CN112168892B - 一种用于改善围绝经期妇女综合征症的中药组合物 - Google Patents
一种用于改善围绝经期妇女综合征症的中药组合物 Download PDFInfo
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Abstract
本发明属于中药技术领域，具体涉及一种用于改善围绝经期妇女综合征症的药物组合物及其制备方法。该中药组合物由如下重量份的原料组成：珍珠母10‑50份、酸枣仁5‑30份、地黄2‑20份、胡黄连2‑20份、白薇2‑20份、丹参2‑20份、贯叶金丝桃1‑10份。本发明结合现代中药药理研究，诸药合用，共奏清心平肝、宁心安神之功。
Description
技术领域
本发明属于中药技术领域，具体涉及一种用于改善围绝经期妇女综合征症状的中药组合物及其制备方法。
背景技术
围绝经期是每个女性在生命的过程中都会经历的一个生理衰变的过渡期。西医认为围绝经期可分为3个阶段，即过渡期、绝经期、绝经后期。围绝经期综合征指女性绝经前后出现性激素波动或减少所致的一系列以自主神经系统功能紊乱为主，伴有心理症状的一序列症状，其主要表现为月经的紊乱、血管舒缩症状的出现、心血管系统症状及代谢综合征、泌尿生殖综合征以及骨质疏松等，90％妇女均存在，影响了围绝经期女性正常的生活及工作。患者可出现潮热、潮红、出汗增多、月经改变、尿频、焦虑、心烦、失眠多梦、皮肤干燥等症状。有报道指出，围绝经期综合征发生率约为85％，而其中症状严重影响正常生活和工作者约占10％～30％；发病年龄多在45～55岁，可持续至绝经后2～3年，少数人可到绝经后5～10年症状才能减轻或消失，给患者带来了极大的痛苦。
在中医学古籍中无“围绝经期综合征”这一病名的记载，根据患者临床表现的侧重点不同，散在的归属于不寐、郁证、汗证、虚劳、脏燥、心悸、眩晕等病的范畴，目前以“绝经前后诸证”赅之。
古籍中对于女性生理衰退变化的描述则与围绝经期相符，《素问·上古天真论》中这样描述：“七七，任脉虚，太冲脉衰少，天癸竭，地道不通，故形坏而无子也。”中医认为大多数女性可以顺利度过围绝经期，但部分女性由于个体因素，不能较好地调节，使得肾阴阳失调，从而导致脏腑阴阳失调，尤其以心、肝、脾为主。综合各家研究认为其病在脏腑、以肾为主，阴虚阳亢，本虚标实。对于围绝经期综合征的治疗，中医学多主张从肾论治，也有不少医家认为该病是因各脏腑综合作用而导致的复杂病证，习以从脏腑辨证论治。另外，亦有主张从痰论治，以疏肝化痰为主；或主张从瘀论治，以调补肝肾、活血化瘀为主。
据我国最新全国人口普查结果显示，我国女性总数已达6亿多人，其中围绝经期女性高达1.6亿，居世界首位。家庭及社会各方面的因素，导致妇女围绝经期症状有明显的上升趋势，其健康状况直接影响到社会发展与稳定，引起一系列疾病的发生，从而大大增加国家的医疗负担。
绝经妇女使用激素补充疗法(HRT)与饮食、运动、戒烟、限酒等生活方式的调节，是维持围绝经期和绝经后妇女健康的全部策略，是缓解绝经综合征最重要的组成部分。
在对有HRT适应证的绝经综合征的女性应用HRT进行治疗一直存在争议，早在2002年，女性健康协会研究者在一项为期1年的跟踪调查中发现，与未使用HRT的女性相比，HRT治疗的患者中，其患冠状动脉、中风、乳腺癌及静脉血栓栓塞的风险增加。2004年女性健康协会的实验表明，在切除子宫的围绝经期女性中，单纯服用雌激素的患者发生冠心病、乳腺癌、中风及静脉血栓栓塞等风险与联合应用雌孕激素无明显区别。2013年女性健康协会实验随访13年的研究表明，雌孕激素联合用药的女性发生乳腺癌及静脉血栓风险显著增加，但骨折风险相对降低。与2004年的研究结果相反的是单独服用雌激素的女性发生乳腺癌的风险降低。
由于我国人口素质参差不齐，大众对激素的认知不足，这直接导致围绝经期综合征女性对激素治疗的恐惧；其次，对于有使用禁忌的患者，不能常规使用激素治疗；再次，激素治疗必须在医生的指导及监管下用药，很多患者由于各种原因而不能坚持用药及复诊等，导致激素治疗不能广泛应用。非激素治疗虽然在一定程度上能缓解围绝经期症状，但目前尚无有效证据表明其效果明显。在此治疗背景下，中医药对围绝经期综合征的疗效更显现出前所未有的新优势。
发明内容
鉴于此，本发明提供了一种用于改善围绝经期妇女综合征症的中药组合物及其制备方法、制剂。
为实现上述目的，本发明采取了以下的技术方案：
本发明的第一个目的在于提供一种用于改善围绝经期妇女综合征症的中药组合物。
一种用于改善围绝经期妇女综合征症的中药组合物，该组合物由以下原料药组成：珍珠母、酸枣仁、地黄、胡黄连、白薇、丹参、贯叶金丝桃。
优选地，该中药组合物由如下重量份的原料组成：珍珠母10-50份、酸枣仁5-30份、地黄2-20份、胡黄连2-20份、白薇2-20份、丹参2-20份、贯叶金丝桃1-10份。
优选地，该中药组合物由如下重量份的原料组成：珍珠母20-40份、酸枣仁5-20份、地黄2-15份、胡黄连2-15份、白薇2-15份、丹参2-15份、贯叶金丝桃1-5份。
更优选地，该中药组合物由如下重量份的原料组成：珍珠母30份、酸枣仁10份、地黄6份、胡黄连6份、白薇4份、丹参6份、贯叶金丝桃2份。
更优选地，该中药组合物由如下重量份的原料组成：珍珠母40份、酸枣仁20份、地黄10份、胡黄连10份、白薇10份、丹参10份、贯叶金丝桃5份。
更优选地，该中药组合物由如下重量份的原料组成：珍珠母40份、酸枣仁15份、地黄15份、胡黄连10份、白薇10份、丹参15份、贯叶金丝桃5份。
在一个具体的实施方案中，本发明的中药组合物中所述地黄为生地黄。
本发明重用珍珠母为君药，咸寒入肝，有平肝潜阳，清泻肝火的作用，又质重入心经，有镇惊安神之功。酸枣仁，味甘，入心、肝经，能养心阴，益肝血而有安神之效，为养心安神要药；生地黄，甘寒养阴，苦寒泄热，入肾经而滋阴降火，养阴津而泄伏热；二者配伍，助君药平肝、清心之功，共为臣药。胡黄连，性寒，入心肝二经血分，有退虚热，除骨蒸，凉血清热之功；白薇，苦寒，善入血分，清热凉血，清退虚热而益阴；二者相须为用，清热益阴凉血；丹参，入心经，既可清热凉血，又可除烦安神，既能活血又能养血以安神定志；三者共为佐药。贯叶金丝桃，辛、寒，入肝经，疏肝解郁，清热利湿为使药。
以上诸药合用，共奏清心平肝、宁心安神之功，治疗围绝经期妇女综合征的症状尤为有效。
以下是本发明中药组合物原料药的性味及功能：
珍珠母
《中国药典》2015年版珍珠母药材收载了蚌科动物三角帆蚌Hyriopsis cumingii(Lea)、褶纹冠蚌Cristaria plicata(Leach)或珍珠贝科动物马氏珍珠贝Pteriamartensii(Dunker)的贝壳。海贝珠母为珍珠贝科动物马氏珍珠贝Pteria martensii(Dunker)的贝壳，现药用已很少。主要来源为蚌科动物三角帆蚌Hyriopsis cumingii(Lea)、褶纹冠蚌Cristaria plicata(Leach)的蚌壳。经了解，三角帆蚌是当前我国培育淡水珍珠的主要母蚌，资源丰富，因此确定所用珍珠母为蚌科动物三角帆蚌Hyriopsiscumingii(Lea)的贝壳。
味咸，性寒。归肝、心经。平肝潜阳，安神定惊，明目退翳。用于头痛眩晕，惊悸失眠，目赤翳障，视物昏花。珍珠母主要含有无机盐、微量元素、氨基酸等几大类成分。主要含有碳酸钙类成分及其他无机盐类成分，如磷酸盐，硫酸盐，硅酸盐等。含有钙、镁、铜、铁、锌、锰、钼、钴、锶、铅、铬、硒、铜、碘、汞等微量元素。珍珠母中还含有少量如多糖等其他有机质成分，磷脂酰乙醇胺、半乳糖神经酰胺、羟基脂肪酸等氧化物。
研究表明，珍珠母具有一定的镇静催眠作用，而珍珠母的生品，烘烤品和超微粉均可增加小鼠脑内5-HT浓度，可能是其镇静催眠作用的机制之一。亦有研究结果表明，在小鼠悬尾实验中，珍珠母生品高剂量组，烘烤品低剂量组、中剂量组和高剂量组，超微粉低剂量组、中剂量组和高剂量组均能减少小鼠悬尾的完全不动时间；在AMPT诱导的小鼠悬尾实验中，珍珠母不同炮制品高剂量组均能减少小鼠悬尾完全不动时间。这说明珍珠母及其炮制品均有一定的抗抑郁作用，其中以超微粉细品为佳，而其作用机制可能与珍珠母蛋白能够抑制酪氨酸羟化酶，阻断酪氨酸合成多巴胺，从而抑制去甲肾上腺素的合成有关。
酸枣仁
酸枣仁为鼠李科植物酸枣Ziziphus jujuba Mill.var.spinosa(Bunge)Hu exH.F.Chou的干燥成熟种子。
性味甘、酸，平。归肝、胆、心经。养心补肝，宁心安神，敛汗，生津。用于虚烦不眠，惊悸多梦，体虚多汗，津伤口渴。酸枣仁的化学成分主要包括皂苷、黄酮、生物碱、脂肪酸等。
酸枣仁总皂苷是其镇静催眠作用的主要活性物质。其对神经细胞、神经递质、受体和睡眠参数均有作用。Zhang等运用微透析技术研究酸枣仁皂苷A对大鼠海马谷氨酸水平的影响。结果显示大剂量的酸枣仁皂苷A可显著拮抗由青霉素钠诱导的海马谷氨酸水平上升，说明酸枣仁皂苷A可影响由谷氨酸(Glu)介导的海马区兴奋性信号通路。Chen等报道酸枣仁皂苷A水解后生成了酸枣仁皂苷元，它可以透过血脑屏障，从而与γ－氨基丁酸(GABA)受体结合位点上的关键残基结合形成氢键从而发挥镇静催眠的作用。Cao等通过脑电图来测定大鼠的睡眠参数，结果显示酸枣仁总皂苷在白天可显著延长总睡眠时间和快动眼睡眠时间(REM)，对非快动眼睡眠时间(NREM)没有显著影响，而在夜间可显著延长总睡眠时间和NREM，而对慢波睡眠(SWS)和REM无显著影响。
酸枣仁总黄酮有较好的抗焦虑、抗抑郁作用。贺一新等研究结果酸枣仁醇提物中黄酮类成分是抗焦虑的活性成分。赵启铎等将酸枣仁总黄酮分为低中高三个剂量组，连续灌胃给予绝望模型小鼠7天，对小鼠进行行为学测试，结果表明三个剂量组均能较少小鼠强迫游泳和悬尾不动时间。杨奕等采用均匀设计法，通过利血平拮抗实验和小鼠强迫游泳实验，筛选出酸枣仁抗抑郁活性组分总皂苷和总黄酮的最佳配伍为：总黄酮17.8mg/kg，总皂苷113.4mg/kg。
近年研究表明，酸枣仁催眠、镇静作用的活性成分还包括酸枣仁油，并且不同工艺提取的酸枣仁油的镇静催眠作用均具有等效性。
生地黄
地黄为玄参科植物地黄Rehmannia glutinosa Libosch.干燥块根。
性味甘，寒。归心、肝、肾经。功能清热凉血，养阴生津。用于热入营血，温毒发斑，吐血衄血，热病伤阴，舌绛烦渴，津伤便秘，阴虚发热，骨蒸劳热，内热消渴。生地黄的主要化学成分包括环烯醚萜、糖类、氨基酸类以及微量元素。
地黄对中枢神经系统具有明显抑制作用。用生地黄水提取液给小鼠腹腔注射(1.5、3g/kg)，40min后观察到小鼠自主活动次数明显下降。实验还显示，同样给药剂量，生地黄水提取液与阈下催眠剂量的戊已比妥钠及硫喷妥钠有协同催眠作用，同时可拮抗安钠咖对小鼠的兴奋作用，但不能对抗硝酸士的宁和戊四氮所致的惊厥作用。这说明生地黄有明显的镇静作用，且作用的部位可能是脑干网状结构上行激动系统及大脑皮层。
熟地黄
本品为生地黄的炮制加工品。
性味甘，微温。归肝、肾经。功能补血滋阴，益精填髓。用于血虚萎黄，心悸怔忡，月经不调，崩漏下血，肝肾阴虚，腰膝酸软，骨蒸潮热，盗汗遗精，内热消渴，眩晕，耳鸣，须发早白。熟地黄的含有少量环烯醚萜、单萜、氨基酸类以及微量元素。
熟地黄具有延缓小鼠衰老的作用。实验表明熟地黄水煎液可增强gSH-Px活性和降低血清中LPO的含量，达到延缓衰老的作用。另有实验研究表明，熟地黄有补血作用，其对造血干细胞亦有一定的增殖、分化作用，且与骨髓造血系统亦有密切相关的作用。熟地黄对甲亢型阴虚有明显改善作用。
胡黄连
玄参科植物胡黄连Picrorhiza scrophulariiflora Pennell的干燥根茎。
性味苦，寒。归肝、胃、大肠经。功能退虚热，除疳热，清湿热。用于骨蒸潮热，小儿疳热，湿热泻痢，黄疸尿赤，痔疮肿痛。胡黄连的化学成分主要有环烯醚萜类、葫芦素类和酚甙类；另外还含有极少量的甘露醇、胡黄连醇、胡黄连甾醇、香荚兰乙酮及芳香酸等。
胡黄连苷Ⅱ通过拮抗下丘脑-垂体-肾上腺轴功能亢进，从而改善抑郁症状，发挥一定的抗抑郁作用。相关研究表明，胡黄连苷Ⅱ具有缓解抑郁模型行为学损伤的作用，可显著降低大鼠血浆中促肾上腺皮质激素和皮质酮的含量，可显著降低抑郁模型大鼠强迫游泳的不动时间。
白薇
白薇为萝藦科植物白薇Cynanchum atratum Bge.或蔓生白薇Cynanchumversicolor Bge.的干燥根和根茎。通过调研市场与访谈药材经销商，了解到目前市场白薇药材商品主要来源于萝藦科植物白薇Cynanchum atratum Bge.，因此确定宁心颗粒所用白薇为萝藦科植物白薇Cynanchum atratum Bge.的干燥根和根茎。
性味苦、咸，寒。归胃、肝、肾经。功能清热凉血，利尿通淋，解毒疗疮。用于温邪伤营发热，阴虚发热，骨蒸劳热，产后血虚发热，热淋，血淋，痈疽肿毒。白薇中含有C21甾体皂苷、白薇素、挥发油、强心苷及微量元素等成分。白薇具有退热作用。薛宝云等使用直立白薇水煎液，醇提取物和醚提取物对大鼠酵母致热后的退热作用的比较，实验结果表明直立白薇水提取物3.4、4.9、7.0/kg对发热均有明显的退热作用，但其醇提取物和醚提取物对大鼠酵母致热后的效果不明显。
丹参
丹参为唇形科植物丹参Salvia miltiorrhiza Bge.的干燥根和根茎。
性味苦，微寒。归心、肝经。功能活血祛瘀，通经止痛，清心除烦，凉血消痈。用于胸痹心痛，脘腹胁痛，癥瘕积聚，热痹疼痛，心烦不眠，月经不调，痛经经闭，疮疡肿痛。丹参化学成分主要包括脂溶性成分和水溶性成分，其中脂溶性成分主要为丹参酮型的二萜类化合物，水溶性成分主要为聚酚酸类化合物。
药理实验结果证明：丹参酮具有雌激素样活性，并通过卵巢才起作用。丹参酮除具雌激素样活性还具有抗雄激素活性。小鼠腹腔注射丹参，显示剂量依赖性抑制自主活动并能显著增强中枢抑制药如氯丙嗪和眠尔通对自主活动的抑制作用。还能增强戊巴比妥钠或巴比妥的睡眠作用。保护戊四唑、士的宁和一叶萩碱的抗强直惊厥，使产生惊厥的剂量增加而抗惊厥作用不明显。丹参使大脑皮层的自发电活动明显减少，重复刺激引起后发放阈值升高，单刺激大脑皮层出现的重复电反应减少，在大脑皮层电活动振幅减少时，对较高频率的组分无明显增加，所以此电活动减少不是去同步的结果。推测丹参对大脑皮层的抑制作用，可能是通过抑制环腺苷酸磷酸酶的活力，增加环腺苷酸水平而实现的。
贯叶连翘
通过查阅《中华本草》、《中药大辞典》、《贵州省中药材民族药材质量标准2003版》等收载贯叶连翘的中药专业书籍及地方标准，发现与《中国药典》2015版收载的贯叶金丝桃，基原、药用部位一致，均为藤黄科植物贯叶金丝桃Hypericum perforatum L.的干燥地上部分。此外在中国植物志中检索“Hypericum perforatum L.”，结果显示植物为藤黄科金丝桃属植物贯叶连翘，有的地区习称“小金丝桃”或“小叶金丝桃”。综合上述资料，可知贯叶连翘与贯叶金丝桃为同一药材，属于同物异名，因此其基原和药用部位应为《中国药典》2015版收载的藤黄科植物贯叶金丝桃Hypericum perforatum L.的干燥地上部分。
辛，寒。归肝经。疏肝解郁，清热利湿，消肿通乳。用于肝气郁结，情志不畅，心胸郁闷，关节肿痛，乳痈，乳少。贯叶金丝桃的主要成分有苯并二蒽酮类、黄酮类、间苯三酚类、挥发油类、香豆素类以及其他成分如原花青素、鞣质、谷甾醇、多种口山酮化合物、多种氨基酸、环氧叶黄素等。
贯叶金丝桃一直是国内外常用的治疗抑郁症的药物，金丝桃素、黄酮类化合物被认为是其主要的抗抑郁成分。储智勇等用小鼠尾悬挂实验和大鼠强迫游泳实验模型对贯叶金丝桃提取物的抗抑郁作用进行研究，证明含有0.35％金丝桃素的贯叶金丝桃提取物在行为绝望动物抑郁模型上有明显抗抑郁作用，可以对抗小鼠、大鼠的失望行为，缩短小鼠尾悬挂的失望时间，显著缩短大鼠强迫游泳的不动时间。Muller等通过研究证明贯叶金丝桃素是多种神经递质包括5－羟色胺(5－HT)、多巴胺(DA)、去甲肾上腺素(NA)、γ－氨基丁酸(GABA)和L－谷氨酸的非竞争性重吸收抑制剂，能够通过竞争转运蛋白的结合位点选择性地抑制神经递质的重吸收，从而达到抗抑郁的作用。Singer等研究证明贯叶金丝桃素可降低突触体细胞钠离子浓度梯度，消除神经递质转运蛋白运作的驱动力，产生抗抑郁作用。
Girzu等研究了不同剂量的贯叶金丝桃提取物对小鼠的镇静作用，发现不同剂量(13.25、19.6、26.5、132.5、662.5、3312.5mg/kg)均能抑制小鼠的运动活性，有镇静催眠作用，但26.5mg/kg时抑制作用最强，抑制率为50.7％，与地西泮组作用相当。
本发明的第二个目的，是提供上述中药组合物的制备方法。
本发明中药组合物所含的有效成分可以这样制备：将上述原料药干燥研成粉末，混匀，得到有效成分。
本发明中药组合物所含的有效成分还可以这样制备：将上述原料药加水或不同浓度的乙醇提取，提取液浓缩干燥得粗提物；和/或进一步采用水提醇沉法、柱层析法、水蒸气蒸馏法精制得到有效成分。
本发明中药组合物所含的有效成分优选下列步骤制备：
方案一：取珍珠母，加水提取1-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，滤过，合并滤液，备用；取酸枣仁等其余六味，加水提取2-3次，每次加水量相当于六味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
方案二：取珍珠母，加水相当于七味药材总重量的6-12倍，提取1-3小时，加入酸枣仁等其余六味，继续提取1-3小时，药渣再加水提取2-3次，每次加水量相当于七味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
方案三：取全部药材，混合后用40-80％乙醇回流提取2-3次，每次乙醇用量为药材总量的4-10倍，提取时间为1-3小时，合并提取液，过滤，滤液浓缩至60－70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
方案四：取珍珠母，加水提取1-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，滤过，合并滤液，备用；取胡黄连、丹参、白薇加40-80％乙醇回流提取2-3次，每次乙醇用量为三味药材总量的4-10倍，提取时间为1-3小时，滤过，合并滤液，减压回收乙醇，备用；取酸枣仁其余三味，加水提取2-3次，每次加水量相当于三味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述两种提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
方案五：取全部药材，混合后加水提取2-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，加入乙醇，使乙醇含量为40-70％，静置12-24小时，滤过，滤液浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
本发明的第三个目的，是提供上述中药组合物的制剂。
该中药组合物的制剂可以是颗粒剂、丸剂、胶囊剂、片剂、混悬剂、糖浆剂。制剂中包含有效量的上述组合物及可接受的药用载体，如填充剂、崩解剂、润湿剂、粘合剂、润滑剂矫味剂等等。
填充剂可以选自淀粉、蔗糖、糊精、硫酸钙、磷酸氢钙、轻质氧化镁、碳酸钙、微晶纤维素、甘露醇、乳糖、预胶化淀粉等。
崩解剂可以选自干淀粉、羟甲淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、表面活性剂、泡腾崩解剂等。
润湿剂可以选自蒸馏水、乙醇等等。
粘合剂可以选自糖粉与糖浆、淀粉浆、聚乙烯吡咯烷酮、纤维素衍生物、胶浆、糊精等。
润滑剂可以选自硬脂酸、硬脂酸钙、硬脂酸镁、微粉硅胶、氢化植物油、聚乙二醇4000和6000、十二烷基硫酸钠或镁、滑石粉等。
矫味剂为可用于颗粒剂调整口感的一种或多种辅料的混合物，包括但不限于阿司帕坦、甘露醇、甜菊糖、蔗糖、柠檬酸钠、樱桃香精等。
优选地，中药组合物的制剂是颗粒剂，所述的颗粒剂的制备步骤如下：
第1步，将中药组合物加水煎煮2-3次，每次加水重量是中药组合物总重量的6-12倍，煎煮时间1-3小时，将每次煎液合并滤除药渣后再减压浓缩至60℃下的相对密度为1.25-1.35的浓缩液，干燥，粉碎成细粉。
第2步，另取赋形剂1-4份，与第1步得到的细粉混匀，加入矫味剂适量，加入适量湿润剂，湿法制粒，干燥，制成，即得。
本发明的第四个目的，是提供上述中药组合物用于改善围绝经期妇女综合征症状的药物中的用途。
优选地，围绝经期妇女综合征症状是指不寐、郁证、汗证、虚劳、脏燥、心悸、眩晕等一种或多种综合症状；这些症状通常表述为潮热、潮红、出汗增多、月经改变、尿频、焦虑、心烦、失眠多梦、皮肤干燥等症状。
本发明的有益效果为：
1、本发明结合现代中药药理研究，以清心平肝，宁心安神为主，用于改善围绝经期妇女综合证的症状。
2、采用该中药组合物用于改善围绝经期妇女综合证的症状，经临床使用验证疗效确切、无明显的毒副反应，处方运用灵活且费用低廉。
3、采用本发明的中药组合物制成颗粒剂，不仅疗效显著，而且疗程短，使用便利，刺激性小。
4、本发明的中药组合物配方科学严谨，制备方法简单，制备成本低，具有很大的临床应用价值。
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。
实施例1
取珍珠母10g，加水相当于七味药材总重量的12倍，提取3小时，取酸枣仁30g、生地黄2g、贯叶金丝桃10g、胡黄连20g、丹参2g、白薇20g，继续提取3小时，药渣再加水提取2次，每次加水量相当于七味药材总重量的8倍，每次提取时间为3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，另取赋形剂(糊精与可溶性淀粉按照重量比1：4的混合物)1份，与细粉混匀，加入阿斯帕坦0.05份，加入湿润剂，湿法制粒，干燥，制成颗粒剂。
实施例2
取珍珠母20g、酸枣仁20g、生地黄10g、贯叶金丝桃8g、胡黄连15g、丹参10g、白薇15g，混合后用80％乙醇回流提取2次，每次乙醇用量为药材总量的4倍，提取时间为3小时，合并提取液，过滤，滤液浓缩至60－70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，加适量辅料，混匀，进一步制粒，制成胶囊剂。
实施例3
取珍珠母30g，加水提取3次，每次加水量相当于药材总重量的8倍，每次提取时间为3小时，滤过，合并滤液，备用；取酸枣仁10g、生地黄6g、贯叶金丝桃6g、胡黄连4g、丹参6g、白薇2g，加水提取2次，每次加水量相当于六味药材总重量的8倍，每次提取时间为3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，和适量辅料混合制成干混悬剂。
实施例4
取珍珠母40g，加水提取1次，加水量相当于药材总重量的12倍，提取时间为1小时，滤过，合并滤液，备用；取胡黄连10g、丹参15g、白薇10g加40％乙醇回流提取2次，每次乙醇用量为三味药材总量的10倍，提取时间为1小时，滤过，合并滤液，减压回收乙醇，备用；取酸枣仁15g、生地15g、贯叶金丝桃5g，加水提取2次，每次加水量相当于三味药材总重量的12倍，每次提取时间为1小时，滤过，滤液与前述两种提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，和适量辅料混合制成片剂。
实施例5
取珍珠母50g、酸枣仁5g、生地黄20g、贯叶金丝桃1g、胡黄连2g、丹参20g、白薇2g，混合后加水提取1次，加水量相当于药材总重量的6倍，提取时间为1小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，加入乙醇，使乙醇含量为70％，静置24小时，滤过，滤液浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，和适量辅料混合，溶于水中，搅匀，加热至沸灭菌、制成口服水溶液。
实施例6
珍珠母30g、酸枣仁10g、生地6g、胡黄连6g、白薇4g、丹参6g、贯叶金丝桃2g将上述所有原料粉碎，混合均匀，加适量粘合剂制成水丸。
实施例7
取珍珠母40g，加水提取2次，每次加水量相当于药材总重量的8倍，提取时间为2小时，滤过，合并滤液，备用；取胡黄连10g、丹参10g、白薇10g加60％乙醇回流提取2次，每次乙醇用量为三味药材总量的6倍，提取时间为2小时，滤过，合并滤液，减压回收乙醇，备用；取酸枣仁20g、生地10、贯叶金丝桃5g，加水提取2次，每次加水量相当于三味药材总重量的8倍，每次提取时间为2小时，滤过，滤液与前述两种提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。另取糖粉1份，与细粉混匀，加入柠檬酸0.01份，樱桃香精0.01份，加入湿润剂，湿法制粒，干燥，制成颗粒剂。实施例8
取珍珠母30g，加水提取2次，每次加水量相当于药材总重量的12倍，每次提取时间为2小时，滤过，合并滤液，备用；取酸枣仁10g、生地黄6g、贯叶金丝桃2g、胡黄连6g、丹参6g、白薇4g，加水提取2次，每次加水量相当于六味药材总重量的12倍，每次提取时间为2小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
实施例9
实施例15：取珍珠母40g、酸枣仁5g、生地黄10g、贯叶金丝桃3g、胡黄连6g、丹参3g、白薇5g，混合后加水提取2次，加水量相当于药材总重量的8倍，提取时间为2小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，干燥，粉碎成细粉，另取乳糖0.2份，与细粉混匀，加入甜菊糖0.01份，加入湿润剂，湿法制粒，干燥，制成，即可。
实施例10：取珍珠母50g、酸枣仁5g、生地黄20g、贯叶金丝桃1g、胡黄连2g、丹参20g、白薇2g，混合后加水提取1次，加水量相当于药材总重量的6倍，提取时间为1小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，加入乙醇，使乙醇含量为70％，静置24小时，滤过，滤液浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，与适量辅料混合制成片剂即可。
实施例11：取珍珠母30g，加水提取3次，每次加水量相当于药材总重量的8倍，每次提取时间为3小时，滤过，合并滤液，备用；取酸枣仁10g、生地黄6g、贯叶金丝桃6g、胡黄连4g、丹参6g、白薇2g，加水提取2次，每次加水量相当于六味药材总重量的8倍，每次提取时间为3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，加入二氧化硅0.01份，干法制粒，制成，即可。
实施例12：取珍珠母珍珠母20g，加水相当于七味药材总重量的12倍6，提取2次，提取2小时，取酸枣仁15g、地黄3g、贯叶金丝桃10g、胡黄连2g、丹参10g、白薇1g，继续提取3小时，药渣再加水提取2次，每次加水量相当于七味药材总重量的8倍，每次提取时间为1小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，另取赋形剂(淀粉)0.2份，与细粉混匀，加入阿斯帕坦0.05份，加入湿润剂，湿法制粒，干燥，制成，即可。
实施例13：取珍珠母40g、酸枣仁5g、地黄10g、贯叶金丝桃3g、胡黄连6g、丹参3g、白薇5g，混合后用60％乙醇回流提取2次，每次乙醇用量为药材总量的6倍，提取时间为2小时，合并提取液，过滤，滤液浓缩至60－70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。另取赋形剂(可溶性淀粉)0.5份，与细粉混匀，加入甘露醇0.03份，加入湿润剂，湿法制粒，干燥，制成，即可。
实施例14：取珍珠母20g，加水提取2次，每次加水量相当于药材总重量的8倍，提取时间为2小时，滤过，合并滤液，备用；取胡黄连2g、丹参10g、白薇1g加60％乙醇回流提取2次，每次乙醇用量为三味药材总量的6倍，提取时间为2小时，滤过，合并滤液，减压回收乙醇，备用；取酸枣仁15g、生地3g、贯叶金丝桃10g，加水提取2次，每次加水量相当于三味药材总重量的8倍，每次提取时间为2小时，滤过，滤液与前述两种提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。另取糖粉1份，与细粉混匀，加入柠檬酸0.01份，樱桃香精0.01份，加入湿润剂，湿法制粒，干燥，制成，即可。
实施例15：取珍珠母40g、酸枣仁5g、生地黄10g、贯叶金丝桃3g、胡黄连6g、丹参3g、白薇5g，混合后加水提取2次，加水量相当于药材总重量的8倍，提取时间为2小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，加入乙醇，使乙醇含量为60％，静置12小时，滤过，滤液浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。另取乳糖0.2份，与细粉混匀，加入甜菊糖0.01份，加入湿润剂，湿法制粒，干燥，制成，即可。
药效试验例：不同提取工艺的本发明中药组合物对更年期综合征大鼠模型神经内分泌调节机制的研究
1、实验药物与仪器
1.1药物
按照日处方量64g生药/人/天的药材提取所得密度在1.20～1.30的浓缩液配置成高、低两个浓度，每只大鼠灌胃给予1ml，将180～220g雌性大鼠分别按数字随机表法分8组：假手术组、模型对照组、水提工艺宁心颗粒低剂量组(2.88g生药/kg)、水提工艺宁心颗粒高剂量组(5.76g生药/kg)、醇沉工艺宁心颗粒低剂量组(2.88g生药/kg)、醇沉工艺宁心颗粒高剂量组(5.76g生药/kg)、水提醇沉工艺宁心颗粒低剂量组(2.88g生药/kg)、水提醇沉工艺宁心颗粒高剂量组(5.76g生药/kg)。大鼠高剂量组与人日处方量按如下公式换算：64*0.018/0.2＝5.76g生药/kg，低剂量组是高剂量组的二分之一。
1.2仪器与试剂
1.2.1仪器
百分之一电子天平：TP-1102，北京赛多利斯仪器系统有限公司；十万分之一分析天平：BP121S，Sartorius(赛多利斯)；Nikon荧光显微镜(上海培清科技有限公司)；TDZ5-WS多管架自动平衡离心机；灌胃针。
1.2.2试剂
生理盐水，乙醇，蒸馏水等。
1.3实验动物
SD大鼠：体重180～220g，雌性大鼠，SPF级(Specific Pathogen Free，无特定病原体)，购自斯贝福(北京)生物技术有限公司；许可证编号：SCXK(京)2018-0011。
动物房：实验设施许可证：SYXK(京)2017-0026；设施管理遵循中华人民共和国国家标准GB14925-2001《实验动物环境及设施》
喂养条件：采用人工光照12小时明暗周期，环境温度维持在19～29℃，湿度在40％～80％，照明时间8:00～17:00，有通风系统保持室内空气流畅；动物饲养于聚碳酸酯小鼠饲养笼，每星期定时更换2次垫料，每天早晨定时换水和添加饲料。
饲料：标准大鼠颗粒饲料，由斯贝福(北京)生物技术有限公司公司提供。
饮用水：试验动物饮用水，动物可自由摄取，每日更换新的水瓶和新鲜水。
2、试验方法
将180～220g雌性大鼠分别按数字随机表法分12组：假手术组、模型对照组、阳性对照组(安今益，即雌二醇0.18mg/kg)、水提珍珠母先煎工艺所得清膏(实施例1)低剂量组(2.88g生药/kg)、水提珍珠母先煎工艺所得清膏(实施例1)高剂量组(5.76g生药/kg)；水提珍珠母与其他药材分煎工艺所得清膏(实施例3)低剂量组(2.88g生药/kg)、水提珍珠母与其他药材分煎工艺所得清膏(实施例3)高剂量组(5.76g生药/kg)；醇提工艺所得清膏(实施例2)低剂量组(2.88g生药/kg)、醇提工艺所得清膏(实施例2)高剂量组(5.76g生药/kg)；部分水提部分醇提工艺所得清膏(实施例4)低剂量组(2.88g生药/kg)、部分水提部分醇提工艺所得清膏(实施例4)高剂量组(5.76g生药/kg)水提醇沉工艺所得清膏(实施例5)低剂量组(2.88g生药/kg)、水提醇沉工艺所得清膏(实施例5)高剂量组(5.76g生药/kg)。除假手术组外，其余各组大鼠行双侧卵巢切除手术，去卵巢1周后连续5d做阴道脱落细胞涂片，若证明无动情周期变化则造模成功。假手术组仅摘除卵巢周围部分脂肪，阴道脱落细胞涂片显示动情周期正常。于术后13d开始灌胃，每日1次，连续灌胃28d，其中假手术组、模型对照组给予蒸馏水，其余各组给予对应受试物，给药体积为1ml/100g。于末次给药24h后，大鼠股动脉取血，血液静置40min后，3500r/min离心15min，分离血清，置于－20℃
低温冰箱保存待测。采用放射免疫分析法测定血清E2，FSH，LH含量，结果如下：
表1大鼠血清LH、FSH、E2的水平
与假手术组相比：◆P＜0.05；◆◆P＜0.05；与模型组相比：▼P＜0.05；▼▼P＜0.05
由表中可以看出，各组大鼠行双侧卵巢切除手术后，大鼠的激素水平改变，与空白组相比具有显著性差异；阳性组雌二醇可明显改善更年期综合征大鼠模型神经内分泌；本发明五种制备工艺高低剂量组均对更年期综合征大鼠模型神经内分泌具有调节作用，五种工艺无统计学意义差异；五种药物高低剂量组间无统计学差异。
Claims (8)
1.一种用于改善围绝经期妇女综合征的中药组合物，其特征在于，该组合物由以下重量份的原料药制成：珍珠母10-50份、酸枣仁5-30份、地黄2-20份、胡黄连2-20份、白薇2-20份、丹参2-20份、贯叶金丝桃1-10份。
2.根据权利要求1所述的中药组合物，其特征在于，该组合物由以下重量份的原料药制成：珍珠母20-40份、酸枣仁5-20份、地黄2-15份、胡黄连2-15份、白薇2-15份、丹参2-15份、贯叶金丝桃1-5份。
3.根据权利要求2所述的中药组合物，其特征在于，该组合物由以下重量份的原料药制成：珍珠母30份、酸枣仁10份、地黄6份、胡黄连6份、白薇4份、丹参6份、贯叶金丝桃2份。
4.根据权利要求2所述的中药组合物，其特征在于，该组合物由以下重量份的原料药制成：珍珠母40份、酸枣仁20份、地黄10份、胡黄连10份、白薇10份、丹参10份、贯叶金丝桃5份。
5.根据权利要求2所述的中药组合物，其特征在于，该组合物由以下重量份的原料药制成：珍珠母40份、酸枣仁15份、地黄15份、胡黄连10份、白薇10份、丹参15份、贯叶金丝桃5份。
6.根据权利要求1所述的中药组合物，其特征在于，所述地黄为生地黄。
7.根据权利要求1-6所述的任一种中药组合物，其特征在于，所述中药组合物的剂型为颗粒剂、片剂、胶囊剂、丸剂、干混悬剂、口服液或汤剂。
8.制备权利要求1-7所述任一种中药组合物的方法，包括：
方法一：取珍珠母，加水提取1-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，滤过，合并滤液，备用；取酸枣仁等其余六味，加水提取2-3次，每次加水量相当于六味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得；
方法二：取珍珠母，加水相当于七味药材总重量的6-12倍，提取1-3小时，加入酸枣仁等其余六味，继续提取1-3小时，药渣再加水提取2-3次，每次加水量相当于七味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得；
方法三：取全部药材，混合后用40-80％乙醇回流提取2-3次，每次乙醇用量为药材总量的4-10倍，提取时间为1-3小时，合并提取液，过滤，滤液浓缩至60－70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得；
方法四：取珍珠母，加水提取1-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，滤过，合并滤液，备用；取胡黄连、丹参、白薇加40-80％乙醇回流提取2-3次，每次乙醇用量为三味药材总量的4-10倍，提取时间为1-3小时，滤过，合并滤液，减压回收乙醇，备用；取酸枣仁其余三味，加水提取2-3次，每次加水量相当于三味药材总重量的6-12倍，每次提取时间为1-3小时，滤过，滤液与前述两种提取液合并，浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得；
方法五：取全部药材，混合后加水提取2-3次，每次加水量相当于药材总重量的6-12倍，每次提取时间为1-3小时，合并提取液，滤过，滤液浓缩至60-70℃时相对密度为1.15-1.20的清膏，加入乙醇，使乙醇含量为40-70％，静置12-24小时，滤过，滤液浓缩至60-70℃时相对密度为1.20-1.30的清膏，干燥，粉碎成细粉，即得。
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