CN112641788A - 5-甲基四氢叶酸组合物用于改善睡眠的应用 - Google Patents
5-甲基四氢叶酸组合物用于改善睡眠的应用 Download PDFInfo
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Abstract
本发明提供了5‑甲基四氢叶酸新的改善睡眠作用的用途以及其与γ‑氨基丁酸联用的用途,本发明的目的是提供一种新的可长期服用的具有改善睡眠的含有5‑甲基四氢叶酸组合物的药物或保健食品,所述组合物中的镇静催眠成分可以长期服用,所述组合物对睡眠改善效果明确,且无副作用。
Description
技术领域
本发明属于医药领域,具体而言,本发明涉及5-甲基四氢叶酸新的改善睡眠作用的用途以及其与γ-氨基丁酸联用的用途等。
背景技术
失眠是一个重要的公共卫生问题,需要有效的诊断和治疗,但是由于睡眠的生理机制尚未完全阐明,导致相关药物的研发进展缓慢以及临床实践中没有良好的治疗失眠的手段。失眠大致可分为短期的和长期慢性失眠(通常持续数月或数年)。流行病学的研究显示,10%~15%的成年人患有慢性失眠,其中女性的患病率较高,老年人及精神疾病患者中约40%存在慢性失眠症。慢性失眠对人们白天的生活存在重大的影响,包括记忆力下降,注意力不集中,对工作以及学习产生严重的干扰,增加了驾驶人员的风险及老人意外摔倒的几率。不仅如此,慢性失眠还会对人体健康产生严重的损害,包括免疫功能的下降,患者心理状态的持续受损,增加了人体对疼痛、噪音的敏感。
导致长期的睡眠障碍的原因有多种,其中一部分原因是由慢性疾病导致的,包括鼻炎、鼻窦炎、过敏、癌症、关节炎、慢性腰痛、头疼、肺部的疾病导致的呼吸困难、泌尿系统疾病导致的夜尿、精神疾病抑郁、帕金森病、癫痫等等。除非睡眠障碍的主要原因被成功的诊断及纠正,否则对失眠的治疗作用有限。而不幸的是所述慢性疾病基于目前的治疗水平,往往无法短时间内治疗纠正,不少慢性疾病长期伴随着患者,有些甚至需要终生服药来控制症状。长期的睡眠障碍的另一部分原因包括了患者的代谢紊乱、精神疾病、心理健康状况,对此需要进行心理介入的治疗。由于包括中国在内的发展中国家的现状,比如相关心理健康的医疗体系不完善,相关的从业人员也较少,部分居民也难以承受心理健康的治疗和服务的费用,同时也对有关治疗和心理咨询服务的认识不到位,导致不少患者没有接受包括放松疗法、认知行为疗法等心理辅导治疗。非药物性的治疗手段需要长期坚持才能对睡眠改善起到明显的作用,需要的时间从数个月持续到数年,这样也导致患者依从性大大降低。
根据一项流行病学统计研究(Chen TY, Winkelman JW, Mao WC, Yeh CB, HuangSY, Kao TW, Yang CC, Kuo TB, Chen WL. Short sleep duration is associated withincreased serum homocysteine: insights from a national survey. J Clin SleepMed. 2019;15(1):139–148)中所述,高同型半胱氨酸水平与睡眠时间小于5小时成高度相关,其OR值男性为1.357,女性高达2.691。人们已经证实了同型半胱氨酸会损伤大脑的血脑屏障,导致血脑屏障通透性增加,但是同型半胱氨酸与失眠二者谁是因,谁是果还不清楚。
目前,临床上常用的治疗失眠的药物主要包括巴比妥类、苯二氮卓类和非苯二氮卓类药物,巴比妥类药物由于依耐性比较大,戒断症状明显等副作用已经渐渐被人们淘汰。苯二氮卓类和非苯二氮卓类药物目前是医生在临床处方上的中流砥柱,但是有关的镇静催眠药依然只是应用在短期的睡眠障碍,长期服用副作用就会明显显现出来,包括生理依赖、反弹性失眠、头疼或引起其他的精神障碍疾病。临床医生也会根据患者的情况开具一些非主治方面的药物,比如抗抑郁的曲唑酮、抗组胺药苯海拉明,以上药物长期服用会导致患者的认知障碍和一些宿醉效应。基于临床药物的种种限制,不少患者选择了以褪黑素或中草药为主要成分的保健食品,来克服睡眠障碍,但是有关研究表明褪黑素对原发性失眠无作用,通过临床观察发现服用褪黑素患者的每个睡眠阶段时间与安慰剂组无明显差异,褪黑素主要起的是短期诱导的作用,长期服用褪黑素对人体也存在其他潜在的危害。
基于以上现状,市场上缺乏可长期服用,能够明确改善患者睡眠质量的药物或保健食品。
γ-氨基丁酸(GABA)是大脑中重要的神经递质,作为一种中枢神经抑制性神经递质,有关GABA用于睡眠障碍却难以得到满意的效果,主要原因是GABA无法通过血脑屏障,仅能通过肠道迷走神经来间接影响中枢神经、自身的代谢产物产物的直接作用或调节内分泌系统等途径来间接的改善患者的睡眠状态。
5-甲基四氢叶酸参与甲硫氨酸循环,通过该循环进一步的参与一些神经递质的合成,包括5-羟色胺及儿茶酚胺。5-甲基四氢叶酸还能够直接通过血脑屏障,参与神经细胞中的DNA的修复,虽然叶酸已经作为营养素应用在人类的方方面面,特别是在预防新生儿神经管畸形领域,但是目前未有叶酸或活性叶酸的改善睡眠的研究报道,有关与镇静催眠的药物的相互作用也未被人们提出。
发明内容
为了解决现有技术问题,本发明的目的是提供一种新的可长期服用的具有改善睡眠的含有5-甲基四氢叶酸组合物的药品或保健食品,所述组合物中的镇静催眠成分可以长期服用,所述组合物对睡眠改善效果明确,且无副作用。
本发明通过小鼠戊巴比妥睡眠模型,证实了5-甲基四氢叶酸具有改善睡眠作用。发明人发现5-甲基四氢叶酸无直接催眠作用,但可以增加戊巴比妥钠阈下的入睡小鼠数量,并且缩短睡眠潜伏期,而且所用剂量仅为0.3mg/kg就能够起效,但是单独使用5-甲基四氢叶酸对小鼠睡眠时长无明显作用,推测其可改善患者的入睡困难,对延长睡眠时间效果不显著。
发明人进一步考察了多种无副作用但具有改善睡眠的成分,发现γ-氨基丁酸与5-甲基四氢叶酸联用具有非常好的效果。γ-氨基丁酸作为国家批准的新资源食品,具有可长期服用无副作用的效果。通过小鼠戊巴比妥睡眠模型,发现γ-氨基丁酸不能增加戊巴比妥钠阈下剂量小鼠的入睡数量,也不能缩短睡眠潜伏期,但是可以改善小鼠的睡眠时长,提示γ-氨基丁酸可改善患者的睡眠质量。
发明人发现γ-氨基丁酸与5-甲基四氢叶酸合用具有显著的改善睡眠作用,既可以显著增加戊巴比妥钠阈下剂量下小鼠的入睡数量又可以缩短小鼠的睡眠潜伏期,还可以增加小鼠的睡眠时长,而且无直接睡眠的作用,提示该组合物能够改善患者的睡眠障碍,改善睡眠质量,并且对神经系统无直接的镇静催眠作用具有十分好的安全性。
本发明的第一个目的在于提供一种已知化合物的新用途,即5-甲基四氢叶酸在制备预防或治疗失眠的药物中的用途。
本发明的第二个目的在于提供一种具有明确改善睡眠效果,且可长期服用的药物组合物,所述组合物含有5-甲基四氢叶酸,γ-氨基丁酸。
本发明所述5-甲基四氢叶酸包含5-甲基-(6S)-四氢叶酸,5-甲基-(6R)-四氢叶酸,5-甲基-(6R,S)-四氢叶酸,即包含5-甲基四氢叶酸的不同旋光异构体,或者单一的手型结构化合物。
本发明所述药学上可接受盐包含5-甲基四氢叶酸的酸性基团与有机碱、无机碱反应所得到的的各种盐,示例性的包含5-甲基四氢叶酸钙盐、钠盐、镁盐、氨基葡萄糖盐、精氨酸盐。
本发明所述组合物包含有效量的5-甲基四氢叶酸和有效量的γ-氨基丁酸,上述组合物可以加一种或多种药学上可接受的辅料,制成各种制剂。用于口服时,可将其制成固体或液体制剂,如片剂、胶囊、软胶囊、分散片、口服液、颗粒、咀嚼片、滴丸等;用于肠胃外给药时,可将其制成注射用的溶液、悬浮液、粉剂,如水针、冻干粉针、油针等。
本发明的组合物的制剂可采用现有制药领域中常规方法生产,需要时候可以添加各种药学上可接受的辅料。所述辅料包括常用的赋性剂、填充剂、粘合剂、崩解剂、表面活性剂、润滑剂等。
本发明提供的药品或保健食品,其每日服用5-甲基四氢叶酸量为0.05~50mg,优选的为5~15mg,每日服用γ-氨基丁酸量为1~500mg,优选的为50~200mg。应当理解本发明提供的药物用剂量不是对本发明的限制,而是对本发明的优选。
2009年作为新资源食品的γ-氨基丁酸与2017年作为食品营养添加剂的5-甲基四氢叶酸,安全性均已经被验证,二者均可以长期服用,以此组合物制成的改善睡眠的保健食品或药品解决了目前市场上缺乏可长期服用、安全有效的改善睡眠产品的问题。
目前市场上提供的安眠药,具有显著效果的,均是以大脑中神经细胞受体,特别是GABA受体或是5-羟色胺受体为靶点,具有直接的作用,长期使用会导致受体功能的丧失、受体表达的改变、受体结构的改变,从而进一步增加神经系统及大脑功能的损害。本发明所述组合物,均没有直接对受体的作用(γ-氨基丁酸由于血脑屏障的缘故所以无法直接进入大脑),具备可长期服用的潜力。5-甲基四氢叶酸与γ-氨基丁酸二者联用,改善睡眠作用更全面,效果也更好。
具体实施方式
实施例1 改善睡眠片剂的制备
15g的5-甲基四氢叶酸钙与370g的微晶纤维素、5g的硬脂酸镁、10g的聚乙烯吡咯烷酮混合,经总混,干法制粒,过筛后,经过压片机压1000片,制成每片含有15mg的5-甲基四氢叶酸的改善睡眠片剂。
实施例2 改善睡眠胶囊的制备
15g的5-甲基四氢叶酸钙与100g的γ-氨基丁酸混合,之后加入300g的微晶纤维素,50g的乳糖,经过总混,干法制粒,过筛后,经胶囊灌装机灌装1000粒胶囊,制成每粒含有15mg的5-甲基四氢叶酸钙及100mg的γ-氨基丁酸的胶囊。
实验例1 5-甲基四氢叶酸钙直接睡眠实验
取昆明小鼠,SPF级,雌雄各半,实验开始时体重均数21.7~28.0g,根据体重随机分为溶媒对照组(纯化水,ig)、5-甲基四氢叶酸钙高剂量组(0.9mg·Kg-1)、5-甲基四氢叶酸钙中剂量组(0.6mg·Kg-1)、5-甲基四氢叶酸钙低剂量组(0.3mg·Kg-1),雌雄各半,每组10只。5-甲基四氢叶酸钙来自连云港金康和信药业有限公司,受试物全部为灌胃给药。每天给药1次,连续7天。末次给药后观察小鼠是否出现睡眠现象,睡眠以翻正反射消失为指标,翻正反射恢复即为小鼠觉醒,翻正反射消失到恢复为小鼠睡眠时间,记录各组小鼠入睡只数及睡眠时间。
结果表明,给药后各组小鼠均未见翻正反射消失现象,提示5-甲基四氢叶酸对小鼠无直接睡眠作用。
实验例2 5-甲基四氢叶酸钙延长戊巴比妥睡眠时间实验
取昆明小鼠,SPF级,雌雄各半,实验开始时体重均数21.7~28.0g,根据体重随机分为溶媒对照组(纯化水,ig)、5-甲基四氢叶酸钙盐高剂量组(0.9 mg·Kg-1)、5-甲基四氢叶酸钙中剂量组(0.6mg·Kg-1)、5-甲基四氢叶酸钙盐低剂量组(0.3 mg·Kg-1)、戊巴比妥组,每组10只。戊巴比妥钠(批号:081213,规格10g,产地:北京化学试剂公司)。通过预实验得到戊巴比妥钠的阈值剂量为50 mg·Kg-1。受试物全部为灌胃给药,戊巴比妥钠为腹腔注射,5-甲基四氢叶酸钙组每天给药1次,连续7天。末次给药1.5h后,各组小鼠按50mg·Kg-1腹腔注射戊巴比妥钠,以翻正反射消失为指标,记录小鼠睡眠时间。结果见表1。
表1 5-甲基四氢叶酸钙盐(叶酸钙)对戊巴比妥钠睡眠时间实验(n=10,± SD)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠时间(min) |
溶媒溶媒对照组 | 20ml•kg<sup>-1</sup> | 104.7±42.9 |
叶酸钙盐低剂量组 | 0.3 | 107.0±20.9 |
叶酸钙盐中剂量组 | 0.6 | 107.4±43.0 |
叶酸钙盐高剂量组 | 0.9 | 104.9±37.4 |
注:各用药组与溶媒对照组同时间点比较P>0.05.
结果表明各剂量组小鼠睡眠时间与溶媒对照组相比较均无显著差异(P>0.05),提示5-甲基四氢叶酸不能延长戊巴比妥钠诱导的小鼠睡眠时间。
实验例3 戊巴比妥钠阈下剂量催眠实验
取昆明小鼠,SPF级,雌雄各半,实验开始时体重均数21.7~28.0g,根据体重随机分为溶媒对照组(纯化水,ig)、5-甲基四氢叶酸钙盐高剂量组(0.9 mg·Kg-1)、5-甲基四氢叶酸钙中剂量组(0.6mg·Kg-1)、5-甲基四氢叶酸钙盐低剂量组(0.3 mg·Kg-1)、戊巴比妥组,每组10只。戊巴比妥钠(批号:081213,规格10g,产地:北京化学试剂公司)。通过预实验得到戊巴比妥钠的阈值剂量为50 mg·Kg-1。受试物全部为灌胃给药,戊巴比妥钠为腹腔注射,5-甲基四氢叶酸钙组每天给药1次,连续7天。末次给药1.5h后,各组小鼠按40 mg·Kg-1腹腔注射戊巴比妥钠,以翻正反射消失为指标,记录30min内小鼠入睡只数。结果表明,各剂量组小鼠入睡只数均显著高于溶媒对照组(P<0.05),提示5-甲基四氢叶酸能增加小鼠入睡的发生率。结果见表2。
表2 叶酸钙盐(5-甲基四氢叶酸钙)对小鼠戊巴比妥钠阈下剂量催眠实验(n=10)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠只数(只) | 睡眠百分比(%) |
溶媒对照组 | 20ml•kg<sup>-1</sup> | 2 | 20 |
叶酸钙盐低剂量组 | 0.3 | 6 | 60* |
叶酸钙盐中剂量组 | 0.6 | 5 | 50* |
叶酸钙盐高剂量组 | 0.9 | 6 | 60* |
注: *:各用药组与溶媒对照组同时间点比较P<0.05.
实验例4 戊巴比妥钠睡眠潜伏期实验
取昆明小鼠,SPF级,雌雄各半,实验开始时体重均数21.7~28.0g,根据体重随机分为溶媒对照组(纯化水,ig)、5-甲基四氢叶酸钙盐高剂量组(0.9 mg·Kg-1)、5-甲基四氢叶酸钙中剂量组(0.6mg·Kg-1)、5-甲基四氢叶酸钙盐低剂量组(0.3 mg·Kg-1)、戊巴比妥组,每组10只。戊巴比妥钠(批号:081213,规格10g,产地:北京化学试剂公司)。通过预实验得到戊巴比妥钠的阈值剂量为50 mg·Kg-1。受试物全部为灌胃给药,戊巴比妥钠为腹腔注射,5-甲基四氢叶酸钙组每天给药1次,连续7天。末次给药1.5h后,各组小鼠按50 mg·Kg-1腹腔注射戊巴比妥钠,以翻正反射消失为指标,观察受试物对戊巴比妥钠睡眠潜伏期的影响。结果表明,各剂量组与溶媒对照组相比较,小鼠睡眠潜伏期均缩短(P<0.05),提示受试物能够缩短戊巴比妥钠诱导的小鼠睡眠潜伏期。结果见表3。
表3 叶酸钙盐对小鼠戊巴比妥钠睡眠潜伏期实验(n=10,± SD)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠时间(min) |
溶媒对照组 | 20ml•kg<sup>-1</sup> | 27.5±6.32 |
叶酸钙盐低剂量组 | 0.3 | 20.4±6.25* |
叶酸钙盐中剂量组 | 0.6 | 21.4±5.17* |
叶酸钙盐高剂量组 | 0.9 | 21.8±6.39* |
注: *:各用药组与溶媒对照组同时间点比较P<0.05.
实施例5 组合物及γ-氨基丁酸对小鼠直接睡眠的影响
取昆明小鼠,SPF级,雌雄各半,考察直接睡眠实验。各个实验均分为8组即溶媒对照组、阳性对照组(褪黑素15 mg·Kg-1)、组合物低剂量组(20 mg·Kg-1)、组合物中剂量组(40mg·Kg-1)、组合物高剂量组(80 mg·Kg-1),γ-氨基丁酸低剂量组(20 mg·Kg-1)、γ-氨基丁酸中剂量组(40 mg·Kg-1)、γ-氨基丁酸高剂量组(80 mg·Kg-1),各组10只。组合物中5-甲基四氢叶酸钙与γ-氨基丁酸质量比为3比20。5-甲基四氢叶酸钙来源为连云港金康和信药业有限公司,γ-氨基丁酸来源为安徽欣诺贝生物科技有限公司。各组动物直接口服给予相应样品后观察是否出现睡眠现象。翻正反射消失至恢复这段时间为动物睡眠时间,记录各组入睡动物数及睡眠情况。
结果表明,给药后各组小鼠均未见翻正反射消失现象,提示组合物及γ-氨基丁酸对小鼠无直接睡眠作用。
实验例6 组合物及γ-氨基丁酸延长戊巴比妥钠睡眠时间实验
取昆明小鼠,SPF级,雌雄各半,考察直接睡眠实验。各个实验均分为8组即溶媒对照组、阳性对照组(褪黑素15 mg·Kg-1)、组合物低剂量组(20 mg·Kg-1)、组合物中剂量组(40mg·Kg-1)、组合物高剂量组(80 mg·Kg-1),γ-氨基丁酸低剂量组(20 mg·Kg-1)、γ-氨基丁酸中剂量组(40 mg·Kg-1)、γ-氨基丁酸高剂量组(80 mg·Kg-1),各组10只。组合物中5-甲基四氢叶酸钙与γ-氨基丁酸质量比为3比20。5-甲基四氢叶酸钙来源为连云港金康和信药业有限公司,γ-氨基丁酸来源为安徽欣诺贝生物科技有限公司,戊巴比妥钠(批号:081213,规格10g,产地:北京化学试剂公司)。各组连续口服给予受试物20天,末次口服后30分钟,80只动物均以50mg/kg剂量腹腔注射戊巴比妥钠,观察是否对睡眠时间有延长作用,结果见表4。
表4对戊巴比妥钠睡眠时间实验(n=10,± SD)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠时间(min) |
溶媒溶媒对照组 | 20ml•kg<sup>-1</sup> | 95.7±41.0 |
阳性药组(褪黑素) | 15 | 125.4±31.2* |
组合物低剂量组 | 20 | 124.4±33.5* |
组合物中剂量组 | 40 | 127.9±36.8* |
组合物高剂量组 | 80 | 134.9±37.1* |
γ-氨基丁酸低剂量组 | 20 | 103.9±40.4 |
γ-氨基丁酸中剂量组 | 40 | 114.9±37.9* |
γ-氨基丁酸高剂量组 | 80 | 124.9±33.7* |
注: *:各用药组与溶媒对照组同时间点比较P<0.05.
结果表明各实验组均有助于延长睡眠时间,组合物组与γ-氨基丁酸组均呈现一定的量效关系,且相同剂量的组合物特别是低剂量组的睡眠时间明显高于γ-氨基丁酸组,具有显著性差异(P<0.05)。令人惊奇的是组合物低剂量组与阳性药组效果接近。
实验例7 组合物及γ-氨基丁酸对戊巴比妥钠阈下剂量催眠实验
取昆明小鼠,SPF级,雌雄各半,考察直接睡眠实验。各个实验均分为8组即溶媒对照组、阳性对照组(褪黑素15 mg·Kg-1)、组合物低剂量组(20 mg·Kg-1)、组合物中剂量组(40mg·Kg-1)、组合物高剂量组(80mg/kg),γ-氨基丁酸低剂量组(20 mg·Kg-1)、γ-氨基丁酸中剂量组(40 mg·Kg-1)、γ-氨基丁酸高剂量组(80 mg·Kg-1),各组10只。组合物中5-甲基四氢叶酸钙与γ-氨基丁酸质量比为3比20。5-甲基四氢叶酸钙来源为连云港金康和信药业有限公司,γ-氨基丁酸来源为安徽欣诺贝生物科技有限公司。各组连续口服给予受试物20天,末次口服后30分钟,各组动物均以40 mg·Kg-1剂量腹腔注射戊巴比妥钠,观察各组在戊巴比妥钠阈下剂量发生睡眠的动物数。以翻正反射消失为指标,记录30min内小鼠入睡只数。结果见表5,结果表明,各剂量组小鼠入睡只数均显著高于溶媒对照组(P<0.05),提示组合物能增加小鼠入睡的发生率。
表5对小鼠戊巴比妥钠阈下剂量催眠实验(n=10)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠只数(只) | 睡眠百分比(%) |
溶媒对照组 | 20ml•kg<sup>-1</sup> | 1 | 10 |
阳性药组(褪黑素) | 15 | 8 | 80* |
组合物低剂量组 | 20 | 6 | 60* |
组合物中剂量组 | 40 | 7 | 70* |
组合物高剂量组 | 80 | 8 | 80* |
γ-氨基丁酸低剂量组 | 20 | 1 | 20 |
γ-氨基丁酸中剂量组 | 40 | 1 | 10 |
γ-氨基丁酸高剂量组 | 80 | 2 | 20 |
注: *:各用药组与溶媒对照组同时间点比较P<0.05.
实验例8 组合物及γ-氨基丁酸对巴比妥钠睡眠潜伏期实验
取昆明小鼠,SPF级,雌雄各半,考察直接睡眠实验。各个实验均分为8组即溶媒对照组、阳性对照组(褪黑素15 mg·Kg-1)、组合物低剂量组(20 mg·Kg-1)、组合物中剂量组(40mg·Kg-1)、组合物高剂量组(80 mg·Kg-1),γ-氨基丁酸低剂量组(20 mg·Kg-1)、γ-氨基丁酸中剂量组(40 mg·Kg-1)、γ-氨基丁酸高剂量组(80 mg·Kg-1),各组10只。组合物中5-甲基四氢叶酸钙与γ-氨基丁酸质量比为3比20。5-甲基四氢叶酸钙来源为连云港金康和信药业有限公司,γ-氨基丁酸来源为安徽欣诺贝生物科技有限公司。各组连续口服给予受试物20天,末次口服后30分钟,各组动物均以50 mg·Kg-1剂量腹腔注射戊巴比妥钠,观察各组受试物对戊巴比妥钠的睡眠潜伏期是否有影响。结果见表6。
表6 组合物及γ-氨基丁酸对戊巴比妥钠的睡眠潜伏期的影响(n=10,± SD)
组别 | 剂量(mg•kg<sup>-1</sup>) | 睡眠时间(min) |
溶媒对照组 | 20ml•kg<sup>-1</sup> | 27.2±6.73 |
阳性药组(褪黑素) | 15 | 26.4±4.65 |
组合物低剂量组 | 20 | 22.4±5.53* |
组合物中剂量组 | 40 | 21.7±6.64* |
组合物高剂量组 | 80 | 21.0±5.89* |
γ-氨基丁酸低剂量组 | 20 | 27.8±6.07 |
γ-氨基丁酸中剂量组 | 40 | 29.1±6.82 |
γ-氨基丁酸高剂量组 | 80 | 27.7±6.21 |
注: *:各用药组与溶媒对照组同时间点比较P<0.05.
结果表明组合物组均能显著降低小鼠注射无巴比妥钠后的睡眠潜伏期,而γ-氨基丁酸与褪黑素则作用不显著。
Claims (7)
1.一种治疗失眠或改善睡眠的组合物,其特征在于所述组合物含有5-甲基四氢叶酸。
2.根据权利要求1所述的组合物,其特征在于所述组合物含有5-甲基四氢叶酸,γ-氨基丁酸。
3.根据权利要求2所述的组合物,其特征在于所述组合物的5-甲基四氢叶酸与γ-氨基丁酸的质量比为1:20至20:1。
4.一种治疗失眠或改善睡眠的药品或保健食品,所述药品或保健食品含有权利要求1或2所述的组合物。
5.根据权利要求1或2所述的组合物,其特征在于所述5-甲基四氢叶酸包括5-甲基-(6S)-四氢叶酸,5-甲基(6R)-四氢叶酸,5-甲基-(6R,S)-四氢叶酸,即包含5-甲基四氢叶酸不同的旋光异构体及其混合物。
6.根据权利要求1或2所述的组合物,其特征在于所述5-甲基四氢叶酸还包括其药学上可接受的盐,示例性的,如5-甲基四氢叶酸钙盐、钠盐、镁盐、氨基葡萄糖盐、精氨酸盐。
7.根据权利要求4所述的药品或保健食品,其特征在于所述药物或保健食品的剂型包括片剂、胶囊剂、颗粒剂、丸剂、注射剂。
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