CN116270941B - 一种具有改善由表皮生长因子受体抑制剂引起皮肤不良反应功效的中药组合物及其制药用途 - Google Patents
一种具有改善由表皮生长因子受体抑制剂引起皮肤不良反应功效的中药组合物及其制药用途 Download PDFInfo
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Abstract
本发明涉及一种具有益气清热功效的中药组合物及其应用,所述中药组合物包括如下中药原料:黄芪、当归、金银花、甘草、乌梅、五味子、土茯苓、白鲜皮、薄盖灵芝、防风、紫草、莪术、白芍、柴胡。本发明所涉及的中药组合物中各中药组分相辅相成,具有益气活血,清热解毒,化瘀祛湿的功效。本发明通过药理试验表明,本发明所涉及的中药复方组合物能够改善EGFRI所致皮肤不良反应小鼠模型的表观特征,改善小鼠皮肤表型,增加皮肤含水量,改善皮肤炎症状态,同时临床经验表明其可改善靶向药所致皮肤不良反应,具有广阔的应用前景。
Description
技术领域
本发明属于中药制剂技术领域,涉及一种具有益气清热功效的中药组合物及其应用,尤其涉及一种具有益气清热功效的中药组合物及其在制备改善由表皮生长因子受体抑制剂引起的皮肤不良反应的药物中的应用。
背景技术
表皮生长因子受体抑制剂(EGFRI)对于EGFR基因突变的肿瘤患者具有良好的治疗效果,然而,临床观察发现,EGFRI的应用常伴有皮肤不良反应,严重者甚至被迫中断靶向药治疗。
虽然目前治疗皮肤不良反应的药物种类较多,能达到一定的预防或缓解症状的目的,但主要集中于抗过敏药物、激素和抗生素等,如抗过敏药物苯海拉明、异丙嗪、西替利嗪等,激素产品强的松、氢化考的松、地塞米松等,但这些治疗药物的长期使用容易产生耐药性或某些难以忍受的不良反应。同时,这些皮肤不良反应治疗后很容易复发,需要一直用药,给患者带来很大的痛苦,也相应增加了患者家庭的经济负担。
中药作为中国医药的瑰宝之一,其在治疗或缓解皮肤疾病方面展现了良好的临床效果,现阶段专门针对靶向肿瘤治疗药物引起皮肤不良反应的中药、中药复方或中成药制剂还比较少。中医临床证候观察发现,靶向药相关性皮肤不良反应大部分表现为皮肤干燥、变薄伴瘙痒,甚至皲裂,并多伴有乏力、气短、心烦等表现,舌象多为色暗红、少苔、质干,脉多沉细,病因应属本虚标实,以气虚毒聚、血燥热结为主。根据皮肤病形成机制和临床症状,开发新的中药治疗处方和现代化制剂是非常有意义的。
发明内容
针对现有技术的不足,本发明的目的在于提供一种具有益气清热功效的中药组合物及其应用,尤其提供一种具有益气清热功效的中药组合物及其在制备改善由表皮生长因子受体抑制剂引起的皮肤不良反应的药物中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种具有益气清热功效的中药组合物,所述中药组合物包括如下中药原料:黄芪、当归、金银花、甘草、乌梅、五味子、土茯苓、白鲜皮、薄盖灵芝、防风、紫草、莪术、白芍、柴胡。
本发明所涉及的中药组合物中各中药组分相辅相成,具有益气活血,清热解毒,化瘀祛湿的功效。方中黄芪性甘,微温,入肺、脾经,益气升阳固表,为补中益气之要药,又能升举阳气。金银花性寒,味甘,清热解毒疏散风热,大凡外疡内痈,热毒壅盛皆宜;其芳香疏散,入肺经,可疏散风热,透热达表。当归性温,味甘辛,入心、肝经,活血补血养血,为养血之要药;性温,又能温散寒凝,血滞能通,血虚能补。以上三味可奏益气活血清热解毒之功,共为君药。
方中灵芝性平,味甘,归肺、肝经,可补气养血;防风性微温,味甘、辛,可祛风、固表,以上二味与黄芪合用可加强黄芪补益肺气固表之力,共为臣药。
方中白芍性微寒,味苦、酸,入肝、脾经,可养血,敛阴津;柴胡性微寒,味苦、辛,归肝、脾经,可疏肝解郁,能条达木郁,畅通气血;莪术性温,味辛、苦,归肝、脾经,可行气破血,既可入血分,又可入气分。以上三味与当归合用可加强活血养血、疏肝益气之力,共为臣药。
方中土茯苓性平,味甘淡,可解毒清热除湿;白鲜皮性寒,味苦,入脾胃经,可清热燥湿解毒,可“行水道”,可导湿热之邪从小便而出;紫草性寒,味甘、咸,归肝经,可清热解毒,凉血,善能“清理血分之热”,并能行血解毒。以上三味与金银花合用可加强清热解毒祛湿之力,共为臣药。
方中五味子性温,味酸、甘,归肺、心经,可收敛肺气,酸能收敛,甘能补虚,能敛能补,标本兼得;乌梅性平,味酸涩,归肺、肝、脾经,可敛肺生津。以上二者合用,收敛肺气耗散之金,以助补益肺气之力,为佐药。
方中甘草性平,味甘,归肺、脾经,可补脾益气,清热解毒,调和诸药,味甘,能益气养心,健运脾胃,性平入肺,亦可益气补肺,能使“调和诸药相协,共为力而不争”,故号国老之名,则为使药。
本发明通过药理试验表明,本发明所涉及的中药复方组合物能够改善EGFRI所致皮肤不良反应小鼠模型的表观特征,改善小鼠皮肤表型,增加皮肤含水量,改善皮肤炎症状态,同时临床经验表明其可改善靶向药所致皮肤不良反应,具有广阔的应用前景。
优选地,所述中药组合物以重量份数计包括如下中药原料:黄芪20-30份、当归20-30份、金银花20-30份、甘草5-10份、乌梅5-10份、五味子5-10份、土茯苓10-20份、白鲜皮10-20份、薄盖灵芝5-10份、防风10-20份、紫草10-20份、莪术10-20份、白芍10-25份、柴胡10-20份。
本发明所涉及的中药组合物中各中药组分按照上述特定的质量配比进行配合时,其在改善EGFRI所致皮肤不良反应方面的功效更为显著。
所述黄芪的重量份数例如可以是20份、22份、23份、24份、25份、26份、27份、28份、29份、30份等;所述当归的重量份数例如可以是20份、22份、23份、24份、25份、26份、27份、28份、29份、30份等;所述金银花的重量份数例如可以是20份、22份、23份、24份、25份、26份、27份、28份、29份、30份等;所述甘草的重量份数例如可以是5份、6份、7份、8份、9份、10份等;所述乌梅的重量份数例如可以是5份、6份、7份、8份、9份、10份等;所述五味子的重量份数例如可以是5份、6份、7份、8份、9份、10份等;所述土茯苓的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等;所述白鲜皮的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等;所述薄盖灵芝的重量份数例如可以是5份、6份、7份、8份、9份、10份等;所述防风的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等;所述紫草的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等;所述莪术的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等;所述白芍的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份、22份、25份等;所述柴胡的重量份数例如可以是10份、12份、13份、14份、15份、16份、17份、18份、19份、20份等。
上述各项数值范围内的其他具体点值均可选择,在此便不再一一赘述。
更优选地,所述中药组合物以重量份数计包括如下中药原料:黄芪28-30份、当归28-30份、金银花28-30份、甘草8-10份、乌梅7-9份、五味子6-8份、土茯苓14-16份、白鲜皮14-16份、薄盖灵芝7-9份、防风14-16份、紫草17-20份、莪术10-13份、白芍18-22份、柴胡14-16份。
优选地,所述中药组合物由包括如下步骤的制备工艺制得:
将各中药原料按配方量混合后用水浸泡,然后大火进行煎煮,待水沸腾后改用文火继续煎煮,过滤,得滤液即所述中药组合物。
本发明所涉及的中药组合物的制备工艺简单易操作,便于实现工业化大规模生产,具有实用性。
优选地,所述用水浸泡的时间为20-50min,例如20min、25min、30min、35min、40min、45min、50min等。
优选地,所述水的用量为中药原料质量的7-15倍,例如7倍、8倍、9倍、10倍、12倍、13倍、15倍等。
优选地,所述文火继续煎煮的时间为30-60min,例如30min、35min、40min、45min、50min、55min、60min等。
优选地,所述滤液为煎煮1-3次合并的滤液,例如1次、2次或3次。
上述各项数值范围内的其他具体点值均可选择,在此便不再一一赘述。
本发明所涉及的中药组合物按照上述特定的工艺参数进行制备时,得到的产物在改善EGFRI所致皮肤不良反应方面的功效更为显著。
第二方面,本发明提供一种根据第一方面所述的具有益气清热功效的中药组合物在制备改善由表皮生长因子受体抑制剂引起的皮肤不良反应的药物中的应用。
优选地,所述表皮生长因子受体抑制剂包括吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达可替尼、奥希替尼、阿美替尼或伏美替尼。
第三方面,本发明提供一种具有改善由表皮生长因子受体抑制剂引起皮肤不良反应功效的药物,所述药物的功效成分为第一方面所述的具有益气清热功效的中药组合物。
优选地,所述药物的剂型包括片剂、胶囊剂、颗粒剂或溶液剂。
优选地,所述药物还包括药学上可接受的辅料。
优选地,所述辅料包括稀释剂、调味剂、粘合剂、填充剂、增稠剂、崩解剂、助溶剂、助悬剂、润滑剂或缓冲剂中的任意一种或至少两种的组合。
第四方面,本发明提供一种抗肿瘤的联合用药物组合物,所述联合用药物组合物包括表皮生长因子受体抑制剂和第一方面所述的具有益气清热功效的中药组合物。
优选地,所述表皮生长因子受体抑制剂包括吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达可替尼、奥希替尼、阿美替尼或伏美替尼。
优选地,所述联合用药物组合物为单一复方制剂或两种单独制剂的组合。
优选地,所述联合用药物组合物为两种单独制剂的组合,两种单独的制剂同时施用或依次施用。
优选地,所述联合用药物组合物的剂型包括片剂、胶囊剂、颗粒剂或溶液剂。
优选地,所述联合用药物组合物还包括药学上可接受的辅料。
优选地,所述辅料包括稀释剂、调味剂、粘合剂、填充剂、增稠剂、崩解剂、助溶剂、助悬剂、润滑剂或缓冲剂中的任意一种或至少两种的组合。
第五方面,本发明还提供一种治疗EGFR基因突变的肿瘤患者的方法,所述方法包括:同时地、依次地或交替地给予患者有效剂量的表皮生长因子受体抑制剂和第一方面所述的具有益气清热功效的中药组合物。
相对于现有技术,本发明具有以下有益效果:
本发明所涉及的中药组合物中各中药组分相辅相成,具有益气活血,清热解毒,化瘀祛湿的功效。方中黄芪性甘,微温,入肺、脾经,益气升阳固表,为补中益气之要药,又能升举阳气。金银花性寒,味甘,清热解毒疏散风热,大凡外疡内痈,热毒壅盛皆宜;其芳香疏散,入肺经,可疏散风热,透热达表。当归性温,味甘辛,入心、肝经,活血补血养血,为养血之要药;性温,又能温散寒凝,血滞能通,血虚能补。以上三味可奏益气活血清热解毒之功,共为君药。
附图说明
图1是各组小鼠面部皮肤状态图;
图2是各组小鼠背部皮肤状态及表皮厚度(HE染色)差异图;
图3是各组小鼠背部皮肤含水量检测结果统计图,“*”表示与模型组相比具有统计学意义,**p<0.01;
图4是各组小鼠皮肤炎症状态评分结果统计图,“*”表示与模型组相比具有统计学意义,**p<0.01,****p<0.001。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
制备例1
本制备例提供一种具有益气清热功效的中药组合物,其配方如下:
黄芪30份、当归30份、金银花30份、甘草10份、乌梅8份、五味子7份、土茯苓15份、白鲜皮15份、薄盖灵芝8份、防风15份、紫草18份、莪术12份、白芍20份、柴胡15份。
制备工艺为:将各中药原料按配方量混合后用10倍质量的水浸泡30min,然后大火进行煎煮,待水沸腾后改用文火继续煎煮45min,四层纱布过滤;滤渣再加8倍质量的水,大火进行煎煮,待水沸腾后改用文火继续煎煮30min,四层纱布过滤;合并两次滤液,浓缩,得到所述中药组合物。
制备例2
本制备例提供一种具有益气清热功效的中药组合物,其配方如下:
黄芪25份、当归25份、金银花25份、甘草8份、乌梅10份、五味子10份、土茯苓20份、白鲜皮20份、薄盖灵芝5份、防风10份、紫草20份、莪术10份、白芍25份、柴胡10份。
制备工艺为:将各中药原料按配方量混合后用10倍质量的水浸泡30min,然后大火进行煎煮,待水沸腾后改用文火继续煎煮45min,四层纱布过滤;滤渣再加8倍质量的水,大火进行煎煮,待水沸腾后改用文火继续煎煮30min,四层纱布过滤;合并两次滤液,浓缩,得到所述中药组合物。
制备例3
本制备例提供一种具有益气清热功效的中药组合物,其配方如下:
黄芪20份、当归20份、金银花20份、甘草5份、乌梅5份、五味子5份、土茯苓10份、白鲜皮10份、薄盖灵芝10份、防风20份、紫草10份、莪术20份、白芍10份、柴胡20份。
制备工艺为:将各中药原料按配方量混合后用10倍质量的水浸泡30min,然后大火进行煎煮,待水沸腾后改用文火继续煎煮45min,四层纱布过滤;滤渣再加8倍质量的水,大火进行煎煮,待水沸腾后改用文火继续煎煮30min,四层纱布过滤;合并两次滤液,浓缩,得到所述中药组合物。
实施例
本实施例以吉非替尼为例,探究本发明所涉及的中药组合物对表皮生长因子受体抑制剂相关性皮肤不良反应的改善作用:
(1)材料准备:
动物:雄性裸鼠(18-20g)购于北京斯贝福生物技术有限公司。
药物:吉非替尼片(易瑞沙,阿斯利康)。
(2)试剂与仪器准备:
4%免疫组化固定液(北京兰博利德商贸有限公司P4500-500 ML)
苏木素染液(武汉赛维尔生物科技有限公司G1004-500 ML)
伊红染液(武汉赛维尔生物科技有限公司G1001-500 ML)
中性树胶(北京酷来搏科技有限公司CN7750-100 ml)
电子天平(上海花潮实业有限公司HTP312)
分析天平(德国赛多利斯CP324S)
智能皮肤检测仪(ES-2600北京伊丽美科技有限公司)
皮肤水分测量仪(芬兰德尔芬)
恒温烘箱(德国美墨尔特IF110)
切片机(德国徕卡RM2255)
超分辨显微组织成像系统(德国徕卡Aperio VERSA)
(3)试验过程:
(3.1)分组:将裸鼠分为5组,每组4只:分别为空白组(纯水)、模型组(吉非替尼)、给药1组(吉非替尼+制备例1中药组合物)、给药2组(吉非替尼+制备例2中药组合物)、给药3组(吉非替尼+制备例3中药组合物)。每日灌胃给药吉非替尼(200mg/kg/d)的同时,每组给予相应的药物80.8g/kg/d(以中药原料的量来计),空白组灌胃纯水。
(3.2)模型制备与给药:除空白组给予蒸馏水外,模型组和三个中药干预组均每日上午9时灌胃给药吉非替尼,中药干预组同时每日下午3时灌胃给药(模型组给予蒸馏水),整个周期为10天。
(3.3)检测指标:
皮肤表型:主要通过观察皮肤状态及皮肤含水量的检测,其中皮肤含水量的检测使用皮肤水分检测探头(Delfin Technologies,Kuopio)检测各组小鼠背部皮肤水分含量,每只小鼠测量两次,读数的平均值作为水分含量(%),具体方法参照文献(Wan,L.,Wang,Y.,Tang,Y.,Tan,Y.,He,F.,Zhang,Y.,Yang,K.,Chen,Z.,Song,C.,Gu,R.,Zhang,C.,Wang,X.,Wei,P.,Liu,T.,Jiang,M.,&Hua,Q.(2020).Gefitinib-Induced CutaneousToxicities in Brown Norway Rats Are Associated with MacrophageInfiltration.Inflammation,43(6),2137–2146.)中公开的方法进行。
皮肤炎症指标:主要通过对皮肤炎症状态评分,具体评分方法参照文献(Sivaprasad,U.,Warrier,M.R.,Gibson,A.M.,Chen,W.,Tabata,Y.,Bass,S.A.,Rothenberg,M.E.,&Khurana Hershey,G.K.(2010).IL-13Rα2has a protective role ina mouse model of cutaneous inflammation.Journal of immunology(Baltimore,Md.:1950),185(11),6802–6808.)中公开的方法进行,小鼠全身1/3处出现炎症为1分,全身2/3处出现炎症为2分,全身大于2/3处出现炎症为3分,没有炎症为0分。
(3.4)统计学方法:采用GraphPad Prism 8.0软件进行数据统计分析,结果用平均值±标准误(mean±SEM)表示。计量资料满足正态分布及方差齐性,选择单因素方差分析(one-way ANOVA)或多因素方差分析(two-way ANOVA);当方差不齐时,采用Dunnett’s T3检验。不满足正态分布时,则采用非参数检验。p<0.05即为具有统计学差异。
(4)试验结果
(4.1)试验结束后收集各组小鼠面部皮肤图片,如图1所示,由图可知,模型组主要表现为鼻、嘴边周边皮肤干燥、脱皮、红肿,三个中药组症状明显缓和,且给药1组的效果更为明显。
(4.2)试验结束后对各组小鼠背部用皮肤检测仪收集放大50倍的背部皮肤图像并进行组织切片观察,结果如图2所示,显示模型组小鼠背部出现明显皮肤干燥、表皮厚度增加,而中药组皮肤干燥现象有所好转,且给药1组和给药2组的药效更为明显。
(4.3)试验结束后测量各组小鼠背部水分含量,统计结果如图3所示,由图可知,中药组可显著提高EGFRI所致的水分含量降低,其中给药1组的作用更为明显。
(4.4)试验结束后对各组小鼠进行皮肤炎症评分,统计结果如图4所示,显示中药组可降低EGFRI所致的皮肤炎症,其中给药1组和给药2组的改善作用更为明显。
申请人声明,本发明通过上述实施例来说明本发明的一种具有益气清热功效的中药组合物及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (17)
1.一种具有改善由表皮生长因子受体抑制剂引起皮肤不良反应功效的中药组合物,其特征在于,所述中药组合物以重量份数计由如下中药原料制成:黄芪28-30份、当归28-30份、金银花28-30份、甘草8-10份、乌梅7-9份、五味子6-8份、土茯苓14-16份、白鲜皮14-16份、薄盖灵芝7-9份、防风14-16份、紫草17-20份、莪术10-13份、白芍18-22份、柴胡14-16份;
所述表皮生长因子受体抑制剂为吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达可替尼、奥希替尼、阿美替尼或伏美替尼。
2.根据权利要求1所述的中药组合物,其特征在于,所述中药组合物由包括如下步骤的制备工艺制得:
将各中药原料按配方量混合后用水浸泡,然后大火进行煎煮,待水沸腾后改用文火继续煎煮,过滤,得滤液即所述中药组合物。
3.根据权利要求2所述的中药组合物,其特征在于,所述用水浸泡的时间为20-50 min。
4.根据权利要求2所述的中药组合物,其特征在于,所述水的用量为中药原料质量的7-15倍。
5.根据权利要求2所述的中药组合物,其特征在于,所述文火继续煎煮的时间为30-60min。
6.根据权利要求2所述的中药组合物,其特征在于,所述滤液为煎煮1-3次合并的滤液。
7.根据权利要求1-6中任一项所述的中药组合物在制备改善由表皮生长因子受体抑制剂引起的皮肤不良反应的药物中的应用。
8.一种具有改善由表皮生长因子受体抑制剂引起皮肤不良反应功效的药物,其特征在于,所述药物的功效成分为权利要求1-6中任一项所述的中药组合物;
所述表皮生长因子受体抑制剂为吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达可替尼、奥希替尼、阿美替尼或伏美替尼。
9.根据权利要求8所述的药物,其特征在于,所述药物的剂型为片剂、胶囊剂、颗粒剂或溶液剂。
10.根据权利要求8所述的药物,其特征在于,所述药物还包括药学上可接受的辅料。
11.根据权利要求10所述的药物,其特征在于,所述辅料为稀释剂、调味剂、粘合剂、填充剂、增稠剂、崩解剂、助溶剂、助悬剂、润滑剂或缓冲剂中的任意一种或至少两种的组合。
12.一种抗肿瘤的联合用药物组合物,其特征在于,所述联合用药物组合物包括表皮生长因子受体抑制剂和权利要求1-6中任一项所述的中药组合物;
所述表皮生长因子受体抑制剂为吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达可替尼、奥希替尼、阿美替尼或伏美替尼。
13.根据权利要求12所述的联合用药物组合物,其特征在于,所述联合用药物组合物为单一复方制剂或两种单独制剂的组合。
14.根据权利要求13所述的联合用药物组合物,其特征在于,所述联合用药物组合物为两种单独制剂的组合,两种单独的制剂同时施用或依次施用。
15.根据权利要求12所述的联合用药物组合物,其特征在于,所述联合用药物组合物的剂型为片剂、胶囊剂、颗粒剂或溶液剂。
16.根据权利要求12所述的联合用药物组合物,其特征在于,所述联合用药物组合物还包括药学上可接受的辅料。
17.根据权利要求16所述的联合用药物组合物,其特征在于,所述辅料为稀释剂、调味剂、粘合剂、填充剂、增稠剂、崩解剂、助溶剂、助悬剂、润滑剂或缓冲剂中的任意一种或至少两种的组合。
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