CN113170896A - 一种含γ-氨基丁酸和瓜氨酸的组合物及其在缓解压力和改善睡眠上的应用 - Google Patents
一种含γ-氨基丁酸和瓜氨酸的组合物及其在缓解压力和改善睡眠上的应用 Download PDFInfo
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- CN113170896A CN113170896A CN202110376145.1A CN202110376145A CN113170896A CN 113170896 A CN113170896 A CN 113170896A CN 202110376145 A CN202110376145 A CN 202110376145A CN 113170896 A CN113170896 A CN 113170896A
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Abstract
本发明提供一种含γ‑氨基丁酸和瓜氨酸的组合物及其在缓解压力和改善睡眠上的应用,瓜氨酸及其衍生物有助于提高γ‑氨基丁酸及其衍生物的脑含量。
Description
技术领域
本发明涉及一种含γ-氨基丁酸组合物,特别涉及一种含γ-氨基丁酸和瓜氨酸的组合物及其在缓解压力和改善睡眠上的应用。
背景技术
γ-氨基丁酸,又称GABA,是人体中枢神经系统中一种重要的抑制性神经递质。Nuss P.Anxiety disorders and GABA neurotransmission:a disturbance ofmodulation.Neuropsychiatr Dis Treat.2015;11:165–175.doi:10.2147/NDT.S58841中报道在大脑中,当GABA和GABA受体结合后,阻碍了某种脑部信号,从而减少了神经元兴奋度。GABA的产生可以减轻人的焦虑和压力等负面情绪,以达到镇静和改善睡眠等功效。
因此,外源性GABA是一种流行的膳食补充剂,市面上有很多商业产品,如美国Now,Nutricost等品牌。人们期望通过补充外源性GABA从而达到改善情绪,帮助睡眠等功效。然而,Kuriyama K,Sze PY(January 1971)."Blood–brain barrier to H3-γ-aminobutyricacid in normal and amino oxyacetic acid-treated animals".Neuropharmacology.10(1):103–108.doi:10.1016/0028-3908(71)90013-X.PMID 5569303.也报道了由于血脑屏障的存在,大脑对GABA的吸收是非常低效的。
另外也有报道,GABA在生理浓度低的时候吸收效率高,生理浓度高的时候吸收效率低,这是因为GABA可自我阻碍被吸收,以维持神经系统中GABA浓度的稳定性。Al-SarrafH.Transport of 14C-gamma-aminobutyric acid into brain,cerebrospinal fluid andchoroid plexus in neonatal and adult rats.Brain Res Dev Brain Res.(2002)中报道,GABA的自我阻碍率最高可以到达80%。
因此,虽然市面上GABA产品众多,但消费者的投诉也多集中在“无效”“无法感知到”等负面评价上。
发明内容
本发明的目的在于针对现有技术的不足之处,提供一种含γ-氨基丁酸及其衍生物和瓜氨酸及其衍生物的组合物。瓜氨酸及其衍生物能够提高人脑对γ-氨基丁酸的吸收率。
瓜氨酸衍生物包括:瓜氨酸盐,酸,酯,多聚体,螯合物或瓜氨酸异构体的盐,酸,酯,多聚体,螯合物及其组合。
进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50份,瓜氨酸及其衍生物的份数为0.1-20份;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20份,瓜氨酸及其衍生物的份数为0.5-10份,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10份,瓜氨酸及其衍生物的份数为1-8份,优选的,γ-氨基丁酸及其衍生物的份数为1-5份,瓜氨酸及其衍生物的份数为3-7份,优选的,γ-氨基丁酸及其衍生物的份数为3份,瓜氨酸及其衍生物的份数为6份。
进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50g,瓜氨酸及其衍生物的份数为0.1-20g;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20g,瓜氨酸及其衍生物的份数为0.5-10g,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10g,瓜氨酸及其衍生物的份数为1-8g,优选的,γ-氨基丁酸及其衍生物的份数为1-5g,瓜氨酸及其衍生物的份数为3-7g,优选的,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
本发明中所述的组合物的产品可以为各种剂型,包括也不局限于药品常见剂型,如粉剂、凝胶、口服液、硬胶囊、软胶囊,也可以为保健食品和膳食补充剂的常见剂型,如饮料、固体饮料、软饮料、硬胶囊、软胶囊、多层硬胶囊、溶豆、冻干粉、奶豆、巧克力、夹心软糖、夹心巧克力、茶饮料、冷萃咖啡,营养棒。
本发明还提供了一种促进γ-氨基丁酸及其衍生物通过血脑屏障的方法,包括在添加γ-氨基丁酸及其衍生物,同时添加瓜氨酸及其衍生物,进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50份,瓜氨酸及其衍生物的份数为0.1-20份;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20份,瓜氨酸及其衍生物的份数为0.5-10份,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10份,瓜氨酸及其衍生物的份数为1-8份,优选的,γ-氨基丁酸及其衍生物的份数为1-5份,瓜氨酸及其衍生物的份数为3-7份,优选的,γ-氨基丁酸及其衍生物的份数为3份,瓜氨酸及其衍生物的份数为6份。
进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50g,瓜氨酸及其衍生物的份数为0.1-20g;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20g,瓜氨酸及其衍生物的份数为0.5-10g,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10g,瓜氨酸及其衍生物的份数为1-8g,优选的,γ-氨基丁酸及其衍生物的份数为1-5g,瓜氨酸及其衍生物的份数为3-7g,优选的,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
本发明还提供了一种提高γ-氨基丁酸及其衍生物在大脑中含量的方法,包括添加瓜氨酸及其衍生物。
本发明还提供了一种提高γ-氨基丁酸及其衍生物在大脑中含量的方法,在添加γ-氨基丁酸及其衍生物,同时添加瓜氨酸及其衍生物。
进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50份,瓜氨酸及其衍生物的份数为0.1-20份;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20份,瓜氨酸及其衍生物的份数为0.5-10份,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10份,瓜氨酸及其衍生物的份数为1-8份,优选的,γ-氨基丁酸及其衍生物的份数为1-5份,瓜氨酸及其衍生物的份数为3-7份,优选的,γ-氨基丁酸及其衍生物的份数为3份,瓜氨酸及其衍生物的份数为6份。
进一步的,γ-氨基丁酸及其衍生物的份数为0.05-50g,瓜氨酸及其衍生物的份数为0.1-20g;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20g,瓜氨酸及其衍生物的份数为0.5-10g,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10g,瓜氨酸及其衍生物的份数为1-8g,优选的,γ-氨基丁酸及其衍生物的份数为1-5g,瓜氨酸及其衍生物的份数为3-7g,优选的,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
发明人偶然发现,当GABA和瓜氨酸组合使用时,可以显著提高脑中GABA含量。本发明可以有效提高大脑对GABA吸收率达2.2倍,降低GABA使用剂量以达到同等吸收量。同时瓜氨酸为人体非必需氨基酸,无毒副作用,有降低疲劳,增强运动表现等功效。
现有技术中对GABA组合以减少痛苦焦虑、镇静、改善睡眠,US10413523B2报道了该组合物含有必需氨基酸苯丙氨酸;谷氨酰胺;非必需氨基酸丝氨酸;GABA(γ-氨基丁酸);和任选的THC,其浓度能有效地影响或调节神经递质五肽脑啡肽。但并没有说明组合物是否具有相互作用,更没有说明GABA通过血脑屏障的问题。
本发明中所述的含有γ-氨基丁酸及其衍生物和瓜氨酸及其衍生物的组合物的产品的各种剂型可以按照药品、保健食品、普通食品、日化、饲料、添加剂等的常规生产制备方法制备。将该组分中的一种或者多种载体混合,然后制成所需的剂型。
本发明还提供一种含有γ-氨基丁酸及其衍生物和瓜氨酸及其衍生物的组合物的产品的制备方法,包括将γ-氨基丁酸及其衍生物与瓜氨酸及其衍生物混合,灌装。
在一个实施方式中,本发明中所述的产品制备方法是:可选择的将需要控制水分指标的物料制粒或不制粒后至生产所需水分指标,将γ-氨基丁酸及其衍生物与瓜氨酸及其衍生物混合,可选择的加入物料所需流动剂后进行胶囊灌装,可选择的将灌装好的胶囊挑选出不合格的后进行包衣(肠溶包衣)或不包衣,可选择的将包衣后的胶囊根据包装所需规格数量灌装至内包材即可。
在一个实施方式中,本发明中所述的产品制备方法是:将γ-氨基丁酸及其衍生物与瓜氨酸及其衍生物混合制备芯材,可选择性的芯材加入甜味剂和/或食用胶,尤其是吸水性高的食用胶,并采用食用胶制备为壁材,可选择的加入物料所需流动剂和/或增稠剂后制备为夹心糖果或软胶囊。
具体实施方式
为了便于本领域技术人员的理解,下面结合实施例对本发明作进一步的说明,实施方式提及的内容并非对本发明的限定。
γ-氨基丁酸及其衍生物的份数为0.05-50g,瓜氨酸及其衍生物的份数为0.1-20g
实施例1
一种组合物,γ-氨基丁酸及其衍生物的份数为0.05g,瓜氨酸及其衍生物的份数为0.1g。
实施例2
一种组合物,γ-氨基丁酸及其衍生物的份数为0.1g,瓜氨酸及其衍生物的份数为0.1g。
实施例3
一种组合物,γ-氨基丁酸及其衍生物的份数为0.2g,瓜氨酸及其衍生物的份数为0.1g。
实施例4
一种组合物,γ-氨基丁酸及其衍生物的份数为0.5g,瓜氨酸及其衍生物的份数为0.1g。
实施例5
一种组合物,γ-氨基丁酸及其衍生物的份数为1g,瓜氨酸及其衍生物的份数为0.1g。
实施例6
一种组合物,γ-氨基丁酸及其衍生物的份数为2g,瓜氨酸及其衍生物的份数为0.1g。
实施例7
一种组合物,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为0.1g。
实施例8
一种组合物,γ-氨基丁酸及其衍生物的份数为10g,瓜氨酸及其衍生物的份数为0.1g。
实施例9
一种组合物,γ-氨基丁酸及其衍生物的份数为20g,瓜氨酸及其衍生物的份数为0.1g。
实施例10
一种组合物,γ-氨基丁酸及其衍生物的份数为50g,瓜氨酸及其衍生物的份数为0.1g。
实施例11
一种组合物,γ-氨基丁酸及其衍生物的份数为0.05g,瓜氨酸及其衍生物的份数为6g。
实施例12
一种组合物,γ-氨基丁酸及其衍生物的份数为0.1g,瓜氨酸及其衍生物的份数为6g。
实施例13
一种组合物,γ-氨基丁酸及其衍生物的份数为0.2g,瓜氨酸及其衍生物的份数为6g。
实施例14
一种组合物,γ-氨基丁酸及其衍生物的份数为0.5g,瓜氨酸及其衍生物的份数为6g。
实施例15
一种组合物,γ-氨基丁酸及其衍生物的份数为1g,瓜氨酸及其衍生物的份数为6g。
实施例16
一种组合物,γ-氨基丁酸及其衍生物的份数为2g,瓜氨酸及其衍生物的份数为6g。
实施例17
一种组合物,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
实施例18
一种组合物,γ-氨基丁酸及其衍生物的份数为10g,瓜氨酸及其衍生物的份数为6g。
实施例19
一种组合物,γ-氨基丁酸及其衍生物的份数为20g,瓜氨酸及其衍生物的份数为6g。
实施例20
一种组合物,γ-氨基丁酸及其衍生物的份数为50g,瓜氨酸及其衍生物的份数为6g。
实施例21
一种组合物,γ-氨基丁酸及其衍生物的份数为0.05g,瓜氨酸及其衍生物的份数为6g。
实施例22
一种组合物,γ-氨基丁酸及其衍生物的份数为0.1g,瓜氨酸及其衍生物的份数为6g。
实施例23
一种组合物,γ-氨基丁酸及其衍生物的份数为0.2g,瓜氨酸及其衍生物的份数为6g。
实施例24
一种组合物,γ-氨基丁酸及其衍生物的份数为0.5g,瓜氨酸及其衍生物的份数为6g。
实施例25
一种组合物,γ-氨基丁酸及其衍生物的份数为1g,瓜氨酸及其衍生物的份数为6g。
实施例26
一种组合物,γ-氨基丁酸及其衍生物的份数为2g,瓜氨酸及其衍生物的份数为6g。
实施例27
一种组合物,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
实施例28
一种组合物,γ-氨基丁酸及其衍生物的份数为10g,瓜氨酸及其衍生物的份数为6g。
实施例29
一种组合物,γ-氨基丁酸及其衍生物的份数为20g,瓜氨酸及其衍生物的份数为6g。
实施例30
一种组合物,γ-氨基丁酸及其衍生物的份数为50g,瓜氨酸及其衍生物的份数为6g。
实验例
抽选大鼠(200g±5g)20只雌雄各半,大鼠在20~25摄氏度条件下喂养,给予日常鼠粮和蒸馏水饲养,不限制进食量及饮水量。分成5组,每组4只雌雄各半。
人工光照周期下动物房内,光照条件如下:明暗比为15h:9h,开灯时间为早6:00:关灯时间为晚21:00。灌喂前6小时停止进食进水。
对照组:灌喂淡盐水1mL;
GABA组:灌喂GABA250mg和淡盐水750mg;
瓜氨酸组:灌喂瓜氨酸500mg和淡盐水500mg;
GABA+瓜氨酸低剂量组:灌喂GABA250mg、瓜氨酸125mg和淡盐水625mg。
GABA+瓜氨酸组:灌喂GABA250mg、瓜氨酸500mg和淡盐水250mg。
小鼠灌喂后2小时后取出脑组织测试GABA含量。
GABA测量方法为:
酶溶液制:每一份冻干的GABA转氨酶-琥珀酸半醛脱氢酶溶于2ml 0.05%beta-巯基乙醇之中,制成酶溶液。
脑组织冷冻后称量,在9体积的冰水中均质,加入1/4体积的浓度为2M的高氯酸。在33000g条件下离心分离15分钟以后去上层澄清液,并在零下25摄氏度保存。
取0.3mL上层澄清液载入1.6mL Dowex-50-X8-H+,200~400目,离子交换柱中。交换柱用8mL水润洗,GABA由7.5mL浓度为1M的氨水洗脱。将洗脱液放于旋转蒸发仪中旋转蒸发。
将蒸发残留溶于0.65mL水中做成待测样。分4个试管培养,另每个试管中含有0.15mL待测样,0.05M的Tris盐酸(pH=8.0),1.36mM NADP,0.0005%beta-巯基乙醇和12.5μL的酶溶液。
第一个试管为空白,其他三个试管加入500mμmoles alpha-酮戊二酸。第四个试管同时加入3mμmoles GABA作为内部标准。四个试管最终体积为0.25mL。将试管至于25摄氏度环境中培养30分钟,培养液转移至微量比色皿,用分光光度法(340nm)测量产生的NADPH。测量值用μmol/g脑组织表示。每组测的含量取平均值。
表1不同组别的脑组织GABA含量情况(mean±SD)
由表1的数据可知,直接灌喂瓜氨酸与对照组相比,脑组织中GABA含量提升(相对于对照组p<0.01),但提升量仅为0.52μmol/g脑组织左右;直接灌喂GABA,虽然脑组织中GABA含量提升(相对于对照组p<0.05),但提升量仅为0.21μmol/g脑组织左右。而GABA+瓜氨酸低剂量组与GABA+瓜氨酸组中,脑组织中GABA含量大幅提升,远远超过GABA组和瓜氨酸组;甚至脑组织中GABA含量的提升量远超过GABA组中GABA含量的提升量和瓜氨酸组中GABA含量的提升量之和。
发明人认为原因应该为,一方面瓜氨酸携带GABA能够大量的通过血脑屏障,或者瓜氨酸的某种代谢产物,能够携带GABA大量的通过血脑屏障,进而提升脑组织中的GABA含量,另一方面血液中的瓜氨酸能够提供血液流量,尤其是脑部的血流量,使得更多的GABA能够更快的进入脑中。
本技术领域技术人员可以理解,除非另外定义,这里使用的所有术语(包括技术术语和科学术语),具有与本发明所属领域中的普通技术人员的一般理解相同的意义。还应该理解的是,诸如通用字典中定义的那些术语,应该被理解为具有与现有技术的上下文中的意义一致的意义,并且除非像这里一样被特定定义,否则不会用理想化或过于正式的含义来解释。
应当理解,以上借助优选实施例对本发明的技术方案进行的详细说明是示意性的而非限制性的。本领域的普通技术人员在阅读本发明说明书的基础上可以对各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
1.一种组合物,其特征在于,包含一种含γ-氨基丁酸及其衍生物;和
瓜氨酸及其衍生物的组合物。
2.根据权利要求1所述的组合物,其特征在于,瓜氨酸衍生物包括:瓜氨酸盐,酸,酯,多聚体,螯合物或瓜氨酸异构体的盐,酸,酯,多聚体,螯合物及其组合。
3.根据权利要求1所述的组合物,其特征在于,γ-氨基丁酸及其衍生物的份数为0.05-50份,瓜氨酸及其衍生物的份数为0.1-20份;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20份,瓜氨酸及其衍生物的份数为0.5-10份,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10份,瓜氨酸及其衍生物的份数为1-8份,优选的,γ-氨基丁酸及其衍生物的份数为1-5份,瓜氨酸及其衍生物的份数为3-7份,优选的,γ-氨基丁酸及其衍生物的份数为3份,瓜氨酸及其衍生物的份数为6份。
4.根据权利要求1所述的组合物,其特征在于,γ-氨基丁酸及其衍生物的份数为0.05-50g,瓜氨酸及其衍生物的份数为0.1-20g;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20g,瓜氨酸及其衍生物的份数为0.5-10g,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10g,瓜氨酸及其衍生物的份数为1-8g,优选的,γ-氨基丁酸及其衍生物的份数为1-5g,瓜氨酸及其衍生物的份数为3-7g,优选的,γ-氨基丁酸及其衍生物的份数为3g,瓜氨酸及其衍生物的份数为6g。
5.一种促进γ-氨基丁酸及其衍生物通过血脑屏障的方法,包括在添加γ-氨基丁酸及其衍生物,同时添加瓜氨酸及其衍生物。
6.根据权利要求5所述的方法,其特征在于,瓜氨酸衍生物包括:瓜氨酸盐,酸,酯,多聚体,螯合物或瓜氨酸异构体的盐,酸,酯,多聚体,螯合物及其组合。
7.根据权利要求5所述的方法,其特征在于,γ-氨基丁酸及其衍生物的份数为0.05-50份,瓜氨酸及其衍生物的份数为0.1-20份;优选的,γ-氨基丁酸及其衍生物的份数为0.1-20份,瓜氨酸及其衍生物的份数为0.5-10份,优选的,γ-氨基丁酸及其衍生物的份数为0.5-10份,瓜氨酸及其衍生物的份数为1-8份,优选的,γ-氨基丁酸及其衍生物的份数为1-5份,瓜氨酸及其衍生物的份数为3-7份,优选的,γ-氨基丁酸及其衍生物的份数为3份,瓜氨酸及其衍生物的份数为6份。
8.一种提高γ-氨基丁酸及其衍生物在大脑中含量的方法,在添加γ-氨基丁酸及其衍生物,同时添加瓜氨酸及其衍生物。
9.一种权利要求1-4之一所述的组合物在制备缓解压力或改善睡眠的药物、保健品、化妆品中的应用。
10.一种产品,其特征在于,包含权利要求1-4之一的组合物,所述产品为缓解压力或改善睡眠的药物、保健品、化妆品。
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