CN110049766A - 以吴茱萸提取物或吴茱萸碱为有效成分的用于预防或治疗由咖啡因中毒导致的疾病的组合物 - Google Patents
以吴茱萸提取物或吴茱萸碱为有效成分的用于预防或治疗由咖啡因中毒导致的疾病的组合物 Download PDFInfo
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- CN110049766A CN110049766A CN201780075654.2A CN201780075654A CN110049766A CN 110049766 A CN110049766 A CN 110049766A CN 201780075654 A CN201780075654 A CN 201780075654A CN 110049766 A CN110049766 A CN 110049766A
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- rutaecarpin
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- caffeine
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Abstract
本发明涉及一种含有吴茱萸碱或吴茱萸提取物的预防或治疗咖啡因中毒的组合物,具体地讲,涉及一种对由咖啡因导致的睡眠障碍及中枢神经兴奋具有预防或改善效果的药学组合物。另外,本发明还涉及一种含有吴茱萸提取物或吴茱萸碱的咖啡因中毒治疗方法及保健功能食品组合物。
Description
技术领域
本发明涉及一种含有吴茱萸提取物或吴茱萸碱的用于预防或治疗由咖啡因中毒导致的疾病的组合物,具体地讲,涉及一种具有预防或改善由咖啡因导致的睡眠障碍及中枢神经兴奋的效果的药学组合物。另外,本发明涉及一种含有吴茱萸碱的用于治疗由咖啡因中毒导致的疾病的方法及保健功能食品组合物。
背景技术
随着西方化的饮食习惯与繁忙的生活方式,现代人摄入各种饮料,在食品的选择标准方面,西方化倾向增加,特别是含有大量咖啡因的嗜好饮料的消费日益增加。由此,各种含咖啡因的加工食品正在被开发,咖啡店或者快餐店的利用在增加,所有年龄段的人对含咖啡因食品的摄取在增加。有关咖啡市场消费现状的研究表明,国民每1人每天摄取0.8杯咖啡,一年饮用的咖啡杯数达到300杯。另外,青少年多数都饮用含有咖啡因的咖啡,如果再考虑到含有过量咖啡因的饮料及巧克力,则是该考虑过量摄取咖啡因的危险性的时候了。嗜好食品即咖啡因在社会上大受欢迎,并且除了咖啡或者茶之外,儿童或者青少年大量摄取的可乐、巧克力等也含有咖啡因,而且除了食品与饮料之外,以头痛药、感冒药、利尿剂及食欲抑制剂为主的非处方药品中也含有咖啡因。
咖啡因广泛混合到咖啡、茶、饮料、药品等中,其主要成分为1,3,7-三甲基黄嘌呤(1,3,7trimethylxanthine),是一种含氮苦味生物碱(alkaloid)化合物,是一种由嘌呤(purine)与尿酸(uric acid)派生的成分。这种咖啡因无气味呈白色针状结晶,在176条件下会升华,并容易溶解于热水,带有一种特有的固有苦味。另外,现在已知大约有60多种植物的叶子与果实中含有咖啡因,主要从咖啡树(coffee arabica)的种子中提取。除此之外,也可以从茶树(Camellia sinensis(L)O.Kuntze)的叶子、可可(Theobroma cacao)树的果实、可乐树(Cola acuminata)的果实、马黛树(Ilex paraguayensis)的叶子中提取。
咖啡因是作为一种刺激中枢神经***与交感神经***的中枢神经***而在身体器官上显示出效果,对表皮、骨髓、脊髓产生影响。通过咖啡因对身体的影响的实验性研究,发现其在体内被吸收的效果,主要是使血液中肾上腺素(adrenaline)、去甲肾上腺素(noradrenaline)、皮质醇等压力荷尔蒙的浓度增加,从而导致血压升高。由于咖啡因具有中枢神经兴奋作用,因此被广泛用作克服困意的清醒剂,这种睡眠障碍及提神效果被广为人知,所以高咖啡因饮料普遍化的同时被广泛利用。但是,长期摄取会对正常睡眠与清醒状态产生严重的影响,据报告,当过量摄取咖啡因时,会带来消化不良、心悸、兴奋、头痛、失眠、高酸性胃炎、利尿作用、矿物质缺乏等危险。
特别是,最近在青少年人群中流行的高咖啡因饮料被误认为是“备考神药”,每当考期来临,有很多青少年在饮用。但是,高咖啡因饮料只具有通过刺激中枢神经而暂时消除困意的效果,并无任何根据表明其能够提高成绩。虽然是这种对高咖啡因饮料的正确理解不足的实情,但是我国目前为止还存在既无保护青少年、儿童过多饮用的特别法律制裁,也无以有害内容为根据的法定销售限制措施的问题。而且,至今还没有出现用于改善这种咖啡因中毒的具体预防及治疗剂。
另外,吴茱萸碱(evodiamine)是一种吲哚类生物碱,其分子式为C19H17N3O,分子量为303.36,其是吴茱萸等芸香科植物果实中含有的化合物。其在色氨酸与邻氨基苯甲酸中生物合成,带有黄色板状结晶,并容易溶解于丙酮中。吴茱萸碱作为从植物中分离出来的天然物质,对生物体内的细胞几乎没有毒性,据报告,吴茱萸碱可用于预防皮肤老化(韩国公开专利10-2016-0085581)及治疗因肥胖导致的炎症(韩国公开专利10-2014-0086213)。
此外,众所周知,吴茱萸碱还能够使身体产生的热量增加,对儿茶酚胺数值产生影响,从而有效地抑制食欲,但是尚未公开,上述吴茱萸碱对于治疗咖啡因中毒导致的疾病的效果。
在这种背景下,本发明人利用吴茱萸碱在小白鼠中确认了吴茱萸碱对预防或改善由咖啡因导致的睡眠障碍及中枢神经兴奋的效果,由此完成了本发明。
发明内容
所要解决的技术问题
本发明的目的在于,提供一种以吴茱萸碱或吴茱萸提取物为有效成分包含的用于预防或治疗由咖啡因中毒导致的疾病的药学组合物。
本发明的另一个目的在于,提供一种包括将上述组合物向个体给药的步骤的、用于预防或治疗由咖啡因中毒导致的疾病的方法。
本发明的又一个目的在于,提供一种上述组合物对由咖啡因中毒导致的疾病的预防或治疗用途。
本发明的又一个目的在于,提供一种以吴茱萸碱或吴茱萸提取物为有效成分包含的用于改善由咖啡因中毒导致的疾病的保健功能食品组合物。
但是,本发明所要解决的技术问题并非仅仅局限于以上提到的课题,对于尚未提到的其它课题,本领域技术人员通过以下记载能够准确地理解。
解决技术问题的方法
为了实现本发明的上述目的,本发明提供一种以吴茱萸碱或吴茱萸提取物为有效成分的用于预防或治疗由咖啡因中毒导致的疾病的药学组合物。
另外,本发明还提供一种包括将上述组合物向个体给药的步骤的、用于预防或治疗由咖啡因中毒导致的疾病的方法。
另外,本发明还提供一种上述组合物对由咖啡因中毒导致的疾病的预防或治疗用途。
同时,本发明还提供一种以吴茱萸碱或吴茱萸提取物为有效成分的用于改善由咖啡因中毒导致的疾病的保健功能食品组合物。
发明的效果
依据本发明的以吴茱萸碱、吴茱萸提取物或其分划物为有效成分包含的组合物,具有抑制由咖啡因中毒导致的中枢神经兴奋及改善睡眠障碍的效果,因此能够用于预防或治疗由咖啡因中毒导致的疾病的药学组合物或保健功能食品组合物。
附图说明
图1是表示根据本发明一实施例的吴茱萸碱相对于随着咖啡因中毒而增加的兴奋性运动活性的次数百分比来体现出相应效果的坐标图(***p<0.001vs溶剂对照组,##P<0.01vs咖啡因对照组);
图2是表示根据本发明一实施例的吴茱萸碱相对于随着咖啡因中毒而增加的兴奋性运动活性的时间百分比来体现出相应效果的坐标图(***p<0.001vs溶剂对照组,#P<0.05vs咖啡因对照组);
图3是表示根据本发明一实施例的吴茱萸碱相对于随着咖啡因中毒而增加的兴奋性运动活性的总移动距离来体现出相应效果的坐标图(***p<0.001vs溶剂对照组,#P<0.05vs咖啡因对照组);
图4是表示根据本发明一实施例的吴茱萸提取物相对于咖啡因中毒睡眠障碍模型达到睡眠的时间来体现出相应效果的坐标图(Evodia officinalis DODE.,吴茱萸提取物;pentobarbital,40Entobar;**p<0.01vs溶剂对照组,#p<0.05vs咖啡因对照组,以下相同);
图5是表示吴茱萸提取物相对于咖啡因中毒睡眠障碍模型的睡眠时间来体现出相应效果的坐标图。
具体实施方式
作为旨在实现上述目的的一种方式,本发明提供一种以吴茱萸碱或吴茱萸提取物为有效成分的用于预防或治疗由咖啡因中毒导致的疾病的药学组合物。
本发明中的术语“吴茱萸碱(evodiamine)”,是一种吲哚类生物碱,其分子式为C19H17N3O,分子量为303.36,是吴茱萸中含有的成分,可以由下述化学式1来表示。
[化学式1]
上述吴茱萸碱既可以使用市场上销售的产品,也可以使用合成的或者从吴茱萸中提取的,但并非限定于此。
本发明中的术语“咖啡因中毒(caffeine poisoning)”,是指由咖啡因引起的中毒,包括:中毒于咖啡、高咖啡因功能饮料、可乐、绿茶、红茶、可可饮料等含有咖啡因的食品或者对其产生依赖的情况。上述由咖啡因中毒引起的疾病是,与咖啡因的给药量及施用次数无关,可以是多种原因,例如:可以是从由失眠、腹泻、兴奋症状、头痛、集中力下降、心慌、呕吐症状、抑郁感、焦虑、手颤症、肌肉痛及戒断症状构成的组中选择的任意一种以上疾病。
在本发明的一个具体实施例中,针对由咖啡因中毒引起的中枢神经兴奋而增加运动活性的小白鼠模型,给药本发明的吴茱萸碱,其结果确认了吴茱萸碱具有抑制中枢神经兴奋的效果(图1至图3)。这表明上述吴茱萸碱能够有效地用于预防、治疗或改善由咖啡因中毒导致的疾病。
在本发明中,上述药学组合物包含吴茱萸提取物或其分划物。
本发明中的术语“吴茱萸”,是一种属于芸香科的落叶小乔木,其原产地为中国,在我国生长于庆尚北道庆州一带。含有挥发性精油,作为主要成分包含上述吴茱萸碱(evodiamine)。吴茱萸既可以购买市场上销售的产品,也可以使用通过栽培或采集的产品。
本发明中的术语“提取物”,包括:将吴茱萸通过提取处理获得的提取液、上述提取液的稀释液或者浓缩液、将上述提取液通过干燥获得的干燥物、上述提取液的初炼品或者精炼品或其混合物等的提取液本身及可利用提取液形成的所有剂型提取物。具体地讲,在本发明中,上述提取物可以在提取之后经过冷冻干燥处理,将其制作成粉末形态使用。
关于本发明的上述吴茱萸提取物,提取上述吴茱萸的方法并没有特别的限制,可以按照本技术领域中通常使用的方法进行提取。作为上述提取溶剂的非限制性实例,包括:水、醇、己烷或其混合溶剂等,将醇作为溶剂的情况下,作为一个实例,可以使用C1~C4的醇。作为另一个实例,具体地讲,本发明的吴茱萸提取物可以是热水提取物。
另外,上述提取物在执行提取或分划过程之后,再执行减压过滤过程或者追加执行浓缩及/或冷冻干燥,从而能够进行浓缩或者将溶剂去除,如上述获取的吴茱萸提取物在使用之前存放在速冻冰箱内。
本发明中的术语“分划物”,是指为了从含有多种构成成分的混合物中分离出特定成分或特定成分组而通过分划操作获得的产品。
在本发明中,获得上述分划物的分划方法并没有特别的限制,可以按照本技术领域中通常使用的方法进行操作。作为上述分划方法的非限制性实例,可以采用以下方法,即向对吴茱萸进行提取而获得的提取物中加入规定的溶剂进行处理,由此从上述提取物中获得分划物。
在本发明中,用于获取上述分划物的分划溶剂种类并没有特别的限制,可以使用本技术领域中公知的任意一种溶剂。作为上述分划溶剂的非限制性实例,包括:水、醇等极性溶剂;己烷(Hexane)、乙酸乙酯(Ethyl acetate)、三氯甲烷(Chloroform)、二氯甲烷(Dichloromethane)等非极性溶剂等。这些溶剂既可以单独使用,也可以将2种以上的溶剂混合使用。在上述分划溶剂中,如果使用醇,具体地讲,则可以使用C1~C4的醇。
上述组合物不包含吴茱萸次碱。
在本发明的一个具体实施例中,针对由咖啡因中毒导致睡眠障碍的小白鼠模型给药本发明的吴茱萸提取物,其结果确认了由施用咖啡因导致的睡眠障碍的改善效果(图4及图5)。这表明上述吴茱萸提取物能够有效地用于预防、治疗或改善由咖啡因中毒导致的疾病。
本发明中的术语“预防”,是指通过给药含有本发明的吴茱萸碱、吴茱萸提取物或其分划物的药学组合物而对由咖啡因中毒导致的疾病进行抑制或者使其病情延缓的所有行为。
本发明中的术语“治疗”,是指通过给药上述药学组合物而使由咖啡因中毒导致的疾病好转或者使病情朝着有利的方向发展的所有行为。
本发明中的药学组合物,相对于总组合物的重量,可以包含0.001~30重量%的吴茱萸碱、吴茱萸提取物或其分划物,具体地讲,可以包含0.1重量%~20重量%,但是并非限定于此。
根据本发明的用于预防或治疗由咖啡因中毒导致的疾病的药学组合物,还包括药学上允许使用的载体,并与上述载体一起配成制剂,最终以食品、药品及饮用水添加剂等形式进行提供。
本发明中的术语“药学上允许使用”,是指对于暴露于上述组合物的细胞或者人类不具有毒性这一特性,在这种情况下,上述载体包括非自然存在载体(non-naturallyoccurin carrier)。包含药学上允许使用载体的组合物可以是口服或非口服的多种剂型。如果配成制剂,可以使用常用的填充剂、增量剂、结合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂进行调配。上述载体、赋形剂及稀释剂,可以从由乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、刺槐胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、生理盐水、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁及矿物油、糊精、碳酸钙、丙二醇与液态石蜡构成的组中选择一种以上,但是并非限定于此,通常的载体、赋形剂或稀释剂都可以使用。上述成分可以被单独或组合添加到上述有效成分即吴茱萸碱、吴茱萸提取物或其分划物。
用于口服给药的固态制剂,包括:精制丸剂、散剂、颗粒剂、胶囊剂等,这种固态制剂,可以在一种以上的化合物中至少混入一种以上的赋形剂,例如:淀粉、碳酸钙、蔗糖或乳糖、明胶等进行调配。另外,除了单纯的赋形剂之外,还可以使用硬脂酸镁、滑石等润滑剂。用于口服给药的液态制剂,有悬浮剂、内服液剂、乳剂、糖浆剂等,其除了常用的单纯稀释剂即水、液态石蜡之外,还包括多种赋形剂,例如:润湿剂、甜味剂、芳香剂、保存剂等。用于非口服给药的制剂包括:灭菌水溶液、非水性溶剂、悬浮剂、乳剂、冷冻干燥制剂、栓剂等。非水性溶剂、悬浮溶剂,可以使用丙二醇(propylene glycol)、聚乙二醇、橄榄油等植物性油以及如油酸乙酯之类能够用于注射的酯类等。栓剂的基质可以使用合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可脂、三月桂酸甘油酯、甘油明胶等。
另外,本发明的药学组合物具有从由片剂、丸剂、散剂、颗粒剂、胶囊剂、悬浮剂、内服液剂、乳剂、糖浆剂、灭菌水溶液、非水性溶剂、悬浮剂、油剂、冷冻干燥制剂及栓剂构成的组中选择的任意一种剂型。
本发明的药学组合物按照药学上规定的有效剂量进行给药。对其给药量并没有特别的限制,可以根据体内吸收率、体重、患者的年龄、性别、健康状况、饮食、给药时间、给药方法、***率及疾病的严重程度等的不同而变化。本发明的药学组合物考虑有效剂量范围进行制备,这样按照各种剂型生产的单位给药型制剂可以根据需要随着对药剂的给药进行监视或观察的专家的判断与个人要求,采用专业化的给药方法,或者按照一定时间间隔进行多次给药。具体地讲,本发明的药学组合物以吴茱萸碱的量为基准,1日给药的量为0.1~50mg/kg,更具体地讲,1日给药的量为10~30mg/kg,上述给药既可以一天给药一次,也可以分多次进行给药。另外,本发明的药学组合物以吴茱萸提取物或其分划物的量为基准,1日给药的量为0.1~500mg/kg,具体地讲,1日给药的量为1~400mg/kg,更具体地讲,1日给药的量为50~350mg/kg,再进一步具体地讲,1日给药的量为100~300mg/kg,上述给药既可以一天给药一次,也可以分多次进行给药。
作为本发明的另一种方式,本发明提供一种包括如下步骤的用于预防或治疗咖啡因中毒导致疾病的方法,该步骤中将以吴茱萸碱、吴茱萸提取物或其分划物为有效成分的药学组合物向个体给药。
在这种情况下,上述吴茱萸碱、吴茱萸、提取物、分划物、预防及治疗的定义与如上所述的说明相同。
本发明中的术语“给药”,是指采用恰当的方法将规定的物质导入个体,上述组合物的给药途径,只要是能够到达目标组织,则能够通过任何普通途径进行给药。可以采用腹腔内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、局部给药、鼻腔给药、肺内给药、直肠内给药等方式,但并非限定于此。
本发明中的术语“个体”,是指包括由咖啡因中毒导致的疾病发生或者可能发病的人类在内的所有动物。作为具体的实例,可以是包括人类在内的哺乳动物。在本发明中,既可以是施用咖啡因的个体,也可以是给药吴茱萸碱、吴茱萸提取物或其分划物的个体。
作为本发明的另一种方式,本发明提供一种含有吴茱萸碱、吴茱萸提取物或其分划物的用于改善由咖啡因中毒导致的疾病的保健功能食品组合物。
在这种情况下,上述吴茱萸碱、吴茱萸、提取物、分划物及预防的定义与如上所述的说明相同。
本发明中的术语“改善”,是指通过给药含有本发明的吴茱萸提取物或吴茱萸碱的组合物而被治疗的状态相关的参数,例如症状的程度至少得到减少的所有行为。
如果将本发明的组合物作为保健功能食品添加剂使用,则可以将上述吴茱萸碱、吴茱萸提取物或其分划物直接添加,或者与其它食品或食品成分一起使用,也可以按照常用的方法恰当使用。有效成分的混合量可以根据使用目的(预防、保健或治疗性处置)而适当确定,本发明的组合物属于环保型产品,从稳定性的层面来看,没有任何问题,因此其混合量没有较大限制。
本发明的保健功能食品组合物可以用于日常摄入,因此对于由咖啡因中毒导致的疾病可以期待其改善效果,因此能够有效地用于增进身体健康。
本发明中的术语“保健功能食品”,是与“特定保健用食品(food for specialhealth use,FoSHU)”相同的术语,是指除了具有供给营养的功能之外,加工成还具有能够有效增强机体调节功能等医学、医疗效果高的食品。在这里,所谓“功能”是指针对人体的结构及机能调节营养成分或者在生理学作用等保健用途方面获得良好效果。本发明的保健功能食品可以通过本行业常用的方法进行生产,在进行上述生产时,可以加入本行业通常添加的原料及成分。另外,只要属于上述保健功能食品的剂型或者被认定为食品的剂型,则可以无限制地进行生产。本发明的保健功能食品用组合物可以按照多种形态的剂型进行生产,与普通药品不同,其以食品为原料,故具有不存在像药品那样长期服用产生的副作用的优点,而且携带非常方便,因此,本发明的保健功能食品可以作为用于增强咖啡因中毒改善效果的辅助剂来摄入。
上述保健功能食品是指比普通食品具有更积极保持或者增进健康效果的食品,健康辅助食品(health supplement food)是指具有健康辅助目的的食品。根据情况不同,保健功能食品、保健食品、健康辅助食品等术语有时也被混用。
具体地讲,上述保健功能食品是指将本发明的化合物添加到饮料、茶类、香辛料、口香糖、糕点类等食品材料中或者将其生产成胶囊剂、粉末剂、悬浮液等形态的食品,当摄入这些食品时,对健康方面会产生特定的效果,但是与普通药品不同,其是以食品为原料,故具有以下优点,即不存在像药品那样长期服用产生的副作用。
上述保健功能食品组合物,还包括生理学上允许使用的载体,载体的种类并没有特别的限制,只要是本技术领域常用的载体,任何一种都可以使用。
另外,上述保健功能食品组合物包括:常用于食品组合物中能够增强气味、味道、视觉等的附加成分。例如:包括维生素A、C、D、E、B1、B2、B6、B12、烟酸(niacin)、生物素(biotin)、叶酸(folate)、泛酸(panthotenic acid)等。另外,还包括锌(Zn)、铁(Fe)、钙(Ca)、铬(Cr)、镁(Mg)、锰(Mn)、铜(Cu)等矿物质;以及赖氨酸、色氨酸、半胱氨酸、缬氨酸等氨基酸。
另外,上述保健功能食品组合物包括:防腐剂(山梨酸钾、苯甲酸钠、水杨酸、脱氢乙酸钠等)、杀菌剂(漂白粉与漂粉精、次氯酸钠等)、抗氧化剂(丁基羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)等)、着色剂(焦油色素等)、发色剂(亚硝酸钠、亚醋酸钠等)、漂白剂(亚硫酸钠)、调味料(MSG谷氨酸钠等)、甜味剂(甘素、甜蜜素、糖精、钠等)、香料(香兰素、内酯类等)、膨胀剂(明矾、D-酒石酸氢钾等)、强化剂、乳化剂、增稠剂(糊料)、被膜剂、胶基剂、泡沫抑制剂、溶剂、改良剂等食品添加剂(food additives)。上述添加剂可以根据食品的种类进行筛选,并使用适当的量。
作为本发明保健功能食品组合物的一例,可以将其用作健康饮料组合物,在这种情况下,诸如普通的饮料,作为追加成分还含有多种增香剂或天然碳水化合物等。如上所述的天然碳水化合物可以是:葡萄糖、果糖等单糖;麦芽糖、蔗糖等双糖;糊精、环糊精等多糖;木糖醇、山梨糖醇、赤藓糖醇等糖醇。甜味剂可以使用:索马甜、甜叶菊提取物等天然甜味剂;糖精、阿斯巴甜等合成甜味剂等。上述天然碳水化合物的比例,一般情况下,本发明的健康饮料组合物每100mL中其用量约为0.01~0.04g,具体地讲,其用量约为0.02~0.03g。
除了上述成分之外,健康饮料组合物包含多种营养剂、维生素、电解质、风味剂、着色剂、果胶酸、果胶酸盐、海藻酸、海藻酸盐、有机酸、保护性胶质增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇或碳酸化剂等。此外,还包含用于生产天然果汁、果汁饮料或蔬菜饮料的果肉。这些成分既可以单独使用,也可以混合使用。虽然这种添加剂的比例并不是特别重要,但是本发明的健康饮料组合物每100重量份中的含量一般在0.01~20重量份的范围内选择。
同时,本发明提供一种将以吴茱萸碱或吴茱萸提取物为有效成分的组合物用于预防或治疗由咖啡因中毒导致的疾病的用途。
下面,将通过实施例对本发明进行更加详细的说明。但是,列举这些实施例的目的在于对本发明进行举例说明,本发明的范围并不限定于这些实施例。
实施例1:药物及试剂
吴茱萸碱、咖啡因、DMSO(dimethyl sulfoxide)及吐温-20(Tween-20)使用从西格玛公司(Sigma-Aldrich Chemistry Co.)购买的产品。Entobar使用从翰林制药株式会社购买的产品。
实施例2:准备实验动物
将由Koatech(大韩民国平泽市)株式会社供应的4周龄ICR系列雄性小白鼠(20~22g)在成均馆大学药学院的动物饲养室内饲养1周以上,使其适应环境之后用于实验,水与饲料自由摄取,温度(23±2℃)、湿度(55±10%)及明暗周期(12小时)均自动进行调节。
实施例3:制备吴茱萸提取物
吴茱萸使用从京东市场(大韩民国首尔特别市)购买的中国产品。将经过烘干处理的吴茱萸193g使其完全干燥后,将其粉碎并放入70~80℃的水中熬煮之后,在40℃的条件下冷却,然后用滤纸(美国Whatman公司生产)进行过滤,接下来利用减压浓缩器(日本EYELA公司生产,N-1000)对其进行减压浓缩处理。经过冷冻干燥之后,获得31g吴茱萸粗提物。
实验例1:吴茱萸碱对咖啡因导致中枢神经兴奋的改善或抑制效果
为了测定吴茱萸碱对由咖啡因导致的中枢神经兴奋的抑制效果,将实施例2中准备的小白鼠分成4组,每组12只,分别按照不同的量对其给药吴茱萸碱及咖啡因。第1组为包含10%DMSO的蒸馏水给药组(对照组),第2组为包含10%DMSO的蒸馏水及咖啡因10mg/kg给药组,第3组为吴茱萸碱10mg/kg及咖啡因10mg/kg给药组,第4组为吴茱萸碱20mg/kg及咖啡因10mg/kg给药组。
将吴茱萸碱溶解于包含10%DMSO的蒸馏水中,按照0,10及20mg/kg的用量向小白鼠口服给药,30分钟之后,腹腔注射咖啡因10mg/kg。然后,30分钟过后,将小白鼠放入运动能力测定箱(直径:30x30x30cm)中,利用视频测定分析***(Neurovision,大韩民国,釜山)总共测定60分钟,将增加的兴奋性运动活性次数(center count)、兴奋性运动活性时间(center time)及兴奋性运动活性总移动距离(total movement)的改善或抑制程度换算成百分比。
如图1所示,将各组的运动活性次数进行比较,结果表明,未施用咖啡因的第1组(对照组)向运动能力测定箱中央移动的百分比为16%,与此相比,施用咖啡因的第2组为23%,因此,由咖啡因导致兴奋性运动次数的百分比显著增加。由此确认咖啡因明显导致中枢神经兴奋。另外,第3组即吴茱萸碱10mg/kg给药组与第4组即吴茱萸碱20mg/kg给药组中,由咖啡因导致的兴奋性运动次数的百分比分别下降至20%及19%。由此可以确认,施用咖啡因导致的中枢神经兴奋因吴茱萸碱而明显下降。
另外,如图2所示,将各组的运动活性时间进行比较,结果表明,未施用咖啡因的第1组(对照组)在运动能力测定箱中央度过的时间百分比为3%,与此相比,施用咖啡因的第2组为9%,因此,由咖啡因导致兴奋性运动时间的百分比显著增加。由此确认,咖啡因明显导致中枢神经兴奋。另外,第3即吴茱萸碱10mg/kg给药组与第4组即吴茱萸碱20mg/kg给药组在运动能力测定箱中央度过的运动活性时间的百分比分别为7%及5%。由此可以确认,施用咖啡因导致的中枢神经兴奋因吴茱萸碱而明显下降。
对各组的总移动距离进行比较,其结果如图3所示。未施用咖啡因的第1组(对照组)在运动能力测定箱中的总移动距离为7107cm,与此相比,施用咖啡因的第2组为15078cm,由此可以确认,由咖啡因导致小白鼠的总移动距离显著增加。另外,第3组即吴茱萸碱10mg/kg给药组与第4组即吴茱萸碱20mg/kg给药组的总移动距离分别下降至12734cm及10910cm。由此可以确认,施用咖啡因导致的中枢神经兴奋因吴茱萸碱而明显下降。
通过上述图1~图3所示结果可以确认,吴茱萸碱能够有效改善或抑制咖啡因导致的中枢神经兴奋。
实验例2:吴茱萸提取物对咖啡因导致的睡眠障碍的改善效果
为了确认吴茱萸提取物对咖啡因导致的睡眠障碍的改善效果,将实施例2中准备的小白鼠分成4组(第1组~第4组),每组12只,并将实施例3中制备的吴茱萸提取物、Entobar及咖啡因按照不同的量分别向各组给药。具体地讲,第1组为包含10%DMSO的蒸馏水及Entobar 40mg/kg给药组,并作为对照组,第2组为包含10%DMSO的蒸馏水、咖啡因50mg/kg及Entobar 40mg/kg给药组,第3组为吴茱萸提取物200mg/kg、咖啡因50mg/kg及Entobar 40mg/kg给药组,第4组为吴茱萸提取物400mg/kg、咖啡因50mg/kg及Entobar40mg/kg给药组。
关于给药方法,将吴茱萸提取物溶解于包含10%DMSO的蒸馏水中,按照0,200及400mg/kg的用量向小白鼠口服给药,1日1次,连续服用3天,最后一次给药30分钟后,通过腹腔注射咖啡因50mg/kg。注射咖啡因30分钟之后,再腹腔注射Entobar 40mg/kg,导致其进入睡眠。刚注射Entobar之后,将小白鼠分别放入笼子里,分别对进入睡眠的时间(sleeponset)和睡眠时间(sleep duration)进行测定。
如图4所示,对各组进入睡眠的时间进行比较,结果显示,未施用咖啡因的第1组(对照组)进入睡眠的时间为219秒,与此相比,施用咖啡因的第2组为371秒。因此,由咖啡因导致进入睡眠的时间显著增加,由此可以确认,咖啡因中毒明显导致产生睡眠障碍。另外,第3组即吴茱萸提取物200mg/kg给药组与第4组即吴茱萸提取物400mg/kg给药组分别为222秒及303秒,这表明进入睡眠状态的时间加快了。由此可以确认,施用咖啡因导致的睡眠障碍因给药吴茱萸提取物而明显得到改善。
另外,如图5所示,对各组的总睡眠时间进行比较,结果显示,未施用咖啡因的第1组(对照组)的睡眠时间为2940秒,与此相比,施用咖啡因的第2组为1812秒。因此,由咖啡因导致睡眠时间显著减少,由此可以确认,咖啡因中毒明显导致产生睡眠障碍。另外,第3组即吴茱萸提取物200mg/kg给药组与第4组即吴茱萸提取物400mg/kg给药组的睡眠时间分别为2558秒及1940秒。这表明其总睡眠时间增加了。由此可以确认,施用咖啡因导致的睡眠障碍因给药吴茱萸提取物而明显得到改善。
通过上述结果可以确认,吴茱萸提取物能够有效改善由咖啡因导致的睡眠障碍。
实验例3:吴茱萸提取物与吴茱萸碱的睡眠障碍改善效果比较
为了比较吴茱萸提取物与吴茱萸碱对咖啡因导致的睡眠障碍改善效果,将实施例3中制备的吴茱萸热水提取物、乙醇提取物及吴茱萸碱向实施例2中准备的小白鼠口服给药,1日1次,连续摄取3天,最后一次给药30分钟之后,腹腔注射咖啡因50mg/kg。然后,再等待30分钟,接着再腹腔注射Entobar 40mg/kg,导致其进入睡眠状态,然后,对进入睡眠(Sleep onset)的时间及总睡眠时间(Sleep duration)进行测定。
上述使用的乙醇提取物,是将吴茱萸600g的粉碎烘干品利用50%乙醇在室温条件下提取3次,然后按照与实施例3中相同的方法进行制备而成(收率为55.5g)。
如表1所示,可以确认,在给药吴茱萸提取物与吴茱萸碱的情况下,进入睡眠的时间与总睡眠时间明显增加。
另外,将吴茱萸热水提取物按照200mg/kg量进行给药或者将吴茱萸碱按照10mg/kg量进行给药的结果显示,进入睡眠的时间彼此接近。这表明,即使将给药量减少至1/20,吴茱萸碱仍然表现出与吴茱萸热水提取物相似水平的睡眠障碍改善效果,这一结果令人惊讶。
另外,将吴茱萸碱按照5mg/kg量进行给药,结果显示,总睡眠时间增加到了未进行咖啡因处理的正常组(Vehicle)的程度,但是,吴茱萸提取物的情况下,与吴茱萸碱相比,即使其给药量增加到40倍(200mg/kg),也显示出吴茱萸碱的效果仍然更加优秀。
由此可以确认,与吴茱萸提取物相比,即使在明显低的浓度条件下,吴茱萸碱仍然对咖啡因导致的睡眠障碍具有改善效果。
另外,如果与吴茱萸乙醇提取物比较,则吴茱萸热水提取物对咖啡因导致的进入睡眠时间障碍的改善效果增加了11%以上,特别是,对总睡眠时间的改善效果,虽然乙醇提取物没有明显的效果,但是热水提取物表现出明显的改善效果。
【表1】
(Vehicle对照组:包含10%DMSO的蒸馏水,DW;吴茱萸热水提取物,EtOH;吴茱萸乙醇提取物,Evo;分别给药吴茱萸碱的组,***P<0.001,**P<0.01vs Vehicle group,#P<0.05vs caffeine group)
实验例4:统计处理
将所有的实验结果利用ANOVA(一种变化分析方法;one way anlysis ofvariance)进行统计处理,在显著性得到了验证的情况下,使用LSD test在p<0.05水平以下对显著性实施评定。
通过以上说明,本发明所属技术领域的技术人员应当能够理解在不改变本发明的技术思想或者必要特征的情况下能够以其它不同的具体方式实施本发明。与此相关,应当理解以上列举的实施例是为了从各个方面对本发明进行举例说明,并不是用于限定本发明的范围。关于本发明的范围,应当解释为相对于如上所述的具体实施方式而言,本发明的范围包括后附的权利要求书的含义与范围、以及通过其等价概念导出的所有变更或变形后的方式。
产业上的可利用性
本发明的以吴茱萸碱、吴茱萸提取物或其分划物为有效成分的组合物,对于由咖啡因中毒导致的中枢神经兴奋具有抑制作用,且对于由咖啡因中毒导致的睡眠障碍具有改善效果,因此,能够有效地用于由咖啡因中毒导致的疾病的预防、治疗或改善用途,以及用于对睡眠障碍的改善用途。
Claims (6)
1.一种药学组合物,其特征在于:
以吴茱萸碱或吴茱萸提取物为有效成分,并用于预防或治疗由咖啡因中毒导致的疾病。
2.根据权利要求1所述的药学组合物,其特征在于:
上述吴茱萸提取物是利用从水或碳原子数量为1~4的醇中选择的1种以上的溶剂进行提取的。
3.根据权利要求1所述的药学组合物,其特征在于:
上述疾病是从由施用咖啡因导致的失眠、腹泻、兴奋症状、头痛、注意力下降、心慌、呕吐症状、抑郁感、焦虑、手颤症及肌肉痛构成的组中选择的疾病。
4.一种由咖啡因中毒导致的疾病的预防或治疗方法,其特征在于:
包括:将权利要求1至3中任意一项所述的组合物向个体给药的步骤。
5.一种由咖啡因中毒导致的疾病的预防或改善用保健功能食品组合物,其特征在于:
以吴茱萸碱或吴茱萸提取物为有效成分。
6.一种权利要求1至3中任意一项所述的组合物对于由咖啡因中毒导致的疾病的预防或治疗用途。
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