CN103804186A - 一种抗临床泌尿系统耐药菌的中药组合物及其组成和应用 - Google Patents
一种抗临床泌尿系统耐药菌的中药组合物及其组成和应用 Download PDFInfo
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- CN103804186A CN103804186A CN201210458454.4A CN201210458454A CN103804186A CN 103804186 A CN103804186 A CN 103804186A CN 201210458454 A CN201210458454 A CN 201210458454A CN 103804186 A CN103804186 A CN 103804186A
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Abstract
本发明涉及的是从猫须草中得到的具有抗临床泌尿系耐药菌活性的组合物及其化学成分的组成。具体包括利用水或(和)醇类溶剂对猫须草全草进行提取,提取物经纯化富集后得到猫须草抗临床泌尿系统耐药菌的有效部位。该有效部位经大孔树脂纯化,得到本发明中的组合物。经体内外药理实验研究发现,该中药组合物及其制剂具有显著性抗临床泌尿系统耐药菌活性,在临床上可用于泌尿系细菌感染引起的膀胱炎、尿道炎,亦可用于急、慢性肾小球肾炎、肾盂肾炎等方面的治疗。本发明还涉及利用各种柱色谱分离技术及重结晶等纯化手段从该组合物中得到35个酚酸类成分,并应用波谱学方法鉴定所得化合物的结构。
Description
技术领域
本发明涉及一种抗临床泌尿系统耐药菌中药组合物的化学组成及其应用,即该中药组合物由35个酚酸类成分组成,该中药组合物及其制剂在临床主要具有清热解毒,利湿等,用于下焦湿热所致的小便短赤,淋沥涩痛;临床上能够用于泌尿系细菌感染引起的膀胱炎、尿道炎,也可用于急、慢性肾小球肾炎、肾盂肾炎等方面的治疗。
背景技术:
泌尿系统感染是常见的医院内感染性疾病。据不完全统计,在我国泌尿系感染为医院感染的第二位,仅次于呼吸道感染。由于严重的泌尿系统感染能引起菌血症和。肾功能不全,最终可导致尿毒症而危及生命,多年来一直被广泛关注。随着高效广谱耐药菌药物大量应用于临床,致使泌尿系统感染病原菌的菌群分布及细菌耐药菌不断发生变化,临床诊治泌尿道感染的难度日益增大。而独具特色的民族药在此方面展示了重要的前景,并逐渐被人们所重视。猫须草Clerodend ranthus spicatus(Thunb)C.丫Wu(Orthosiphonstamineus Benth.)为唇形科肾茶属植物。该属植物全世界仅有5种,产于东南亚的印度尼西亚、马来西亚、缅甸、菲律宾等国家,澳大利亚也有分布。我国仅有猫须草一种,主要分布于广‘东、海南、广西南部、云南南部、台湾及福建。作为一种传统的傣药,猫须草用于治疗小便热、涩、疼痛等泌尿系统疾病已有两千多年的历史,疗效确切。民间认为其全草具有利尿、抗菌、消炎、溶石、排石和抗肿瘤作用,对于急慢性肾炎、膀胱炎、尿路结石、风湿性下肢关节炎和咽炎有特殊疗效。猫须草是一种珍贵的药用保健植物,具有广阔的研究开发前景。前期研究表明,猫须草中的主要特征性成分及活性成分为多酚类类化合物,并已申请专利并已公开(公开号:CN102688285A)。迄今为止,尚未见有关猫须草抗临床泌尿系耐药菌有效部位的组合物及其组成的研究报道和专利。
发明内容:
本发明所涉及的是一种抗临床泌尿系统耐药菌中药的组合物及其组成。具体包括:Clerodendranoic acidA (1),Clerodendranoic acid B(2),Clerodendranoic acid C(3),Clerodendranoic acid D(4),Clerodendranoicacid E(5),Clerodendranoic acid F(6),Clerodendranoic acid G(7),Clerodendranoic acid H(8),Clerodendranoicacid I(9),Clerodendranoic acid J(10),Clerodendranoic acid(11),Helisterculins A(12),Helisterculins B(13),3′-O-(8″-Z-caffeoyl)rosmarinic acid(14),3′-O-(8″-Z-caffeoyl)rosmarinic acid methyl ester(15)迷迭香酸(16),迷迭香酸甲酯(17),迷迭香酸乙酯(18),咖啡酸(19),咖啡酸甲酯(20),咖啡酸乙酯(21),二氢咖啡酸乙酯(22),香草酸(23),原儿茶醛(24),原儿茶酸(25),3,5-二羟基苯甲醛(26),3,5-二氧甲基没食子酸(27),对羟基苯甲酸(28),对羟基苯甲醛(29),紫草酸(30),紫草酸甲酯(31),紫草酸二甲酯(32),丹参素(33),丹参素甲酯(34),丹参素乙酯(35)。
根据本发明的另一个方面,提过了一种制备本组合物中各个化合物的方法,所述方法包括如下步骤:
(1)猫须草有效活性部位用水溶解;
(2)将步骤(1)中所得的水液经大孔树脂D101柱层析,依次用水,30%乙醇,60%乙醇和95%乙醇洗脱,弃去水洗脱部位,依次得到30%乙醇洗脱物,60%乙醇洗脱物和95%乙醇洗脱物;
(3)将步骤(2)中得到的大孔树脂30%乙醇洗脱物浓缩,热水溶解并经MCI柱层析,用水:甲醇的体积比为100:0至0:100的混合溶剂进行梯度洗脱,按照所使用的不同梯度的洗脱液收集流分;
(4)将步骤(3)中使用水:甲醇体积比为90:10的混合溶剂洗脱下来的流分(Ft 22-28)经高效液相制各色谱,得到化合物24,25,26,28和29;
(5)将步骤(3)中使用水:甲醇体积比为85:15的混合溶剂洗脱下来的流分(Fr.34-42)经凝胶柱层析及反相C18柱层析,高效液相制备色谱,得到化合物1,19和20;
(6)将步骤(3)中使用水:甲醇体积比为80:20的混合溶剂洗脱下来的流分(Fr.49)经凝胶柱层析,高效液相制备色谱,得到化合物23,33,34和35;
(7)将步骤(3)中使用水:甲醇体积比为80:20至75:25的混合溶剂洗脱下来的流分(Fr.50-62)经凝胶柱层析,高效液相制备色谱,得到化合物27;
(8)将步骤(3)中使用水:甲醇体积比为75:25至70:30的混合溶剂洗脱下来的流分(Fr.63-83)经凝胶柱层析,高效液相制备色谱,得到化合物2,3,4,5,6,7,12,12,30,31和32;
(9)将步骤(3)中使用水:甲醇体积比为70:20至65:35的混合溶剂洗脱下来的流分(Fr.84-108)经凝胶柱层析,高效液相制备色谱,得到化合物16,17和18;
(10)将步骤(3)中使用水:甲醇体积比为65:35至60:40的混合溶剂洗脱下来的流分(Fr.115-121)经凝胶柱层析,高效液相制备色谱,得到化合物9和17;
(11)将步骤(3)中使用水:甲醇体积比为60:40的混合溶剂洗脱下来的流分(Fr.132-145)经凝胶柱层析,高效液相制各色谱,得到化合物8,9,10和13;
(12)将步骤(3)中使用水:甲醇体积比为60:40至50:50的混合溶剂洗脱下来的流分(Fr.156-163)经凝胶柱层析,高效液相制备色谱,得到化合物21和22;
(13)将步骤(2)中得到的大孔树脂60%乙醇洗脱物浓缩,热水溶解并经MCI柱层析,用水:甲醇的体积比为15:85至0:100的混合溶剂进行梯度洗脱,按照所使用的不同梯度的洗脱液收集流分;
(14)将步骤(13)中使用水:甲醇体积比为30:70的混合溶剂洗脱下来的流分(Fr.1-4)经凝胶柱层析,高效液相制备色谱,得到化合物33;
(15)将步骤(13)中使用水:甲醇体积比为35:65的混合溶剂洗脱下来的流分(Fr.19-22)经凝胶柱层析,高效液相制备色谱,得到化合物2;
(16)将步骤(13)中使用水:甲醇体积比为50:50的混合溶剂洗脱下来的流分(Fr.46-49)经凝胶柱层析,高效液相制备色谱,得到化合物18;
(17)将步骤(2)中得到的大孔树脂95%乙醇洗脱物浓缩,甲醇溶解并经凝胶柱层析,甲醇洗脱,收集流分;
(18)将步骤(17)中的洗脱流分(Fr.4)经高效液相制各色谱,得到化合物14;
(19)将步骤(17)中的洗脱流分(Fr.6-9)经高效液相制备色谱,得到化合物11和15。
根据本发明的具体实施方法,其中上述步骤中所使用的凝胶柱为Sephadex LH-20柱和HW-40C柱;同时,所述方法中还包括使用薄层色谱。
本发明提供了一种抗临床泌尿系统耐药菌的中药组合物,所述组合物应含有至少一种本发明的化合物。
迄今为止,以上研究成果尚未有专利或文献报道。
本发明的有益效果和意义在于:本发明之目的在于充分利用我国丰富的猫须草药用植物资源,深入进行研究开发,在前期申请的猫须草抗临床泌尿系耐药菌有效部位制备的专利基础上,进一步明确该中药有效部位的中药组合物及其制剂的临床应用,即该中药组合物由35个酚酸类成分组成,该中药组合物及其制剂在临床主要具有清热解毒,利湿等,用于下焦湿热所致的小便短赤,淋沥涩痛;临床上能够用于泌尿系细菌感染引起的膀胱炎、尿道炎,也可用于急、慢性肾小球肾炎、肾盂肾炎等方面的治疗。以期为临床提供一种抗临床泌尿系耐药菌的现代中药制剂。
附图说明
图1化合物提取分离流程
图2化合物结构
具体实施方式
根据本发明所公开的技术内容,本领域技术人员将很清楚本发明的其他实施方案,下述实施方案仅作示例。在不违反本发明主旨及范围的情况下,可对本发明进行各种改变和改进。这些改变和改进均应在本发明的保护范围之内。
猫须草有效活性部位A经大孔树脂层析,以乙醇-水(30%,60%和95%)为洗脱剂,得到30%大孔树脂洗脱部位A1,65%大孔树脂洗脱部A2及95%大孔树脂洗脱部位A3。分别对这三个洗脱部位进行系统分离。A1利用反相MCI柱色谱进行粗分离,以甲醇-水(0:100-100:0)梯度洗脱,得到173个流分。Fr.22-28经凝胶柱层析,以甲醇-水洗脱,薄层检测示踪合并相同组分,得到10个流分。所得流分经反相高效液相制备色谱分离,得到化合物24,25,26,28和29;Fr.34-42经凝胶及ODS柱色谱分离,以甲醇-水洗脱,经薄层示踪合并相同组分,共得12个流分,所得流分经反相高效液相制备色谱分离,得到化合物1,20及20。Fr.49经凝胶柱色谱分离,以甲醇.水系统洗脱,薄层示踪合并相同组分,共得6个流分,所得流分经反相高效液相制备色谱分离,得到化合物23,33,34和35。Fr.50-62经凝胶柱层析,以甲醇-水洗脱,薄层检测示踪合并相同组分,经制备液相分离,得到化合物27。Fr.63-83经凝胶柱分离,以甲醇-水系统洗脱,薄层示踪合并相同组分,共得13个流分,所得流分经反相高效液相制备色谱分离,得到化合物2,3,4,5,6,7,12,30,31和32。Fr.84-108经凝胶柱分离,以甲醇-水系统洗脱,薄层示踪合并相同组分,共得32个流分,所得流分经反相高效液相制备色谱分离,得到化合物16,17和18。Fr.115-121经凝胶柱色谱分离,以甲醇-水系统洗脱,薄层示踪合并相同组分,共得16个流分,所得流分经反相高效液相制备色谱分离,得到化合物9和17。Fr.32-145经凝胶柱色谱分离,以甲醇-水系统洗脱,薄层示踪合并相同组分,共得12个流分,所得流分经反相高效液相制备色谱分离,得到化合物8,9,1O和13。Fr.156-163经凝胶柱色谱分离,以甲醇-水系统洗脱,薄层示踪合并相同组分,共得10个流分,所得流分经反相高效液相制备色谱分离,得到化合物21和22。A2利用反相MCI柱色谱进行粗分离,以甲醇-水(30∶70-100∶0)梯度洗脱,Fr.1-4经凝胶柱层析,以甲醇-水洗脱,薄层检测示踪合并相同组分,得到13个流分。所得流分经反相高效液相制备色谱分离,得到化合物33。Fr.19-22经凝胶柱层析,以甲醇-水洗脱,薄层检测示踪合并相同组分,得到20个流分。所得流分经反相高效液相制备色谱分离,得到化合物2。Fr.46-49经凝胶柱层析,以甲醇-水洗脱,薄层检测示踪合并相同组分,得到6个流分。所得流分经反相高效液相制备色谱分离,得到化合物18。A3经Sephadex LH-20柱层析,以甲醇洗脱,薄层示踪合并相同组分,得到16个流分。所得流分经反相高效液相制备色谱分离,得到化合物11,14和15。
Claims (8)
1.从猫须草(Clerodend ranthus spicatus(Thunb)C.Y.Wu)中得到的一个具有抗临床泌尿系统耐药菌的组合物,其特征在于该组合物为中药提取物且具有体内和体外显著的抗临床泌尿系统耐药菌活性。
权利要求1中的中药组合物的主要成分包括以下35个酚酸类化学成分,即:Clerodendranoic acid A(1),Clerodendranoic acid B(2),Clerodendranoic acid C(3),Clerodendranoic acid D(4),Clerodendranoic acid E(5),Clerodendranoic acid F(6),Clerodendranoic acid G(7),Clerodendranoic acid H(8),Clerodendranoic acidI(9),Clerodendranoic acid J(10),Clerodendranoic acid (11),Helisterculins A(12),Helisterculins B(13),3′-O-(8″-Z-caffeoyl)rosmarinic acid(14),3′-O-(8″-Z-caffeoyl)rosmarinic acid methyl ester(15)迷迭香酸(16),迷迭香酸甲酯(17),迷迭香酸乙酯(18),咖啡酸(19),咖啡酸甲酯(20),咖啡酸乙酯(21),二氢咖啡酸乙酯(22),香草酸(23),原儿茶醛(24),原儿茶酸(25),3,5-二羟基苯甲醛(26),3,5-二氧甲基没食子酸(27),对羟基苯甲酸(28),对羟基苯甲醛(29),紫草酸(30),紫草酸甲酯(31),紫草酸二甲酯(32),丹参素(33),丹参素甲酯(34),丹参素乙酯(35)。
2.一种制备权利要求1中所述化合物的方法,包括下述步骤:
(1)猫须草有效活性部位用水溶解;
(2)将步骤(1)中所得的水液经大孔树脂D101柱层析,依次用水,30%乙醇,60%乙醇和95%乙醇洗脱,弃去水洗脱部位,依次得到30%乙醇洗脱物,60%乙醇洗脱物和95%乙醇洗脱物;
(3)将步骤(2)中得到的大孔树脂30%乙醇洗脱物浓缩,热水溶解并经MCI柱层析,用水∶甲醇的体积比为100∶0至0∶100的混合溶剂进行梯度洗脱,按照所使用的不同梯度的洗脱液收集流分;
(4)将步骤(3)中使用水∶甲醇体积比为90∶10的混合溶剂洗脱下来的流分(Fr.22-28)经高效液相制备色谱,得到化合物24,25,26,28和29;
(5)将步骤(3)中使用水∶甲醇体积比为85∶15的混合溶剂洗脱下来的流分(Fr.34-42)经凝胶柱层析及反相C18柱层析,高效液相制备色谱,得到化合物1,19和20;
(6)将步骤(3)中使用水∶甲醇体积比为80∶20的混合溶剂洗脱下来的流分(Fr.49)经凝胶柱层析,高效液相制备色谱,得到化合物23,33,34和35;
(7)将步骤(3)中使用水∶甲醇体积比为80∶20至75∶25的混合溶剂洗脱下来的流分(Fr.50-62)经凝胶柱层析,高效液相制备色谱,得到化合物27;
(8)将步骤(3)中使用水∶甲醇体积比为75∶25至70∶30的混合溶剂洗脱下来的流分(Fr.63-83)经凝胶柱层析,高效液相制备色谱,得到化合物2,3,4,5,6,7,12,12,30,31和32;
(9)将步骤(3)中使用水∶甲醇体积比为70∶20至65∶35的混合溶剂洗脱下来的流分(Fr.84-108)经凝胶柱层析,高效液相制备色谱,得到化合物16,17和18;
(10)将步骤(3)中使用水:甲醇体积比为65:35至60:40的混合溶剂洗脱下来的流分(Fr.115-121)经凝胶柱层析,高效液相制备色谱,得到化合物9和17;
(11)将步骤(3)中使用水:甲醇体积比为60:40的混合溶剂洗脱下来的流分(Fr.132-145)经凝胶柱层析,高效液相制备色谱,得到化合物8,9,10和13;
(12)将步骤(3)中使用水:甲醇体积比为60:40至50:50的混合溶剂洗脱下来的流分(Fr.156-163)经凝胶柱层析,高效液相制备色谱,得到化合物21和22;
(13)将步骤(2)中得到的大孔树脂60%乙醇洗脱物浓缩,热水溶解并经MCI柱层析,用水:甲醇的体积比为15:85至0:100的混合溶剂进行梯度洗脱,按照所使用的不同梯度的洗脱液收集流分;
(14)将步骤(13)中使用水:甲醇体积比为30:70的混合溶剂洗脱下来的流分(Fr.1-4)经凝胶柱层析,高效液相制备色谱,得到化合物33;
(15)将步骤(13)中使用水:甲醇体积比为35:65的混合溶剂洗脱下来的流分(Fr.19-22)经凝胶柱层析,高效液相制备色谱,得到化合物2;
(16)将步骤(13)中使用水:甲醇体积比为50:50的混合溶剂洗脱下来的流分(Fr.46-49)经凝胶柱层析,高效液相制备色谱,得到化合物18;
(17)将步骤(2)中得到的火孔树脂95%乙醇洗脱物浓缩,甲醇溶解并经凝胶柱层析,甲醇洗脱,收集流分;
(18)将步骤(17)中的洗脱流分(Fr.4)经高效液相制备色谱,得到化合物14;
(19)将步骤(17)中的洗脱流分(Fr.6-9)经高效液相制备色谱,得到化合物11和15。
3.根据权利2要求的方法,上述步骤中所使用的凝胶柱为Sephadex LH-20柱和HW-40C柱。
4.根据权利2要求的方法,所述方法中还包括使用薄层色谱检验所的的各化合物。
5.权利要求1所述中药组合物及其制剂在临床主要具有清热解毒,利湿等,用于下焦湿热所致的小便短赤,淋沥涩痛;临床上能够用于泌尿系细菌感染引起的膀胱炎、尿道炎,也可用于急、慢性肾小球肾炎、肾盂肾炎等方面的治疗。
6.一种具有抗临床泌尿系统耐药菌的组合物,含有只有一种权利要求1的化合物。
7.权利要求1所述中药组合物在制备辅助治疗临床泌尿系统耐药菌感染引起的有关疾病的保健品中的应用。
8.根据权利要求1所述的抗临床泌尿系耐药菌的中药,其特征在于:所述的中药为胶囊(软胶囊)、颗粒剂(干混悬剂)、片剂(分散片、泡腾片、咀嚼片、口崩片)、溶液剂(糖浆)、丸剂(浓缩丸、滴丸、微丸),或者为注射剂型。
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CN104262155A (zh) * | 2014-08-29 | 2015-01-07 | 中国药科大学 | 一种酚酸类化合物及其制备方法与药物用途 |
WO2016043667A1 (en) * | 2014-09-18 | 2016-03-24 | Root King Pte Ltd | Composition for prevention or treatment of urinary tract infection |
WO2019120235A1 (zh) * | 2017-12-22 | 2019-06-27 | 中国科学院上海药物研究所 | 一类苯基羧酸衍生物、其制备方法及其用途 |
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CN104262155A (zh) * | 2014-08-29 | 2015-01-07 | 中国药科大学 | 一种酚酸类化合物及其制备方法与药物用途 |
WO2016043667A1 (en) * | 2014-09-18 | 2016-03-24 | Root King Pte Ltd | Composition for prevention or treatment of urinary tract infection |
WO2019120235A1 (zh) * | 2017-12-22 | 2019-06-27 | 中国科学院上海药物研究所 | 一类苯基羧酸衍生物、其制备方法及其用途 |
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