CN116531421A - 十大功劳或其提取物在制备抗抑郁症药物中的应用 - Google Patents
十大功劳或其提取物在制备抗抑郁症药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种十大功劳或其提取物在制备抗抑郁症药物中的应用,所述十大功劳为被子植物门小檗科[Mahonia bealei(Fort.)Carr.]的干燥根,十大功劳提取物为十大功劳的水提物或十大功劳的有机溶剂提取物,十大功劳提取物的提取方法为:取十大功劳,加入溶剂进行浸泡处理,再加热进行提取,合并多次提取的药液进行浓缩即得。本发明首次发现十大功劳或其提取物具有明显的抗抑郁症活性,具有制备预防或治疗抑郁症及其相关疾病的药物制剂的成药潜力,且药物制剂的制备方法简单,成本低,成药经济效益好。
Description
技术领域
本发明属于中医药技术领域,具体涉及一种十大功劳或其提取物在制备抗抑郁症药物中的应用。
背景技术
抑郁症是一种以睡眠障碍、情绪低落、兴趣缺乏等为主要特征的情感障碍性精神类疾病,具有发病率高、复发率高、治愈难的特点。据预测,到2020年抑郁症将会成为威胁人类健康的第二大杀手,其危害性仅次于心脏病。目前,中国的抑郁症患者已超过2600多万。抑郁症的发病在各个阶段的人群中均可发生。近年来死于抑郁症的人数不断增多,抑郁症不仅给患本人造成了巨大的精神折磨,也给自身家庭及社会造成了沉重的负担。
生物胺假说指出,脑内五羟色胺(5-HT)、去甲肾上腺素(NA)等单胺神经递质水平低下与抑郁症的发生密切相关。若能阻断特定单胺神经递质再摄取,抑制单胺氧化酶(MAO),减少单胺神经递质的存储与释放,以及阻断突触前膜α2自身受体增加单胺递质释放,即可改善抑郁症症状。多项研究表明,抑郁症的发生与炎症因子水平相关,抑制炎症因子的释放能起到抗抑郁作用。现阶段用于治疗抑郁症的药物主要为单胺氧化酶抑制剂、单胺氧化酶再摄取抑制剂、三环类药物等,这些药物普遍存在起效慢、有效率低、不良反应多等缺点。中医药典籍有使用中药治疗抑郁症的记载,且民间临床实践中使用中药治疗抑郁症疗效确切,安全性高,但是,目前缺少对治疗抑郁症中药的系统性研究与开发应用。因此,开发高效低毒的抗抑郁中药制剂具有重要的社会意义及经济价值。
现有专利文件以及学术文献都公开了一些有关于抑郁症治疗的中药提取物或中药组合物,如,河南中医学院在其专利申请CN104083549A、CN104069141A、CN104083476A、CN102178721A分别公开了仙茅、锁阳、玫瑰花、绞股蓝的提取物具有抗抑郁作用,可有效用于制备抗抑郁药物。专利申请CN106822098A公开了牛蒡子的提取物牛蒡子苷元能够有效治疗或预防抑郁症,抗抑郁症效果明显。专利CN102166341B公开了按逍遥散处方重量比例称取柴胡、当归、茯苓、白芍、白术、炙甘草、薄荷、生姜,加乙酸乙酯回流提取,过滤,干燥,制得的逍遥散提取物具有明显的抗抑郁作用。专利申请CN108303480A公开了甘松甲醇提取物与甘松新酮、去氧甘松香醇A、蒙花苷、异甘松新酮、甘松香酮H、(-)-马兜铃酮六种成分均具有不同程度的5-羟色胺转运体(SERT)增强或抑制活性,可在制备用于抗抑郁症、焦虑症、精神分裂症、强迫症、神经退行性等疾病的药物方面进行应用、以及药物成瘾性和消化系统功能紊乱等疾病的治疗药物制备方面进行应用。可见,不少中药材的提取物或中药复方制剂都在抗抑郁方面具有一定的活性的,而且,中药具有副作用小、综合治疗能力强等优点,因此,开发中药材提取物的新用途,积极探索新的抗抑郁症的潜在药物靶标,寻找新型的抗抑郁药物是当今临床亟需解决的重要问题。
十大功劳(学名:Mahonia bealei(Fort.)Carr.)属被子植物门小檗科,是我国传统药用植物,亦是苗族习用药材之一。阔叶十大功劳别名土黄柏、土黄连、八角刺等,味苦,性寒,入肝、胃、大肠经,具有清热燥湿、泻火解毒的功效,用于湿热泻痢、黄疸尿赤、目赤肿痛、胃火牙痛和疮疖痈肿。研究表明,十大功劳所含的化学成分主要是小檗碱、小檗胺、药根碱和巴马汀。药理研究表明,十大功劳发挥了抗氧化、抗炎和抗菌的作用。李燕婧等人采用小鼠耳廓肿胀法,醋酸扭体法,番泻叶致小鼠腹泻法,异硫氰酸萘酯所致肝损伤模型对2种十大功药醇提限进行药效学评价,并对长柱十大功劳醇提物进行急性毒性试验。结果:2种十大功劳醇提物都具有抗炎、镇痛、止泻、保护黄疸型肝炎对肝脏损伤的作用,长柱十大功劳醇提物止泻作用效果优于阔叶十大功劳醇提物,其半数致死量(LD50)为33.45g.kg-1,95%可信限为(29.64~37.62)g.kg-1。结论:长柱十大功劳与阔叶十大功劳醇提物药理作用相近,均具有抗炎、镇痛、止泻和保护黄疸型肝炎对肝脏损伤的作用(李燕婧,钟正贤,陈学芬等.长柱十大功劳与阔叶十大功劳醇提物药理作用比较[J],《云南中医中药杂志》2010年8期)。
从文献检索了解到,现有技术中还没有将十大功劳提取物用于治疗抑郁症及其引起的相关疾病的药物,且治疗或抑制抑郁症的药物中也没含有十大功劳提取物;现有技术中只将十大功劳作为降血糖、拮抗小鼠热痛及二甲苯致小鼠耳肿胀炎症的药物进行公开;但是,未见应用于抑郁症及其引起的相关疾病的药物,所以,如何将十大功劳扩大化的使用,使之产生最大的功效,发挥出应有的效能,至今仍是医学医药研究的主攻方向。
发明内容
本发明的目的是提供一种十大功劳或其提取物在制备抗抑郁症药物中的应用,本发明首次发现十大功劳或其提取物具有明显的抗抑郁活性,具有制备预防或治疗抑郁症及其相关疾病的药物制剂的成药潜力,且药物制剂的制备方法简单,成本低,成药经济效益好。
为实现上述目的,本发明采用如下技术方案:
十大功劳或其提取物在制备预防/治疗抑郁症的药物、食品或保健品中的应用。
所述十大功劳为被子植物门小檗科的干燥根,十大功劳提取物为十大功劳的水提物或十大功劳的有机溶剂提取物。
所述十大功劳水提物的提取方法为:
(1)取十大功劳,加入4~8倍质量水先浸泡40~80min,然后加热至80~98℃提取40~80min,过滤,收集滤液;
(2)滤渣再加入4~8倍质量水加热至80~98℃提取40~80min,过滤,收集滤液;
(3)重复提取滤渣1~3次,合并多次提取得到的滤液并进行浓缩,即得。
所述十大功劳的有机溶剂提取物为十大功劳的乙醇提取物,提取方法为:
(1)取十大功劳,加入4~8倍量体积浓度为85~95%的乙醇先浸泡40~80min,然后加热进行回流提取40~80min,过滤,收集滤液;
(2)滤渣再加入4~8倍量体积浓度为85~95%的乙醇,继续加热进行回流提取40~80min,过滤,收集滤液;
(3)重复提取滤渣1~3次,合并多次提取得到的滤液并进行浓缩回收乙醇,即得。
以上所述的十大功劳提取物选择性添加常规辅料,按照常规工艺制成临床可接受的用于预防或治疗抑郁症及其相关疾病的药物制剂。
所述制剂包括片剂、胶囊剂、滴丸或颗粒剂。
所述的常规辅料包括淀粉、乳糖、微晶纤维素、糊精、磷酸钙、聚乙二醇-4000、聚乙二醇-6000、豆油、蜂胶、羧甲基纤维素钠、羟丙纤维素或交联聚维酮中一种以上。
本发明的有益效果是:
1、本发明首次发现十大功劳或十大功劳提取物具有明显的抗抑郁活性,可将其加入到食品或保健品中起到预防抑郁症的作用;同时,还可以将十大功劳或十大功劳提取物制备成预防或治疗抑郁症及其相关疾病的药物制剂,为开发抗抑郁症创新药物提供新的物质基础,具有潜在且巨大的社会效益和经济效益。
2、本发明的十大功劳提取物提取方法简单、成本低、污染小,有利于节能减排条件下的大规模生产,产业化前景好。
3、本发明分别通过悬尾实验(tail suspension test,TST)和强迫游泳实验(forced swimming,FST)研究了十大功劳提取物对小鼠悬尾和强迫游泳的影响,以及通过研究十大功劳提取物对利血平诱导的抑郁症大鼠行为学、血清神经递质及炎症因子的影响等,有力证明了本发明的十大功劳提取物在抑郁症状上具有明显的抗抑郁活性。
4、本发明的十大功劳或十大功劳提取物还具有祛风除湿、舒筋活血等功效,可用于湿热泻痢、黄疸尿赤、目赤肿痛、胃火牙痛和疮疖痈肿等症,可以在用于预防或治疗抑郁症的同时起到治疗其他合并症的效果。
5、十大功劳可以与其他药材进行配伍组成复方药用于预防或治疗抑郁症,还可以将十大功劳提取物与辅料混合制成片剂、胶囊、滴丸或颗粒剂,这些制剂较为方便服用,能单独或者搭配其他药剂服用,通过内服能将药性通过血液快速输送至病症部位进行有效治疗。
附图说明
图1显示十大功劳提取物对小鼠悬尾的影响结果;
图2显示十大功劳提取物对小鼠强迫游泳的影响结果;
图3显示造模后第4天,十大功劳提取物对利血平诱导的抑郁症大鼠眼脸下垂的影响结果;
图4显示造模后第4天,十大功劳提取物对利血平诱导的抑郁症大鼠圈内保留时间的影响结果;
图5显示十大功劳提取物对利血平诱导的抑郁症大鼠血清中5-HT水平的影响结果;
图6显示十大功劳提取物对利血平诱导的抑郁症大鼠血清中NE水平的影响结果;
图7显示十大功劳提取物对利血平诱导的抑郁症大鼠血清中DA水平的影响结果;
图8显示十大功劳提取物对利血平诱导的抑郁症大鼠血清中IL-6水平的影响结果;
图9显示十大功劳提取物对利血平诱导的抑郁症大鼠血清中TNF-α水平的影响结果。
具体实施方式
为了更加详细的介绍本发明,下面结合实施例,对本发明做进一步说明。
实施例1 十大功劳提取物的制备
取十大功劳1kg,加入6L蒸馏水浸泡60min,然后加热至80℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至80℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至80℃提取60min,过滤,收集滤液;合并3次提取液,浓缩至1.0~1.2g/mL,即得。
实施例2 十大功劳提取物的制备
取十大功劳1kg,加入6L蒸馏水浸泡60min,然后加热至90℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至90℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至90℃提取60min,过滤,收集滤液;合并3次提取液,浓缩至1.0~1.2g/mL,即得。
实施例3 十大功劳提取物的制备
取十大功劳1kg,加入6L蒸馏水浸泡60min,然后加热至98℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至98℃提取60min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至98℃提取60min,过滤,收集滤液;合并3次提取液,浓缩至1.0~1.2g/mL,即得。
实施例4 十大功劳提取物的制备
取十大功劳1kg,加入8L蒸馏水浸泡80min,然后加热至80℃提取80min,过滤,收集滤液;滤渣再加入6L蒸馏水加热至90℃提取60min,过滤,收集滤液;滤渣再加入4L蒸馏水加热至98℃提取40min,过滤,收集滤液;合并3次提取液,浓缩至1.0~1.2g/mL,即得。
实施例5 十大功劳提取物的制备
取十大功劳1kg,加入6L体积浓度为90%的乙醇先浸泡60min,然后加热进行回流提取60min,过滤,收集滤液;滤渣再加入6L体积浓度为90%的乙醇,继续加热进行回流提取60min,过滤,收集滤液;滤渣再加入6L体积浓度为90%的乙醇,继续加热进行回流提取60min,过滤,收集滤液;合并3次提取液并进行浓缩回收乙醇成膏,即得。
实施例6 十大功劳提取物片剂的制备
【处方】由实施例3的方法制得的十大功劳水提物(取相当于十大功劳药材3kg的量)、干淀粉550g;
【制备方法】将所得的十大功劳水提物、干淀粉混匀,加入适量羧甲基纤维素钠、滑石粉,制成颗粒,干燥,压制成1000片,所得的半枫荷提取物片,每片含十大功劳药材3g。
以上所述的干淀粉、羧甲基纤维素钠和滑石粉均可在市场上购买得到。
实施例7 十大功劳提取物胶囊的制备
【处方】由实施例3的方法制得的十大功劳水提物(取相当于十大功劳药材3kg的量)、干淀粉550g;
【制备方法】将所得的十大功劳水提物、干淀粉混匀,加入适量羧甲基纤维素钠、滑石粉,制成颗粒,干燥,分装成1000粒,所得的半枫荷提取物胶囊,每粒含十大功劳药材3g。
以上所述的干淀粉、羧甲基纤维素钠和滑石粉均可在市场上售得到。
实施例8 十大功劳提取物颗粒剂的制备
【处方】由实施例3的方法制得的十大功劳水提物(取相当于十大功劳药材10kg的量)、干淀粉550g;
【制备方法】将所得的十大功劳水提物、干淀粉混匀,加入适量羧甲基纤维素钠、滑石粉,制成颗粒,干燥,分装成1000袋,所得的十大功劳提取物颗粒,每袋含十大功劳药材10g。
以上所述的干淀粉、羧甲基纤维素钠和滑石粉均可在市场上购买得到。
药性试验
为了验证本发明十大功劳提取物的抗抑郁活性,本申请人进行了以下试验:
1、十大功劳提取物对小鼠悬尾的影响
供试品:所述十大功劳提取物均是由实施例3中所述方法制备而成。
处理方法:采用雄性昆明小鼠,体重18-22g,每组10只。分别设置对照组,阳性组(氟西汀3.6mg.kg-1),十大功劳提取物高、低剂量组(分别相当于半枫荷药材10、2.5g.kg-1)。对照组给予等量的蒸馏水,各组均连续灌胃给药10d,末次给药1h后测试。将单个小鼠在距尾尖部约2cm处用医用胶布固定在悬尾箱(长30cm×宽30cm×高25cm)上部支架上,使其成倒挂状态,头部离箱底约5cm。悬挂6min,记录后4min内累计不动的时间(不动状态即小鼠停止挣扎不动或无任何活动)。
结果:如图1所示,与对照组相比,灌胃给予十大功劳提取物10d后,高、低剂量组均可显著缩短小鼠悬尾不动时间,差异有统计学意义(*P<0.05)。
2、十大功劳提取物对小鼠强迫游泳的影响
供试品:所述十大功劳提取物均是由实施例3中所述方法制备而成。
处理方法:采用雄性昆明小鼠,体重18-22g,每组10只。分别设置对照组,阳性组(氟西汀3.6mg.kg-1),十大功劳提取物高、低剂量组(分别相当于十大功劳药材10、2.5g.kg-1)。对照组给予等量的蒸馏水,各组均连续灌胃给药10d,末次给药1h后测试。将小鼠单独放入缸内水深10cm的圆柱形玻璃缸中(高20cm、直径14cm),水温25℃±2℃,从小鼠进入水面后计时6min,记录后4min内游泳累计不动的时间(指小鼠在水中停止挣扎或显示漂浮状态,仅有微小的肢体运动以保持头部浮在水面)。
结果:如图2所示,与对照组相比,灌胃给予十大功劳提取物10d后,高、低剂量组均可显著缩短小鼠游泳不动时间(*P<0.05)。
3、十大功劳提取物对利血平引起的抑郁症大鼠的影响
供试品:所述十大功劳提取物均是由实施例3中所述方法制备而成。
处理方法:雄性SD大鼠50只,体重180-220g,喂养适应1周后,按空腹体重随机分为5组,即对照组、模型组、阳性组、十大功劳提取物高剂量组、十大功劳提取物低剂量组,每组10只。对照组大鼠每天腹腔注射生理盐水0.5mL.kg-1,其余各组大鼠每天腹腔注射利血平0.5mg.kg-1造模,连续注射10天;自第一天开始造膜后开始,注射完生理盐水或利血平后按照以下给药方式灌胃给药:阳性组给予氟西汀1.8mg.kg-1,大功劳提取物高剂量组给予相当于十大功劳药材10g.kg-1的十大功劳提取物,十大功劳提取物低剂量组给予相当于十大功劳药材2.5g.kg-1的大功劳提取物,对照组、模型组给予同等体积的蒸馏水,每天1次。
自造模后,每天观察各组大鼠行为学情况:记录各组大鼠上睑下垂、运动抑制等情况。上睑下垂观察时,将大鼠放在支架上,观察大鼠眼睑不能睁开1/2的动物只数,计算对抗率,对抗率=(1-上睑下垂大鼠/组内动物总数)×100%;运动抑制观察时,将动物放于直径40cm的圆形白板的中心位置观察30S,观察不同组中大鼠呆在圈内的时间。
末次给药后1h,于大鼠腹主动脉取血,离心取血清,检测血清中5-HT、NE、DA、IL-6、TNF-α的水平,观察十大功劳提取物对利血平诱导大鼠抑郁症血清神经递质及炎症因子的影响。
结果:(1)十大功劳提取物对利血平诱导的抑郁症大鼠行为学的影响
如图3所示,造模后第4天,对照组大鼠没有眼睑下垂现象;模型组有8只出现眼睑下垂,与空白对照组相比其对抗率差异有统计学意义(##P<0.01);十大功劳提取物高剂量组出现6只眼睑下垂,与模型组相比其对抗率有统计学差异(*P<0.05)。造模后第5天,与空白组相比,模型组大鼠在圈内保留时间显著增加(**P<0.01);与模型组相比,十大功劳提取物高剂量组在圈内保留时间显著减少(*P<0.05)。
(2)十大功劳提取物对利血平诱导的抑郁症大鼠血清神经递质及炎症因子的影响
如图5所示,与空白组相比,模型组大鼠5-HT的水平明显降低(#P<0.05),与模型组相比,十大功劳提取物高低剂量组5-HT的水平明显升高(*P<0.05)。如图6所示,与空白组相比,模型组大鼠NE的水平明显降低(#P<0.05);与模型组相比,十大功劳提取物高剂量组NE的水平明显升高(*P<0.05);低剂量组与模型组相比没有显著性差异;阳性对照组NE的水平与模型组相比具有显著性差异(*P<0.05)。如图7所示,与空白组相比,模型组大鼠DA的水平明显降低(#P<0.05);与模型组相比,十大功劳提取物高剂量组DA的水平明显升高(**P<0.01);低剂量组与模型组相比没有显著性差异;阳性对照组DA的水平与模型组相比具有显著性差异(*P<0.05)。如图8所示,与空白组相比,模型组大鼠IL-6的水平明显降低(#P<0.05);与模型组相比,十大功劳提取物高、低剂量组IL-6的水平均显著降低(**P<0.01,**P<0.01);阳性对照组IL-6的水平与模型组相比也显著降低(*P<0.05)。如图9所示,与空白组相比,模型组大鼠TNF-α的水平明显降低(#P<0.05);与模型组相比,十大功劳提取物高剂量组TNF-α的水平显著降低(*P<0.05);低剂量组及阳性对照组TNF-α的水平与模型组相比没有显著性差异。
Claims (8)
1.十大功劳或其提取物在制备预防/治疗抑郁症的药物、食品或保健品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述十大功劳为被子植物门小檗科的干燥根,十大功劳提取物为十大功劳的水提物或十大功劳的有机溶剂提取物。
3.根据权利要求2所述的应用,其特征在于,所述十大功劳水提物的提取方法为:
(1)取十大功劳,加入4~8倍质量水先浸泡40~80min,然后加热至80~98℃提取40~80min,过滤,收集滤液;
(2)滤渣再加入4~8倍质量水加热至80~98℃提取40~80min,过滤,收集滤液;
(3)重复提取滤渣1~3次,合并多次提取得到的滤液并进行浓缩,即得。
4.根据权利要求2所述的应用,其特征在于,所述十大功劳的有机溶剂提取物为十大功劳的乙醇提取物。
5.根据权利要求4所述的应用,其特征在于,所述十大功劳的乙醇提取物的提取方法为:
(1)取十大功劳,加入4~8倍量体积浓度为85~95%的乙醇先浸泡40~80min,然后加热进行回流提取40~80min,过滤,收集滤液;
(2)滤渣再加入4~8倍量体积浓度为85~95%的乙醇,继续加热进行回流提取40~80min,过滤,收集滤液;
(3)重复提取滤渣1~3次,合并多次提取得到的滤液并进行浓缩回收乙醇,即得。
6.根据权利要求1~5任意一项所述的应用,其特征在于,十大功劳提取物选择性添加常规辅料,按照常规工艺制成临床可接受的用于预防或治疗抑郁症及其相关疾病的药物制剂。
7.根据权利要求6所述的应用,其特征在于,所述制剂包括片剂、胶囊剂、滴丸或颗粒剂。
8.根据权利要求6所述的应用,其特征在于,所述的常规辅料包括淀粉、乳糖、微晶纤维素、糊精、磷酸钙、聚乙二醇-4000、聚乙二醇-6000、羧甲基纤维素钠、羟丙纤维素或交联聚维酮中一种以上。
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