CN116392563A - 一种治疗乳腺结节的中药组合物及其制剂和应用 - Google Patents
一种治疗乳腺结节的中药组合物及其制剂和应用 Download PDFInfo
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Abstract
本发明公开了一种治疗乳腺结节的中药组合物及其制剂和应用,属于中医药及网络药理学技术领域,所述中药组合物包含如下重量份的原料药:浙贝母、半夏、鳖甲、柴胡、香附、山慈菇、乳香、没药、郁金、黄芪、当归、熟地。本发明的中药组合物所用原料价廉,制备简便,使用方便,经多年临床应用和药理研究,在缩小乳腺结节、减少结节数目发展与反复发作、大大减少其生长与恶化可能等方面疗效显著。本发明的中药组合物相关作用机理明确,并且通过网络药理学研究,为临床遣方用药提供了更多选择与探讨依据。
Description
技术领域
本发明涉及中医药及网络药理学技术领域,特别是涉及一种治疗乳腺结节的中药组合物及其制剂和应用。
背景技术
随着社会及生活压力的增加与各方面环境的影响,乳腺结节在女性群体中的发病率逐年升高。临床可能患乳腺良性结节者约有50%,其中非绝经期女性约90%为良性。现代医学认为乳腺结节为乳房腺体的囊性增生类疾病,是乳腺包括导管及小叶的结缔组织生长异常导致,其发病因素与压力、情绪等关系密切,但对于早期乳腺结节西医方面并无特效疗法与特异性药物,临床治疗一般以外科手术切除并行细胞学检查为主,但手术治疗易生成疤痕影响美观。但临床中患者多见手术后复发结节或者复发多发纤维瘤等情况更为困扰。并且良性结节依然存在许多临床病例不能完全排除恶性可能或则和存在恶变趋势等。
在中医方面,乳腺结节多属于“乳中结核”、“乳癖”的范畴,《疡医大全》中陈实功曰:“乳癖乃乳中结核,形如丸卵,或坠重作痛,或不痛,皮色不变,其核随喜怒消长,多由思虑伤脾,怒恼伤肝,郁结而成也”,其基础致病机制为情志内伤,肝脾郁滞进而气血失调,痰瘀凝滞。李敏指出乳癖可见于西医所讲的乳腺的小叶增生、囊性增生及纤维瘤等多种乳腺结节类疾病,与肝经、脾经、胃经及冲任二脉此类主女子胎产经带的经脉密切相关。临床表现多为乳房不适或见局部疼痛或痛引肩臂,扪之见或不见硬块肿物,超声检查下可见囊性或不等回声结节多数伴乳腺增生存在,并伴有汗出失调、脾气急躁易怒或乏力忧郁或悲伤易哭或口干口苦及失眠多梦等证候。故中医临床治疗以疏肝理脾、行气止痛、调和冲任为主要原则。中药方面,高秉钧逍遥散加减疏肝导滞汤治乳癖,景岳疏肝清热疗乳症,汪机青皮汤加减四物安乳证,陈自明连翘饮子加减八珍而消乳核。
虽然目前中医对于治疗乳腺结节已有广泛研究,但目前临床治疗乳腺结节多以定期复查与外科手术为主,对于良性与性质不确定的乳腺结节类疾病目前暂无明确的针对性药物,现有相关中成药物不能满足患者缓解症状与消散结节的需求,作用机制不明确,且久服伤及脾胃。
发明内容
基于此,有必要针对目前用于治疗乳腺结节的中药组方治疗效果欠佳、临床作用机制不明确等问题,提供一种治疗乳腺结节的中药组合物及其制剂和应用。
本发明提供了一种治疗乳腺结节的中药组合物,所述中药组合物包含如下原料药:浙贝母、半夏、鳖甲、柴胡、香附、山慈菇、乳香、没药、郁金、黄芪、当归、熟地。
优选地,所述中药组合物包含如下重量份的原料药:浙贝母10-30份、半夏5-15份、鳖甲5-20份、柴胡5-20份、香附5-20份、山慈菇10-30份、乳香5-20份、没药5-20份、郁金5-20份、黄芪10-60份、当归10-45份、熟地10-45份。
优选地,所述中药组合物包含如下重量份的原料药:浙贝母15份、半夏9份、鳖甲10份、柴胡12份、香附10份、山慈菇10份、乳香10份、没药10份、郁金12份、黄芪30份、当归15份、熟地15份。
本发明还提供了一种治疗乳腺结节的中药制剂,所述中药制剂由前任一技术方案中所述的治疗乳腺结节的中药组合物制备得到。
优选地,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照质量份称取鳖甲,加入5-10倍质量份的水浸泡30-120分钟;
(2)按照质量份称取其余原料药,加入5-10倍质量份的水浸泡30-120分钟;
(3)将浸泡后的鳖甲连水一同加热煎煮,过滤,收集滤液
(4)将浸泡后的其余原料药连水一同加热煎煮,过滤,收集滤液;
(5)将步骤(3)和(4)的滤渣合并,重新加入5-10倍质量份的水,煎煮,过滤,收集滤液;
(6)将三次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
优选地,两次煎煮的时间均为30-60分钟。
优选地,滤液合并后加热浓缩至原体积的10%-20%。
此外,本发明还提供了如前任一技术方案中所述的治疗乳腺结节的中药组合物在制备治疗乳腺结节的药物中的应用。
本发明治疗乳腺结节的中药组合物方解如下:
本发明治疗乳腺结节的中药组合物中,浙贝、山慈菇清热解毒、化痰散结,为君药;柴胡、香附疏肝解郁,调经止痛,为臣药;配伍半夏以行中焦,燥湿化痰散结;鳖甲滋阴,清热除蒸、软坚散结;配以乳香、没药与郁金,行活血止痛、行气解郁之功,黄芪、当归并熟地共奏益气养血、补血活血、滋阴清热、调经止痛之效;该中药组合物的诸药合用,气血同调,标本兼顾,共奏软坚散结,养血益气、疏肝调经之功效。
具体地,各中药原料药具有以下药理特性:
山慈菇:为兰科植物杜鹃兰Cremastra appendiculata(D.Don)Makino、独蒜兰Pleione bulbocodioides(Franch.)Rolfe或云南独蒜兰Pleione yunnanensis Rolfe的干燥假鳞茎,味甘、微辛,凉。归肝、脾经,有清热解毒,化痰散结之功效;
浙贝母:为百合科植物浙贝母Fritillaria thunbergii Miq.的干燥鳞茎,味苦,寒。归肺、心经,有清热化痰止咳,解毒散结消痈之功效;
柴胡:为伞形科植物柴胡Bupleurum chinenseDC.或狭叶柴胡Bupleurumscorzonerifolium Willd.的干燥根,味辛、苦,微寒。归肝、胆、肺经,有疏散退热,疏肝解郁,升举阳气之功效;
香附:为莎草科植物莎草Cyperus rotundus L.的干燥根茎,味辛、微苦、微甘,平。归肝、脾、三焦经,有疏肝解郁,理气宽中,调经止痛之功效;
半夏:为天南星科植物半夏Pinellia ternata(Thunb.)Breit.的干燥块茎,味辛、温;有毒。归脾、胃、肺经,有燥湿化痰,降逆止呕,消痞散结之功效;
鳖甲:为鳖科动物鳖Trionyx sinensis Wiegmann的背甲,味咸,微寒。归肝、肾经,有滋阴潜阳,退热除蒸,软坚散结之功效;
乳香:为橄榄科植物乳香树Boswellia carterii Birdw.及同属植物Boswelliabhaw-dajiana Birdw.树皮渗出的树脂,味辛、苦,温。归心、肝、脾经,有活血定痛,消肿生肌之功效;
没药:为橄榄科植物地丁树Commiphora myrrha Engl.或哈地丁树Commiphoramolmol Engl.的干燥树脂,味辛、苦,平。归心、肝、脾经,有散瘀定痛,消肿生肌之功效;
郁金:为姜科植物温郁金Curcuma wenyujin Y.H.Chen et C.Ling、姜黄CurcumaLonga L.、广西莪术Curcuma kwangsiensis S.g.Lee et C.F.Liang或蓬莪术Curcumaphaeocaulis Vai.的干燥块根,味辛、苦,寒。归肝、心、肺经,有活血止痛,行气解郁,清心凉血,利胆退黄之功效;
黄芪:为豆科植物蒙古黄芪Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao或膜荚黄芪Astragalus membranaceus(Fisch.)Bge.的干燥根,味甘,微温。归肺、脾经,有补气升阳,固表止汗,利水消肿,生津养血,行滞通痹,托毒排脓,敛疮生肌之功效;
当归:为伞形科植物当归Angelica sinensis(Oliv.)Diels的干燥根,味甘、辛,温。归肝、心、脾经,有补血活血,调经止痛,润肠通便之功效;
熟地:为玄参科植物地黄Rehmannia glutinosa Libosch.的新鲜或干燥块根的炮制品,味甘,微温。归肝、肾经,有补血滋阴,益精填髓之功效。
本发明治疗乳腺结节的中药组合物经网络药理学研究得出作用机制、靶点和通路具体情况如下:
通过网络药理学方法筛选出本发明治疗乳腺结节的中药组合物的主要有效成分共128个,发现β-谷甾醇、豆甾醇、异鼠李素、姜黄素及葛根素等为其核心成分。有研究表明,β-谷甾醇为膳食植物甾醇的一种,除抗炎作用外对多种癌症有抗癌活性,认为其鞘磷脂循环活化与其抗癌活性、启动凋亡细胞死亡程序及细胞周期停滞相关,并可抑制乳腺癌(MCF-7和MDB-MB-231)。其中豆甾醇具有抗炎、免疫调节及神经保护等多方面作用,可下调TNF-α和VEGFR-2信号而抑制肿瘤细胞血管生成。异鼠李素是天然存在的小分子黄酮类化合物,具有抗炎、抗癌等多种作用,异鼠李素可阻滞细胞周期、诱导细胞凋亡,通过下调Bcl-2以增加Bax的表达,促进PI3K/Akt/mTOR通路的激活,促进细胞凋亡,也能通过增强caspase3、caspase9蛋白的切割来诱导癌细胞的凋亡。姜黄素与葛根素均有明显确切乳腺相关的抗炎及抗癌活性作用。其中葛根素还具有雌激素活性作用;也可调节乳腺癌中的miR-133a-3p促进DUSP1表达从而治疗乳腺癌。
通过Cytoscape3.9.1软件构建蛋白-蛋白互作网络图,发现AKT1、IL6、EGFR及ESR1等为其重要基因。其中AKT,又称蛋白激酶B,也是PI3K/AKT通路重要基因,对乳腺细胞生长,转移和血管生成有明显影响,AKT1通过调控p21与p27及cyclinD1等促进细胞增殖,调控p53以抑制凋亡;也可调控TSC2等蛋白减少细胞侵袭、转移,从而抑制乳腺结节生成,加速其消散速度,进一步防止结节增大。研究表明,细胞因子白细胞介素6(IL6)及其下游效应子STAT3与乳腺癌中的雌激素受体α(ER)功能相关,乳腺变化受激素周期变化影响,调控其细胞因子以抑制激素受体作用表达异常进而控制乳腺结节发展。EGFR可是调节上皮组织生长与平衡,是癌细胞的驱动因子,是乳腺相关疾病的危险因素,其受体在乳腺发育中具有重要作用,抑制EGFR失控维持上皮细胞稳定可减少异常增生与结节。ESR1为雌激素受体,乳腺为该受体重要作用器官受下丘脑-垂体-卵巢轴调控,激素平衡受到影响时,乳房腺体组织对相关激素敏感性会异常增高,进而发生病变。而中药复方及有效成分通过共同作用靶点与基因调控乳腺结节的发生发展进而达到改善症状治疗结节防止恶化的临床效果。
根据GO和KEGG富集分析结果发现,本发明的中药组合物治疗乳腺结节作用机制主要包含血管内皮生长因子、炎症与癌症因子、细胞黏附、蛋白聚糖、及激素调节等方面。
本发明与现有技术相比具有如下优点:
本发明的中药组合物所用原料价廉,制备简便,使用方便,经多年临床应用和药理研究,在缩小乳腺结节、减少结节数目发展与反复发作、大大减少其生长与恶化可能等方面疗效显著。
本发明的中药组合物中药物治疗乳腺结节核心化合物为β-谷甾醇、豆甾醇、异鼠李素、姜黄素及葛根素等,可通过PI3K-Akt、MAPK、Ras及Rap1信号传导通路调控AKT1、IL6、EGFR、SRC及ESR1等靶点,作用于乳腺器官,从而改善患者临床不适,以达到抑制乳腺结节生成与发展甚或消散结节以治疗乳腺结节的作用,相关作用机理明确。同时通过网络药理学研究,为临床遣方用药提供了更多选择与探讨依据。
附图说明
图1为本发明实施例中药组合物治疗乳腺结节的潜在治疗靶点和乳腺结节疾病靶点的韦恩图;
图2为本发明实施例117个潜在治疗靶点的蛋白-蛋白互作网络图;
图3为本发明实施例中药组合物重要功能模块基因图;
图4为本发明实施例中药组合物潜在核心基因靶点图;
图5为本发明实施例中药组合物潜在治疗靶点GO功能富集分析图;
图6为本发明实施例中药组合物潜在治疗靶点KEGG通路富集分析图。
具体实施方式
一种治疗乳腺结节的中药组合物,所述中药组合物包含如下原料药:浙贝母、半夏、鳖甲、柴胡、香附、山慈菇、乳香、没药、郁金、黄芪、当归、熟地。
在其中一个较佳的实施例中,所述中药组合物包含如下重量份的原料药:浙贝母10-30份、半夏5-15份、鳖甲5-20份、柴胡5-20份、香附5-20份、山慈菇10-30份、乳香5-20份、没药5-20份、郁金5-20份、黄芪10-60份、当归10-45份、熟地10-45份。
在其中一个较佳的实施例中,所述中药组合物包含如下重量份的原料药:浙贝母15份、半夏9份、鳖甲10份、柴胡12份、香附10份、山慈菇10份、乳香10份、没药10份、郁金12份、黄芪30份、当归15份、熟地15份。
一种治疗乳腺结节的中药制剂,所述中药制剂由前任一技术方案中所述的治疗乳腺结节的中药组合物制备得到。
在其中一个较佳的实施例中,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照质量份称取鳖甲,加入5-10倍质量份的水浸泡30-120分钟;
(2)按照质量份称取其余原料药,加入5-10倍质量份的水浸泡30-120分钟;
(3)将浸泡后的鳖甲连水一同加热煎煮,过滤,收集滤液
(4)将浸泡后的其余原料药连水一同加热煎煮,过滤,收集滤液;
(5)将步骤(3)和(4)的滤渣合并,重新加入5-10倍质量份的水,煎煮,过滤,收集滤液;
(6)将三次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
在其中一个较佳的实施例中,两次煎煮的时间均为30-60分钟。
在其中一个较佳的实施例中,滤液合并后加热浓缩至原体积的10%-20%。
所述治疗乳腺结节的中药组合物可以应用于制备治疗乳腺结节的药物中。
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似改进,因此本发明不受下面公开的具体实施例的限制。
实施例1
治疗乳腺结节的中药组合物有效成分的筛选
利用中药系统药理学数据库(TCMSP,http://lsp.Nwsuaf.edu.cn/tcmsp.php)、TCMID(http://www.megabionet.org/tcmid/)、symMap数据库等常用中药数据库收集本发明的中药组合物12味中药的有效成分,并以口服生物利用度(oral bioavailability,OB)≥30%及类药性指数(drug-like index,DL)≥0.18为标准筛选活性化合物。
在上述常用中药数据库中检索整合得到本发明中药组合物有效成分128个(其中浙贝母7个、半夏13个、鳖甲2个、柴胡17个、香附18个、山慈菇3个、乳香8个、没药45个、郁金15个、黄芪20个、当归2个、熟地2个,部分成分有重复),如表1所示(列出每味药前5位有效成分)。
表1中药组合物的主要有效成分
实施例2
治疗乳腺结节的中药组合物药物作用靶点筛选、乳腺结节相关靶点收集及治疗乳腺结节潜在靶点预测
在PubChem中检索药物化合物对应的SMILES结构,并在Swiss Target Prediction数据库中查找其有效对应靶点,保留“Probability>0.12”的靶点。
在GengCards疾病基因数据库中以“Breast Nodules”为关键词,以“Homosapiens”及“SCORE≥2”为条件检索并筛选乳腺结节相关靶点。
将药物靶点与疾病基因在Venny2.1中进行韦恩分析,以筛选出潜在治疗靶点;在STRIG中绘制蛋白-蛋白互连作业网络图;并在Cytoscape 3.9.1中可视化,同时应用cytoHubba插件筛选出核心基因及作用靶点。
在Swiss Target Prediction中检索整合得到本发明中药组合物128个有效成分共包含256个靶点;在疾病基因数据库中检索并删除重复后得到1996个乳腺结节相关作用靶点。将256个药物靶点与1996个疾病基因进行基因映射,分析后得到117个潜在治疗靶点,见图1。在STRING中对117个靶点进行蛋白-蛋白互作网络分析并绘图,见图2。在Cytoscape中可视化,包含个116节点,1071条边,并应用cytoHubba插件筛选出TOP10关键作用靶点,见图3;同时取节点连接度排名前15的靶点绘制条形图,见图4。
实施例3
治疗乳腺结节的中药组合物治疗乳腺结节潜在相关靶点的功能富集分析
以“Homo sapiens”为条件,在DAVID数据库中对潜在治疗靶点进行GO功能富集分析与KEGG通路富集分析,其中“FDR<0.05”的条目有意义。
将得到的117个潜在治疗靶点进行GO功能富集分析后,得到137条结果,根据FDR值筛选后,符合要求的BP有40项、CC有8项、MF有35项,各取其前10个条目可视化分析,见图5。在BP方面,涉及RNA聚合酶II启动子转录正向与负向调节、蛋白质磷酸化与自磷酸化、跨膜受体蛋白酪氨酸激酶信号传导途径及DNA诱导型转录正向调节等;在CC中,涉及浆膜成分、受体复合物、染色质及微管细胞骨架等;在MF方面,包含ATP结合、锌离子结合、蛋白激酶活性及跨膜受体蛋白酪氨酸激酶活性等。
将117个潜在治疗靶点进行KEGG通路富集分析后,共得到117条通路,其中有87条符合条件,取前25条通路可视化分析,相关通路主要有PI3K-Akt信号传导通路、MAPK信号传导通路、Ras信号传导途径及Rap1信号传导通路等,见图6。
实施例4
治疗乳腺结节的中药组合物的实际临床应用
病例1:郭某,女,2022年2月25号首诊,诉发现左侧乳腺结节2月,2021年12月27日乳腺超声提示:右乳切除术后,腺体稍增厚、紊乱,回声不均,左乳12点方向约0.5×0.3cm低回声结节。患者2020年曾确诊右乳浸润性癌,并行右乳切除术,术后恢复尚可。自诉平素一般情况尚可,时有颈椎关节处疼痛,大便溏结不调,舌淡黯苔白腻,脉虚数稍弦。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉服药后大便情况好转,颈椎、关节疼痛明显改善且无不良反应,复查乳腺超声提示(2022-3-30):右乳切除术后,腺体稍增厚、紊乱,回声不均,左乳未见。随诊5月,患者结节消散,乳腺超声提示:右乳同前,左乳未见结节。
病例2:陈某,女,35岁,2022年9月26首诊。诉发现乳腺结节半个月。患者平素性情急躁,易烦躁,睡眠差,多梦易醒,常常容易疲劳,有时汗出,时或胃中不适,消化稍差,偶尔关节疼痛。乳腺超声提示(2022-9-9):双侧乳腺小叶增生,内部散在片状、条索状低回声区左乳低-无回声结节,约7×3mm,双乳导管扩张,较宽处左16.mm,右1.7mm;双侧腋窝多发淋巴结,大者右侧12×6mm,左侧14×4mm。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉服药后自诉情绪及症状均见好转,睡眠改善、疼痛减轻,余下皆有明显好转,且无不良反应,后定期复诊,随证加减。随诊3月余,复查增生改善,结节消散。(2022-11-25)乳腺超声提示:双乳腺体增厚,内部散在片状、条索状低回声区,未见结节;左乳局部导管扩张,较宽处1.8mm,双侧腋窝未见异常。
病例3:王某,女,50岁,2022年4月1号首诊,诉发现乳腺结节1年余,查右侧见低回声结节,平素情绪急躁易生气,偶尔失眠,口干,心悸数月,小便色黄,大便溏舌暗红苔薄白。乳腺超声:(2021-4-20)提示:右乳散在4个类圆形低密度灶,较大者直径约1.9cm,右乳外上象限局限钙化灶。(2021-10-21)提示:右乳多个低回声结节,较大者于10点钟方向,约0.8×0.4cm。(2022-3-9)提示:右乳多发结节,较大者10点钟方向低回声,约0.8×0.4cm。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉服药后自诉症状好转,情绪较前明显平和,失眠口干心悸等明显好转,且无不良反应,后定期复诊,随证加减。随诊3月余,复查乳腺结节较前明显减小,(2022-7-8)乳腺超声提示:右乳3点方向乳头旁可见大小约0.4×0.3cm低回声结节。
虽然在实施例中已经通过一般性说明、具体实施方式及试验对本发明作出了详尽的描述,但在不偏离本发明核心的基础上,仍可以作出的修改或改进,均属于本发明要求保护的范围。
Claims (8)
1.一种治疗乳腺结节的中药组合物,其特征在于,所述中药组合物包含如下原料药:浙贝母、半夏、鳖甲、柴胡、香附、山慈菇、乳香、没药、郁金、黄芪、当归、熟地。
2.根据权利要求1所述的治疗乳腺结节的中药组合物,其特征在于,所述中药组合物包含如下重量份的原料药:浙贝母10-30份、半夏5-15份、鳖甲5-20份、柴胡5-20份、香附5-20份、山慈菇10-30份、乳香5-20份、没药5-20份、郁金5-20份、黄芪10-60份、当归10-45份、熟地10-45份。
3.根据权利要求2所述的治疗乳腺结节的中药组合物,其特征在于,所述中药组合物包含如下重量份的原料药:浙贝母15份、半夏9份、鳖甲10份、柴胡12份、香附10份、山慈菇10份、乳香10份、没药10份、郁金12份、黄芪30份、当归15份、熟地15份。
4.一种治疗乳腺结节的中药制剂,其特征在于,所述中药制剂由权利要求1-3任一项所述的治疗乳腺结节的中药组合物制备得到。
5.根据权利要求4所述的治疗乳腺结节的中药制剂,其特征在于,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照质量份称取鳖甲,加入5-10倍质量份的水浸泡30-120分钟;
(2)按照质量份称取其余原料药,加入5-10倍质量份的水浸泡30-120分钟;
(3)将浸泡后的鳖甲连水一同加热煎煮,过滤,收集滤液
(4)将浸泡后的其余原料药连水一同加热煎煮,过滤,收集滤液;
(5)将步骤(3)和(4)的滤渣合并,重新加入5-10倍质量份的水,煎煮,过滤,收集滤液;
(6)将三次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
6.根据权利要求5所述的治疗乳腺结节的中药制剂,其特征在于,两次煎煮的时间均为30-60分钟。
7.根据权利要求5所述的治疗乳腺结节的中药制剂,其特征在于,滤液合并后加热浓缩至原体积的10%-20%。
8.根据权利要求1-3任一项所述的治疗乳腺结节的中药组合物在制备治疗乳腺结节的药物中的应用。
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