CN113350436A - 一种治疗***症的中药组合物及其制备方法、应用 - Google Patents
一种治疗***症的中药组合物及其制备方法、应用 Download PDFInfo
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Abstract
本发明属于***症中药研究技术领域,具体涉及一种治疗***症的中药组合物及其制备方法、应用。该中药组合物按重量份数计由以下原料组成:当归10‑15份、炒白术15‑25份、炒白芍20‑25份、炒香附子8‑12份、牡丹皮10‑12份、茯苓12‑15份、天花粉7‑9份、苦楝子4‑6份、路路通10‑12份、王不留行6‑12份、蒲公英8‑12份。本发明提供的治疗***症的中药组合物,能够降低泌素激素水平、增长子宫内膜厚度并恢复卵巢卵泡正常发育,最终有效助孕。
Description
技术领域
本发明属于***症中药研究技术领域,具体涉及一种治疗***症的中药组合物及其制备方法、应用。
背景技术
高泌乳素血症是指由内外环境因素引起的,以催乳素升高、闭经、溢乳、无***和***为特征的综合征。在育龄期间,备受关注的除了月经的异常外,应该就是高泌乳素血症所致的***功能障碍性***症了。在生育年龄妇女中的发病率约为6%-10%,基于其混乱的内分泌状态及持续的无***,导致了相当一部分患者发生了生殖障碍,此类患者***症发病率很高,据统计由此导致的***症约占到女性无***性***症的75%之多。
中医将高泌乳素血症归属于“闭经”、“乳汁自出”、“月经过少”等范畴。引起高泌乳素血症的原因主要是肾虚肝郁,肾为先天之本,主生殖、藏精,肾精亏虚则冲任失调,血海空虚,无血可下而致闭经,若肝郁疏泄失职,气血逆乱,则乳汁自出。
西医研究中,高泌乳素血症的病理生理及发病机制非常的复杂,至今仍无定论,可能与肾上腺功能初现时功能过盛、膜岛素样生长因子异常、神经内分泌功能失调及遗传等诸多因素相关。但迄今都尚未能够形成较为完整而成熟的理论。
目前国内外公认的高泌乳素血症的治疗方法主要有以下几种:溴隐亭、左旋多巴(Levo-Dopa)、八氢苯并喹啉(CV205-502)、维生素B6等及促***治疗等,但都价格昂贵,且目前都尚未获得循证医学证据的明确支持。中药用时长,一般需要持续用药三个***(即连续三个月时间),但其相对西药在有效性方面具有明显优势。开郁种玉汤在治疗肝郁型***症显示出较好效果,但是其针对高泌乳素血症型***症、卵泡张力不足及发育不良迟缓症的治疗未见报道。
发明内容
针对以上技术问题,本发明提供一种治疗***症的中药组合物,能够降低泌素激素水平、增长子宫内膜厚度并恢复卵泡正常发育,最终有效助孕。
本发明提供一种治疗***症的中药组合物,其按重量份数计由以下原料组成:当归10-15份、炒白术15-25份、炒白芍20-25份、炒香附子8-12份、牡丹皮10-12份,茯苓12-15份、天花粉7-9份、苦楝子4-6份、路路通10-12份、王不留行6-12份、蒲公英8-12份。
优选地,其按重量份数计由以下原料组成:当归10份、炒白术15份、炒白芍20份、炒香附子12份、牡丹皮12份、茯苓15份、天花粉7份、苦楝子6份、路路通10份、王不留行12份、蒲公英8份。
优选地,所述炒白术为土炒制,所述炒白芍为黄酒炒制,所述炒香附子为醋炒制,所述苦楝子及所述王不留行均为清炒。
本发明还提供了上述治疗***症的中药组合物的制备方法,包括以下步骤:按重量份数称取各中药原料,混合后加水煎煮,收集煎煮液,浓缩,即得所述中药组合物。
优选地,所述加水煎煮的具体步骤是:将各中药原料混合,加入相当于药材总重量6-8倍量的水浸泡30±5min后,煎煮30±5min,过滤,收集第一次滤液;滤渣再次加入相当于药材总重量4-6倍量的水,继续煎煮30±5min,过滤,收集第二次滤液;合并两次滤液,即得所述煎煮液。
优选地,所述浓缩是将所述煎煮液浓缩至含生药量为2g/ml。
本发明还提供了上述治疗***症的中药组合物在制备治疗高泌乳素血症型***症的药物中的应用。
本发明的另一个目的是提供一种用于治疗高泌乳素血症型***症的中药制剂,其以上述中药组合物为活性成分,并辅以药学上可接受的辅料及载体。
本发明提供的治疗***症的中药组合物,方中重用白芍,养血调肝、解其郁;牡丹皮,苦辛微寒,入心、肝血分,专功凉血散瘀,且具有凉血而不留瘀,活血而不妄行的特点,此二药为君;当归、香附子,养血疏肝、解郁柔肝,为臣;佐以白术培土健脾,制约肝克脾土,又以茯苓健脾宁心;使以天花粉滋阴生津,再助养肝阴为最妙;新增王不留行、路路通、蒲公英,三药同入肝胃经,通利血脉、通经络、散结消肿,加入少量苦楝子,此四药为使,四药联用,更增强化解肝气郁结,辅助臣药养血疏肝、解郁柔肝的功效,降低泌乳素功效倍增。全方具有疏肝解郁、滋阴养血、清热除烦的功效,用于经前期紧张综合症、***症伴有血清泌乳素增高,症属肝郁化热、阴血亏虚者。
对比现有技术,本发明的有益效果为:
1、本发明提供的中药组合物,全方具有疏肝解郁、滋阴养血、清热除烦、用于经前期紧张综合症、***症伴有血清泌乳素增高,症属肝郁化热、阴血亏虚者,症见***或闭经,或婚后久不受孕,胸胁或***胀痛,头晕目眩,心烦易怒,失眠,多梦,口燥咽干,腰膝酸软,舌红苔薄黄或薄白而干,脉弦细而数;临床验用结果表明安全、有效、对人体无毒副作用。
2、与传统“开郁种玉汤”比较,临床应用和基础实验结果显示,本方剂可以通过增加其对降低高泌素激素水平、增长子宫内膜厚度及恢复卵泡正常发育的疗效并最终有效助孕。
3、传统“开郁种玉汤”主要用于疏肝解郁、调经种子,治妇人肝气郁结所致的***症;本发明方组治疗高泌乳素血症型***症主要针对泌乳素激素水平较高的肝郁型患者无法成功受孕,主要通过养血疏肝、柔肝健脾的方式进行调理,且根据患者***关键时间节点进行周期性合理用药,达到让患者高泌乳素血征的症状消失、子宫内膜增厚、卵泡发育成熟后成功受孕直至成功生产的目的。
附图说明
图1是在体外诱导原代小鼠子宫内膜上皮MEEC细胞的增殖结果;
图2是在体外诱导人脐静脉血管内皮细胞的增殖结果;
图3是对小鼠体重、卵巢重量、子宫重量的影响;A、体重;B、子宫重量;C、卵巢重量;
图4是PRL模型小鼠卵巢组织的H&E染色结果;A、正常对照组;B、模型组;C、对比例1组;D、对比例2组;E、本发明方组;
图5是高泌乳素血症***症的育龄女性患者的临床B超检测结果;A、治疗前;B、本发明方治疗后。
具体实施方式
下面通过实施例进一步描述本发明,但是本发明不受这些实施例的限制。凡在本发明的精神和原则之内所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
本发明提供一种治疗***症的中药组合物,其按重量份数计由以下原料组成:当归10-15份、炒白术15-25份、炒白芍20-25份、炒香附子8-12份、牡丹皮10-12份、茯苓12-15份、天花粉7-9份、苦楝子4-6份、路路通10-12份、王不留行6-12份、蒲公英8-12份。
上述中药组合物能够治疗高泌乳素血症型***症,于月经前期10天使用。
下面结合具体实施例对本发明提供的中药组合物进行说明:
实施例1
一种治疗***症的中药组合物,其由以下原料组成:当归12g、炒白术15g、炒白芍20g、炒香附子8g、牡丹皮10g、茯苓12g、天花粉9g、苦楝子4g、路路通10g、王不留行6g、蒲公英8g。
实施例2
一种治疗***症的中药组合物,其由以下原料组成:当归15g、炒白术25g、炒白芍25g、炒香附子12g、牡丹皮10g、茯苓15g、天花粉9g、苦楝子6g、路路通12g、王不留行12g、蒲公英12g。
实施例3
一种治疗***症的中药组合物,其由以下原料组成:当归10g、炒白术15g、炒白芍20g、炒香附子12g、牡丹皮12g、茯苓15g、天花粉7g、苦楝子6g、路路通10g、王不留行12g、蒲公英8g。
实施例4
一种治疗***症的中药组合物,其由以下原料组成:当归12g、炒白术20g、炒白芍22g、炒香附子10g、牡丹皮12g、茯苓15g、天花粉8g、苦楝子5g、路路通12g、王不留行8g、蒲公英8g。
实施例5
一种治疗***症的中药组合物,其由以下原料组成:当归15g、炒白术25g、炒白芍20g、炒香附子8g、牡丹皮12g、茯苓15g、天花粉9g、苦楝子6g、路路通10g、王不留行12g、蒲公英8g。
实施例6
一种治疗***症的中药组合物,其由以下原料组成:当归12g、炒白术18g、炒白芍25g、炒香附子12g、牡丹皮10g、茯苓12g、天花粉9g、苦楝子4g、路路通10g、王不留行6g、蒲公英10g。
对比例1
一种治疗***症的中药组合物,其由以下原料组成:白芍30g、香附子9g、当归15g、炒白术15g、牡丹皮9g、茯苓9g、天花粉6g。
对比例2
一种治疗***症的中药组合物,其由以下原料组成:当归10g、炒白术15g、炒白芍20g、炒香附子12g、牡丹皮12g、茯苓15g、天花粉7g、王不留行12g、蒲公英8g。
上述实施例1-6及对比例1-2的中药组合物的制备方法均是按照以下步骤进行:按重量份数称取各中药原料后混合于非铁质煮器后,加入相当于药材总重量6-8倍量的水浸泡30±5min后,煎煮30±5min,过滤,收集第一次滤液;滤渣再次加入相当于药材总重量4-6倍量的水,继续煎煮30±5min,过滤,收集第二次滤液;合并两次滤液,浓缩至含生药量为2g/ml。
下面对本发明提供的中药组合物的治疗效果进行说明:
一、对人源细胞和鼠源原代细胞增殖的影响
1、分离和培养小鼠原代子宫内膜上皮细胞(MEEC)
动物饲养、检疫、处死解剖后,于无菌条件下收集用PBS清洗后的小鼠子宫组织,剪成约1mm3小碎块,用含1mg/ml胶原酶、2ng/ml DNase的消化液于37℃消化30分钟,再用含10%FBS的DMEM培养基终止消化;继续用40μm无菌细胞过滤器收集细胞悬液于离心管中,并用无血清培养基反洗细胞过滤器后,收集细胞过滤器中的腺团块于离心管中,500×g离心5分钟,弃上清,收集沉淀,加如1ml 0.25%胰酶(含EDTA)于37℃摇床孵育10分钟,加9ml培养基终止消化,500×g离心5分钟,弃上清,收集MEEC细胞至细胞培养皿中,于37℃、5%CO2细胞培养箱中培养过夜,开展MEEC纯度鉴定用于后续实验。
2、CCK-8法检测细胞增殖的活性
选取人脐静脉血管内皮细胞HUVEC(ATCC,美国)、原代小鼠子宫内膜上皮细胞(MEEC)培养于含10%FBS、青霉素100U/ml、链霉素100U/ml的DMEM培养基中,按照5×103个细胞(3×103HUVEC细胞)/孔接种于96孔板培养过夜后,用对比例1组(基础方组)、对比例2组(基础方加味王不留行和蒲公英方组)、本发明实施例3(基础方加味王不留行、蒲公英、路路通、苦楝子方组)制备得到的中药组合物分别对细胞(设1.25、2.5、5.0、10.0、15.0、20.0mg/ml等5个浓度梯度,每个浓度5个复孔,并设溶剂对照组)处理48h后,弃去孔板培养基后,加入CKK-8溶液50μl/孔后,置于37℃培养箱内避光孵育2h-4h,用全波长酶标仪(Thermo Lab systems,USA)测定各孔在450nm波长的光吸收值(OD450),计算细胞增殖率值。
3、结果
3.1、CCK-8法检测在体外诱导人脐静脉血管内皮细胞、原代小鼠子宫内膜上皮细胞的增殖活性
结果如图1-2所示。
CCK-8实验结果显示(参照图1),应用对比例1组(即传统“开郁种玉汤”组)、对比例2组(基础方加味王不留行和蒲公英方组)、本发明实施例3提供的中药组合物处理原代小鼠子宫内膜上皮MEEC细胞48h后,本发明实施例3组效果优于对比例1组、对比例2组,呈浓度依赖式地诱导了MEEC细胞的增殖活力。
此外,结果显示(参照图2),实施例3提供的中药组合物可以较好诱导人脐静脉血管内皮细胞HUVEC的增殖活力,例如,5.0mg/ml处理HUVEC细胞48h后,其对细胞增殖的诱导率达到64.65%,证明本发明方具有促进细胞增殖及血管新生的作用。
二、小鼠体内药效学分析实验
1.本发明方在体内改善甲氧氯普胺所致小鼠高泌乳素血症综合征
1.1高泌乳素血症(PRL)小鼠模型的造模及给药方法
将饲养于SPF级屏障***动物室并经检疫后的10周龄雌性昆明小鼠(安徽实验动物中心,安徽)随机分为正常对照组、PRL模型组;模型组小鼠经背部皮下注射0.1ml灭吐灵(即盐酸甲氧氯普胺注射液,国药集团),24mg/kg,正常对照组给予0.1ml生理盐水,每日二次,连续注射6天。于末次给药的次日,称量小鼠体重,10%水合氯醛按照3ml/kg经腹腔注射(i.p.)麻醉小鼠,经腹主动脉穿刺采血后ELISA法测定小鼠血清泌乳素(PRL)水平。小鼠血清泌乳素升高者为PRL小鼠模型造模成功。
随后,将造模成功的PRL模型小鼠随机分为模型组、对比例1组、对比例2组、本发明实施例3组各10只,并取正常对照组10只;各组小鼠均常规同条件喂养。治疗组使用本发明实施例3制备得到的中药组合物给药;对比例1组、对比例2组及本发明实施例3组经口服灌胃治疗20.0g生药/kg,模型组给予等量生理盐水口服灌胃;各组均连续给药20天,并观察动物临床表现。按照上述实验方法称重,解剖各组小鼠采集动脉血进行血清学泌乳素(PRL)水平测定,收集称重小鼠子宫、卵巢等脏器组织后于10%***溶液中固定保存,制备标本用于组织学检测。
1.2组织标本的制备
病理切片的制备包括脱水、浸蜡、包埋、切片、染色、封片等步骤,最后置于显微镜下观察。具体步骤如下:
(1)脱水:取出固定好的小鼠脏器组织,自来水流水下充分冲洗,然后采用梯度浓度的乙醇对固定好的组织进行脱水,即乙醇浓度由低到高,逐层将组织中水分以乙醇置换出来,将组织按照梯度乙醇的浓度为50%处理2h、70%处理2h、80%处理2h、95%(2次)处理各1h、100%(2次)处理个1h的顺序处理;
(2)透明:将脱水处理后的组织浸入二甲苯Ⅰ处理60min和二甲苯Ⅱ处理60min透明;
(3)浸蜡与包埋:将固定好的组织浸入融化的石蜡(55-60℃)中处理40分钟,重复2-3次。然后进行包埋,将蜡块模具放置到包埋机制冷板上,先少量滴加融化的石蜡,在石蜡未完全凝固前,将浸蜡充分的组织立于模具内,待模具底部的石蜡完全凝固后,继续加入新的液态石蜡,淹没整个组织块,然后将包埋框反向固定在模具上,包埋框中继续加入石蜡,待整个蜡块完全凝固后,将模具取下,即为包埋好的蜡块;
(4)切片:将蜡块表面修理平整,直到切下的石蜡薄膜上面可见少量组织时,再将切片机的切片厚度调整为5μm,继续休整蜡块,待肉眼观察切下的石蜡薄膜所涵组织面完整,即可进行切片,切片厚度为4-5μm。将切片薄膜平摊在摊片机中(温度55-60℃)展平组织切片,应用载玻片缓缓向上捞出薄膜切片,使薄膜附着在载玻片中央位置后,将载玻片置烘片机上烘烤2h以上;
(5)脱蜡:二甲苯Ⅰ和Ⅱ各处理20分钟后,梯度乙醇(100%、95%、80%、70%、50%),每次5分钟,最后于蒸馏水中浸泡5分钟;
(6)H&E染色:首先,用0.5%苏木素染色液染色组织切片3分钟,自来水冲洗浮色后,1%氨水反蓝,再用自来水冲洗后,以1%盐酸乙醇分化,将不应着色部分的颜色脱掉,自来水冲洗30分钟以上,对细胞核进行染色。其次,用0.5%伊红溶液进行复染10分钟,使胞质染成红色后,经95%的乙醇2次,每次1分钟,100%的乙醇2次,每次5分钟,进行彻底脱水。再次,将切片浸入二甲苯中2次,每次10分钟进行透明处理;
(7)封片:用中性树胶对染色好的切片进行封片。在连接照相***的生物显微镜下观察组织的病理变化并拍照。
1.4结果
1.4.1对小鼠体重、卵巢重量、子宫重量的影响
结果如图3所示。
由图3可知,与正常对照组比较,模型组小鼠体重无较大变化(P>0.05,图3A)、子宫重量降低(##P<0.01,图3B)、卵巢重量降低(#P<0.05,图3C)。与模型组比较,本发明实施例3组小鼠体重并无变化(P>0.05),且与正常对照组比较无统计学差异,说明本发明方组用药具有较好的初步安全性。
与模型组比较,对比例1组、对比例2组、本发明实施例3组小鼠子宫重量均恢复正常水平,且本发明实施例3组较对比例1组、对比例2组的恢复效果更好(**P<0.01,图3B);与模型组比较,对比例1组、对比例2组、本发明实施例3组小鼠卵巢重量均较模型组升高,其中本发明实施例3组效果最佳(*P<0.05,图3C),与正常对照组无统计学显著性差别;说明本发明实施例3组用药具有较好的效果。
1.4.2对PRL模型小鼠卵巢组织形态学变化的影响
结果如图4所示。
H&E染色结果显示,与正常对照组比较,模型组小鼠的卵巢呈弥漫性囊样重度改变,可见较多大小不一的裹腔,卵泡膜细胞层较厚并可见部分脱落,粒层细胞多数呈扁平或立方形的不完整形态(图4A-B;50×);与模型组、对比例1组、对比例2组比较,本发明实施例3组小鼠卵巢中有黄体和多个卵泡,近成熟期卵泡有***、放射冠,颗粒细胞排列紧密,较为明显地改善了卵巢的病变损伤(图4C-E;50×)。
1.4.3血清性激素水平影响的测定结果
结果如表1所示。
表1对小鼠血清泌乳素(PRL)性激素水平的影响结果
注:泌乳素:Prolactin(PRL)。
由表1可知,与正常对照组比较,PRL模型组小鼠血清泌乳素(PRL)水平显著升高,且有显著的统计学意义(P<0.05);与模型组比较,本发明实施例3方组小鼠血清PRL水平显著降低,而且本发明实施例3方组的改善作用显著优于对比例1组、对比例2组,均有统计学意义(P<0.05)。
三、本发明方对高泌乳素血症临床患者治疗效果分析
1、高泌乳素血症临床患者治疗有效率统计分析
对88个患有高泌乳素血症女性(24岁-40岁)患者的临床检测结果发现,于患者每个月的月经前10天开始连续使用本申请提供的中药组合物10天(每天一剂),计算为一个疗程,连续治疗1-3个疗程后,有效率达到约96%以上。
2、临床患者激素水平统计
结果如表2所示。
表2对高泌乳素血症临床患者血清泌乳素(PRL)水平的影响结果
组别 | 数量(n) | 泌乳素PRL(ng/mL) | SEM |
治疗前 | 88 | 34.83 | 2.86 |
治疗后 | 88 | 16.65 | 2.63 |
由表2可知,对高泌乳素血症***症的女性患者的临床检测发现,泌乳素(PRL)明显升高,使用本申请提供的中药组合物1-3个疗程后,临床检测结果表明,泌乳素PRL明显被下调到正常水平范围,且有显著的统计学意义(P<0.05),提示本发明方有利于恢复卵泡正常发育提高受孕成功率。
3、恢复卵巢功能、卵泡正常发育能力并增强卵泡张力的统计
结果如图5所示。
对高泌乳素血症***症的育龄女性患者的临床检测结果发现,患者由于泌乳素增高导致了双侧卵巢多囊样声像改变、子宫内膜薄型发展(有的子宫内膜厚度仅约为5mm),使用本申请提供的中药组合物1-3个疗程后,子宫形态大小恢复正常、子宫内膜增厚,卵巢功能能恢复到正常水平,较大程度增强卵泡发育并形成发育成熟的卵泡、宫内妊娠,成功受孕并顺利生产。
以上公开的仅为本发明的具体实施例,但是,本发明实施例并非局限于此,任何本领域的技术人员能思之的变化都应落入本发明的保护范围。
Claims (8)
1.一种治疗***症的中药组合物,其特征在于,其按重量份数计由以下原料组成:当归10-15份、炒白术15-25份、炒白芍20-25份、炒香附子8-12份、牡丹皮10-12份、茯苓12-15份、天花粉7-9份、苦楝子4-6份、路路通10-12份、王不留行6-12份、蒲公英8-12份。
2.根据权利要求1所述的治疗***症的中药组合物,其特征在于,其按重量份数计由以下原料组成:当归10份、炒白术15份、炒白芍20份、炒香附子12份、牡丹皮12份、茯苓15份、天花粉7份、苦楝子6份、路路通10份、王不留行12份、蒲公英8份。
3.根据权利要求1或2所述的治疗***症的中药组合物,其特征在于,所述炒白术为土炒制,所述炒白芍为黄酒炒制,所述炒香附子为醋炒制,所述苦楝子及所述王不留行均为清炒。
4.一种权利要求1所述的治疗***症的中药组合物的制备方法,其特征在于,包括以下步骤:按重量份数称取各中药原料,混合后加水煎煮,收集煎煮液,浓缩,即得所述中药组合物。
5.根据权利要求4所述的治疗***症的中药组合物的制备方法,其特征在于,所述加水煎煮的具体步骤是:将各中药原料混合,加入相当于药材总重量6-8倍量的水浸泡30±5min后,煎煮30±5min,过滤,收集第一次滤液;滤渣再次加入相当于药材总重量4-6倍量的水,继续煎煮30±5min,过滤,收集第二次滤液;合并两次滤液,即得所述煎煮液。
6.根据权利要求4所述的治疗***症的中药组合物的制备方法,其特征在于,所述浓缩是将所述煎煮液浓缩至含生药量为2g/ml。
7.一种权利要求1所述的治疗***症的中药组合物在制备治疗高泌乳素血症型***症的药物中的应用。
8.一种用于治疗高泌乳素血症型***症的中药制剂,其特征在于,其以权利要求1所述的中药组合物为活性成分,并辅以药学上可接受的辅料及载体。
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