CN101606977B - 一种丁香叶总环烯醚萜苷的制备方法及用途 - Google Patents
一种丁香叶总环烯醚萜苷的制备方法及用途 Download PDFInfo
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Abstract
本发明提供一种丁香叶总环烯醚萜苷提取物的制备方法,是将丁香叶药材粉碎,加水或水/醇溶剂系统,采用加热回流/渗漉或超声提取,过滤,离心,调pH值至2-5,提取液通过大孔吸附树脂层析柱,用水及醇洗脱剂洗涤树脂,洗脱液减压回收醇,冷冻或喷雾干燥,即得总环烯醚萜苷。用本发明方法制备的丁香叶总环烯醚萜苷转移率可达75%以上,其中丁香苦苷含量达53.42%。通过添加各种药用辅料可制成用于治疗上呼吸道感染、急慢性扁桃体炎、急性肠炎及菌痢等感染性疾病的药物,制备药物的剂型为固体制剂。
Description
技术领域
本发明属植物及中药提取物领域,具体涉及丁香叶中总环烯醚萜苷提取物的制备方法及用途。
背景技术
炎症为万病之源,是临床常见的一个病理过程,可以产生于机体各部位及组织、器官。由于炎症是一种高发性、普遍性的疾病,临床主要采用抗菌消炎的方法进行治疗。有资料显示在欧美的发达国家抗生素的使用量大致占到所有药品的10%左右,而我国三甲医院占到30%,基层医院可能高达50%,由此可见抗生素在我国的使用频率非常之高(http://drug.sosyao.com)。在抗生素六十多年的发展过程中,前三十年是比较好的,但在后三十年中,人类却面临着细菌对抗生素耐药性的不断的挑战。进入二十一世纪,随着人们文化水平和生活质量的提高,滥用抗生素的危害已为人们所重视,如何找到一种既安全、又可靠的消炎药物已是世界范围迫切需要解决的难题。而中药安全、可靠、副作用小的特点已为世界所公认。
丁香叶为木樨科丁香属植物紫丁香(syringa oblata lindl.)、洋丁香(syringavulgaris L.)和朝鲜丁香(syringa diatata Nakai)的干燥叶,味苦,性寒,有清热解毒、利湿退黄作用。丁香叶作为药用已有悠久的历史,《新华本草纲要》中记载主治“急性黄疽型肝炎,外用抗菌,爆发性火眼,多种疮疡肿毒。”《长白山植物药志》有“治腹泻、肝炎”的记载。在民间,用丁香叶煎剂来治疗暴火眼和防治痢疾非常普遍[李永吉,吕邵娃,王艳宏,等.丁香叶药用研究进展[J].中医药信息,2003,20(1):22]。丁香叶植物资源丰富,主要分布于中国东北、内蒙古、华北、华东等地。近几年研究表明,丁香叶提取物具有广谱抗菌消炎[王丹丹,刘盛泉,陈英杰,等.紫丁香有效成分的研究[J].药学学报,1982,17(12):951]、抗病毒[薛俊玲,张宁,腾慧梅,张晓强.甲丁胶囊的抗病毒实验研究[J].中医药信息,1997,2:471]和保肝利胆[王迪,张贵军,李仁郁.黑龙江省丁香属植物药用资源研究[J],中医药信息,1985,3:32]作用。药理研究证明:丁香叶提取物对金黄色葡萄球菌、表皮葡萄球菌、肺炎杆菌、绿脓杆菌、伤寒杆菌、乙型副伤寒杆菌、宋内氏痢疾杆菌、变形杆菌有较强的抗菌作用[胡桂清,李建志,张春艳等.黑龙江地产中药抗菌作用的实验研究黑龙江中医药1993,5:47.],是替代化学合成抗生素,解决抗生素滥用问题的优秀中药。
丁香叶作为常用中草药已收载于黑龙江省药品标准(2001年版1~2),丁香叶制剂炎立消胶囊(书页号:Z20-176,标准编号:WS3-B-3881-98)、片剂(书页号:Z9-100,标准编号:WS3-B-1760-94)收载于《中华人民共和国卫生部颁药品标准》,用于治疗属于热症的急性肠炎、细菌性痢疾、上呼吸道感染、急慢性支气管炎、肝炎、溃疡性结肠炎、急性乳腺炎及急性扁桃体炎等感染性疾病,疗效显著。丁香叶的化学成分主要有环烯醚萜苷类、3,4-二羟基苯甲酸、3,4-二羟基苯乙醇等,其中环烯醚萜苷含量较高,以丁香苦苷为主要活性成分,体内抑菌作用强。生理活性试验表明,环烯醚萜苷对金黄色葡萄球菌、痢疾杆菌、大肠杆菌及绿脓杆菌均有不同程度的抑制作用[王丹丹,刘盛泉,陈英杰,等.紫丁香有效成分的研究[J].药学学报,1982,17(12):951-954]。
丁香叶总提取物由于成分复杂,导致制剂成品难以摆脱中药传统剂型粗、大、黑的固有缺点,且总提取物中含有较多的糖类等杂质,使原料药具有较大的吸湿性,导致服用剂量过大,也限制了剂型的选择。
发明内容
本发明的目的在于提供一种丁香叶总环烯醚萜苷的制备方法,是利用大孔吸附树脂制备丁香叶总环烯醚萜苷类成分的方法,该工艺过程简单,质量可控。用这种方法制备出的环烯醚萜苷有效部位,可通过添加药用辅料制成医学上可接受的各种剂型用于临床治疗。
本发明方法通过以下步骤实现:将丁香叶粉碎至10~20目,加8~15倍体积水或体积百分比浓度为10%~50%的醇,提取2~3次,提取方法可采用加热回流法、温浸法、渗漉法或超声提取法,每次1~3h,过滤,合并提取液,浓缩至0.5~1.5g生药/ml,离心或过滤后得上柱溶液,加盐酸调pH值至2~5,优选pH4,上柱溶液以2BV/h的流速通过大孔吸附树脂层析柱,上柱溶液按固形物与干树脂的比例为1∶5~1∶10,优选1∶8,径高比为1∶3~1∶10,先用4~6BV的水洗涤树脂,洗脱流速为1~4BV/h,弃去水洗脱液;再用体积百分比浓度为50%~80%的醇洗脱剂洗脱,洗脱流速为1~4BV/h,洗脱液减压回收醇,浓缩至相对密度为1.15~1.30,冷冻或喷雾干燥,即得丁香叶总环烯醚萜苷。
本发明所述的大孔吸附树脂为聚苯乙烯类型中极性、弱极性和非极性大孔树脂,选用D-101、SP-825、DM-301、NKA-9、CAD45或860021,优选大孔吸附树脂D-101型。离心分离时,离心速度在5000~15000转/分钟范围内。
醇洗脱剂浓度优选70%。洗脱流速优选2BV/h。洗脱剂体积为4BV~6BV,优选5BV。
本发明方法获得的丁香叶总环烯醚萜苷提取物在制备治疗上呼吸道感染、急慢性扁桃体炎、肝炎、急性肠炎、菌痢及溃疡性结肠炎等感染性疾病的药物中的应用。
所述药物的制剂形式为固体制剂,包括注射用冻干粉针、喷雾剂、气雾剂及滴丸、片剂、胶囊剂及肠溶制剂等。
本发明的优点是:
1.本发明首次从丁香叶中制备出含量达75%以上的总环烯醚萜苷提取物,并可通过添加各种药用辅料制成多种剂型,为从丁香叶中开发出中药五类抗菌消炎新药提供了物质基础;
2.本发明设计合理,工艺简单,采用水/醇法提取,大孔吸附树脂柱层析方法,即可获得较高纯度的丁香叶总环烯醚萜苷,无环境污染,操作简便快捷,成本较低,非常适合工业化生产;
3.本发明所选用的大孔吸附树脂纯化方法,具有吸附量大,解吸率高,树脂再生后可反复使用等优点,因此具有很好的应用前景。
所得到的总环烯醚萜苷,通过添加各种药用辅料可制成喷雾剂、气雾剂、注射剂以及滴丸、胶囊、片剂、颗粒剂及肠溶制剂、结肠定位制剂等各种固体制剂。
附图说明
图1为本发明丁香叶总环烯醚萜苷制备工艺流程图。
图2为大孔吸附树脂纯化前、后样品中丁香苦苷含量的HPLC色谱图。
具体实施方式
本发明结合以下实施例作进一步的说明。必须说明下述实施例是用于说明本发明而不是对本发明的限制。
实施例1丁香叶总环烯醚萜苷的制备
参见图1,将丁香叶1kg粉碎至10~20目,加12倍体积百分比浓度为30%的乙醇,渗漉提取,第一次浸泡一周收集流出液,第二次浸泡三天收集流出液,过滤,合并提取液,浓缩至0.5g生药/ml,加盐酸调pH值至4,以2BV/h的流速通过D-101大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶5,径高比为1∶6,先用4BV的水洗涤树脂,洗脱流速为2BV/h,弃去水洗脱液;再用体积百分比浓度为50%的乙醇洗脱,洗脱流速为2BV/h,洗脱液减压回收乙醇,浓缩至相对密度为1.15(50℃测得),冷冻或喷雾干燥,即得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量76.73%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量53.42%(HPLC法,重量百分比)。
实施例2丁香叶总环烯醚萜苷的制备
参见图1,在粉碎至10~20目的2kg丁香叶中,加15倍量的水,加热回流提取3次,每次2h,过滤,合并提取液,浓缩至浓度为1.0g生药/ml,过滤后加盐酸调pH值至4,以3BV/h的流速通过DM-301大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶8,径高比为1∶10,先用6BV的水洗涤树脂,洗脱流速为4BV/h,弃去水洗脱液;再用体积百分比浓度为80%的甲醇洗脱,洗脱流速为3BV/h,洗脱液减压回收甲醇,浓缩至相对密度为1.25(50℃测得),冷冻干燥,得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量75.42%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量50.73%(HPLC法,重量百分比)。
实施例3丁香叶总环烯醚萜苷的制备
参见图1,丁香叶5kg适度粉碎,加8倍量的10%乙醇,超声提取3次,每次0.5h,过滤,合并提取液,减压回收乙醇,加水调节浓度至1.5g生药/ml,加盐酸调pH值至4,通过NKA-9大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶9,径高比为1∶8,先用4BV的水洗涤树脂,洗脱流速为2BV/h,弃去水洗脱液;再用体积百分比浓度为70%的乙醇洗脱,洗脱流速为3BV/h,洗脱液减压回收乙醇,浓缩至相对密度为1.15(50℃测得),喷雾干燥,得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量65.84%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量47.56%(HPLC法,重量百分比),参见图2。
实施例4丁香叶总环烯醚萜苷的制备
参见图1,丁香叶5kg适度粉碎,加12倍量的20%甲醇,加热回流提取3次,每次1.5h,过滤,合并提取液,减压回收甲醇,加水调节浓度至1.5g生药/ml,加盐酸调pH值至4,通过CAD45大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶10,径高比为1∶8,先用4BV的水洗涤树脂,洗脱流速为2BV/h,弃去水洗脱液;再用体积百分比浓度为50%的乙醇洗脱,洗脱流速为3BV/h,洗脱液减压回收乙醇,浓缩至相对密度为1.15(50℃测得),喷雾干燥,得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量56.92%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量38.46%(HPLC法,重量百分比),参见图2。
实施例5丁香叶总环烯醚萜苷的制备
参见图1,丁香叶5kg适度粉碎,加13倍量的50%乙醇,加热回流提取3次,每次2.5h,过滤,合并提取液,减压回收乙醇,加水调节浓度至0.5g生药/ml,加盐酸调pH值至4,通过SP-825大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶6,径高比为1∶8,先用4BV的水洗涤树脂,洗脱流速为2BV/h,弃去水洗脱液;再用体积百分比浓度为60%的乙醇洗脱,洗脱流速为3BV/h,洗脱液减压回收乙醇,浓缩至相对密度为1.20(50℃测得),喷雾干燥,得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量59.76%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量43.52%(HPLC法,重量百分比),参见图2。
实施例6丁香叶总环烯醚萜苷的制备
参见图1,丁香叶5kg适度粉碎,加10倍量的50%乙醇,加热回流提取2次,每次2h,过滤,合并提取液,减压回收乙醇,加水调节浓度至0.5g生药/ml,加盐酸调pH值至4,通过860021大孔吸附树脂层析柱,上样液按固形物质量与干树脂的比例为1∶6,径高比为1∶8,先用4BV的水洗涤树脂,洗脱流速为2BV/h,弃去水洗脱液;再用体积百分比浓度为60%的乙醇洗脱,洗脱流速为3BV/h,洗脱液减压回收乙醇,浓缩至相对密度为1.20(50℃测得),喷雾干燥,得丁香叶总环烯醚萜苷。测得总环烯醚萜苷含量63.76%(UV法,以丁香苦苷计,重量百分比),丁香苦苷含量46.27%(HPLC法,重量百分比),参见图2。
制剂的制备
实施例7:喷雾剂的制备
丁香叶总环烯醚萜苷5g,以乙醇50ml溶解,加入薄荷脑、丙二醇,加蒸馏水定容至100ml后,定量分装成10瓶,制成喷雾剂。
实施例8:气雾剂的制备
丁香叶总环烯醚萜苷5g,乙醇溶解定容100ml后加入适量薄荷脑、丙二醇、泊洛沙姆,定量分装于10ml的气雾剂耐压瓶内,压盖后在800~1000kPa压力下向瓶内压入适量抛射剂四氟乙烷,制成气雾剂。
实施例9:滴丸的制备
丁香叶总环烯醚萜苷25g,加入75g熔融的PEG6000,搅拌均匀后转移至贮液瓶中,密闭并保温在75℃,用定量泵滴丸机由上往下滴制,冷却剂为甲基硅油,滴速30丸/分钟,每丸25mg,收集滴丸,吸去表面冷却剂,干燥,即得。
实施例10:注射用冻干粉针的制备
丁香叶总环烯醚萜苷15g,加入20g甘露醇,加注射用水至200ml溶解,用1mol/L的NaOH溶液调pH至7.5,加入0.5%活性炭,保持pH至7.5,加热微沸15分钟,在此过程中不断搅拌,冷却至50℃左右滤过,冷却至室温后经0.45μm微孔滤膜过滤,按每瓶2ml分装于5ml的西林瓶内,115℃流通蒸汽灭菌30分钟,冷冻干燥,取出后压盖包装即得。
实施例11:胶囊剂的制备
取丁香叶总环烯醚萜20g,与乳糖20g、淀粉60g混匀,加95%乙醇制成软材,用14目筛制粒后,置60℃~70℃干燥后于12目筛整粒,套入1号空心胶囊中即得,每粒胶囊含药40mg。
实施例12:片剂的制备
取丁香叶总环烯醚萜苷50g,与淀粉24g、微晶纤维素15g、乳糖8g、羧甲基淀粉钠8g混匀,加10%淀粉浆适量制成软材,加入硬脂酸镁0.5g,混匀后30目筛制粒,24目筛整粒,压制成片,每片含药150mg。
实施例13:肠溶片的制备
将实施例11制备的片剂作为片芯,另取丙烯酸树脂II号20g,丙烯酸树脂III号8g,加入95%乙醇溶解,配制成浓度为5%的溶液,加入适量邻苯二甲酸二乙酯、滑石粉分别作为增塑剂和抗粘剂,制得肠溶包衣液。片芯在包衣锅内预热至40~45℃,转速50转/分钟,喷雾包衣,包衣增重5%~7%。
丁香叶总环烯醚萜苷的药理活性研究
实施例14:丁香叶总环烯醚萜苷对大鼠溃疡性结肠炎的保护作用
1.实验材料
2,4,6,-三硝基苯磺酸TNBS(美国Sigma公司),分子式:C6H3N3O9S,规格:5%的水溶液,10mL/瓶,批号:P-2297。
无水乙醇(分析纯,北京化工厂)
乌拉坦,又名氨基甲酸乙酯(上海山浦化工公司)
硫酸镁(分析纯,)蒸馏水配制成10%的溶液
柳氮磺胺吡啶SASP(上海信谊嘉华药业有限公司)批号:20070204。使用前以0.5%CMC溶液配成0.25g/kg浓度。
髓过氧化物酶(MPO)试剂盒(南京建成生物工程研究所)
2.实验动物分组:
SD大鼠,体重:180-220g(上海斯莱克实验动物有限责任公司提供)。购入后适应性饲养7天,自由进食饮水,每日更换饲料、饮水,保持大鼠生活环境、通风和清洁卫生。观察进食、饮水、行为活动、大小便情况,确认为健康大鼠后,随机分为5组,即模型组、柳氮磺吡啶组、环烯醚萜苷高剂量组(1.0g/kg)、环烯醚萜苷中剂量组(0.5g/kg)、环烯醚萜苷低剂量组(0.25g/kg),每组10只,雌雄各半,各组体重统计学比较无显着差异(P>0.05)。
3.模型建立:
参照文献[1,2],将大鼠在实验室常规条件下饲养一周后,灌胃给予10%的MgSO4溶液清洁肠道,3mL/只,早晚各一次,连续三次,同时禁食24h后,大鼠用20%乌拉坦腹腔注射麻醉(0.4ml/100g),背位固定,将聚乙烯导管(外径1.7mm)经肛门插入结肠内,头端距肛门约8cm,缓慢注入三硝基苯磺酸与无水乙醇的混合液1mL(比例2∶1,TNBS 33mg/只),正常组注入生理盐水1mL,大鼠采取臀高头低体位倒置约30min,避免液体流出。待大鼠清醒后饲养观察一周,受试药物组和阳性对照药物组开始给药。
[1]Morris GP,Beck PL,Herridge MS,et al.Hapten induced model of chronicinflannation and ulceration in the rat colon[J].Gastroenterology 1989,96:795
[2]王浩,欧阳钦,胡仁伟.三硝基苯磺酸结肠炎动物模型的建立.胃肠病学2001,6(1):7-10
4.实验结果:
4.1丁香叶总环烯醚萜苷对大鼠溃疡性结肠炎结肠损伤清况的影响
造模第7天,大鼠开始禁食24h后,用20%乌拉坦腹腔注射麻醉(0.4ml/100g),背位固定,剖开腹部,取出全结肠(从回盲部至耻骨联合上乙状结肠部分,冰上操作),纵向剪开,以冰生理盐水冲洗掉肠内污物,测量结肠长度及最大宽度,肉眼观察结肠损伤的情况,结肠称重,考察总环烯醚萜苷对大鼠溃疡性结肠炎结肠损伤情况的影响。参见表1。
表1丁香叶总环烯醚萜苷对大鼠溃疡性结肠炎结肠损伤清况的影响(x±s)
注:与正常组比较,△P<0.05,△△P<0.01;
与模型组比较,*P<0.05,**P<0.01
4.2丁香叶总环烯醚萜苷对溃疡性结肠炎大鼠MPO的影响
参见表2,髓过氧化物酶(MPO)在中性粒细胞中含量较高,在单核和巨噬细胞中也有少量存在,其含量的增高可以反映中性粒细胞在某一组织中的增高,间接反映炎症在组织的存在,MPO活性可以提示组织炎性细胞的浸润程度。因此,认为MPO是衡量炎症程度最敏感和可靠的指标,MPO的含量可直观反映结肠组织的病理损害程度,对于溃疡性结肠炎病情发展的评估及药物治疗效果的判断,具有潜在的指导意义。
表2
注:与正常组比较,△P<0.05,△△P<0.01;
与模型组比较,*P<0.05,**P<0.01
Claims (5)
1.一种丁香叶总环烯醚萜苷的制备方法,其特征在于,通过以下步骤实现:将丁香叶粉碎,加8~15倍体积水或体积百分比浓度为10%~50%的醇,加热回流提取2~3次,每次1~3h,过滤,合并提取液,浓缩至0.5~1.5g生药/ml,离心或过滤后,得上柱溶液,加盐酸调pH值至2~5,上柱溶液以2BV/h的流速通过大孔吸附树脂层析柱,上柱溶液按固形物与干树脂的比例为1∶5~10,先用4~6BV的水洗涤树脂,洗脱流速为2~4BV/h,弃去水洗脱液;再用体积百分比浓度为50%~80%的醇洗脱剂洗脱,洗脱流速为1~4BV/h,洗脱液减压回收醇,浓缩至相对密度为1.15~1.30,冷冻或喷雾干燥,即得丁香叶总环烯醚萜苷。
2.根据权利要求1所述的一种丁香叶总环烯醚萜苷的制备方法,其特征在于,所述的大孔吸附树脂选用D-101、SP-825、DM-301、NKA-9、CAD45或860021。
3.根据权利要求1所述的一种丁香叶总环烯醚萜苷的制备方法,其特征在于,所述的醇洗脱剂为甲醇或乙醇。
4.根据权利要求1制备方法获得的一种丁香叶总环烯醚萜苷在制备治疗上呼吸道感染、急慢性扁桃体炎、肝炎、急性肠炎、菌痢及溃疡性结肠炎感染性疾病的药物中的应用。
5.根据权利要求4所述的药物,其特征在于,所述药物的制剂形式为固体制剂。
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