CN104367688B - 一种中药组合物在制备破坏肺炎克雷伯菌生物膜的药物中的应用 - Google Patents
一种中药组合物在制备破坏肺炎克雷伯菌生物膜的药物中的应用 Download PDFInfo
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- CN104367688B CN104367688B CN201310347948.XA CN201310347948A CN104367688B CN 104367688 B CN104367688 B CN 104367688B CN 201310347948 A CN201310347948 A CN 201310347948A CN 104367688 B CN104367688 B CN 104367688B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明公开了一种中药组合物在制备破坏细菌生物膜的药物中的应用,属于中药领域,由连翘、金银花、板蓝根、大黄、广藿香等药味组成,本发明药物可以破坏细菌生物被膜,杀灭细菌。
Description
技术领域
本发明属于中药领域,具体涉及一种中药组合物的应用。
背景技术
细菌生物膜是指细菌在不利于其生长的环境下,通过自身产生的胞外多糖被膜多聚物相互粘连形成的细菌群落。目前认为99%的细菌以生物膜的形式存在。人类感染疾病,80%涉及细菌生物膜。
细菌生物被膜(Biofilm,BF)中水分含量可高达97%,除了水和细菌外,BF还含有大分子多聚物,如蛋白质、多糖、DNA、RNA、肽聚糖、脂和磷脂等,同时还含有吸附的营养物质和代谢产物。BF具有极强的耐药性及免疫逃避性,针对BF形成的药物渗透屏障,采取了联合用药,用一种药物破坏BF,用另一种药物进入BF杀菌,由于BF的顽固性,用药量难以控制,用量低,难以去除BF,会产生耐药性,用药量高,又会涉及药物的毒性问题。因此,目前还没有有效的药物破坏细菌生物膜。
发明内容
本发明目的是提供一种中药组合物在制备破坏细菌生物膜的药物中的应用,所述中药组合物由如下重量份的原料药制成:
连翘210-280 金银花210-280 板蓝根210-280 大黄45-55
广藿香75-100 绵马贯众210-280 红景天75-100 薄荷脑5.5-8.5
麻黄75-100 苦杏仁75-100 鱼腥草210-280 甘草75-100
石膏210-280。
作为优选方式,所述中药组合物由下列重量份的原料药制成:
连翘 210 金银花 280 板蓝根 210 大黄 45 广藿香 100
绵马贯众 280 红景天 75 薄荷脑5.5 麻黄 75 苦杏仁 100
鱼腥草 210 甘草 100 石膏 280。
或
连翘 280 金银花 210 板蓝根 280 大黄 55 广藿香 75
绵马贯众 210 红景天 100 薄荷脑 8.5 麻黄 100 苦杏仁 75
鱼腥草 280 甘草75 石膏 210。
或
连翘258 金银花 258 板蓝根 258 大黄50 广藿香 88
绵马贯众 258 红景天 88 薄荷脑 8 麻黄 85 苦杏仁 85
鱼腥草 255 甘草 85 石膏 255。
本发明还提供了所述中药组合物的活性成分由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调解至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
步骤(5)所得干膏粉、步骤(2)所得挥发油与薄荷脑共同构成该中药组合物的活性成分。
本发明药物的剂型为胶囊剂、片剂、散剂、口服液、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
为使上述剂型能够实现,需在制备这些剂型时加入药学可接受的辅料,例如:填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括:淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等;崩解剂包括:淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠等;润滑剂包括:硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等;助悬剂包括:聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等;粘合剂包括,淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等;甜味剂包括:糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等;矫味剂包括:甜味剂及各种香精;防腐剂包括:尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等;基质包括:PEG6000,PEG4000,虫蜡等(范碧亭《中药药剂学》,上海科学出版社 . 1997年12月第1版 .各剂型记载的辅料)。
其中胶囊剂的制备方法,是由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调解至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
(6) 将步骤(5)所得干膏粉加入适当药学上可接受的辅料制粒;
(7) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(6)所得颗粒,密闭,混匀,装入胶囊,即得。
其中颗粒剂的制备方法,是由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选,酌情碎断;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调解至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
(6) 将步骤(5)所得干膏粉加入适当药学上可接受的辅料制粒;
(7) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(6)所得颗粒,密闭,混匀,装袋,即得。
所述细菌为耐甲氧西林耐药菌。
所述耐甲氧西林耐药菌为大肠杆菌、肺炎克雷伯菌。
本发明药物的其他剂型按比例称取原料药后,采用常规的制备方法制备,例如,范碧亭《中药药剂学》(上海科学出版社1997年12月第1版)记载的制备工艺,制成药剂学可接受的常规剂型。
本发明的各药味的范围是经过优化筛选的,超出权利要求1中连翘210-280 金银花210-280 板蓝根210-280 大黄45-55 广藿香75-100 绵马贯众210-280 红景天75-100 薄荷脑5.5-8.5 麻黄75-100 苦杏仁75-100 鱼腥草210-280 甘草75-100 石膏210-280的范围,药物的作用效果不明显。
为证实本发明药物组合物破坏细菌生物膜的作用效果,用实施例制得的胶囊剂,进行了如下实验:
1 材料和方法
1.1 材料
1.1.1 菌株
大肠杆菌(Escherichia coli,ATCC 25922),肺炎克雷伯菌。
药品制备及分组
注射用青霉素钠,80万单位,华北制药生产,批号X1108105。甲氧西林钠盐(methicillin sodium salt),购自Sigma公司,批号1371696V。
本发明药物胶囊内容物,由石家庄以岭药业股份有限公司提供,批号111006,每克含生药9.78g,进行离体实验时,配置成内容物粉末,按以下方法将其分为三部分:
(1)乙酸乙酯提取物(YSYZ):反复用乙酸乙酯适量溶解100g内容物粉末,离心4分钟,转速1000转/分,取上清,至所收集的乙酸乙酯上清肉眼观为无色透明。水浴80℃(稍高于乙酸乙酯的沸点)加热至蒸干,并用乙醇溶解备用。(2)残渣水提物(CZ):100g内容物粉末乙酸乙酯提取后剩余的药残渣用纯水定溶于500ml容量瓶中水浴80℃加热2小时,充分溶解反复离心药液,除去药渣1000转/分离心4分钟。将澄清药液蒸干以同体积培养基溶解备用。(3)总水提液(ZS):将100g内容物粉末用纯水定溶于500ml容量瓶中水浴80℃加热,反复离心(1000转/min,4min)取上清药液,将药液蒸干,以同体积含葡萄糖0.25%培养基溶解备用。
药物浓度及分组:(1)抗生素组共10个浓度,为青霉素或甲氧西林,浓度范围20~0.04 μg/ml。(2)YSYZ组共10个浓度,浓度范围为6370 μg/ml~12.4 μg/ml。(3)CZ组共10个浓度,浓度范围为122750~239.75 μg/ml。(4)ZS组共 10个浓度,浓度范围为173000~237.89μg/ml。
主要试剂与仪器
胰蛋白胨、酵母提取物(英国OXOID公司),TSB、TSA培养基(美国BD公司),氯化钠(国药集团),结晶紫(美国AMRESCO公司),微生物活性检测试剂盒(日本同仁化学研究所),Matrix染色剂、LIVE/DEAD® BacLight Bacterial Viability试剂盒(美国MolecularProbes公司),戊二醛(上海化学试剂公司),自动洗板机(美国伯腾仪器有限公司),恒温恒湿培养箱(上海森信实验仪器有限公司),高压蒸汽灭菌锅(日本三洋)、超净台、恒温摇床、恒温水浴锅,分光光度计、酶标仪(美国伯乐公司),激光共聚焦显微镜(日本奥林巴斯公司)。
方法
1.2.1细菌常规培养
大肠杆菌:LB培养基,37℃常规培养。
肺炎克雷伯菌:LB培养基,37℃常规培养。
微孔板法检测本发明药物对细菌生物膜形成的影响
将YSYZ、CZ、ZS和青霉素(或甲氧西林)分别用含0.25%葡萄糖的培养液于96孔平底培养板进行倍比稀释,每孔加入摇床过夜培养的菌液(37℃,280转/分),稀释菌液使其孔中浓度达到OD600=0.05,阴性对照以同体积含糖培养液代替药物。每个浓度作3个复孔,将板子置于37℃培养24小时。染色前用洗板机以0.9%生理盐水将培养的96孔板清洗2次,洗去孔中未粘附的细菌。以结晶紫(CV)和细菌生物活性染色试剂盒(WST)分别染色后用酶标仪分别对每孔BF的生物总量和活菌量进行测定。
微孔板法检测本发明药物对成熟细菌生物膜的作用
细菌于摇床过夜培养(37℃,280转/分),将用含0.25%葡萄糖的培养液稀释好的菌液加入96孔板,使孔中浓度达到OD600=0.05,以37℃在恒温箱中培养成熟细菌生物膜,24h后,弃去上清,将稀释好的药物加入孔中继续培养于37℃培养24h,以CV染色和WST检测方法用酶标仪分别对每孔的生物总量和活菌量进行测定。
抑菌率的半抑制率的计算
半抑制率(IC50)为IC50为50%抑制浓度时所对应的浓度,实验应用logit法将数据进行处理,算出药物IC50值。
激光共聚焦观察药物对生物膜的影响
药物对S.a细菌生物膜形成的影响:细菌于摇床培养过夜(37℃,280转/分),同时在小皿中加入1ml药液和1ml稀释的菌液,使菌液浓度达OD600=0.05,所加入的青霉素/甲氧西林小皿中终浓度为20μg/ml, ZS为173000μg/ml。将小皿置于37℃培养24小时后弃去上清,用0.9%生理盐水小心清洗两次,去掉未粘附细菌,加入200μl matrix染料,同时以1.5μl/ml浓度分别加入PI和Syto9染色,将标本染色30min,在激光共聚焦上观察,PI、Syto9、matrix所需的激发波长分别为488nm 、559nm、 559nm。
药物对成熟S.a细菌生物膜的影响:细菌于摇床培养过夜(37℃,280转/min),在小皿中加入1ml药液和1ml稀释的菌液,使菌液浓度达OD600=0.05,所加入的青霉素/甲氧西林小皿中终浓度为20μg/ml, ZS为173000μg/ml。将小皿置于37℃培养24小时后弃去上清,后加入药物再于37℃培养24小时。染色前,用0.9%生理盐水小心清洗两次,加入三种染色剂染色30分钟后,于激光共聚焦上观察。
扫描电镜观察药物对生物膜的影响
将大小 5mm×5mm的载玻片放入24孔板,每孔一个,孔中菌液OD600值为0.05,将玻片于37℃培养24小时后,弃去培养液,取各药物组最大浓度药物加入其中,继续于37℃培养24小时。取出载玻片,将样本进行处理:(1)固定,前固定为使用4%戊二醛固定2小时,后固定为1%锇酸固定液固定2小时,固定后,以PBS缓冲液漂洗2次,5 分钟/次,(2)梯度脱水,将样本依次放入50%丙酮、70%丙酮、90%丙酮、100%丙酮、100%丙酮各15分钟,进行梯度脱水,(3)用100%叔丁醇浸透样本,放入-20℃冰箱30分钟。(4)取出样品真空冷冻干燥仪干燥4小时。(5)将干燥好的样品粘于样品台,将其喷金镀膜,后于扫描电镜下观察。
透射电镜观察药物对生物膜的影响
将细菌增菌菌液用培养液稀释,使其OD600值为0.05,加入离心管中以37℃培养24小时后,弃去管中一半上清,分别加入药物,取各药物组最大浓度,继续培养24小时。将样本离心,8000转/分,10分钟。样品按下列步骤处理:(1)前固定 4%戊二醛固定≥2小时。固定完毕,用PBS缓冲液漂洗3次,5分钟/次(2)后固定 1%锇酸固定液固定1~2小时。固定完毕,用PBS缓冲液漂洗3次,5分钟/次。(3)梯度脱水:依次经50% 丙酮脱水15分钟,70% 丙酮15分钟,90%丙酮15分钟,100%丙酮10分钟脱水两次。(4)梯度浸透:依次经丙酮2:1包埋剂2小时,丙酮1:1包埋剂2小时,纯包埋剂2小时。(5)包埋操作:将组织块包埋在多孔橡胶包埋模板中孔顶,然后置烤箱烘干,依次在烤箱37℃加温12小时,45℃ 12小时,60℃ 24小时,形成包埋块。(6)将样本切成超薄切片(5μm)后在透射电镜下观察。
结果
2.1 本发明药物对大肠杆菌生物膜的影响
(1)微孔板法检测本发明药物对大肠杆菌生物膜的影响
为观察本发明药物对大肠杆菌生物膜生物总量和活菌数的影响,行CV和WST染色后测量,结果分别见图1和图2。
图1中,与对照组相比,*P<0.05; **P<0.01; CV染色法示各给药组对BF生物总量的影响;WST染色法示各给药组对BF内活菌数的影响。
与对照组相比, CZ(122750~15343.75μg/ml),ZS(86500、21625μg/ml),能够减少大肠杆菌生物膜形成过程中的生物总量以及活菌数。从半抑制率(IC50)看, CZ组抑制效果最佳,其对生物总量IC50为58188μg/ml,对活菌数IC50为56528μg/ml。
乙醇溶剂对照组中一些浓度对BF中活菌数的抑制具统计学意义,但从IC50看,抑制作用不明显。
本发明三药物组中,CZ组效果相对最好,能抑制大肠杆菌BF形成阶段的生物总量(CV)。
图2中,与对照组相比,*P<0.05; **P<0.01; CV染色法示各给药组对BF生物总量的影响;WST染色法示各给药组对BF内活菌数的影响。
可以看到,与对照组相比, YSYZ、CZ、ZS对成熟大肠杆菌生物膜生物总量及和活菌数无明显抑制作用。青霉素(2.5、0.041μg/ml)对生物膜内活菌数有影响。本发明药物三个药物组对成熟大肠杆菌BF抑制效果均不明显。
(2)激光共聚焦观察本发明药物对大肠杆菌生物膜的影响
为研究本发明药物对大肠杆菌细菌生物膜厚度和成分,即活菌、死菌、胞外基质的作用情况,对生物膜进行活(syto-9)、死菌(PI)及细菌外基质(matrix)荧光染色后,激光共聚焦下观察生物膜形态及荧光强度,结果分别如图3、图 4所示。
图3示,与对照组相比抗生素组(青霉素,20μg/ml)活菌荧光强度和胞外基质荧光强度上升,ZS组,(173000μg/ml)胞外基质强度上升而活菌荧光强度、死菌荧光强度下降。
图4示,与对照组相比,可以看出抗生素组(青霉素,20μg/ml)成熟BF中活菌、死菌、胞外基质染色荧光强度均有不同程度的增强;ZS组(173000μg/ml)胞外基质大幅上升,而活菌、死荧光强度大幅下降。
本发明药物对肺炎克雷伯的影响
(1)微孔板法检测本发明药物对肺炎克雷伯菌生物膜的影响
为观察本发明药物对肺炎克雷伯菌生物膜生物总量和活菌数的影响,行CV和WST染色法测量,结果分别见图5、图6。
图5中,与对照组相比,*P<0.05; **P<0.01; CV染色法示各给药组对BF生物总量的影响;WST染色法示各给药组对BF内活菌数的影响。
与对照组相比, YSYZ(6370~3185μg/ml)、CZ(122750~479.49μg/ml)、ZS(86500~675.78μg/ml),能够减少肺炎克雷伯菌生物膜形成过程中的活菌数,而各药物组对生物总量无明显抑制。从半抑菌率看,本发明药物三种提取物对细菌生物膜活菌(WST)都有一定的抑制,其中CZ组对活菌数的IC50为3160μg/ml,效果最佳。Fig 15中,乙醇溶剂一些浓度对照组对生物抑制作用也具统计学意义。
本发明药物三个药物组均对肺炎克雷伯BF中活菌数有抑制作用。其中YSYZ组和CZ组效果较好。
图6中,与对照组相比,*P<0.05; **P<0.01; CV染色法示各给药组对BF生物总量的影响;WST染色法示各给药组对BF内活菌数的影响。
乙醇溶剂对照组对BF影响无统计学意义。与对照组相比,青霉素(1.25、0.623μg/ml)对肺炎克雷伯菌生物膜生物总量有抑制作用。
YSYZ(6370~1592.5μg/ml)、CZ(122750μg/ml),ZS(173000-86500μg/ml)CZ、ZS能够减少活菌数。从半抑制率(IC50)看,CZ组效果相对差,而ZS较好,为208353μg/ml。
本发明药物三个药物组中,从抑菌率看,YSYZ组因其乙醇溶剂对照组的阳性结果影响,对成熟BF抑制作用不突出,而ZS组抗生物膜作用相对较好,能抑制肺炎克雷伯BF活菌数(IC50为208353μg/ml)。
(2)激光共聚焦观察本发明药物对肺炎克雷伯菌生物膜的影响
为研究本发明药物对肺炎克雷伯菌生物膜厚度和成分,即活菌、死菌、胞外基质的作用情况,对生物膜进行活(syto-9)、死菌(PI)及细菌外基质(matrix)荧光染色后,激光共聚焦下观察生物膜形态及荧光强度,结果分别如图7、图8所示。
图7中,与对照组相比,可以看出抗生素组(青霉素,20μg/ml)BF活菌、死菌、胞外基质染色中均有下降。本发明药物组(ZS,173000μg/ml)BF中活菌、死菌、胞外基质染色荧光强度大幅度下降。
图8中,与对照组相比可以看出抗生素组(青霉素,20μg/ml)活菌、死菌、胞外基质荧光强度均有下降。本发明药物组(ZS,173000μg/ml)活菌荧光强度大幅下降,死菌和胞外基质无明显变化。
结论
本发明药物主要表现在其对于生物膜厚度及细菌数量的抑制,可以抑制膜中活菌量和死菌量。
附图说明
图1是各给药组对大肠杆菌生物膜形成影响图,CV染色法各给药组对BF生物总量的影响以及WST染色法示各给药组对BF内活菌数的影响;
图2是各给药组对成熟大肠杆菌生物膜形成影响图,CV染色法各给药组对BF生物总量的影响以及WST染色法示各给药组对BF内活菌数的影响;
图3是激光共聚焦观察药物对大肠杆菌生物膜的影响;
图4是激光共聚焦观察药物对成熟大肠杆菌生物膜的影响;
图5是各给药组对肺炎克雷伯菌生物膜形成影响图,CV染色法各给药组对BF生物总量的影响以及WST染色法示各给药组对BF内活菌数的影响;
图6是各给药组对成熟肺炎克雷伯菌生物膜形成影响图,CV染色法各给药组对BF生物总量的影响以及WST染色法示各给药组对BF内活菌数的影响;
图7是激光共聚焦观察药物对肺炎克雷伯菌生物膜的影响;
图8是激光共聚焦观察药物对成熟肺炎克雷伯菌生物膜的影响。
具体实施方式
实施例1:
原料药配方为:
连翘 258g 金银花 258 g 板蓝根 258 g 大黄 50 g 广藿香 88 g
绵马贯众 258 g 红景天 88 g 薄荷脑 8 g 麻黄 85 g 苦杏仁 85 g
鱼腥草 255 g 甘草 85 g 石膏 255g。
制备方法为:
(1) 按照上述处方称取中药材,净选,酌情碎断;
(2) 广藿香碎断,加6倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用8倍量70%的乙醇提取2次,第一次2小时,第二次1.5小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加9倍量水煎煮至沸,加入苦杏仁煎煮2次,第一次1.5小时,第二次1小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10的清膏,加乙醇,调节至醇浓度为70%,冷藏放置24小时,过滤,回收乙醇至无醇味,所得滤液与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15的清膏,喷雾干燥,得干膏粉,备用;
(5) 将步骤(4)所得干膏粉加入淀粉138克,用85%乙醇制粒;
(6) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(5)所得颗粒,密闭,混匀,装入1000粒胶囊,即得。
实施例2:
原料药配方为:
连翘 210 g 金银花 280 g 板蓝根 210 g 大黄 45 g 广藿香 100 g
绵马贯众 280 g 红景天 75 g 薄荷脑5.5 g 麻黄 75 g 苦杏仁 100 g
鱼腥草 210 g 甘草 100 g 石膏 280g。
制备方法为:
(1) 按照上述处方称取中药材,净选,酌情碎断;
(2) 广藿香碎断,加5倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6倍量50%的乙醇提取2次,第一次3小时,第二次1小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7倍量水煎煮至沸,加入苦杏仁煎煮2次,第一次0.5小时,第二次2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.15的清膏,加乙醇,调节至醇浓度为70%,冷藏放置24小时,过滤,回收乙醇至无醇味,所得滤液与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.20的清膏,喷雾干燥,得干膏粉,备用;
(5) 将步骤(4)所得干膏粉加入淀粉134克,用85%乙醇制粒;
(6) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(5)所得颗粒,按常规制剂方法制成片剂即得。
实施例3:
原料药配方为:
连翘 280 g 金银花 210 g 板蓝根 280 g 大黄 55 g 广藿香 75 g
绵马贯众 210 g 红景天 100 g 薄荷脑 8.5 g 麻黄 100 g 苦杏仁 75 g
鱼腥草 280 g 甘草 75 g 石膏 210g。
制备方法为:
(1) 按照上述处方称取中药材,净选,酌情碎断;
(2) 广藿香碎断,加8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用10倍量90%的乙醇提取2次,第一次1小时,第二次3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加11倍量水煎煮至沸,加入苦杏仁煎煮2次,第一次2.5小时,第二次0.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.12的清膏,加乙醇,调节至醇浓度为70%,冷藏放置24小时,过滤,回收乙醇至无醇味,所得滤液与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.13的清膏,喷雾干燥,得干膏粉,备用;
(5) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(4)所得干膏粉,按常规制剂方法制成丸剂即得。
实施例4:
原料药配方为:
连翘 280g 金银花 210g 板蓝根 280g 大黄 55g 广藿香 75g
绵马贯众 210g 红景天 100g 薄荷脑 8.5g 麻黄 100g 苦杏仁 75g
鱼腥草 280g 甘草 75g 石膏 210g。
制备方法:
(一)提取工艺:
(1) 按照上述处方量称取中药材,净选,酌情碎断;
(2) 广藿香加6倍量水提取挥发油,提油时间4h,收集挥发油,出油率为0.33±0.05%,提取液过滤后备用,残渣弃去;
(3) 连翘、炙麻黄、鱼腥草、大黄,用8倍量70%的乙醇提取2次,第一次2小时,第二次1.5小时,提取液过滤,滤液合并,回收乙醇至无醇味,备用;
(4) 金银花、苦杏仁、石膏、板蓝根、绵马贯众、甘草、红景天,加9倍量水煎煮至沸,加入苦杏仁,煎煮2次,第一次1.5小时,第二次1小时,提取液过滤,滤液合并同时加入步骤(2)广藿香提油后的水溶液,浓缩成60℃测定相对密度为1.10清膏,加95%乙醇,边加边搅拌,至醇浓度70%,冷藏放置24小时,过滤,滤液回收乙醇至无醇味,与醇提液合并,浓缩至浓缩成60℃测定相对密度为1.20稠膏,备用;
(二)制剂工艺:
(5) 制剂配方为:步骤(4)所得稠膏335.5g 薄荷脑5g
步骤(2)所得广藿香油0.2ml 糖粉342.5g 糊精514.0g
(6) 制粒:将糖粉和糊精混合均匀,用稠膏作粘合剂制软材,14目筛网制粒,60—65℃烘干,10目筛网整粒;
(7) 分装:筛出细粉适量,将薄荷脑、广藿香挥发油加入适量乙醇,溶解,喷入细粉中,混合均匀,并与颗粒混合均匀,密闭半小时,装袋,即得,以上处方可制成颗粒1000g。
Claims (8)
1.一种中药组合物在制备破坏肺炎克雷伯菌生物膜的药物中的应用,其特征在于所述中药组合物由下列重量份的原料药制成:
连翘210-280 金银花210-280 板蓝根210-280 大黄45-55
广藿香75-100 绵马贯众210-280 红景天75-100 薄荷脑5.5-8.5
麻黄75-100 苦杏仁75-100 鱼腥草210-280 甘草75-100
石膏210-280。
2.根据权利要求1所述的应用,其特征在于所述中药组合物由下列重量份的原料药制成:
连翘 210 金银花 280 板蓝根 210 大黄 45 广藿香 100
绵马贯众 280 红景天 75 薄荷脑5.5 麻黄 75 苦杏仁 100
鱼腥草 210 甘草 100 石膏 280。
3.根据权利要求1所述的应用,其特征在于所述中药组合物由下列重量份的原料药制成:
连翘 280 金银花 210 板蓝根 280 大黄 55 广藿香 75
绵马贯众 210 红景天 100 薄荷脑 8.5 麻黄 100 苦杏仁 75
鱼腥草 280 甘草 75 石膏210。
4.根据权利要求1所述的应用,其特征在于所述中药组合物由下列重量份的原料药制成:
连翘 258 金银花 258 板蓝根 258 大黄 50 广藿香 88
绵马贯众 258 红景天 88 薄荷脑 8 麻黄 85 苦杏仁 85
鱼腥草 255 甘草 85 石膏 255。
5.根据权利要求1-4任一项所述的应用,其特征在于所述中药组合物的活性成分由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调节至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
(6) 步骤(5)所得干膏粉、步骤(2)所得挥发油与薄荷脑共同构成该中药组合物的活性成分。
6.根据权利要求1-4任一项所述的应用,其特征在于所述的药物剂型为胶囊剂、片剂、散剂、颗粒剂、口服液、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
7.根据权利要求6所述的应用,其特征在于所述胶囊剂是由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调节至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
(6) 将步骤(5)所得干膏粉加入适当药学上可接受的辅料制粒;
(7) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(6)所得颗粒,密闭,混匀,装入胶囊,即得。
8.根据权利要求6所述的应用,其特征在于颗粒剂的制备方法是由以下步骤制成:
(1) 按照原料药重量比例称取中药材,净选,酌情碎断;
(2) 广藿香碎断,加5-8倍量水提取挥发油,提油时间4小时,收集挥发油,备用;提取液过滤后,残渣弃去,滤液备用;
(3) 连翘、麻黄、鱼腥草、大黄,用6-10倍量50-90%的乙醇提取2次,每次1-3小时,提取液合并过滤,回收乙醇,滤液备用;
(4) 金银花、石膏、板蓝根、绵马贯众、甘草、红景天,加7-11倍量水煎煮至沸,加入苦杏仁,煎煮2次,每次0.5-2.5小时,提取液合并过滤,所得滤液与步骤(2)广藿香提油后的滤液合并,浓缩成在60℃时测定相对密度为1.10-1.15的清膏,加入乙醇,调节至醇浓度为70%,冷藏放置,过滤,回收乙醇至无醇味,得清膏备用;
(5) 将步骤(4)所得清膏与步骤(3)所得醇提液合并,浓缩至在60℃时测定相对密度为1.15-1.20的清膏,干燥,得干膏粉,备用;
(6) 将步骤(5)所得干膏粉加入适当药学上可接受的辅料制粒;
(7) 将薄荷脑、步骤(2)所得挥发油加入乙醇溶解,喷入步骤(6)所得颗粒,密闭,混匀,装袋,即得。
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