由本领域技术人员适当地选择。
3.用于预防或缓解宿醉的方法
本发明的又一方面提供了一种用于预防或缓解宿醉的方法,该方法包括对有此需要的受试者施用芝麻酚和肽的缀合物或包含该缀合物作为活性成分的组合物。
芝麻酚和肽的缀合物与“1.用于预防或缓解宿醉的药物组合物”部分中描述的芝麻酚和肽的缀合物相同,因此,使用“1.用于预防或缓解宿醉的药物组合物”部分以进行详细描述。
如上所述,本发明的芝麻酚和肽的缀合物或包含该缀合物作为活性成分的组合物(例如,药物组合物)可以迅速降低体内的酒精浓度,并且改善酒精诱发的运动障碍,从而当对受试者(例如,有此需要的人)施用缀合物或组合物时,实现了优异的缓解宿醉的效果。
在下文中,通过制备例和实验例对本发明进行详细说明。
然而,以下制备例和实验例仅是对本发明的说明,并且本发明的内容不限于以下制备例和实验例。
[制备例1]琥珀酰化肽的制备
通过使用自动肽合成仪(Milligen 9050,Millipore,美国)分别合成具有下表1所示的SEQ ID NO:1的氨基酸序列的肽和具有下表1所示的SEQ ID NO:2的氨基酸序列的肽,并且将各个肽(1mmol)和琥珀酸酐(200mg,2.0当量)溶解在N,N-二甲基甲酰胺(DMF,10ml)中,并且添加N,N-二异丙基乙胺(DIEA)(388mg,3.0当量),并在室温反应2小时,以使各个肽琥珀酰化。分别使用C18反相高效液相色谱(HPLC)(Waters Associates,美国)纯化这些合成的琥珀酰化肽。柱使用ACQUITY UPLC BEH300 C18(2.1 100mm,1.7μm,Waters Co,美国)。
[表1]
序列No. | 氨基酸序列 |
1 | SIPCKLQSG |
2 | WLNRRAN |
[制备例2]本发明的芝麻酚和肽的缀合物的制备
在肽反应器中,将[制备例1]中制备的琥珀酰化肽(1mmol)溶解在二甲基甲酰胺(DMF,10ml)中,添加1-羟基苯并三唑(HOBt,270mg,2.0当量)、六氟磷酸(苯并三唑-1-基氧基)三吡咯烷基磷(PyBOP,1.04g,2.0当量)和芝麻酚(277mg,2.0当量),并且搅拌30分钟。向混合物中添加N,N-二异丙基乙胺(DIEA,388mg,3当量),并且在室温反应4小时,然后使用乙醚(10ml,10mmol)进行重结晶、过滤以及干燥过程,以分别获得芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物以及芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物。
[实验例1]提高醛脱氢酶活性的效果的证实
通过酒精分解酶即乙醇脱氢酶(ADH)将酒精转化为乙醛,并且通过醛脱氢酶(ALDH)将经转化的乙醛转化并分解为乙酸。因此,为了证实提高酒精分解过程中涉及的ALDH的活性的效果,用[制备例2]中制备的芝麻酚和肽的两种缀合物分别处理肝癌细胞,然后进行ALDH活性分析。
具体而言,将肝脏肝细胞癌(HepG2)细胞(其为人肝癌细胞)以4×105细胞/孔的密度接种到6孔板中,然后孵育过夜。然后,分别用浓度为50μM或100μM的[制备例2]中制备的芝麻酚和肽的两种缀合物进行处理,并孵育24小时,并且收集细胞,随后使用ALDH活性分析试剂盒(abcam,ab155893)分析ALDH活性。同时,阳性对照组用5μM的萝卜硫素进行处理。
对于ALDH活性分析,用包括在试剂盒中的ALDH活性分析缓冲液处理各个收集的细胞,然后使用冰的情况下用均化器使细胞溶解。然后,在4℃和13,000rpm的条件下对细胞进行10分钟的离心,然后收集上清液。用ALDH分析缓冲液、ALDH底物和乙醛处理收集的上清液,并在室温下反应1小时,并使用分光光度计以2分钟的间隔测定450nm处的吸光度,持续测定20分钟。然后,使用以下[式1]计算ALDH活性。
[式1]
-B:实验组产生的NADH量(nmol)
-ΔT:反应时间(min)
-V:用于反应孔中的实验组的体积(ml)
作为结果,如图1和图2所示,与未处理的对照组相比,本发明的芝麻酚和肽的两种缀合物分别显著提高了ALDH活性(图1和图2)。
[实验例2]提高ADH和ALDH的表达的效果的证实
为了证实提高酒精分解过程中涉及的ADH和ALDH的表达的效果,分别用[制备例2]中制备的芝麻酚和肽的两种缀合物处理肝癌细胞,然后进行RT-PCR。
具体而言,将HepG2细胞以4×105细胞/孔的密度接种到6孔板中,然后孵育过夜。然后,分别用10μM或50μM浓度的[制备例2]中制备的芝麻酚和肽的两种缀合物进行处理,并孵育6小时,并且收集细胞。随后,根据制造商的方案使用Trizol(Invitrogen,美国)从收集的细胞中分离出总RNA,然后根据制造商的方案使用cDNA合成试剂盒(Intron,韩国)将1g的分离出的RNA合成为cDNA。使用下表2所示的引物对cDNA进行PCR,然后在5%琼脂糖凝胶上进行电泳以证实ADH4、ALDH1和ALDH2的mRNA表达水平。
[表2]
作为结果,如图3所示,与无关对照组相比,本发明的芝麻酚和肽的两种缀合物分别显著提高了ADH4、ALDH1和ALDH2的mRNA表达(参见图3)。为了使酒精迅速分解,必须通过提高酒精分解中涉及的酶即ADH和ALDH的活性,从而引起迅速分解,因此,从[实验例1]和[实验例2]的结果可以看出,本发明的芝麻酚和肽的缀合物可以显著提高ADH和ALDH的活性和表达,从而引起酒精的迅速分解。
[实验例3]改善施用酒精的小鼠模型的运动能力的效果的证实
为了证实在施用酒精的动物模型中改善运动能力的效果,对小鼠模型施用[制备例2]中制备的芝麻酚和肽的缀合物与酒精,然后使用转棒装置进行行为测试。
具体而言,将8周龄的雄性Balb/c小鼠用作小鼠模型,并且通过自由饲喂固体饲料和自来水进行1周的预饲养,然后用于测试。此外,将小鼠分成①正常对照组、②施加酒精组和③实验组,并且每组5只小鼠用于测试。
对于行为测试,将小鼠置于转棒装置上,并且进行三次或更多次适应性训练。
在进行行为测试之前,使小鼠维持4小时空腹,在施用酒精之前将小鼠置于转棒装置上,使小鼠在rpm从4rpm逐渐增加至40rpm的条件下行走,然后丧失运动能力,测定跌落在底墩花费的时间,并转化为以秒为单位的值,从而获得跌落延迟(秒)值。
然后,将芝麻酚和具有SEQ ID NO:1的氨基酸序列的肽的缀合物以及芝麻酚和具有SEQ ID NO:2的氨基酸序列的肽的缀合物以1:1的重量比混合,以制备复合物(下文中称为“缀合物复合物”),然后将该复合物溶解在水中,以100mg/kg的剂量对实验组的小鼠进行口服施用,然后放置30分钟。同时,在正常对照组的情况中,口服施用相同体积的水。随后,以每个体400μl对施用酒精组和实验组中的个体小鼠口服施用20%酒精,并且在30分钟、1小时和2小时后,以与上述相同的方式使用转棒装置获得每组的跌落延迟(秒)值。
作为结果,如图4所示,在进行行为测试之前,正常对照组、施用酒精组和实验组都具有约250的平均跌落延迟(秒)值,并且所有三组都具有相似的跌落延迟(秒)值。
另一方面,在施用酒精30分钟、1小时和2小时后进行行为测试的结果证实,施用酒精组显著降低了跌落延迟(秒)值,而与施用酒精组相比,将本发明的缀合物复合物与酒精一起施用的实验组显著延长了跌落延迟(秒)值(图4)。
从上述结果可以看出,本发明的芝麻酚和肽的缀合物显著改善了由酒精摄入而降低的运动能力。
[实验例4]对施用酒精的小鼠模型的酒精分解效果的证实
为了证实在施用酒精的动物模型中的酒精分解效果,进行小鼠血清中的醛分析。
具体而言,分别提取[实验例3]中完成2小时行为测试后的①正常对照组、②施用酒精组和③实验组中的血液。然后,将提取的血液在室温凝固20分钟,然后以3,000rpm离心,从而获得作为上清液的血清。使用醛定量分析试剂盒(abcam,ab112113)进行所得血清中的醛分析。更具体而言,将获得的血清和试剂盒的2×Yellos反应混合物以1:1进行混合,然后在室温反应1小时,随后使用分光光度计测定550nm处的吸光度。
作为结果,如图5所示,证实了施用酒精组的血清与正常对照组的血清相比具有更高的醛浓度,而将本发明的缀合物复合物与酒精一起施用的实验组的血清与施用酒精组的血清相比具有显著更低的醛浓度(图5)。
从上述结果可以看出,本发明的芝麻酚和肽的缀合物可以显著提高ADH和ALDH的活性和表达,从而引起酒精的迅速分解。
[实验例5]缓解宿醉的效果的证实
为了证实缓解宿醉的效果,使用缀合物复合物进行临床试验。
具体而言,招募年龄为20岁至40岁的4名成年男性和4名成年女性以进行临床试验。然后,进行对照测试以检查受试者的基本酒精吸收模式。更具体而言,在食用相同的膳食后,受试者维持3小时的空腹,并且饮用一瓶市售的20%酒(烧酒)30分钟。在饮用1小时和2小时后,使用呼气式酒精测试仪(Sentek Korea,AL-9000)测定血液酒精浓度。
此后,为了证实缀合物复合物缓解宿醉的效果,在对照测试3天后,将100ml的包含100ppm的[制备例2]中制备的芝麻酚和肽的两种缀合物中每一种的饮品给相同的受试者服用,并且30分钟后,以与上述方法相同的方式服用酒精,并且测定血液酒精浓度,然后将该血液酒精浓度与对照测试结果进行比较并分析以绘图。
作为结果,如图6所示,证实了与仅服用酒精的组相比,服用本发明的缀合物复合物的组在摄入酒精1小时和2小时后的血液酒精浓度显著降低(图6)。
因此,从上述结果可以看出,本发明的芝麻酚和肽的缀合物引起酒精的迅速分解,从而缓解了宿醉。
<110> 凯尔格恩有限公司
<120> 包含芝麻酚和肽的缀合物作为活性成分的缓解宿醉的组合物
<130> 2018OPA1539
<150> KR 10-2017-0133836
<151> 2017-10-16
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Claims (9)
1.一种用于预防或缓解宿醉的药物组合物,该药物组合物包含芝麻酚和肽的缀合物作为活性成分,其中所述肽的氨基酸序列如SEQ ID NO:1或SEQ ID NO:2所示。
2.根据权利要求1所述的用于预防或缓解宿醉的药物组合物,其中所述芝麻酚和所述肽通过接头彼此连接。
3.根据权利要求2所述的用于预防或缓解宿醉的药物组合物,其中所述接头为二羧酸。
4.根据权利要求1所述的用于预防或缓解宿醉的药物组合物,其中所述组合物包含芝麻酚和氨基酸序列如SEQ ID NO:1所示的肽的缀合物、芝麻酚和氨基酸序列如SEQ ID NO:2所示的肽的缀合物、或它们的混合物。
5.根据权利要求1至3中任一项所述的用于预防或缓解宿醉的药物组合物,其中所述组合物提高了乙醇脱氢酶(ADH)或醛脱氢酶(ALDH)的活性。
6.根据权利要求1至3中任一项所述的用于预防或缓解宿醉的药物组合物,其中所述组合物改善了酒精诱发的运动障碍。
7.根据权利要求1至3中任一项所述的用于预防或缓解宿醉的药物组合物,其中所述组合物具有选自由粉剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳剂、糖浆剂、外用制剂、栓剂和无菌注射液组成的组中的制剂。
8.一种用于预防或缓解宿醉的组合物,该组合物包含芝麻酚和肽的缀合物作为活性成分,其中所述肽的氨基酸序列如SEQ ID NO:1或SEQ ID NO:2所示。
9.根据权利要求8所述的用于预防或缓解宿醉的组合物,其中所述组合物包含芝麻酚和氨基酸序列如SEQ ID NO:1所示的肽的缀合物、芝麻酚和氨基酸序列如SEQ ID NO:2所示的肽的缀合物、或它们的混合物。
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KR10-2017-0133836 | 2017-10-16 | ||
PCT/KR2018/012149 WO2019078570A2 (ko) | 2017-10-16 | 2018-10-16 | 세사몰과 펩타이드의 결합체를 유효성분으로 함유하는 숙취 해소용 조성물 |
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US20110159128A1 (en) * | 2004-12-14 | 2011-06-30 | Toyo Shinyaku Co., Ltd. | Alcohol metabolism enhancer and alcoholic beverage |
EP2754665A1 (en) * | 2011-09-09 | 2014-07-16 | Caregen Co., Ltd. | Peptide inhibiting matrix metalloproteanases activity and use thereof |
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KR101762136B1 (ko) | 2015-09-22 | 2017-07-27 | 대상 주식회사 | 엘라그산 및 아세트산이 포함된 숙취해소 조성물 및 이의 제조방법 |
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US20110159128A1 (en) * | 2004-12-14 | 2011-06-30 | Toyo Shinyaku Co., Ltd. | Alcohol metabolism enhancer and alcoholic beverage |
EP2754665A1 (en) * | 2011-09-09 | 2014-07-16 | Caregen Co., Ltd. | Peptide inhibiting matrix metalloproteanases activity and use thereof |
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JP7033197B2 (ja) | 2022-03-09 |
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KR102011979B1 (ko) | 2019-08-19 |
EP3698786A4 (en) | 2020-12-30 |
US20200330546A1 (en) | 2020-10-22 |
WO2019078570A3 (ko) | 2019-06-27 |
EP3698786A2 (en) | 2020-08-26 |
BR112020007399A2 (pt) | 2020-09-29 |
WO2019078570A2 (ko) | 2019-04-25 |
EA202090950A1 (ru) | 2020-07-08 |
CN111212639A (zh) | 2020-05-29 |
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