CN113995779A - 一种柿叶提取物在治疗失眠中的应用 - Google Patents
一种柿叶提取物在治疗失眠中的应用 Download PDFInfo
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- CN113995779A CN113995779A CN202111413241.5A CN202111413241A CN113995779A CN 113995779 A CN113995779 A CN 113995779A CN 202111413241 A CN202111413241 A CN 202111413241A CN 113995779 A CN113995779 A CN 113995779A
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Abstract
本发明涉及一种柿叶提取物在制备治疗原发性失眠，尤其是入睡困难型失眠的药物中的应用。所述柿叶提取物各剂量组可以剂量依赖性地增加阈下剂量戊巴比妥钠引起入睡的小鼠数量，还可以剂量依赖性地缩短阈上剂量戊巴比妥纳所致的入睡潜伏期并延长阈上剂量戊巴比妥纳所致的睡眠持续时间。本发明所述柿叶提取物治疗原发性失眠，起效剂量低，患者依从性和安全性好。
Description
本发明是申请号：CN201711334516.X，申请日：2017-12-12，发明名称是“一种柿叶提取物在治疗失眠中的应用”的分案申请。
技术领域
本发明属于医药学领域，具体涉及一种柿叶提取物的新的医药用途。
背景技术
失眠是睡眠障碍的表现形式之一，通常是指睡眠的发生和(或)维持发生障碍致使睡眠缺失，表现为入睡困难、易醒、早醒和再次入睡困难，睡眠的质和量不能满足个体生理需要，导致白日嗜睡、萎靡和一系列神经精神症状。
现代医学将失眠症按病程分类分为：短暂性失眠(小于1周)、短期性失眠(1周至1个月)和慢性失眠(大于1个月)。按病因则分为原发性失眠和继发性失眠：①原发性失眠：根据美国精神障碍诊断和统计手册(DSM-4)原发性失眠症诊断标准，原发性失眠症是指“主诉难以入睡和维持睡眠困难，起病至少1月；睡眠紊乱引起苦恼或社会、职业等方面的障碍；且排除由发作性疾病、与呼吸相关的睡眠障碍、生物节律睡眠障碍等障碍所致；排除由重性抑郁症、广泛性焦虑等障碍所致；排除由各种躯体疾病、酒精或药物的心理作用所致的一类身心疾病”；②继发性失眠：是由疼痛、焦虑或抑郁引起的失眠，因此也有观点提出用“共病性失眠”代替“继发性失眠”。
目前临床对需就医的失眠患者的治疗仍以药物为主。这些药物主要包括γ-氨基丁酸A(GABAA)复合体激动药、褪黑素受体激动药、抗抑郁药、非经典抗精神病药、抗组胺药。但是，获得美国食品药品管理局(FDA)失眠适应证批准的为数不多，仅包括GABAA复合体激动药(苯二氮
类5种、非苯二氮
类4种)、拉迈酮(褪黑素受体激动药)和小剂量多塞平(抗抑郁药)。国内治疗失眠以GABAA复合体激动药为主。
对不同形式的失眠，要选择不同的药物。如入睡困难型失眠，选用诱导入睡作用快速的药物，其中绝大多数为短半衰期的镇静催眠药，如三唑仑、咪达唑仑、奥沙西泮、扎来普隆、右佐匹克隆、唑吡坦等。对夜间易醒型失眠，选择能够延长NREM睡眠第三、四期和缩短REM睡眠时间的催眠药，如艾司唑仑、替马西泮、硝西泮、氟西泮等。早醒型失眠多见于抑郁症病人，在治疗原发病的同时，可选用中效或长效的镇静催眠药，如地西泮、硝西泮、氯硝西泮等。有报道称，抗抑郁药，如米氮平对于浅睡和早醒患者有效，但是对于入睡困难的患者无效。
理想的镇静催眠药物应能快速诱导睡眠，对睡眠结构无影响，无次日残留作用，不影响记忆功能，无呼吸抑制作用，长期使用无依赖或戒断症状。但是目前临床上常见的治疗入睡困难型失眠的药物，如上述的三唑仑、咪达唑仑、奥沙西泮、扎来普隆、右佐匹克隆、唑吡坦等，都有或多或少的副作用。其中，三唑仑、咪达唑仑、奥沙西泮属于苯二氮
类，由于作用靶点选择性差，长期使用可引起药物耐受性、依赖性与戒断症状；目前国外已不作为治疗失眠的首选药物，特别是老年人和伴有呼吸系统疾病患者。因此，入睡困难型失眠患者的用药选择是比较局限的。
在社会节奏加快、竞争加剧的今天，失眠的发生率逐年上升，据WHO的资料显示，全球有近1/4的人受到失眠困扰，发展中国家的失眠患者约占普通人群的30％～35％。失眠对个体及社会均有很大影响，表现在因为失眠所致交通事故的费用及治疗支出逐年增加。可见失眠既是医学问题，也是社会问题，已经引起国内外的高度重视。因此，研究和开发新的更安全高效的治疗失眠的药物，将是一个持续的研发热点。
临床资料显示，中药治疗失眠疗效好，不良反应少，为新的失眠治疗药物提供了丰富的资源。
柿叶(Persimmon leaf)为柿科柿属植物柿的新鲜或干燥叶，其入药始载于明代《滇南本草》“经霜叶敷臃疮”，而《本草再新》则记载用于“治咳嗽吐血，止渴生津”。现载于《中国药典》的柿叶提取物以活血化瘀、通络为主，主治气滞血瘀，可用于冠心病、脑动脉粥样硬化症等心脑血管疾病。以柿叶醋酸乙酯提取物制成的处方药脑心清片在临床应用上得到大力的推广。脑心清片治疗老年H型高血压疗效观察中发现对眩晕、头痛、失眠症状有一定的改善作用(脑心清片治疗老年H型高血压疗效观察[J],周静,等；新中医，2014，46(5)：38-39)。但如前所述，脑心清片在治疗高血压的同时观察到改善失眠症状应该属于有疼痛、焦虑或抑郁引起的继发性失眠。该研究未公开失眠症状的具体评定标准、失眠改善结果指标或是失眠的具体类型，对临床精准用药缺乏指导。
由于失眠原因复杂，治疗失眠机理也不明确，安全有效地改善睡眠一直是个难题，加上提取物的活性物质构成复杂，对于采用现代分离技术工艺制备的柿叶提取物，柿叶中的活性物质或提取物能否对失眠有效或者是对哪种失眠具有效果，以及其安全性，目前并不清楚。
发明内容
针对现有技术的不足，本发明的目的在于提供一种柿叶提取物及其制剂(例如脑心清片、脑心清胶囊等)在治疗失眠中的新的医药用途。
为了实现上述发明目的，本发明采用了如下的技术方案：
一种柿叶提取物在制备治疗患者原发性失眠，并减少睡眠后遗效应，或睡眠后遗效应弱或不产生睡眠后遗效应的药物中的应用；
所述柿叶提取物通过如下方法制备：
取干燥柿叶，加水煎煮2次，每次1～2小时，合并水煎液，滤过，浓缩至60℃时的相对密度为1.12～1.15，加乙醇至含醇量达80～90％；静置过夜，滤取上清液，备用；沉淀物用60～70％乙醇洗涤，合并洗涤液，静置过夜，滤取上清液，与备用上清液合并，回收乙醇，加入适量水，混匀，滤过，滤液用醋酸乙酯提取4次及以上，合并醋酸乙酯液，回收醋酸乙酯并浓缩成稠膏，低温干燥，即得。
所述原发性失眠为入睡困难型原发性失眠。
后遗效应后遗效应是指停药后血药浓度已降至阈浓度以下时残存的药理效应。本申请的发明人发现，仅仅使用上述制备方法生产的柿叶提取物(NXQ)对入睡困难型原发性失眠具有很好的疗效，特别是，其不产生睡眠后遗效应，或睡眠后遗效应弱或不产生睡眠后遗效应，即其能缩短入睡时间，但不会延长正常范围内的睡眠持续时间。特别是，其达到上述效果，使用剂量低，具有很好的安全性。
所述柿叶提取物作为所述药物的唯一活性成分时，其剂量为每天1.0～10mg/kg，还可以优选为1.0～5mg/kg。
优选的，所述治疗原发性失眠的药物为临床上可以接受的制剂，包括或不包括药学上可以接受的辅料。
优选的，所述临床上可以接受的制剂为口服制剂或非口服制剂；更优选为口服制剂。
所述口服制剂选自散剂、普通口服片剂、胶囊剂、软胶囊剂、丸剂、滴丸剂、微丸剂、颗粒剂、口腔崩解片和口腔速溶膜剂中的一种或多种。
所述非口服制剂选自注射剂、冻干粉针和大容量输液剂中的一种或多种。
本发明所述的应用，施与对象是有需要的哺乳动物，优选为有需要的人。
优选的，治疗原发性失眠的药物为口服制剂。
优选的，上述柿叶提取物通过如下方法制备：
取干燥柿叶，加水煎煮2次，每次1～2小时，合并水煎液，滤过，浓缩至相对密度(60℃)1.12～1.15，加乙醇至含醇量达80～90％；静置过夜，滤取上清液，备用；沉淀物用60～70％乙醇洗涤，合并洗涤液，静置过夜，滤取上清液，与备用上清液合并，回收乙醇，加入适量水，混匀，滤过，滤液用醋酸乙酯提取4次及以上，合并醋酸乙酯液，回收醋酸乙酯并浓缩成稠膏，低温干燥，即得。
作为一个优选的实施方案，所述治疗原发性失眠的药物为脑心清片或脑心清胶囊。
所述治疗原发性失眠的药物，通过口服方式施与有需要的人时，以所述柿叶提取物计，给药剂量可以为每天1.0～10mg/kg体重。
将所述柿叶提取物，加入或不加入药学上可以接受的辅料，按照本领域常规的方法，即可制备得到上述治疗原发性失眠的药物。
本发明的说明书中，上述药学上可以接受的辅料，包括但不限于：
稀释剂：例如选自淀粉、糊精、预胶化淀粉、乳糖、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙、氧化镁、碳酸镁、氢氧化铝凝胶、β-环糊精、甘露醇、山梨醇、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、羟甲基纤维素钠中的一种或多种。
粘合剂：例如选自蒸馏水、乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素和乙基纤维素、羟丙甲纤维素中的一种或多种。
润滑剂：例如选自十二烷基硫酸镁、聚乙二醇、微粉硅胶、硬脂酸镁、滑石粉中的一种或多种。
崩解剂：例如选自淀粉(玉米、马铃薯)、微晶纤维素、海藻酸、海藻酸钠、离子交换树脂、泡腾酸-碱系统、羟丙基淀粉、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、羧甲基纤维素、羧甲基纤维素钙、低取代羟丙基纤维素、部分α化淀粉和微晶纤维素中的一种或多种。
成膜材料：明胶、虫胶、阿拉伯胶、琼脂、淀粉、糊精、PVA05-88、PVA17-88和乙烯-醋酸乙烯共聚物(EVA)中的一种或多种。
矫味剂：例如选自糖精钠、甜蜜素、阿斯巴甜、甜菊苷以及香精类中的一种或多种。
注射用溶剂：例如选自注射用水、麻油、茶油、花生油、玉米油、橄榄油、棉籽油、豆油、蓖麻油及桃仁油、油酸乙酯、苯甲酸苄酯、丙二醇、聚乙二醇400、二甲基乙酰胺(DMA)、乙醇和甘油中的一种或多种。
本发明通过实验证明，柿叶提取物各剂量组可以剂量依赖性地增加阈下剂量戊巴比妥钠引起入睡的小鼠数量，且高剂量的作用与阳性对照药阿普唑仑相当。柿叶提取物各剂量组还可以剂量依赖性地缩短阈上剂量戊巴比妥纳所致的入睡潜伏期和延长阈上剂量戊巴比妥纳所致的睡眠持续时间，且高剂量组的入睡时间短于阳性对照药组，且睡眠持续时间则略短于阳性对照药阿普唑仑。上述实验结果提示柿叶提取物可以缩短入睡时间，但是不过多延长睡眠持续时间，因此可以用于治疗入睡困难型失眠，同时还可以一定程度上减少后遗效应。另外，根据动物实验结果换算，柿叶提取物治疗入睡困难型失眠的有效剂量低于其治疗心脑血管疾病的剂量。因此，以本发明所述有效剂量的柿叶提取物应用于原发性失眠(入睡困难型失眠)的治疗，患者依从性好，从而保证疗效。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。其中，部分试剂和仪器购买情况如下：
柿叶提取物(NXQ)：广州白云山和记黄埔中药有限公司，批号H16P006，制备方法为：
取干燥柿叶，加水煎煮2次，第1次2小时，第2次1小时，合并滤液，滤过，浓缩汁相对密度1.12～1.15(60℃)，加乙醇至含醇量达85％；静置过夜，滤取上清液，备用；沉淀物用65％乙醇洗涤2次，合并洗涤液，静置过夜，滤取上清液，与备用上清液合并，回收乙醇，加入适量水，混匀，滤过，滤液用醋酸乙酯提取4次，合并醋酸乙酯液，回收醋酸乙酯并浓缩成稠膏，低温干燥，即得。
戊巴比妥钠：(默克化工技术上海有限公司。
阿普唑仑片：北京益民药业有限公司；
实施例1本发明所述柿叶提取物对戊巴比妥钠所致小鼠入睡的影响1.实验动物
健康昆明小鼠60只，清洁级，雄雌各半，体重18～22g。实验动物许可证号：SCXK(京)2014-0004；实验前小鼠适应饲养环境一周，所有小鼠饲养在温度21±2℃的普通级实验动物房，并遵循昼夜节律。小鼠可自由摄食饮水。
2.实验药物
柿叶提取物(NXQ)与阿普唑仑均采用0.5％羧甲基纤维素钠作为溶剂进行配制，药物在给药之前应充分涡旋混匀。
柿叶提取物(NXQ)的配制：将40mg柿叶提取物溶解于10ml的0.5％羧甲基纤维素钠，配制成4mg/ml的储存液，使用前按给药需要，稀释成相应的工作液。如NXQ高剂量40mg/kg，按给药体积0.1ml/10g，给药浓度即为4mg/ml。
阿普唑仑的配制，将0.25mg阿普唑仑溶解于10ml的0.5％羧甲基纤维素钠，配制成0.025mg/ml的储存液，使用前按给药需要，稀释成相应的工作液。3.实验分组与给药
60只昆明小鼠按体重、性别随机分为5组，每组12只：1)空白对照组，灌胃给予溶剂，2)NXQ低剂量组(10mg/kg体重)，3)NXQ中剂量组(20mg/kg体重)，4)NXQ高剂量组(40mg/kg体重)，5)阿普唑仑(0.25mg/kg体重)组；各组均灌胃给药，按小鼠实际体重给药，给药体积为0.1ml/10g体重，空白组给予同体积的0.5％羧甲基纤维素钠水溶液。
4.实验方法
4.1对阈下剂量戊巴比妥钠所致小鼠入睡的影响
各组小鼠灌胃给药30min后,小鼠腹腔注射28mg/kg体重的戊巴比妥钠,以小鼠翻正反射消失1min以上为入睡指标,记录各组小鼠的入睡数量。
实验结束后，对小鼠进行1周药物洗脱处理：自由饮水和饮食，不以任何形式给予任何药物。洗脱结束后，各组小鼠进行阈上剂量戊巴比妥钠所致小鼠入睡的影响实验。
4.2对阈上剂量戊巴比妥钠所致小鼠入睡的影响
各组小鼠灌胃给药30min后,腹腔注射40mg/kg的戊巴比妥钠,观察小鼠睡眠持续时间计算小鼠从翻正反射消失至翻正反射重复出现的时间。
5.统计分析
采用SPSS19.0统计学软件，计量资料采用均数±标准差
表示，组间比较采用单因素方差分析；计数资料组间比较采用χ2检验，P＜0.05为差异有统计学意义。
6.实验结果
6.1脑心清片对阈下剂量戊巴比妥致小鼠入睡数量的影响
结果如表1所示，与空白对照组比较，柿叶提取物(NXQ)各剂量均能一定程度上增加阈下剂量戊巴比妥钠引起入睡的小鼠数量，其作用呈剂量依赖关系。此外，柿叶提取物高剂量组入睡小鼠为7只，入睡率达到58.3％，作用接近于阳性药阿普唑仑(入睡小鼠8只，入睡率66.7％)。
表1柿叶提取物对阈下剂量戊巴比妥致小鼠入睡数量和入睡率的影响
6.2脑心清片对阈上剂量戊巴比妥致小鼠入睡潜伏期和睡眠持续时间的影响
结果如表2所示，与空白对照组比较，柿叶提取物(NXQ)各剂量均能一定程度上缩短阈上剂量戊巴比妥纳所致的入睡潜伏期和延长阈上剂量戊巴比妥纳所致的睡眠持续时间，作用呈剂量依赖关系；其中NXQ中、高剂量的作用具有显著性的统计学意义(P<0.05)。此外，柿叶提取物高剂量诱导小鼠入睡的潜伏期短于阳性药阿普唑仑，但睡眠时间略少于阿普唑仑，该结果提示柿叶提取物可缩短小鼠入睡潜伏期而不至于引起过长的睡眠时间。
表2脑心清片对阈上剂量戊巴比妥致小鼠入睡潜伏期和睡眠持续时间的作用
*P<0.05,**P<0.01vs.空白对照组
7.结论
柿叶提取物各剂量组可以剂量依赖性地增加阈下剂量戊巴比妥钠引起入睡的小鼠数量，且高剂量的作用与阳性对照药阿普唑仑相当。
柿叶提取物各剂量组还可以剂量依赖性地缩短阈上剂量戊巴比妥纳所致的入睡潜伏期和延长阈上剂量戊巴比妥纳所致的睡眠持续时间，且高剂量组的入睡时间短于阳性对照药组，而睡眠持续时间则略短于阳性对照药阿普唑仑，说明柿叶提取物高剂量可以显著缩短小鼠入睡潜伏期而不至于引起过长的睡眠时间，其诱导小鼠入睡的作用优于阿普唑仑。
本实施例的结果提示：柿叶提取物可以用于治疗入睡困难型失眠，缩短入睡时间，但是不过多延长睡眠持续时间，从而可以一定程度上减少后遗效应，提高用药安全性。
上述试验的柿叶提取物的剂量范围10～40mg/kg，根据体表面积系数换算成临床人用剂量范围约为1.1～4.4mg/kg体重；而《中国药典》规定用于治疗冠心病、脑动脉硬化症时，柿叶提取物用法用量为口服300～600mg/天，折算成kg体重剂量为：4.3～8.6mg/kg。显然，柿叶提取物用于本发明的入睡困难型失眠的剂量将可能低于现有技术治疗冠心病、脑动脉硬化症的剂量。相同规格的制剂，则入睡困难型失眠的患者服用量会显著少于目前临床常规使用量，从而可以大大提高用药患者的依从性、安全性，并减少药物耐受性。
总之，本发明提供了柿叶提取物的新的医药用途：用于治疗原发性失眠，尤其是入睡困难型失眠。而且更重要的是，相较现有技术中已经报道的对冠心病、脑动脉粥样硬化症等心脑血管疾病的治疗，柿叶提取物可以在小剂量就发挥缩短入睡时间、改善睡眠的作用。
Claims (10)
1.一种柿叶提取物在制备治疗患者原发性失眠，减少睡眠后遗效应、或睡眠后遗效应弱或不产生睡眠后遗效应的药物中的应用；
所述柿叶提取物通过如下方法制备：
取干燥柿叶，加水煎煮2次，每次1～2小时，合并水煎液，滤过，浓缩至60℃时的相对密度为1.12～1.15，加乙醇至含醇量达80～90％；静置过夜，滤取上清液，备用；沉淀物用60～70％乙醇洗涤，合并洗涤液，静置过夜，滤取上清液，与备用上清液合并，回收乙醇，加入适量水，混匀，滤过，滤液用醋酸乙酯提取4次及以上，合并醋酸乙酯液，回收醋酸乙酯并浓缩成稠膏，低温干燥，即得。
2.根据权利要求1所述的应用，其特征在于，所述睡眠后遗效应为患者睡眠持续时间延长。
3.根据权利要求1所述的应用，其特征在于，所述原发性失眠为入睡困难型原发性失眠。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述柿叶提取物作为所述药物的唯一活性成分，其剂量为每天1.0～10mg/kg。
5.根据权利要求1-3任一项所述的应用，其特征在于，所述治疗原发性失眠的药物为临床上可以接受的制剂，包括或不包括药学上可以接受的辅料，。
6.根据权利要求5所述的应用，其特征在于，所述临床上可以接受的制剂为口服制剂或非口服制剂。
7.根据权利要求6所述的应用，其特征在于，所述口服制剂选自散剂、普通片剂、胶囊剂、软胶囊剂、丸剂、滴丸剂、微丸剂、颗粒剂、口腔崩解片和口腔速溶膜剂中的一种或多种。
8.根据权利要求6所述的应用，其特征在于，所述非口服制剂选自注射剂、冻干粉针和大容量输液剂中的一种或多种。
9.根据权利要求1所述的应用，其特征在于，所述治疗原发性失眠的药物为脑心清片。
10.根据权利要求1所述的应用，其特征在于，所述治疗原发性失眠的药物为者脑心清胶囊。
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| 周静等: "脑心清片治疗老年H 型高血压疗效观察", 《新中医》 * |
| 牛林敬等: "《养心安神看这本就够了》", 31 January 2017, 河北科学技术出版社 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2018101247A4 (en) | 2018-09-27 |
| CN108014162A (zh) | 2018-05-11 |
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