WO2024041084A1 - 一种治疗银屑病的外用中药组合物及其制备方法与应用 - Google Patents
一种治疗银屑病的外用中药组合物及其制备方法与应用 Download PDFInfo
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Abstract
一种治疗银屑病的外用中药组合物，包括按照重量份数计的如下原料：茜草10～20份，紫草10～20份，夏枯草10～20份，生甘草30～50份。所述中药组合物中各药味共奏清热解毒、凉血散瘀之功，外用治疗银屑病有显著疗效。
Description
本发明属于银屑病治疗技术领域，尤其涉及一种治疗银屑病的外用中药组合物及其制备方法与应用。
银屑病是一种常见的慢性复发性炎症性皮肤病。基本皮损为红斑、丘疹，或斑块上覆有多层银白色鳞屑。发生部位多见于身体表面及头部，常是红斑上反复出现多层银白色干燥鳞屑。银屑病的病因并不完全清楚且顽固难治，被世界卫生组织列为十大顽症之一。目前对银屑病的治疗，多是采用局部外用药物，如角质促成剂、皮质类因醇霜剂等；而对全身使用的药物，则有免疫抑制剂、维甲酸、抗生素、皮质类因醇等。这些药物对银屑病是有较好的近期治疗效果，但长期使用副作用大，并且复发率较高。比如甲氨蝶呤是银屑病一线系统治疗药物，部分患者用药后存在轻微不良反应，表现为腹泻、恶心、食欲缺乏、溃疡、嗜睡、皮肤糜烂等。维甲酸类药物多用于治疗中重度的寻常型、红皮病型及腺癌型银屑病，但对关节型银屑病效果欠佳，常见不良发应包括皮肤粘膜症状、眼毒性、肝酶或血脂升高、骨髓发育异常及致畸性，需监测血脂及生长曲线图等指标。生物制剂(如阿达木单抗、英夫利昔单抗、依法利珠单抗等)治疗银屑病虽见效快，但是存在很多副作用，如部分患者使用后出现结节性血管炎、严重感染、心衰及恶性肿瘤风险。外用糖皮质激素可能会出现皮肤萎缩、毛细血管扩展、萎缩纹、紫癜、多毛等症状。
中医药在改善轻中度银屑病患者临床症状、减少复发率方面表现出了一定的优势。但中药内服治疗周期长，故患者依从性不强，且部分药物存在潜在肝肾损伤可能，患者往往无法长期服用。随着人们对生活品质及身体健康的高水平要求，人们越来越要求更全面的治疗方法，银屑病的临床治疗方案应遵循更安全、有效、经济和便捷的原则。
发明内容
有鉴于此，本发明的目的在于提供一种治疗银屑病的中药组合物，各药味协同共奏清热解毒、凉血散瘀之功，在外用治疗银屑病上有显著疗效，且
具有安全、经济、操作便捷的优势。
为了实现上述发明目的，本发明提供了以下技术方案：
本发明提供了一种治疗银屑病的外用中药组合物，包括按照重量份数计的如下原料：茜草10～20份，紫草10～20份，夏枯草10～20份，生甘草30～50份。
优选的，所述外用中药组合物的制剂类型包括水剂、油剂、散剂、酊剂、洗剂、乳膏剂、软膏剂、沐浴剂和凝胶剂。
本发明还提供了一种上述外用中药组合物的制备方法，包括如下步骤：将茜草、紫草、夏枯草和生甘草与油剂混合，浸泡，小火煎至焦黄色，去除药渣，得药油。
优选的，所述油剂包括葵花籽油或芝麻油。
优选的，茜草、紫草、夏枯草和生甘草四种原料总和与油剂的料液比为1g：4.1ml～9.2ml。
优选的，所述浸泡的时间为24h～28h。
本发明还提供了一种上述外用中药组合物在制备治疗银屑病产品中的应用。
优选的，所述外用中药组合物通过影响角质形成细胞分化、细胞因子活性和/或表皮细胞分化，发挥治疗作用。
优选的，所述外用中药组合物通过参与细胞因子受体相互作用、IL-17信号通路、雌激素信号通路和/或蛋白质消化吸收途径，发挥治疗作用。
优选的，所述产品包括药品。
本发明的有益效果：
本发明外用中药组合物中茜草凉血行血、祛瘀活血，为君药，紫草清热解毒、凉血止血，夏枯草清热解毒，共为臣药，生甘草为佐，解毒和药，四药配合共奏清热解毒，凉血润燥之功，能够很好的治疗银屑病，具有疗效明确显著、安全、经济且操作便捷的优势。
图1各组小鼠银屑病相关表型的变化(n＝4)，其中A：各组小鼠第12天背部与耳部皮损外观；B：各组小鼠背部皮肤PASI评分(红斑、鳞屑、厚度及总分)；C：各组小鼠耳朵厚度及耳部皮肤PASI评分(红斑、鳞屑)；注：与模型组相比，*p<0.05，**p<0.01，***p<0.001；与正常组相比，#p<0.05，##p<0.01，###p<0.001；
图2各组小鼠组织病理变化，其中A：各组小鼠背部与耳部组织病理学变化(×200)，B：各组小鼠第12天背部厚度定量，C：各组小鼠第12天耳部厚度定量，注：与模型组相比，*p<0.05，**p<0.01；与正常组相比，###p<0.001；
图3数据分析流程；
图4IMQ+SCY组和IMQ组背部皮肤组织的mRNA-seq分析结果，其中A：IMQ+SCY组与IMQ组差异表达蛋白(DEPs)火山图，绿色的圆点表示下调的DEPs，红色的点表示上调的DEPs，灰色的点表示非显著的DEPs；B：IMQ+SCY组与IMQ组289个DEPs热图，根据基因表达量进行聚类分析，红色表示高表达的DEPs，绿色表示低表达的DEPs，每行表示每个DEPs在不同组中的表达水平；
图5SCY干预后银屑病皮损中差异基因的GO与KEGG富集分析，其中A：对SCY干预后的DEPs进行GO分析结果，B：对SCY干预后的DEPs进行KEGG分析结果。
本发明提供了一种治疗银屑病的外用中药组合物，包括按照重量份数计的如下原料：茜草10～20份，紫草10～20份，夏枯草10～20份，生甘草30～50份。
本发明对于上述各原料的具体来源没有特殊限定。在本发明中，所述各原料的重量份数优选的为茜草13～18份，紫草12～16份，夏枯草14～17份，生甘草35～45份，更优选的为茜草14～16份，紫草14～15份，夏枯草15～16份，生甘草38～42份。本发明所述治疗银屑病的外用中药组合物优选的可制成水剂、油剂、散剂、酊剂、洗剂、乳膏剂、软膏剂、沐浴剂和凝胶剂。
本发明还提供了一种上述外用中药组合物的制备方法，包括如下步骤：将茜草、紫草、夏枯草和生甘草与油剂混合，浸泡，小火煎至焦黄色，去除药渣，得药油。
在本发明中，所述油剂优选的包括葵花籽油或芝麻油，茜草、紫草、夏枯草和生甘草四种原料总和与油剂的料液比优选为1g：4.1ml～9.2ml，更优选为1g：5ml～8.5ml。本发明对于葵花籽油或芝麻油的具体来源没有特殊限定，采用本领域常规市售产品均可。在本发明中，所述浸泡的时间优选为24h～28h，更优选为25h～26h。本发明对于去除药渣的具体方式没有特殊限定，采用本领域常规去除方法均可。
本发明还提供了一种上述外用中药组合物在制备治疗银屑病产品中的应用。
在本发明中，所述产品优选的包括药品。本发明所述外用中药组合物优选的通过影响角质形成细胞分化、细胞因子活性和/或表皮细胞分化，发挥治疗作用，更优选的通过参与细胞因子受体相互作用、IL-17信号通路、雌激素信号通路和/或蛋白质消化吸收途径，发挥治疗作用。
下面结合实施例对本发明提供的技术方案进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
下述实施例中，如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
取紫草10g，茜草10g，夏枯草10g，生甘草50g，混合后用500ml葵花籽油浸泡24h，小火煎至药材变成焦黄色，去除药渣，得四草油，置于4℃冰箱备用。
实施例2
取紫草20g，茜草20g，夏枯草20g，生甘草30g，混合后用550ml芝麻油浸泡24h，小火煎至药材变成焦黄色，去除药渣，得四草油，置于4℃冰箱备用。
实施例3
取紫草15g，茜草14g，夏枯草16g，生甘草40g，混合后用600ml葵花籽油浸泡24h，小火煎至药材变成焦黄色，去除药渣，得四草油，置于4℃冰箱备用。
实施例4
将雄性、6-8周龄、体重20g±2g的BABLc小鼠随机分为3组，每组4只小鼠：(1)空白对照组(Control组)：用凡士林乳膏62.5mg每日涂抹小鼠背部与双耳廓内外侧。(2)模型组(IMQ组)：将5％IMQ乳膏62.5mg分别涂抹小鼠背部与双耳廓内外侧。6h后用凡士林乳膏62.5mg涂抹小鼠背部与双耳廓内外侧。(3)四草油组(IMQ+SCY组)：将5％IMQ乳膏62.5mg涂抹小鼠背部与双耳廓内外侧。6h后用实施例1制备所得的150ul四草油涂抹小鼠背部与双耳廓内外侧。小鼠所有治疗从应用IMQ之日起(第0天)开始，每天1次，连续12天。
采用银屑病临床面积和严重程度指数(PASI)对小鼠背部与耳部皮肤炎症的严重程度进行评分，包括红斑、厚度和鳞屑。分值表示严重程度：0(无)，1(轻度)，2(中度)，3(重度)及4(极重度)。小鼠在采集标本前禁食，允许饮水12h。第13天实验结束后小鼠用CO2处死，分别采集耳朵皮损、背部皮损进行进一步实验。
实验结果
1)四草油可改善IMQ诱导的银屑病样小鼠背部与耳部皮损
结果如图1所示，IMQ造模第12天，Control组外用凡士林软膏，背部与耳部皮肤均无红斑、鳞屑、皮肤增厚现象；IMQ组小鼠背部与耳部均出现明显红斑、鳞屑、皮肤增厚现象。与Control组相比，IMQ组PASI评分均显著升高，耳朵肿胀明显。与IMQ组相比，IMQ+SCY组小鼠PASI评分及耳朵肿胀程度减轻。
2)四草油可改善IMQ诱导的银屑病样小鼠模型的组织病理
结果如图2所示：各组小鼠的背部与耳部的组织病理切片显示，IMQ造模第12天，Control组小鼠背部与耳部皮肤表皮层较薄，未出现炎性细胞浸润。与Control组相比，IMQ组小鼠背部与耳部皮肤表现为角化过度伴角化不全，角化不全区可见中性粒细胞微脓肿，颗粒层明显减少，基层增厚表皮突向下延伸。可观察到中性粒细胞、淋巴细胞等浸润(p<0.001)。IMQ+SCY组小鼠背部与耳部皮肤炎性细胞浸润和表皮增生减少(p<0.05)。
实施例5
为了探究本发明四草油治疗银屑病的作用机制，为四草油外用提供理论依据，特此进行下述mRNA-seq分析：
1.建库流程
(1)总RNA质检
采用RNeasy Mini Kit(Cat#74106,Qiagen)并且根据生产厂商提供的标准操作流程进行实施例4中IMQ组和IMQ+SCY组小鼠样品的total RNA抽提。总RNA经NanoDrop ND-2000分光光度计及Agilent Bioanalyzer 4200(Agilent technologies,Santa Clara,CA,US)进行质检，质检合格的RNA可进行后续的文库构建。
(2)文库构建与质检
对于特定真核物种，利用磁珠去除rRNA。接下来对去除rRNA的RNA进行片段化、双链cDNA合成、降解第二链、末端修复、3’末端加A、连接接头、扩增实验。构建的文库使用2.0 Fluorometer检测浓度，Agilent 2100检测大小。
(3)上机测序
质检合格的文库，准备进行Illumina测序，测序策略为PE150。测序基本原理为边合成边测序(SBS，Sequencing by Synthesis)：将携有cluster的flow cell上机，并在flow cell中加入四种荧光标记的dNTP、DNA聚合酶以及接头引物进行扩增，在每一个测序簇延伸互补链时，每加入一个被荧光标记的dNTP就能释放出相对应的荧光，测序仪通过捕获荧光信号，并通过计算机软件将光信号转化为测序峰，从而获得待测片段的序列信息。
2.数据分析流程
如图3所示。
3.实验结果
(1)四草油干预后差异基因表达鉴定
通过mRNA-seq分析，共鉴定出718个差异基因。根据差异基因筛选条件：Foldchange＝2倍且p-value<0.05，在IMQ+SCY组和IMQ组中筛选了160个上调基因和129个下调基因。结果见火山图(图4A)和聚类分析热图(图4B)。
(2)GO和KEGG富集分析揭示差异基因的功能和生物学途径
为了揭示差异表达蛋白(DEPs)的功能和生物学途径，对IMQ+SCY组SCY干预后小鼠银屑病皮损中的差异基因进行了GO和KEGG富集分析。GO分析表明IMQ+SCY组的DEPs主要与角质形成细胞分化、细胞因子活性、表皮细胞分化等有关(图5A)。KEGG富集分析表明，IMQ+SCY组的DEPs主要参与细胞因子受体相互作用、IL-17信号通路、雌激素信号通路、蛋白质消化吸收等(图5B)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
- 一种治疗银屑病的外用中药组合物，其特征在于，包括按照重量份数计的如下原料：茜草10～20份，紫草10～20份，夏枯草10～20份，生甘草30～50份。
- 根据权利要求1所述的外用中药组合物，其特征在于，所述外用中药组合物的制剂类型包括水剂、油剂、散剂、酊剂、洗剂、乳膏剂、软膏剂、沐浴剂和凝胶剂。
- 权利要求1所述外用中药组合物的制备方法，其特征在于，包括如下步骤：将茜草、紫草、夏枯草和生甘草与油剂混合，浸泡，小火煎至焦黄色，去除药渣，得药油。
- 根据权利要求3所述的制备方法，其特征在于，所述油剂包括葵花籽油或芝麻油。
- 根据权利要求3所述的制备方法，其特征在于，茜草、紫草、夏枯草和生甘草四种原料总和与油剂的料液比为1g：4.1ml～9.2ml。
- 根据权利要求3所述的制备方法，其特征在于，所述浸泡的时间为24h～28h。
- 权利要求1所述外用中药组合物在制备治疗银屑病产品中的应用。
- 根据权利要求7所述的应用，其特征在于，所述外用中药组合物通过影响角质形成细胞分化、细胞因子活性和/或表皮细胞分化，发挥治疗作用。
- 根据权利要求7所述的应用，其特征在于，所述外用中药组合物通过参与细胞因子受体相互作用、IL-17信号通路、雌激素信号通路和/或蛋白质消化吸收途径，发挥治疗作用。
- 根据权利要求7所述的应用，其特征在于，所述产品包括药品。
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