CN110063952A - 二氢杨梅素衍生物在治疗改善睡眠中的用途 - Google Patents
二氢杨梅素衍生物在治疗改善睡眠中的用途 Download PDFInfo
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- CN110063952A CN110063952A CN201810057170.1A CN201810057170A CN110063952A CN 110063952 A CN110063952 A CN 110063952A CN 201810057170 A CN201810057170 A CN 201810057170A CN 110063952 A CN110063952 A CN 110063952A
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Abstract
本发明提供了二氢杨梅素衍生物,特别是二氢杨梅素在制备用于治疗改善睡眠中的药物中的用途。本发明的二氢杨梅素在治疗改善睡眠中具有优异的效果。本发明也提供了二氢杨梅素的制备方法和组合物。
Description
技术领域
本发明属于药品及保健品制剂领域。具体地,本发明涉及二氢杨梅素及其他多种盐在制备用于治疗改善睡眠中的药物中的用途。本发明也涉及二氢杨梅素及其他多种盐的制备方法。
背景技术
二氢杨梅素是一种较为特殊的黄酮类化合物,多提取自葡萄科蛇葡萄属的一种木质藤本植物,也有用拐枣提取。二氢杨梅素解除醇中毒、预防酒精肝、脂肪肝、抑制肝细胞恶化、降低肝癌的发病率、抗高血压、抑制体外血小板聚集和体内血栓的形成、降低血脂和血糖水平,提高SOD活性以及保肝护肝等方面具有特殊功效。
睡眠问题日益突出,已成为重要的公共卫生问题。《2015年中国睡眠指数报告》显示,我国约有三分之一的人存在严重的睡眠问题。令人忧心的是,随着生活节奏的加快和社会压力的增加,这一比例还在日益升高。高于国外发达国家的失眠发生率。医学研究表明,偶尔失眠会造成第二天疲倦和动作不协调,长期失眠则会带来注意力不能集中、记忆出现障碍和工作力不从心等后果。
最常见的睡眠问题是失眠。表现为不易入睡或睡中反复苏醒或早醒后不能再睡,甚至彻底不能入睡。除失眠外,睡眠疾病还包括:睡眠过度关注,睡眠不足综合症,梦游症,磨牙症,嗜睡症,发作性睡病,不宁腿综合症,时差综合症,睡眠遗尿症,睡眠呼吸暂停综合症等,男女老幼均可发生。
目前治疗睡眠障碍的处方药主要包括以下几大类:
1、苯二氮类药物
苯二氮类药物的化学结构及药理作用类似,可与GABAA受体的α1、α2、α3、α5亚单位结合,增加氯离子通道开放频率,进而发挥镇静、抗焦虑及抗惊厥作用,具体临床效应与剂量有关。半衰期和效价是区别此类药物的重要依据。
针对失眠,苯二氮类药物起效通常较快,尤其是缩短入睡潜伏期,很多患者的主观睡眠质量也可改善,但对总睡眠时长的影响不大。此类药物的副作用包括次日过度镇静、共济失调、跌倒、呼吸抑制、低血压等,长期应用可出现认知损害、耐受及依赖,骤停还可能引起原有症状的反跳甚至恶化。
指南一般建议,除极个别品种外,此类药物连续使用不宜超过4周(也有2-3周之说),且需逐步减停。
2、非苯二氮类助眠药
已获FDA批准用于治疗失眠的非苯二氮类药物包括唑吡坦、艾司佐匹克隆及扎来普隆,因英文化学名均含字母Z,故常统称为“Z药”。此类药物选择性较高,主要与GABAA受体α1亚单位相结合,发挥镇静助眠效应。针对一般人群,此类药物可有效缩短睡眠潜伏期(10-20分钟),延长总睡眠时间,艾司佐匹克隆还可缩短入睡后觉醒时间(10.8分钟);从数值上看,针对老年患者的疗效相对差一些。
此类药物的耐受性总体优于苯二氮类药物,目前应用相当广泛,但同样存在嗜睡、幻觉等潜在副作用。今年的一项新研究显示,近期使用唑吡坦可升高65岁以上老年人创伤性脑损伤及髋关节骨折风险,而艾司佐匹克隆则不升高相关风险。
苯二氮类药物和非苯二氮类助眠药同属于苯二氮受体激动剂(BzRAs)。
3、褪黑素受体激动剂
褪黑素可影响昼夜节律,进而被作为助眠治疗的靶点。抗抑郁药阿戈美拉汀是首个褪黑素受体激动剂,同时拮抗5-HT2C受体。该药对睡眠具有正向时相调整作用,诱导睡眠时相提前,针对抑郁伴发失眠症状疗效突出,显著改善睡眠连续性及质量,反而是其抗抑郁焦虑效应一度受到质疑。
此外,雷美替胺(Ramelteon)可有效缩短一般失眠群体的入睡潜伏期(10.1分钟),已获FDA批准治疗入睡障碍性失眠。
4、TCAs
证据显示,低剂量的三环类抗抑郁药多塞平(多虑平)可改善中间失眠,并于2010年获FDA批准治疗该临床状况。与其他TCAs一样,该药可抑制5-HT及NE的再摄取,同时对胆碱能、组胺及α1受体具有阻断效应。剂量低于10mg时,该药主要发挥抗组胺效应,进而产生较强的镇静效应。阿米替林也可用于失眠治疗,尤其是当失眠继发于抑郁症时。
由于TCAs药物整体耐受性不佳,尽管治疗失眠时的剂量较低,目前临床已较少使用。
5、SARI
低剂量时,5-HT平衡抗抑郁药(SARI)曲唑酮对5-HT2A受体、H1受体及α1受体具有拮抗作用,进而常用于镇静助眠,尤其是针对伴抑郁症状的患者。该药的副作用包括日间镇静、直立性低血压、心律不齐及认知/运动功能损害。该药还可能导致泌尿科急症——阴茎异常勃起,治疗不及时可引发严重后果,须加以警惕。
治疗失眠时,曲唑酮的起始剂量一般为25-50mg,可加量至50-100mg。该药对失眠的改善效应快于抗抑郁效应。针对顽固性失眠,可在该药基础上尝试短期联用苯二氮类药物。
6、NaSSA
NE及特异性5-HT能抗抑郁药(NaSSA)米氮平具有较强的H1受体拮抗作用,临床中也常超适应证用于失眠治疗,且单次给药后立即起效,而抗抑郁起效则一般需要2周。该药的镇静作用并不随着剂量的升高而增加,反而在低剂量时(7.5-15mg)更为突出。
该药可导致显著的体重增加,故应考虑患者是否已处于超重或肥胖状态,并评估代谢风险。
7、部分抗精神病药
因精神分裂症或双相障碍相关激越导致失眠时,入睡前使用具有镇静作用的抗精神病药可提供抗精神病及助眠的双重获益。目前,低剂量奥氮平及喹硫平可有效改善精神分裂症患者的失眠症状,但代谢风险须加以重视,且治疗成本较高。若有其他选择,一般不建议无其他精神障碍的患者出于助眠目的使用此类药物。
8、食欲素(Orexin)拮抗剂
Suvorexant是首个被FDA批准(2014年8月)用于治疗失眠的食欲素受体拮抗剂。研究中,15mg及30mg的用量可为受试者带来改善入睡及睡眠维持方面的获益,但出于对次日镇静副作用的考虑,FDA所批准的治疗剂量为10-20mg。
目前治疗睡眠障碍的中药情况如下:
1、柏子养心丹:失眠伴有易于惊醒,胆怯心悸,遇事善惊,气短倦怠,秀清长,舌淡者适用。
2、朱砂安神丸:失眠,伴有心悸不安,头晕耳鸣,健忘,腰酸梦遗,手足心热,口干津少者适用。
3、人参归脾丸:失眠伴有多梦易醒,心悸健忘,头晕目眩,肢倦神疲,饮食无味,面色少华,舌质淡,苔薄少者适用。
4、龙胆泻肝丸:失眠伴有性情急躁易怒,不思饮食,口渴喜饮,目赤口苦,秀黄赤,大便秘结,舌质红,苔黄者适用。
5、六味地黄丸:六味地黄丸具有滋阴补肾、治疗失眠头晕的功效,头容易晕的失眠患者适用。
6、解郁安神颗粒:解郁安神颗粒具有抚平情绪、治疗心烦、胸闷的功效,如果是由于情绪过于紧张不适引起失眠者适用。
7、归脾丸:归脾丸具有养血安神、健脾益气的功效,对于治疗失眠多梦、心悸烦躁者适用。
8、安神补心丸:安神补心丸具有养心安神的功效,对于心悸失眠、头晕者适用。
9、复方五味子糖浆:复方五味子糖浆可以用来治疗头晕、心悸失眠、四肢乏力者适用。但需注意的是,孕妇尽量不要服用此药物,过敏者慎用。
因此,可见目前尚缺少一种能够安全且有效改善睡眠的药品或保健品。
发明内容
二氢杨梅素衍生物在治疗改善睡眠中的用途。
其中所述二氢杨梅素衍生物:
R1-R6可以为1个或多个(最多6个)基团和氢的组合。
其中,A为1C-16C的烷烃,1C-16C的烯烃,1C-16C的炔烃;4C-7C的环烷烃;4C-7C的环烯烃。
A还可以是:1-6取代的苯基;1-5取代的吡啶基;1-3取代的呋喃基;1-3取代的吡咯基。
M可以为1个或多个(最多5个)金属离子和氢的组合。
金属离子包括:钠、钾、锂
实施例1:
原料加入二氯甲烷中,加入2eq三乙胺,降温至零摄氏度,缓慢滴加乙酰氯5eq。滴毕,升至室温反应5小时。停止反应,加水分液,水层用二氯甲烷萃取3次,合并有机相,减压蒸干后柱层析纯化,得到产物。
实施例2:
原料加入甲醇和水的混合溶剂中,加入5eq氢氧化钠,室温反应10小时。停止反应,反应液浓缩至干。甲醇洗涤后,得到产物。
其中所述二氢杨梅素衍生物为二氢杨梅素、二氢杨梅素衍生物及含有二氢杨梅素的植物提取物,包含且不限于拐枣提取物、藤茶提取物、枳椇子提取物、显齿蛇葡萄提取物。
其中所述药物与其他有助睡眠作用成分组合使用,优选与磷脂酰丝氨酸或金丝桃素或贯叶连翘提取物组合使用。
其中所述药物为经口服途径给药。
如式(I)所示的二氢杨梅素,
制备如式(I)所示的二氢杨梅素的方法,包括将二氢杨梅素和盐在加热或催化条件下反应制得。
药物组合物,其包含如式(I)的二氢杨梅素,以及一种或多种药学上可接受的载体。
具体实施方式
1.二氢杨梅素(衍生物)的制剂处方
二氢杨梅素(衍生物)的制剂
A.二氢杨梅素(衍生物)片剂
配方:
制备工艺:
将乳糖粉碎,过80目筛,备用;将原料二氢杨梅素(衍生物)、微晶纤维素分别过80目筛,备用;称取处方量的交联聚维酮,配制成5%的溶液,备用;称取处方量二氢杨梅素(衍生物)、乳糖、微晶纤维素加入到高效湿法制粒机中,干混6-10min,缓慢加入配制好的交联聚维酮粘合剂,进行湿法制粒,得二氢杨梅素(衍生物)湿颗粒,将湿颗粒进行干燥,干燥温度为60-70℃,干燥时间15-30min,采用14目筛网对干燥后的颗粒进行整粒,得二氢杨梅素(衍生物)干燥颗粒,将干燥颗粒、处方量硬脂酸镁、处方量滑石粉分别加入到多向运动混合机中,混合,压片,即得二氢杨梅素(衍生物)片。
B.二氢杨梅素(衍生物)压片糖果
制备工艺:
将三氯蔗糖、DL-苹果酸粉碎,过80目筛,备用;将原料二氢杨梅素(衍生物)、微晶纤维素分别过80目筛,备用;称取处方量的D-甘露糖醇,配制成5%的溶液,备用;称取处方量二氢杨梅素(衍生物)、三氯蔗糖、DL-苹果酸、微晶纤维素加入到高效湿法制粒机中,干混6-10min,缓慢加入配制好的D-甘露糖醇粘合剂,进行湿法制粒,得二氢杨梅素(衍生物)湿颗粒,将湿颗粒进行干燥,干燥温度为60-70℃,干燥时间15-30min,采用14目筛网对干燥后的颗粒进行整粒,得二氢杨梅素(衍生物)干燥颗粒,将干燥颗粒、处方量硬脂酸镁加入到多向运动混合机中,混合,压片,即得二氢杨梅素(衍生物)压片糖果。
C.二氢杨梅素(衍生物)与其他有助睡眠作用成分组合制备的压片糖
制备工艺:
将三氯蔗糖、DL-苹果酸粉碎,过80目筛,备用;将原料二氢杨梅素(衍生物)、贯叶连翘提取物、酸枣仁提取物、磷脂酰丝氨酸、γ-氨基丁酸、褪黑素、微晶纤维素分别过80目筛,备用;称取处方量的D-甘露糖醇,配制成5%的溶液,备用;称取处方量二氢杨梅素(衍生物)、贯叶连翘提取物、酸枣仁提取物、磷脂酰丝氨酸、γ-氨基丁酸、褪黑素、三氯蔗糖、DL-苹果酸、微晶纤维素加入到高效湿法制粒机中,干混6-10min,缓慢加入配制好的D-甘露糖醇粘合剂,进行湿法制粒,得二氢杨梅素(衍生物)湿颗粒,将湿颗粒进行干燥,干燥温度为60-70℃,干燥时间15-30min,采用14目筛网对干燥后的颗粒进行整粒,得二氢杨梅素(衍生物)干燥颗粒,将干燥颗粒、处方量硬脂酸镁加入到多向运动混合机中,混合,压片,即得二氢杨梅素(衍生物)压片糖果。
2.二氢杨梅素(衍生物)改善睡眠的动物实验
二氢杨梅素(衍生物)改善睡眠保健功能的研究
将小鼠随机分为二氢杨梅素(衍生物)13mg/kg组、26mg/kg组、39mg/kg组和蒸馏水组,观察二氢杨梅素(衍生物)对小鼠睡眠的影响,并考察其对小鼠中枢的直接作用以及多次给二氢杨梅素(衍生物)后致小鼠催眠作用的影响。
实验结果表明:二氢杨梅素(衍生物)各剂量组和蒸馏水组比较,能显著延长小鼠睡眠时间,缩短潜伏期;目前的研究表明,二氢杨梅素(衍生物)是一种对多巴胺神经元的调节Akt/GSK-3β通路有效的神经保护剂。
表1 二氢杨梅素(衍生物)对各组小鼠药后睡眠率的影响(n=12)
表2 二氢杨梅素(衍生物)对各组小鼠给药后潜伏期及睡眠时间的影响
3.二氢杨梅素(衍生物)片改善睡眠的试食实验
选择轻度、中度睡眠障碍的受试者,31人为试食组,服用二氢杨梅素(衍生物)片;24人为对照组,服用安慰剂片。均为2次/d,1片(420mg)/次,下午1片,临睡前1片,连续15d。试验开始前和试验结束时对受试者进行睡眠情况调查。服用产品后,对受试者的睡眠时间、入睡潜伏期及觉醒后身体状态及睡眠质量改善情况进行评估和记录。
结果:试食组睡眠时间显著延长,入睡潜伏期缩短,睡眠质量及觉醒后身体疲劳度的恢复感受都高于安慰剂对照组。
结论:二氢杨梅素(衍生物)片具有改善睡眠功能。
上述具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明内容所实施的技术方案均落入于本发明的范围。
Claims (9)
1.二氢杨梅素衍生物在制备用于预防和/或治疗对象中改善睡眠的药物中的用途。
2.权利要求1的用途,其中所述二氢杨梅素衍生物:
其中,A为1C-16C的烷烃,1C-16C的烯烃,1C-16C的炔烃;4C-7C的环烷烃;4C-7C的环烯烃。
A还可以是:1-6取代的苯基;1-5取代的吡啶基;1-3取代的呋喃基;1-3取代的吡咯基。
M可以为1个或多个(最多5个)金属离子和氢的组合。
金属离子包括:钠、钾、锂
实施例1:
原料加入二氯甲烷中,加入2eq三乙胺,降温至零摄氏度,缓慢滴加乙酰氯5eq。滴毕,升至室温反应5小时。停止反应,加水分液,水层用二氯甲烷萃取3次,合并有机相,减压蒸干后柱层析纯化,得到产物。
实施例2:
原料加入甲醇和水的混合溶剂中,加入5eq氢氧化钠,室温反应10小时。停止反应,反应液浓缩至干。甲醇洗涤后,得到产物。
3.权利要求1的用途,其中所述二氢杨梅素衍生物为二氢杨梅素,含有二氢杨梅素的植物提取物,包含且不限于拐枣提取物、藤茶提取物、枳椇子提取物、显齿蛇葡萄提取物。
4.权利要求1-3任一项的用途,其中所述药物与其他有助睡眠作用成分组合使用。
5.权利要求4的用途,其中所述药物与磷脂酰丝氨酸或金丝桃素或贯叶连翘提取物组合使用。
6.权利要求1-5的用途,其中所述药物为经口服途径给药。
7.如式(I)所示的二氢杨梅素,
8.制备如式(I)所示的二氢杨梅素的方法,包括将二氢杨梅素和盐在加热或催化条件下反应制得。
9.药物组合物,其包含权利要求7的二氢杨梅素,或者权利要求8的方法制备的二氢杨梅素,以及一种或多种药学上可接受的载体。
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