CN1283312C - 抗抑郁组合物及其制备方法 - Google Patents
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Abstract
本发明公开了一种治疗抑郁症的药物组合物，它是由厚朴酚性成分、茯苓多糖和姜油三种活性成分所组成；或者由厚朴酚性成分和茯苓多糖二种活性成分所组成，其用量为厚朴酚性成分0.1-1g、茯苓多糖3.5-14g、姜油0.2-3.5g。其制备方法是按上述重量配比，用β-环糊精包合姜油后混合而分别获得MPG、MP药物组合物。该组合物可用于制备治疗抑郁症的药物，且具有疗效稳定，安全可靠、工艺简单、易于生产等优点。
Description
一、技术领域：
本发明涉及天然植物有效成分的组合物及其制备方法和药物用途，特别是涉及将厚朴酚性成分、茯苓多糖和(或)姜油的组合物制备成治疗抑郁症的药物。
二、背景技术：
抑郁症指情感性精神障碍综合症，以心境低落为主要特征。临床主要表现为抑郁心情、疲劳感、快感缺乏、思维和运动迟滞，伴有焦虑、睡眠障碍、食欲不振、绝望及自杀妄想等。抑郁症是危害全人类身心健康的常见病、多发病。据世界卫生组织精神病流行情况调查报告，全世界抑郁症患病率高达3～5％，重性抑郁症患者自杀率高达15～18％，终身罹患率高达8～12％(男)、20～25％(女)。在临床上，抑郁症常与其它严重疾病如心脏病、脑中风、癌症、免疫性疾病等并存。有关抑郁症流行病学的研究表明：随着世界范围的社会工业化、都市化进程的加快，社会生活中应激因素大大增多，抑郁症患病率在不断上升，患病人群日益扩大，其中在老年人群中的发病将更为突出。抑郁症将成为21世纪人类面临的主要病症之一。
抑郁症流行趋势的严重性以及患者因精神障碍所致心理素质的下降和社会功能的损害，已引起世界各国的广泛重视。世界范围内对抗抑郁药品的需求量闩益增大，近年来该类药品全球市场销售量以每年16.2％的速度增长。抑郁症的防治和抗抑郁新药的研制已成为当今国际医药界前沿热点研究课题之一。
抑郁症病因复杂，与生理心理密切相关，至今仍未明确。可能与长期应激和情感引发的大脑5-羟色胺(5-HT)、去甲肾上腺素(NE)等单胺类神经递质代谢及功能失调有关，通过过度激活SAM(sympathetic adrenal-medullary)系统、HPA(hypothalamic-pituitary-adrenocortical)系统，与内分泌系统和免疫系统相联，介导相关的行为和生理效应。
目前临床治疗抑郁症的西药有多种。单胺氧化酶抑制剂(MAO-AI)(如吗氯贝胺)对中枢单胺类神经递质降解起抑制作用；5-羟色胺重摄取抑制剂(SSRI)(氟西汀)，则选择性抑制5-HT再摄取；而5-羟色胺-去甲肾上腺上素重摄取抑制剂(SNRI)(如venlafaxine)可选择性地抑制5-HT和NE重吸收；双重作用于5-羟色胺环节的抗抑郁药(如奈法唑酮)既抑制5-HT的重摄取又阻断突触后5-HT2受体；NE和DA重摄取抑制剂(如bupropin)选择性抑制NE和DA重摄取。这些药物大多因其本身作用特点所限，存在抗抑郁谱较窄、毒副作用较大、价格高昂、停药后易复发等缺点。
中医郁证指情志不宁、气机郁滞引起的一类病证，与西医的抑郁症有许多共通之处。中药含多种活性成分，可从整体上调节各系统，达到安全治愈的效果。已陆续报道了小柴胡汤(柴胡、酒黄芩、党参、姜半夏、甘草、生姜、大枣)、半夏厚朴汤(半夏、厚朴、茯苓、生姜、苏叶)及白金散(白矾、郁金、九节菖蒲、硃砂、人造牛黄)治疗“梅核气”、抑郁症、抑郁性精神病；胡思荣用平心忘忧汤(磁石、礞石、枳实、黄柏、半夏、厚朴、朱茯苓、神肉、肉桂、苏叶、菖蒲、生姜)治疗抑郁症470例，痊愈70.2％，好转20.2％，总有效率90.4％；赵志升自拟中药‘抑虑康’胶囊治疗抑郁，总体疗效优于西药对照组；马云枝等人用舒郁调神汤(柴胡、郁金、菖蒲、枳实、桃仁、红花、柏子仁、远志、煅龙牡、丹参)治疗中风后抑郁症，其治愈率为39.06％，显效率为30.40％，有效率为21.09％，无效率为9.45％，并明显改善主要及伴随症状；日本尾崎哲发现小建中汤(桂芝、生姜、芍药、甘草、大枣、饴糖末)对抑郁性神经症患者情绪具有调节作用；研究还发现柴胡加龙骨牡蛎汤(柴胡、半夏、桂枝、茯苓、黄苓、大枣、人参、牡蛎、龙骨、生姜)治疗有效性表现在疲劳、头痛、眩晕等植物神经性症状方面无显著性差异，侧重治疗抑郁、紧张。
上述传统中药复方起效慢，组份比较复杂，药效不够显著，难以制定和实施严格的质量控制标准。
厚朴为木兰科Magnolia officinalis Rehd et Wils的树皮，酚性成分约为1-3％，其中以厚朴酚(magnolol)及和厚朴酚(honokiol)为主。《别录》记载厚朴“温中益气，消痰下气”，具有行气解郁之作用。茯苓为多孔菌科PoriacocoS(Schw.)Wolf的干燥菌核，多糖可占干重的80-93％，主要为β-茯苓聚糖等。《药性论》记载，茯苓“开胃，止呕逆，善安心神”，具有益脾和胃、宁心安神之功效。生姜为姜科Zingiber officinale Rosc的鲜根茎，含挥发油0.25-3.0％，其中主要成分为姜醇、姜烯、水芹烯、莰烯等。《食疗本草》记载，生姜“止逆，散烦闷，开胃气”，可解厚朴之毒。
药理试验表明，厚朴酚具有中枢抑制、清除自由基、抗肿瘤、抗菌作用，厚朴酚还能抑制化学性低氧诱发物(如KCN)诱导的低密度脂蛋白的大量释放，从而保护神经元细胞。茯苓多糖有显著的镇静作用和免疫调节功能，并具有抗肿瘤作用。姜油中6-姜烯、6-姜酚、6-姜烯醇为主要成分，具有中枢神经系统抑制作用以及抗氧化、抗肿瘤、抗炎和保护胃粘膜等多种作用。
三、发明内容：
1.发明目的
本发明的目的就是为了解决上述问题，而提供一种由厚朴酚性成分、茯苓多糖和姜油三种有效成分或其中两种有效成分制备成的组合物及其制备方法，以及在制备治疗抑郁症药物中的应用。
2.技术方案
本发明的药物组合物，其特征在于它是由以下重量配比的植物提取物组分所组成：厚朴酚性成分0.1-1g、茯苓多糖3.5-14g、姜油0.2-3.5g；或者由厚朴酚性成分0.1-1g、茯苓多糖3.5-14g；上述提取物组分优选的用量为，厚朴酚性成分0.4g、茯苓多糖10.0g和姜油1.0g。
将组合物与β-环糊精等量混合，以增加组合物组份的稳定性。β-环糊精的用量也可以根据具体情况在适当范围内变化。
本发明的药物组合物的制备方法，其步骤为：
(1)厚朴用饱和石灰水提取，提取液调pH至1-3，析出沉淀即为厚朴酚性成分，或用超临界CO2萃取获得厚朴酚性成分；
(2)茯苓经水提取后，浓缩液中加95％乙醇至乙醇浓度为50-80％，所得沉淀即为茯苓多糖；
(3)生姜用超临界CO2萃取、石油醚提取、水蒸气蒸馏得姜油；
(4)按厚朴酚性成分0.1-1g、茯苓多糖3.5-14g、姜油0.2-3.5g，用β-环糊精包合姜油后混合即得组合物MPG；或者将厚朴酚性成分0.1-1g、茯苓多糖3.5-14g，混合后即得到组合物MP。
然后在组合物中加入适量的辅料，可制成片剂、颗粒剂或胶囊剂等口服制剂。这些剂型是按照本领域的技术人员所熟知方法制备的。用于制造片剂、颗粒剂、胶囊剂等成型工艺的辅料是常用的助剂，例如淀粉、明胶、阿拉伯胶、聚乙二醇等，此外还有表面活性剂、润滑剂、崩解剂、防腐剂、矫味剂、色素等。
3.有益效果
本发明的优点是：
(1)所得组合物组成简洁，配方合理，主要活性成分明确。从三种天然植物厚朴、茯苓、生姜中提取的活性成分，按重量配比组成MPG组合物。
(2)药效显著、安全可靠。动物试验结果表明各组合物高、低剂量组均能显著减少小鼠的绝对不动时间，表明各组合物具有明显的抗抑郁活性。其中以MPG药效显著。
四、具体实施方式：
实施例1药物组合物的制备方法，其步骤为：
(1)取干燥厚朴，用饱和石灰水渗漉至渗漉液无酚性反应，渗漉液用6M HCl调pH1-3，洗涤沉淀，即得厚朴酚性成分，得率为1.2％；
(2)取干燥茯苓菌核，用10倍体积的水提取三次，合并提取液，浓缩后加95％乙醇至乙醇浓度为80％，所得沉淀即为茯苓多糖，得率为80.1％；
(3)取干燥生姜，用常规水蒸气提取三次，得率为1.0％。
(4)取厚朴酚性成分0.4g、茯苓多糖10g和姜油1g，用β-环糊精包合姜油后，混合即得组合物MPG。
实施例2组合物对绝望模型小鼠行为及生化指标的影响
动物模型：小鼠强迫游泳实验和小鼠悬尾游泳实验
动物：雄性昆明种小鼠，体重28±2g，随机分组。
灌胃给药15天后，进行行为实验，测定小鼠强迫游泳和悬尾实验中的绝对不动时间；眼眶后静脉丛取血，测定红细胞SOD活性和血清MDA水平；取全脑，测定中枢神经递质含量。
各组合物组份对小鼠强迫游泳实验和悬尾实验的作用结果见表1。抑郁症的一个主要症状是动机行为的减少，强迫游泳实验和悬尾实验中的挣扎是动物的动机行为，而绝对不动则反映了实验中动物消极的无动机状态。大多数抗抑郁药物能增加受试动物的动机行为，减少强迫游泳实验和悬尾实验中的绝对不动时间。阳性药氟西汀高低两个剂量均能显著降低强迫游泳和悬尾实验中小鼠的绝对不动时间。各组合物高剂量组均能显著减少两个实验中小鼠的绝对不动时间，其中组合物MPG与氟西汀相当，其低剂量组也能极显著减少小鼠的绝对不动时间。结果表明各组合物具有明显的抗抑郁活性，其中MPG药效最佳。
组合物MPG对行为绝望模型下小鼠全脑中枢神经递质含量的作用结果见表2。MPG能显著地升高行为绝望模型下小鼠全脑5-HT水平，作用强度与氟西汀相当，MPG还能显著地提高DA含量，而对NA和5-HIAA有一定升高，但无显著性差异。结果表明组合物MPG可以通过影响中枢神经递质而达到抗抑郁的目的。
组合物MPG对小鼠行为绝望模型下小鼠红细胞SOD活性和MDA含量的影响结果见表3。组合物MPG能显著地降低小鼠红细胞SOD活性，降低血清MDA水平，其作用与氟西汀相当。
说明书
| 表1组合物对小鼠行为绝望模型中不动时间的影响( x±s) | |||
| 组别 | 剂量(mg/kg) | 绝对不动时间(s) | |
| 强迫游泳实验 | 悬尾实验 | ||
| 空白对照氟西汀MPGMPMG | -1020640320530265340170 | 124.2±3.570.1±1.5***31.6±2.1***80.4±2.8**26.4±1.9***95.4±2.4*56.1±1.5***88.7±4.2*60.4±3.1*** | 88.4±2.043.0±1.2***25.2±1.1***42.7±0.9***18.4±1.3***63.2±1.7*45.8±2.1***67.1±3.4*53.7±1.6** |
*P＜0.05，**P＜0.01，***P＜0.001，与对照组比较。
表2组合物MPG对行为绝望模型中小鼠全脑单胺神经递质的影响(
x±s)
| 组别 | 剂量(mg/kg) | 5-HT | 5-HIAA | NA | DA ng/g |
| 空白对照氟西汀MPG | -20640320 | 334.5±7.4519.5±11.7***489.0±12.0**389.0±11.6 | 59.5±0.005103.1±0.006*71.8±0.02566.3±0.016 | 319.5±10.5279.0±17.4311.1±3.8270.0±8.0 | 163.2±9.0166.5±8.1235.5±5.7**201.0±6.2 |
P＜0.05，**P＜0.01，***P＜0.001，与对照组比较。
表3组合物MPG对行为绝望模型中小鼠
红细胞SOD活性和血清MDA含量的影响(
x±s)
| 组别 | 剂量(mg/kg) | SOD(Unit/ml) | MDA(nmol/ml) |
| 对照氟西汀MPG | -1020640320 | 115.2±1.094.3±0.3*62.1±0.4**97.4±0.7*64.5±0.6** | 8.0±0.26.0±0.3*4.3±0.2**6.2±0.3*4.1±0.4** |
*P＜0.05，**P＜0.01，与对照组比较。
Claims (9)
1.一种治疗抑郁症的药物组合物，其特征在于它是由以下重量配比的植物提取物有效成分所组成：
厚朴酚性成分0.1-1g、茯苓多糖3.5-14g、姜油0.2-3.5g。
2.一种治疗抑郁症的药物组合物，其特征在于它是由以下重量配比的植物提取物有效成分所组成：
厚朴酚性成分0.1-1g、茯苓多糖3.5-14g、
3.根据权利要求1所述的药物组合物，其特征是提取物有效成分的重量配比为：厚朴酚性成分0.4g、茯苓多糖10g、姜油1.0g。
4.一种制备权利要求1的药物组合物的方法，其制备方法步骤为：
(1)厚朴用饱和石灰水提取，提取液调pH至1-3，析出沉淀即为厚朴酚性成分，或用超临界CO2萃取获得厚朴酚性成分；
(2)茯苓用水提取，所得提取液适当浓缩，加95％乙醇至提取液乙醇浓度为50-80％，所得沉淀即为茯苓多糖；
(3)生姜用超临界CO2萃取、石油醚提取、水蒸气提取即得姜油；(4)将厚朴酚性成分0.1-1g、茯苓多糖3.5-14g和姜油0.2-3.5g，用β-环糊精包合姜油后混合即得组合物。
5.一种制备权利要求2的药物组合物的方法，其制备方法步骤为：
(1)厚朴用饱和石灰水提取，提取液调pH至1-3，析出沉淀即为厚朴酚性成分，或用超临界CO2萃取获得厚朴酚性成分；
(2)茯苓用水提取，所得提取液适当浓缩，加95％乙醇至提取液乙醇浓度为50-80％，所得沉淀即为茯苓多糖；
(3)将厚朴酚性成分0.1-1g、茯苓多糖3.5-14g混合即得组合物。
6.根据权利要求1所述的药物组合物，其特征是在组合物中加入适量的辅料，用常规的制备方法制成片剂，颗粒剂或胶囊剂的固体口服制剂。
7.根据权利要求2所述的药物组合物，其特征是在组合物中加入适量的辅料，用常规的制备方法制成片剂，颗粒剂或胶囊剂的固体口服制剂。
8.权利要求1所述的药物组合物在制备治疗抑郁症药物中的应用。
9.权利要求2所述的药物组合物在制备治疗抑郁症药物中的应用。
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| CN108143741B (zh) * | 2018-01-04 | 2020-09-18 | 中国科学院昆明植物研究所 | 厚朴酚糖苷在制备治疗中枢神经系统疾病药物中的应用 |
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