CN104324094B - 金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用 - Google Patents
金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用 Download PDFInfo
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- CN104324094B CN104324094B CN201410690595.8A CN201410690595A CN104324094B CN 104324094 B CN104324094 B CN 104324094B CN 201410690595 A CN201410690595 A CN 201410690595A CN 104324094 B CN104324094 B CN 104324094B
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Abstract
本发明公开了金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用,拓宽了金莲花总黄酮的应用范围,并且为瘙痒性皮肤病的治疗提供了新的药物;经药理学实验可以看出金莲花总黄酮对小鼠慢性湿疹模型有很好的防治作用,对2、4‑二硝基氟苯所致小鼠迟发型变态反应有明显抑制作用,对二甲苯所致小鼠耳肿胀有明显的抗炎作用,对冰醋酸致小鼠毛细血管通透性增加有显著抑制作用,并能对磷酸组胺所致豚鼠瘙痒较好的对抗作用,且毒性低,使用安全,具有较好的应用前景。
Description
技术领域
本发明属于医药领域,具体涉及金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用。
背景技术
瘙痒性皮肤病是指以皮肤瘙痒为主要特征的一组皮肤病,包括湿疹、银屑病、丘疹性荨麻疹、虫咬皮炎、毛发红糠疹等。近年来,瘙痒性皮肤病的发病率呈上升趋势,这与气候环境变化,大量化学制品在生活中的应用,精神紧张,生活节奏加快,饮食结构改变均有关,该病因其复发性、顽固性、瘙痒性及病程的缠绵而影响患者的生活质量,给患者带来极大的困扰。目前用于治疗瘙痒性皮肤病的外用药物主要为糖皮质内固醇和少许中成药制剂,糖皮质内固醇初用效果良好,但会引起糖皮质内固醇依赖和撤药复发,继续使用其疗效明显下降,目前用于治疗皮肤瘙痒的外用中成药制剂较少,且疗效欠佳。因此,积极寻找和开发一种治疗瘙痒性皮肤病疗效好、副作用少且价格合适的外用制剂具有极大地临床价值和需求潜力。
中药金莲花为毛茛科植物金莲花Trollius chinensis Bunge和短瓣金莲花T.ledebouri Reichb.的干燥花,始载于《本草纲目拾遗》,其味苦、性凉,具有清热解毒的功效,用于急慢性扁桃体炎、急性中耳炎、急性鼓膜炎、急性结膜炎和急性淋巴管炎等疾病。现代医学研究表明,金莲花含有藜芦酸、荭草苷、牡荆苷、藜芦酰胺、棕榈酸等化学成分,具有抑菌、抗病毒、抗氧化、抗癌、降压、解痉等药理作用。但有关金莲花总黄酮的抗皮肤瘙痒生物活性尚未见报道。
发明内容
有鉴于此,本发明的目的在于提供金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用。为实现上述发明目的,本发明提供如下技术方案:
金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用。所述的瘙痒性皮肤病为湿疹、银屑病、丘疹性荨麻疹、虫咬皮炎或毛发红糠疹。
优选的,所述金莲花总黄酮采用以下方法制得:将金莲花水煎提取,提取液上弱极性大孔吸附树脂柱,然后先用无机酸溶液洗至流出液无色,再用水洗至流出液呈中性,接着用体积分数为30%~70%的乙醇溶液洗脱,收集洗脱液,浓缩,干燥,即得金莲花总黄酮。
更优选的,所述弱极性大孔吸附树脂为大孔吸附树脂D101。
优选的,所述水煎提取是取金莲花药材,加入相当于药材重量10倍的水煎煮2次,每次煎煮1小时,将煎煮液滤过后合并滤液,离心得收集上清,得提取液。
优选的,提取液的纯化方法如下:取提取液上大孔吸附树脂D101柱,然后先用质量分数为0.2%的盐酸溶液洗至流出液无色,再用蒸馏水洗至流出液呈中性,接着用体积分数为50%的乙醇溶液洗脱,收集乙醇洗脱液,减压浓缩,干燥,得金莲花总黄酮。
本发明的有益效果在于:本发明公开了金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用,不仅拓宽了金莲花总黄酮的应用范围,提高了其市场价值,而且进一步明确了中药金莲花的药效物质基础,利于控制中药金莲花及其制剂的质量。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,下面对金莲花总黄酮的药理作用及其效果进行详细的阐述。
实施例1、金莲花总黄酮的制备及含量测定
金莲花总黄酮的制备方法,具体步骤如下:称取金莲花药材2kg,加入相当于药材重量10倍的水煎煮2次,每次煎煮1小时,将煎煮液滤过后合并滤液,离心,取上清液上过大孔吸附树脂D101柱(弱极性,天津市海光化工有限公司),然后先用质量分数为0.2%的盐酸溶液洗至流出液无色,再用蒸馏水洗至流出液呈中性,接着用体积分数为50%的乙醇溶液洗脱,收集乙醇洗脱液,减压浓缩,干燥,得金莲花总黄酮。利用该方法获得金莲花总黄酮的量为100g。
金莲花总黄酮的含量测定
对照品溶液的制备:取芦丁对照品适量,精密称定,加甲醇制成每1mL含0.25mg的溶液即得。
标准曲线的制备:精密吸取制备的对照品溶液1.0、2.0、3.0、4.0、5.0、6.0mL分别置25ml量瓶中,各加体积分数为30%的乙醇至6mL,摇匀,然后加入1mL质量分数为6%的亚硝酸钠溶液,摇匀,放置6min,再加1mL质量分数为10%的硝酸铝溶液,摇匀,放置6min,接着加入10mL氢氧化钠溶液,再加体积分数为30%的乙醇至刻度,摇匀,放置15min;不含对照品的溶液并加入相应试剂的溶液做空白,照紫外-可见分光光度法(中国药典2010年版一部附录V A),在500nm波长处测定吸光度,以吸光度为纵坐标,浓度为横坐标绘制标准曲线,计算得回归方程为y=0.10789x-0.0028(r=0.9999)。
金莲花总黄酮测定:精密称取制备的金莲花总黄酮20mg,置25mL容量瓶中,加体积分数为60%的乙醇使溶解并稀释至刻度,摇匀,精密量取4mL至25mL量瓶中,加体积分数为30%的乙醇2mL,摇匀,然后加入1mL质量分数为6%的亚硝酸钠溶液,摇匀,放置6min,再加1mL质量分数为10%的硝酸铝溶液,摇匀,放置6min,接着加入10mL氢氧化钠溶液,再加体积分数为30%的乙醇至刻度,摇匀,放置15min;最后按照标准曲线的制备测定样品吸光度。测定结果根据标准曲线计算金莲花总黄酮纯度,结果显示以芦丁计纯度为85.64%。
按标准曲线制备项下的方法,自“加6%的亚硝酸钠溶液1ml”起依法操作,测定吸光度。
然后将制得的金莲花总黄酮加入药学上可接受的辅料制成乳膏剂、软膏剂、喷雾剂等外用制剂。
实施例2、金莲花总黄酮的药理作用
1、以实施例1中金莲花总黄酮制成的乳膏检测金莲花总黄酮对慢性湿疹模型的影响
取体重为20g左右的昆明雄性小鼠50只,随机分成5组,每组10只,分别为对照组、模型组、艾洛松组、金莲花总黄酮高(含药量2%,w/w)、中(含药量1%,w/w)、低剂量组(含药量0.5%,w/w)。于实验前一天在腹部脱毛,面积约为3×3cm2。除对照组外,其余各组在其腹部脱毛区均匀涂布质量分数为1%的2,4二硝基氟苯(DNFB),100μL/只致敏,次日加强一次,并于首次致敏后第7天、第12天及第16天用体积分数为0.1%的DNFB背部涂着小鼠背部,50μL/只。然后各给药组每日小鼠背部给药,按0.01g/10g给药,艾洛松组给艾洛松,对照组给基质,金莲花总黄酮高、中、低剂量组分别给,每日1次,连续给药17天。于末次给药后24小时处死,取小鼠背部皮肤用体积分数为10%的福尔马林缓冲溶液固定作病理学组织检查,HE染色进行显微观察。
显微检测结果显示,对照组表皮正常无角化过度和角化不全,表皮突未延长,未见海绵细胞,无细胞间水肿,真皮内无炎性细胞浸润;模型组表皮角化过度和局灶性角化不全,棘层肥厚,表皮突延长,可见海绵细胞和细胞间水肿,真皮周围浅层血管炎性细胞浸润明显,毛细血管数目增多,管壁增厚;艾洛松组表皮接近正常角质,棘层微增厚,表皮突未见延长,无海绵细胞,真皮周围浅层血管炎性细胞浸润不明显;金莲花总黄酮低剂量组表皮角化过度较模型组减轻,棘层增厚,可见海绵细胞和细胞间水肿,真皮周围浅层血管炎性细胞浸润较模型组减轻;金莲花总黄酮中剂量组表皮接近正常角质,棘层微增厚,表皮突未见延长,无海绵细胞,真皮周围浅层血管炎性细胞浸润减轻,毛细血管数量明显减少;金莲花总黄酮高剂量组:表皮接近正常角质,棘层微增厚,表皮突未见延长,无海绵细胞,真皮周围浅层血管炎性细胞浸润不明显。
上述结果表明,金莲花总黄酮对小鼠湿疹模型有很好的防治作用。
2.以实施例1中金莲花总黄酮制成的乳膏检测金莲花总黄酮对2、4-二硝基氟苯致小鼠迟发型变态反应的影响
取体重为20g左右的昆明雄性小鼠60只,随机分成6组,每组10只,分别为对照组、模型组、艾洛松组、金莲花总黄酮高、中、低剂量组。于实验前一天在腹部脱毛,面积约为3×3cm2。除对照组外,其余各组在其腹部脱毛区均匀涂布质量分数为1%的2、4-二硝基氟苯,100μL/只致敏,次日加强一次,并于首次致敏后第6天在各小鼠右耳均匀涂布质量分数为0.1%的DNFB激发,20μL/只。期间各组动物分别在其右耳廓按10mg/10g均匀涂布相应霜剂或软膏,对照组、模型组给予等量基质,每日一次,连续给药7天。于末次给药后1小时处死,搽去双耳上的药物,用8mm打孔器沿左右耳廓相同部位打孔取下左右耳片,称重,以左右耳片重量之差表示肿胀程度,同时取脾脏和胸腺称重,计算脾脏指数和胸腺指数,结果如表1和表2所示。
表1、金莲花总黄酮对DNFB所致小鼠DTH的影响(n=10)
与模型组比较*P<0.05,**P<0.01。
从表1可知,DNFB可引起小鼠耳肿胀度,与对照组有统计学差异,且金莲花总黄酮组和艾洛松组能明显抑制DNFB所致的小鼠耳肿胀,与模型组比较有显著的统计学差异。表明金莲花总黄酮对DNFB所致小鼠DTH反应有明显抑制作用。
表2、金莲花总黄酮对DNFB所致小鼠皮肤迟发性超敏反应胸腺及脾脏的影响(n=10)
与模型组比较*P<0.05,**P<0.01。
从表2可知,DNFB可引起小鼠胸腺指数下降,脾脏指数增加,与对照组比较有统计学差异;艾洛松组小鼠胸腺指数和脾脏指数均明显减小,与模型组比较有显著的统计学差异;金莲花总黄酮中剂量小鼠胸腺指数提高,与模型组比较有显著的统计学差异;金莲花总黄酮各剂量组脾脏指数较模型组均有减少趋势,但较弱,与模型组比较没有统计学差异。
3.以实施例1中金莲花总黄酮制成的乳膏检测金莲花总黄酮对二甲苯致小鼠耳廓肿胀的影响
取体重为20g左右的昆明雄性小鼠50只,随机分成5组,每组10只,分别为模型组、艾洛松组、金莲花总黄酮高、中、低剂量组。各组动物分别在其右耳廓均匀涂布相应霜剂或软膏10mg/10g,对照组、模型组给予等量基质,每日2次,连续给药5天。于末次给药后1小时,搽去双耳上的药物,将二甲苯30μL/只滴于小鼠右耳前后两面致炎,在致炎30min后处死小鼠,用8mm打孔器沿左右耳廓相同部位打孔取下左右耳片,称重,以左右耳片重量之差表示肿胀程度,并计算肿胀抑制率(%),结果见表3。
表3、金莲花总黄酮对二甲苯所致小鼠耳廓肿胀的影响(n=10)
与模型组比较*P<0.05,**P<0.01.
从表3可知,艾洛松组、金莲花总黄酮各组与模型组比较均能明显减轻二甲苯所致小鼠耳肿胀,有统计学差异。表明金莲花总黄酮对二甲苯致小鼠耳廓肿胀具有一定的抗炎作用。
4.以实施例1中金莲花总黄酮制成的乳膏检测金莲花总黄酮对冰醋酸所致小鼠毛细血管通透性增加的影响
取体重为20g左右的昆明雄性小鼠60只,随机分成6组,每组10只,分别为对照组、模型组、艾洛松组、金莲花总黄酮高、中、低剂量组。于实验前一天在腹部脱毛,面积约为3×3cm2。各给药组每日小鼠腹部脱毛区给药0.01g/10g,艾洛松组给艾洛松,对照组、模型组给予等量基质,每日一次,连续给药5天。在末次给药后1小时,在动物尾静脉注射2%伊文思蓝溶液,按0.1ml/10g注射,同时除对照组外,其余各组动物均腹腔注射0.7%冰醋酸,按0.1ml/10g注射,注射后30min处死动物,腹腔注射生理盐水4mL/只,揉搓腹部后剪开腹部,收集腹腔洗出液,1500r/min,离心15min,取上清液1ml在590nm处测定吸光度(A),结果见表4。
表4、金莲花总黄酮对冰醋酸所致小鼠小鼠毛细血管通透性增加的影响(n=10)
与模型组比较*P<0.05,**P<0.01.
从表4可知,小鼠在腹腔注射冰醋酸后,其通透性较对照组显著增加,具有统计学差异;各药物组对冰醋酸致小鼠毛细血管通透性增加均有显著抑制作用,与模型组比较有统计学差异。
5.金莲花总黄酮乳膏对豚鼠止痒作用的影响
取体重为180g左右的雄性豚鼠50只,随机分成5组,每组10只,分别为模型组、苯海拉明组、金莲花总黄酮高、中、低剂量组。于实验前一天在豚鼠右足背部脱毛,在脱毛后24小时在脱毛区均匀涂布相应软膏,按100mg/100g涂抹,对照组和模型组则给予等量基质。每日两次,连续给药5天。在末次给药24小时后在右足背剃毛处用砂纸擦伤(以渗血为度),涂药后10min在创面处从低浓度到高浓度依次滴磷酸组织胺溶液(0.01%、0.02%、0.03%····0.2),至出现豚鼠回头舔右足,统计致痒浓度值,结果见表5。
表5、金莲花总黄酮对豚鼠致痒浓度值的影响(n=10)
与模型组比较*P<0.05,**P<0.01。
从表5可知,各药物组均能提高磷酸组胺所致豚鼠致痒浓度值,与模型组比较有统计学意义,表明金莲花总黄酮对磷酸组胺所致豚鼠瘙痒较好的对抗作用。
实施例3、金莲花总黄酮的急性毒性
取体重20±2g的小鼠40只,雌雄各半,每只小鼠按照1.0g/kg(体重)的剂量给予金莲花总黄酮(相当于生药20g/kg),每天经口灌胃给药3次,连续给药7天,观察小鼠有无急性毒性反应。
结果显示,在口服给予小鼠(小鼠中剂量用药10mg/kg)相当于人体用药剂量100倍的金莲花总黄酮时,未见小鼠死亡,未测得LD50。上述结果表明,金莲花总黄酮的安全性好,相当于人体用药剂量100倍时未见小鼠死亡。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.金莲花总黄酮在制备治疗瘙痒性皮肤病的药物中的应用,所述金莲花总黄酮采用以下方法制得:将金莲花水煎提取,提取液上大孔吸附树脂D101,然后先用无机酸溶液洗至流出液无色,再用水洗至流出液呈中性,接着用体积分数为30%~70%的乙醇溶液洗脱,收集洗脱液,浓缩,干燥,即得金莲花总黄酮。
2.根据权利要求1所述的应用,其特征在于,所述的瘙痒性皮肤病为湿疹、银屑病、丘疹性荨麻疹、虫咬皮炎或毛发红糠疹。
3.根据权利要求1所述的应用,其特征在于:所述水煎提取是取金莲花药材,加入相当于药材重量10倍的水煎煮2次,每次煎煮1小时,将煎煮液滤过后合并滤液,离心得收集上清,得提取液。
4.根据权利要求1所述的应用,其特征在于:提取液的纯化方法如下:取提取液上大孔吸附树脂D101柱,然后先用质量分数为0.2%的盐酸溶液洗至流出液无色,再用蒸馏水洗至流出液呈中性,接着用体积分数为50%的乙醇溶液洗脱,收集乙醇洗脱液,减压浓缩,干燥,得金莲花总黄酮。
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