CN106728205B - 化橘红提取物在制备防治pm2.5颗粒诱导慢性阻塞性肺疾病急性发作药物中的应用 - Google Patents
化橘红提取物在制备防治pm2.5颗粒诱导慢性阻塞性肺疾病急性发作药物中的应用 Download PDFInfo
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Abstract
本发明涉及化橘红提取物的新用途。本发明首次公开了化橘红总黄酮提取物在制备防治PM2.5颗粒诱导慢性阻塞性肺疾病急性发作药物、慢性阻塞性肺疾病急性加重发作期气流受限加重药物及呼吸系统高气道反应性、低肺动态顺应性疾病药物中的应用。优选黄酮类化合物总含量高于50%的化橘红总黄酮提取物。与现有技术相比,本发明的化橘红总黄酮提取物制备方法简单,成本低,疗效确切;为天然植物提取物,无副作用,可作为预防保健食品或治疗药品。
Description
技术领域
本发明涉及化橘红提取物的新用途,尤其是涉及化橘红提取物用于制备防治PM2.5诱导慢性阻塞性肺疾病急性发作药物的用途。
背景技术
慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种常见以持续性气流受限为特征的疾病。气流受限进行性发展,与气道和肺脏对有毒颗粒或气体的慢性炎性反应增强有关。COPD是全世界范围内发病率和死亡率最高的疾病之一,已成为一个重要的公共卫生问题。全球目前有6亿人患有慢阻肺;根据《中国居民营养与慢性病状况报告(2015)》,我国40岁及以上人群的慢阻肺患病率高达9.9%。
慢性阻塞性肺疾病全球倡议组织发布的2015年版GOLD慢阻肺诊断治疗和预防的全球策略指出:吸入香烟烟雾和其他有毒颗粒,是COPD发生的重要原因。户外大气污染是促进COPD急性加重发作,而急性加重影响着疾病的严重程度和对个体的预后,导致住院率和病死率的增加。近年来,随着我国经济的快速发展,环境污染问题日益严重,以雾霾为主的大气污染已经成为全国性的环境问题,许多地区已严重受雾霾影响。霾天气的本质是大气细颗粒物PM2.5污染,因此,目前雾霾对健康影响的研究主要集中在PM2.5上。PM2.5是指大气中空气动力学粒径小于或等于2.5微米的颗粒物,也称为可入肺颗粒物。PM2.5富含大量有毒、有害物质,进入肺部后可诱导呼吸系统炎症,增加人群患COPD、肺气肿及其他呼吸系统疾病的危险性;对于COPD患者,PM2.5可干扰呼吸系统换气功能和引起肺功能障碍,诱发COPD急性加重发作和气流受限的加重。目前,COPD急性加重期的治疗,主要是针对病毒或细菌诱发的呼吸道感染,常采用氧疗、支气管舒张剂、全身性应用糖皮质激素、抗生素等加以治疗。而针对PM2.5诱发的COPD急性加重发作和气流受限的加重,主要集中在改善环境,提高空气质量或减少外出,降低暴露损害等消极应对方法,缺少具有针对性的预防或治疗药物。因此,有必要研制用于预防和治疗诱发COPD急性加重发作和气流受限加重的药物和新型保健产品。
化橘红是芸香科植物化州柚Citrus grandis‘Tomentosa’或柚Citrus grandis‘Tomentosa’的未成熟或近成熟的干燥外层果皮。传统中医药理论认为,化橘红味辛、苦,性温,归肺、脾经,具有理气宽中,燥湿化痰的功效,用于咳嗽痰多,多积伤酒,呕恶痞闷。现代药理研究表明,化橘红具有止咳化痰平喘的作用,但尚未有报道化橘红用于制备预防和治疗PM2.5诱导COPD急性加重发作期气流受限加重的药物的用途。
发明内容
本发明公开了化橘红总黄酮提取物在制备防治PM2.5颗粒诱导慢性阻塞性肺疾病急性发作药物中的应用。
并进一步公开化橘红总黄酮提取物在制备防治PM2.5颗粒诱导慢性阻塞性肺疾病急性加重发作期气流受限加重药物中的应用。
化橘红总黄酮提取物在制备防治PM2.5颗粒诱导呼吸系统高气道反应性、低肺动态顺应性疾病药物中的应用。
优选黄酮类化合物的总含量高于50%的化橘红总黄酮提取物。
最优选黄酮类化合物的总含量高于70%的化橘红总黄酮提取物。
实验研究中发现:化橘红总黄酮提取物灌胃给予PM2.5诱导COPD急性加重发作大鼠,能显著降低气道阻力,提高肺顺应性,增加0.2s呼气量(FEV0.2)/最大肺活量(FVC)与呼气峰流速(PEF),说明化橘红总黄酮提取物具有很好的抑制PM2.5诱导COPD急性发作的作用;特别是防治PM2.5颗粒诱导慢性阻塞性肺疾病急性加重发作期气流受限加重的作用。本发明的化橘红总黄酮提取物制备方法简单,成本低,疗效确切;为天然植物提取物,无副作用,可作为预防保健食品或治疗药品。
具体实施方式
下面结合实施例对本发明做进一步的说明。
各实施例中所涉及的固体混合物中之固体,液体中之液体,以及液体中之固体的百分比分别是以wt/wt、vol/vol、wt/vol计算,除非另有说明。
实施例1:化橘红总黄酮提取物的制备
化橘红总黄酮提取物的制备方法为:取化橘红药材,加水煎煮,滤过,水煎液浓缩至相对密度为1.05~1.30,加入乙醇或(和)甲醇进行醇沉,有沉淀物出现,滤过,滤液回收醇至无醇味的浸膏,加水调相对密度至1.05~1.15间,放置3天以上,有沉淀物析出,过滤,得到沉淀物,干燥,即为化橘红总黄酮提取物。
化橘红总黄酮提取物的总黄酮含量测定方法为:采用《中国药典》2010年版第一部化橘红项下所载方法进行测定含量。即取化橘红提取物1mg,精密称定,置10ml量瓶中,加甲醇稀释至刻度,摇匀,滤过,作为供试品溶液;另取柚皮苷对照品适量,精密称定,加甲醇溶解并定量稀释成每1ml中约含柚皮苷60μg的溶液,作为对照品溶液。分别吸取对照品溶液和供试品溶液各10μl,注入液相色谱仪,按药典所载色谱条件进行测定,计算,即得。
按上述方法,共取用三批不同化橘红药材进行提取,得到三批化橘红总黄酮提取物P1、P2、P3,该三批样品的黄酮类化合物含量见表1。
表1三批化橘红总黄酮提取物中黄酮类化合物含量
实施例2:化橘红总黄酮提取物对PM2.5诱导COPD急性加重发作期气流受限加重的抑制作用。
选取实施例1所得三批化橘红总黄酮提取物进行以下实施例的实验。
1、实验动物:
健康Wistar大鼠72只,体重(180±20)g,SPF级,雌雄各半,由广东省医学实验动物中心提供,动物生产许可证号:SCXK(粤)2013-0002。
2、药品分组与处理:
正常对照组:正常动物不经造模处理,实验期间每日灌胃等体积的蒸馏水。
COPD模型组(COPD组):采用烟熏复合气道内注入细菌脂多糖(以下简称LPS)法造成COPD模型,实验期间每日灌胃等体积的蒸馏水;在烟熏8周的最后一天,按2ml/kg体重的剂量给予大鼠气管滴注生理盐水。
PM2.5诱导的COPD急性加重发作模型组(COPD+PM2.5组):采用烟熏复合气道内注入LPS法造成COPD模型,在烟熏8周的最后一天,以PM2.5混悬液气管滴注染毒造成PM2.5诱导COPD急性加重发作模型。
化橘红总黄酮提取物P1组(COPD+PM2.5+P1组):采用烟熏复合气道内注入LPS法造成COPD模型,在烟熏8周的最后一天,以PM2.5混悬液气管滴注染毒造成PM2.5诱导COPD急性加重发作模型;从烟熏第七周的第一天起,每天于实验前取P1批化橘红总黄酮提取物粉末(黄酮类化合物含量为53.5%),加蒸馏水配成浓度为0.1mg/ml的混悬液,所有动物按1ml/100g体重的剂量灌胃给药,1次/天(d),连续1周。
化橘红总黄酮提取物P2组(COPD+PM2.5+P2组):采用烟熏复合气道内注入LPS法造成COPD模型,在烟熏8周的最后一天,以PM2.5混悬液气管滴注染毒造成PM2.5诱导COPD急性加重发作模型;从烟熏第七周的第一天起,每天于实验前取P2批化橘红总黄酮提取物粉末(黄酮类化合物含量为67.9%),加蒸馏水配成浓度为0.1mg/ml的混悬液,所有动物按1ml/100g体重的剂量灌胃给药,1次/天(d),连续1周。
化橘红总黄酮提取物P3组(COPD+PM2.5+P3组):采用烟熏复合气道内注入LPS法造成COPD模型,在烟熏8周的最后一天,以PM2.5混悬液气管滴注染毒造成PM2.5诱导COPD急性加重发作模型;从烟熏第七周的第一天起,每天于实验前取P3批化橘红总黄酮提取物粉末(黄酮类化合物含量为76.1%),加蒸馏水配成浓度为0.1mg/ml的混悬液,所有动物按1ml/100g体重的剂量灌胃给药,1次/天(d),连续1周。
3、实验方法:
3.1分组与COPD造模:
按随机数字表法将大鼠按随机数字表法随机分为6组,正常对照组、COPD模型组、PM2.5诱导的COPD急性加重发作模型组、化橘红总黄酮提取物P1组、化橘红总黄酮提取物P2组、化橘红总黄酮提取物P3组,每组12只。正常对照组大鼠饲养于无烟的正常环境,每天灌予等体积蒸馏水;其它各组大鼠分别于实验第1、15、30天乙醚麻醉动物后气道内注入200μg/200μL生理盐水脂多糖溶液(当天不进行香烟熏染毒),其余造模时间内每天将大鼠置入密闭的不锈钢烟熏箱(0.8m×0.8m×1m)进行烟熏染毒,烟熏染毒方法为:每天2次,中间间隔4h,每次烟熏30min,10支烟/次,6天/周,共8周,每支烟含焦油量11mg,烟气烟碱量1.0mg,一氧化碳量13mg。烟熏箱带水冷夹层,使箱内温度维持在26℃左右。
3.2 PM2.5的采样与处理:
于2014月7月1日起,在广州市区用Thermo Anderson G-2.5大流量采样器(美国热电子公司)用聚四氟乙烯滤膜采样PM2.5,连续4周。将载有颗粒物的滤膜剪裁成1cm×3cm大小,置于去离子蒸馏水中,超声振荡3次,每次1小时,洗脱颗粒物,震荡液经六层纱布过滤,滤液于4℃、12000r/min离心30min,收集下层悬液冷冻真空干燥,得到PM2.5粉末。用生理盐水将PM2.5粉末配成所需浓度后超声震荡15min,混匀并灭菌,4℃保存,临用前振荡使颗粒物充分混匀。
3.3 PM2.5诱导的COPD急性加重发作模型:
取PM2.5诱导的COPD急性加重发作模型组、化橘红总黄酮提取物P1组、化橘红总黄酮提取物P2组、化橘红总黄酮提取物P3组的所有大鼠,按2mg/kg体重的剂量给动物进行PM2.5混悬液气管滴注染毒造模,气管一次滴注量为2ml/kg体重,染毒时间为24h。
3.4呼吸功能检测:
用3%戊巴比妥钠(5mg/kg)腹腔注射麻醉,然后将大鼠仰卧固定在操作台上,纵行切开颈部皮肤,机械钝性分离皮下组织暴露气管,在环状软骨下切一个倒“T”型切口,进行气管插管。采用美国Buxco公司PFT/Maneuvers动物肺功能检测分析系统测量气道阻力、肺顺应性、0.2s呼气量(FEV0.2)/最大肺活量(FVC)、呼吸峰流速(PEF)等呼吸指标。
4、实验结果:
由表2可见,与空白对照组比较,COPD组大鼠的气道阻力显著升高(P<0.01),肺顺应性显著降低(P<0.01),0.2s呼气量(FEV0.2)/最大肺活量(FVC)与呼气峰流速(PEF)显著下降(P<0.01),说明烟熏复合气道内注入LPS法可造成大鼠表现出明显的气流受限现象。与COPD组比较,COPD+PM2.5组的气流受限明显加重,表现为气道阻力显著升高(P<0.01),肺顺应性显著降低(P<0.01),0.2s呼气量(FEV0.2)/最大肺活量(FVC)与呼气峰流速(PEF)显著下降(P<0.01)。与COPD+PM2.5组比较,COPD+PM2.5+P1组、COPD+PM2.5+P2组和COPD+PM2.5+P3组大鼠的气道阻力显著降低(P<0.05或0.01),肺顺应性显著升高(P<0.01),0.2s呼气量(FEV0.2)/最大肺活量(FVC)与呼气峰流速(PEF)显著提高(P<0.05或0.01),提示化橘红总黄酮提取物具有很好的抑制PM2.5诱导COPD急性发作的作用;尤其是抑制PM2.5诱导COPD急性加重发作期的气流受限加重的作用。
注:与正常对照组比较:##P<0.01;与COPD组比较:$$P<0.01;与COPD+PM2.5组比较:*P<0.05,**P<0.01。
Claims (4)
1.化橘红总黄酮提取物在制备防治PM2.5颗粒诱导慢性阻塞性肺疾病急性发作药物中的应用,所述的化橘红总黄酮提取物由以下方法制备:取化橘红药材,加水煎煮,水煎液浓缩至相对密度为1.05~1.30,加入乙醇或甲醇进行醇沉,滤液回收醇至无醇味的浸膏,加水调相对密度至1.05~1.15间,放置3天以上,过滤,得到沉淀物干燥,即为化橘红总黄酮提取物。
2.化橘红总黄酮提取物在制备防治PM2.5颗粒诱导慢性阻塞性肺疾病急性加重发作期气流受限加重药物中的应用,所述的化橘红总黄酮提取物由以下方法制备:取化橘红药材,加水煎煮,水煎液浓缩至相对密度为1.05~1.30,加入乙醇或甲醇进行醇沉,滤液回收醇至无醇味的浸膏,加水调相对密度至1.05~1.15间,放置3天以上,过滤,得到沉淀物干燥,即为化橘红总黄酮提取物。
3.如权利要求1或2所述的应用,其特征在于:所述的化橘红总黄酮提取物中,黄酮类化合物的总含量高于50%。
4.如权利要求3所述的应用,其特征在于:所述的化橘红总黄酮提取物中,黄酮类化合物的总含量高于70%。
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