CN1468859A - 蒲黄总黄酮提取物及其制备工艺和用途 - Google Patents
蒲黄总黄酮提取物及其制备工艺和用途 Download PDFInfo
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- CN1468859A CN1468859A CNA021361150A CN02136115A CN1468859A CN 1468859 A CN1468859 A CN 1468859A CN A021361150 A CNA021361150 A CN A021361150A CN 02136115 A CN02136115 A CN 02136115A CN 1468859 A CN1468859 A CN 1468859A
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Abstract
本发明涉及一种从中药蒲黄中提取的总黄酮活性组份，该提取物主要包括一些以异鼠李素、槲皮素、山柰酚以及以其为母核的糖甙类衍生物。此外，还包括这些组份的降解产物，以及与钾盐、钠盐等形成的金属盐衍生物，与某些金属离子形成的金属络合物等。该提取物可用溶剂萃取法等多种方法制备获得。该提取物具有降血脂、抗动脉粥样硬化、提高心脑组织对缺氧缺血的耐受性、抗血小板凝集、抗血栓、止血等药理作用，可用于预防和治疗心脑血管疾病、各种血瘀所致的胸痛、跌打损伤、妇女产后瘀痛等病症以及各种出血病症等。
Description
技术领域
本发明属医药技术领域，具体涉及一种中药蒲黄的总黄酮提取物及其制备工艺和在药物和保健食品方面的应用。
背景技术
蒲黄为常用中药，来源于香蒲科植物水烛香蒲Typha angustifolia L.，东方香蒲T.arientalis Presl.或同属其它植物的干燥花粉。中医理论认为，蒲黄具有止血、化瘀、通淋等功效，常用于吐血、衄血、咯血、崩漏、外伤出血、经闭痛经、脘腹刺痛、跌扑肿痛血淋涩痛等症。现代药理研究表明蒲黄的水提或醇提物可以明显增加冠脉流量、改善微循环、提高心肌及脑对缺氧的耐受性或降低心脑组织的氧耗、扩张血管、降血脂、抗动脉粥样硬化、抗血小板聚集等多种生物活性。各种来源的蒲黄中均含有有机酸、黄酮类、甾醇类、长链烷酮或烷醇类以及多糖等。有关这些成分的药理活性和应用，仅见有一项公开的发明专利1006015，涉及蒲黄中甾醇类、长链烷酮及烷醇类的降血脂活性及其用途。迄今，尚未发现涉及蒲黄总黄酮提取物的专利及文献发表。
发明内容
本发明的目的在于提供一种蒲黄总黄酮提取物及其制备方法。
本发明的另一个目的在于提供一种蒲黄总黄酮提取物的降解产物。
本发明的再一个目的在于提供一种蒲黄总黄酮提取物与某些碱或金属盐形成的金属盐类衍生物。
本发明的再一个目的在于提供一种蒲黄总黄酮提取物与某些金属离子形成的金属络合物。
本发明的再一个目的在于提供蒲黄总黄酮及其某些降解产物、某些金属盐类衍生物和某些金属络合物的用途。
本发明提出的蒲黄总黄酮提取物，是从中药蒲黄中提取的含有多种黄酮类活性成份的组合，其结构式如下：
其中：1.R1＝R2＝H；2.R1＝H，R2＝neohesperidoside；3.R1＝H，R2＝(2G-rham)-rutinoside4.R1＝rhamnose，R2＝rutinoside
其中：5.R1＝R2＝H；6.R1＝H，R2＝neohesperidoside；7.R1＝H，R2＝(2G-rham)-rutinoside8.R1＝rhamnoside，R2＝rutinoside其中：9.R1＝R2＝H；10.R1＝H，R2＝neohesperidoside；11.R1＝H，R2＝rutinoside12.R1＝H，R2＝(2G-rham)-rutinoside13.R1＝rhamnoside，R2＝rutinoside上述结构式中各编号的化学成份名称如下：
1.山柰酚；2.山柰酚-3-O-新橙皮糖甙；3.山柰酚-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；4.山柰酚-3-芸香糖-7-鼠李糖甙；5.槲皮素；6.槲皮素-3-O-新橙皮糖甙；7.槲皮素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；8.槲皮素-3-芸香糖-7-鼠李糖甙；9.异鼠李素；10.异鼠李素-3-O-新橙皮糖甙；11.异鼠李素-3-O-芸香糖甙；12.异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；13.异鼠李素-3-芸香糖-7-鼠李糖甙。
本发明所述原料物蒲黄，来源于香蒲科香蒲属的任一一种植物。有关香蒲科及香蒲属的科学定义和范畴，参见《中国高等植物科属词典》(修订版)第506页(候宽昭编，北京：科学出版社，1984.12)。作为提取蒲黄总黄酮的原材料，可以是这些植物的花粉、花穗、果实、茎、叶、地下根茎及根等任一部位或全部植株，其中优选的部位是这些植物的成熟花粉。并且所叙述的蒲黄花粉不仅包括未经任何炮制的生花粉，即俗称“生蒲黄”，也包括其各种炮制品，如“炒蒲黄”，“蒲黄炭”，“酒制蒲黄”以及“醋制蒲黄”等。
本发明所述的蒲黄总黄酮提取物，是指从上述任一一种植物的任何部位提取的，包含有多种黄酮类活性成分的组合物，其中最优选的是以上述任一植物的成熟花粉中提取制备的，含多种黄酮类活性成分的组合物。这些黄酮类活性成分，主要包括一些以异鼠李素、槲皮素、山柰酚以及以其为母核的糖甙类衍生物。
作为蒲黄总黄酮提取物，其中各种黄酮类成分百分含量的总和，应为5～100％(w/w)，其中优选的是50～100％(w/w)，最优选的是95～100％(w/w)。
本发明所述的蒲黄总黄酮提取物，还包含因长时间加热、或在酸、碱及酶的作用下发生部分降解所形成的降解产物，如异鼠李素、山柰酚及槲皮素的3-O-葡萄糖甙、3-O-芸香糖甙、7-O-鼠李糖甙等。这里所指的长时间加热，是指在40～100℃下加热1小时以上。所用的酸，可以是无机酸，如盐酸、硫酸、磷酸、硝酸、亚硝酸、亚硫酸、碳酸(或CO2水溶液)、氢氟酸等，也可以是有机酸，如甲酸、乙酸、冰醋酸、三氯醋酸、醋酐、枸橼酸、草酸等。所用碱可以是氢氧化钾、氢氧化钠、碳酸氢钠、碳酸氢二钠、吡啶、氨水、二乙胺、三乙胺等。所用的酶如转化糖酶、麦芽糖酶、苦杏仁酶、纤维素酶、蜗牛酶、橙皮甙酶、柑桔甙酶等各种糖甙键水解酶。以上酸、碱和酶的降解反应一般均在加热条件下进行。
本发明所述的蒲黄总黄酮提取物，可以与某些碱或钠盐、钾盐等金属盐，如氢氧化钾、氢氧化钠、碳酸氢钠、碳酸氢二钠、醋酸钠等，形成金属盐类衍生物。这些衍生物具有与上述蒲黄总黄酮提取物相同或相近的药理活性和用途。将所述提取物与0.01～5N的碱或盐溶液混合后适当加热即可制备成相应的金属盐衍生物。
本发明所述的蒲黄总黄酮提取物，还可以与铁、锌、镁、鉻、铝、铜、钙、钴、钡、锶、锆等金属离子形成金属络合物。这些金属络合物不仅具有与上述蒲黄总黄酮相同或相近的药理活性和用途，而且具有某些新的用途，如铁络合物可以用作补铁剂；锌络合物可用作补锌剂；铬络合物可用于防治糖尿病等。在所述提取物的水或醇溶液中加入0.01～5N的金属盐溶液，混合后适当加热即可制备成相应的金属络合物。
本发明中，在上述蒲黄总黄酮提取物所涵盖的各种黄酮类活性成分之中，最主要的是异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙(俗称香蒲新甙)，以及异鼠李素-3-O-新橙皮糖甙二种成分。作为蒲黄总黄酮提取物，其中异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙和(或)异鼠李素-3-O-新橙皮糖甙占全部总黄酮含量的20～100％(w/w)，优选结果为50～100％(w/w)，最优选结果为95～100％(w/w)。
本发明还提出了所述蒲黄总黄酮提取物的制备工艺，它可采用以下任一一种方法，或这些方法的任意组合进行制备：(1)溶剂萃取法；(2)大孔吸附树脂法；(3)铅盐沉淀法；(4)超临界CO2萃取法；(5)柱层析法，(6)液—液逆流分配层析法。其中优选方法为大孔吸附树脂法和(或)柱层析法。
在使用这些方法进行制备时，一般均包括以下几个步骤：
(1)提取：所用溶剂可以是水或任一一种醇类、酮类及酯类溶剂，或由这些溶剂按一定比例配成的混合溶剂，或由这些溶剂与酸、碱配成的酸性或碱性溶剂，其中优选结果为70％的乙醇。提取方法可以是加热回流、冷浸渗漉，超声提取、微波提取或高压提取等。
(2)过滤：包括离心、抽滤、压滤、超滤等方法，使用或不使用以下任一种澄清剂或其组合：醇沉剂；明胶；活性炭；硅藻土：高岭土；各种树脂；聚乙二醇；聚乙三醇；壳聚糖以及天然澄清剂成品，如101果汁澄清剂、ZTC1+1天然澄清剂等。
(3)浓缩：包括常压或减压条件下的薄膜蒸发、旋转蒸发及煎煮浓缩等。
(4)干燥：包括真空干燥、喷雾干燥、冷冻干燥等方法；
当采用溶剂萃取法进行制备时，一般是先将提取物混悬于水中，接着用低极性的酯类、烷类或醚类溶剂(如石油醚、乙醚、己烷、乙酸乙酯、汽油等)萃取除去脂溶性杂质，然后用合适极性的溶剂，如正丁醇、异丙醇、氯仿等，或这些溶剂的组合物，萃取获得其中的总黄酮成分，其中最优选的萃取溶剂是正丁醇。
当采用大孔吸附树脂法进行制备时，所用的大孔吸附树脂可以是非极性、弱极性，中等极性，弱碱性和弱酸性任何一种类型，这些树脂的代号由于生产厂家不同而不同，如D101(天津农药厂)、DA20，HZ-802，HZ-806，1300，1400(上海华震科贸公司)，860021，DM130(山东鲁抗医药集团)等，其中优选的是非极性大孔吸附树脂，如D101、HZ-802、DM130等。所用的洗脱剂是水及含水的乙醇、甲醇、丙酮等，其中优选的是0～100％的乙醇。
当采用铅盐沉淀法进行制备时，所用的铅盐试剂是醋酸铅或碱式醋酸铅，所有的脱盐剂为H2S，磷酸盐及硫酸盐等。
当采用超临界CO2萃取法进行制备时，可以对蒲黄原材料直接实施萃取，也可以对上述任一方法和步骤所获的产品实施萃取。萃取时可以使用或不使用如下任一种类溶剂及其组合物：水、醇类、酮类及酯类溶剂。
当采用柱层析法进行制备时，其处理的对象可以是上述提取步骤所获得的产物，也可以是经上述溶剂萃取法、大孔吸附树脂法、铅盐沉淀法或超临界CO2萃取法初步纯化后的产物。所用的固定相可以是硅胶、聚酰胺、氧化铝、葡聚糖(Sephadex系列或Sephadex-LH20系列)、C-8、C-18、活性炭、纤维素等，所用的洗脱液因固定相的不同而不同，一般是由水、甲醇、乙醇、丙酮、氯仿、乙酸乙酯等组成的混合溶剂。其中优选的方法是硅胶和Sephadex-LH20。
当采用液—液逆流萃取法进行制备时，其处理的对象可以是上述提取步骤所或的产物，也可以是经上述溶剂萃取法、大孔吸附树脂法、铅盐沉淀法或超临界CO2萃取法初步纯化后的产物。一般是先将提取物混悬于水中，接着用低极性的酯类、烷类或醚类溶剂(如石油醚、乙醚、己烷、乙酸乙酯、汽油等)萃取除去脂溶性杂质，然后用合适极性的溶剂，如正丁醇、异丙醇、氯仿等，或这些溶剂的组合物，萃取获得其中的总黄酮成分，其中最优选的萃取溶剂是正丁醇。
本发明对上述蒲黄总黄酮提取物进行动物试验，表明它对心血管疾病、出血症等具有明显的治疗作用。具体试验结果如下：试验例1：急性毒性试验给大白鼠灌胃蒲黄总黄酮提取物，测定大鼠急性毒性LD50(g/kg)，用BLISS法计算，为3.285g/kg。试验例2：降血脂及抗动脉粥样硬化作用选体重2.0±0.2kg白色家兔，雌雄不拘，随机分成5组，每组10只。各组动物在基本饲料基础上，每天灌胃胆固醇0.2g/kg(加猪油2ml溶入)，一日一次。小剂量组以蒲黄总黄酮提取物10mg/kg灌胃，大剂量组以蒲黄总黄酮提取物30mg/kg灌胃，蒲黄总黄酮钠盐组和铝络合物组均以30mg/kg灌胃，对照组以等体积的生理盐水灌胃，每日给药二次，连续8周。于造型后的第2、4、6、8周由耳静脉采血，以3000rpm离心，分离血清备测。血清总胆固醇及甘油三酯的含量测定的方法均参见文献(陈奇主编.中药药理研究方法学，北京：人民卫生出版社，1993，第620页及第624页)，测定结果如表1和表2所示。
表1.蒲黄总黄酮提取物对血清总胆固醇含量的影响
*P＞0.05，**P＜0.05，***P＜0.01
| 实验组 | 动物数 | 给药剂量(mg/kg) | 总胆固醇含量(mg/kg)(±SD) | ||||
| 正常值 | 2周 | 4周 | 6周 | 8周 | |||
| 对照组 | 10 | 生理盐水 | 80.20±10.08 | 376.35±21.40 | 560.45±70.80 | 590.54±50.31 | 694.35±50.80 |
| 小剂量组 | 10 | 10 | 82.15±15.40 | 330.63±53.36 | 320.80±68.75** | 310.58±34.19** | 293.51±20.30*** |
| 大剂量组 | 10 | 30 | 78.30±11.58 | 299.16±30.16 | 263.56±7.30** | 230.29±18.65*** | 160.34±23.60*** |
| 钠盐衍生物 | 10 | 30 | 77.2±10.70 | 296.5±9.08 | 260.30±8.96** | 224.93±13.80*** | 158.26±10.08*** |
| 铝络合物 | 10 | 30 | 79.42±12.76 | 300.64±9.08 | 265.43±11.64** | 232.39±12.44*** | 162.65±12.83*** |
另于8周后将动物处死，取出主动脉(自心脑至骼动脉分叉处)，剔除动脉外膜的脂肪组织。在背侧面纵行切开，展铺于方盘内，以0.5ml/ml的福尔马林固定24小时，然后用苏丹III染色30分钟。染色后乳白色斑块着色成金红色。按照文献(同上，第626页)所述的方法进行主动脉斑块的分级和斑面积的测算，从而确定斑块指数及抑制百分率，结果如表3所示。
表2.蒲黄总黄酮提取物对血清甘油三酯的影响
*P＞0.05，**P＜0.05，***P＜0.01
| 实验组 | 动物数 | 给药剂量(mg/kg) | 总胆固醇含量(mg/kg)(±SD) | ||||
| 正常值 | 2周 | 4周 | 6周 | 8周 | |||
| 对照组 | 10 | 生理盐水 | 12.78±2.45 | 14.80±1.80 | 22.78±3.56 | 34.20±6.50 | 58.60±7.85 |
| 小剂量组 | 10 | 10 | 13.89±1.80 | 14.75±3.60 | 20.44±5.85 | 21.35±4.62** | 22.45±4.60*** |
| 大剂量组 | 10 | 30 | 14.58±1.65 | 13.98±2.56 | 13.86±4.35 | 12.89±2.56*** | 11.86±1.75*** |
| 钠盐衍生物 | 10 | 30 | 13.64±1.78 | 13.44±1.89 | 13.06±3.23 | 12.22±1.33*** | 10.68±2.56*** |
| 铝络合物 | 10 | 30 | 13.96±2.43 | 13.88±1.35 | 13.67±3.32 | 13.16±2.05*** | 12.33±2.66*** |
表3.蒲黄总黄酮提取物对家兔动脉粥样硬化的影响
*P＞0.05，**P＜0.05，***P＜0.01试验例3：对家兔离体心脏冠脉流量和心跳曲线的影响
| 实验组 | 动物数 | 给药剂量(mg/kg) | 斑块指数(±SD)正常值 | 抑制百分率(％) |
| 对照组 | 10 | 生理盐水 | 3.05±0.32 | |
| 小剂量组 | 10 | 10 | 1.76±0.05*** | 49.7 |
| 大剂量组 | 10 | 30 | 0.80±0.03*** | 77.1 |
| 钠盐衍生物 | 10 | 30 | 0.78±0.12*** | 79.6 |
| 铝络合物 | 10 | 30 | 0.82±0.23*** | 76.3 |
蒲黄总黄酮提取物制成1mg/ml的水溶液，调pH值至7.0，离心除去混浊物后备用。蒲黄总黄酮钠盐衍生物及铝络合物均制成1mg/ml的水溶液。对照组复方丹参注射液(每支2ml，每ml相当于生药丹参和降香各1g，上海第九制药厂产品)。
实验分成蒲黄总黄酮低剂量组(0.5ml)、高剂量组(1.5ml)、钠盐衍生物组(1.5ml)、铝络合物(1.5ml)和复方丹参注射液对照组(1.5ml)，每组10只家兔，按Langendoff氏法制备离体心脏，连于灌流装置，心跳平稳后收集测量30s冠脉流量，同时描记心跳曲线，作为给药前的基础值。然后各组分别从管上端注入蒲黄总黄酮水溶液0.5ml、1.5ml、钠盐衍生物水溶液1.5ml、铝络合物水溶液1.5ml和复方丹参注射液1.5ml，给药5s后，立即收集30s内冠脉流量，同时描记心跳曲线，比较给药前后冠脉流量和心跳曲线的振幅评价药物的作用。实验结果分别如表4和表5。
表4.蒲黄总黄酮提取物对离体家兔心冠脉流量的影响
**P＜0.05，***P＜0.01
| 实验组 | 动物数(n) | 给药剂量(ml) | 冠脉流量(±SD，ml/30s) | |
| 给药前 | 给药后 | |||
| 蒲黄总黄酮低剂量 | 10 | 0.5 | 6.84±1.25 | 9.85±1.86** |
| 蒲黄总黄酮高剂量 | 10 | 1.5 | 6.73±1.04 | 17.02±2.18*** |
| 钠盐衍生物 | 10 | 1.5 | 6.98±1.04 | 18.52±1.88*** |
| 铝络合物 | 10 | 1.5 | 7.12±1.04 | 16.35±2.43*** |
| 复方丹参注射液 | 10 | 1.5 | 7.08±1.12 | 15.18±1.68*** |
表5.蒲黄总黄酮提取物对离体家兔心收缩曲线振幅的影响
*P＞0.05，**P＜0.05，***P＜0.01试验例4：对脑垂体后叶素致大鼠急性心肌缺血的影响所用试验药物如试验例3。Wistar大鼠48只，雌雄各半，随机分成6组。股静脉注射0.5ml/kg脑垂体后叶素，描记15″、30″、45″、1′、1′30″、2′30″、3′、4′、5′II导心电图，无心肌缺血者弃去。待大鼠心电图恢复正常后，于股静脉注入药物，5′后再同法注入脑垂体后叶素，对照组给予等体积生理盐水，同上法立即描记心电图，观察药物对ST段上移和T波升高最大百分率。结果如表6。表6.蒲黄总黄酮提取物对脑垂体后叶素致大鼠急性心肌缺血心电图的影响(±SD)
n＝8，*P＞0.05，**P＜0.05试验例5：对ADP诱导的家兔血小板聚集的影响试验所用药物如试验例3。家兔50只，随机分为5组：生理盐水组、蒲黄总黄酮提取物低剂量组、高剂量组、钠盐衍生物组及铝络合物组，每组10只。给药组耳缘静脉注射给药，对照组注射等量生理盐水，给药后4h耳缘静脉取血，3.8％柠檬酸钠1∶9抗凝，离心制备富含血小板血浆(PRP，1000r/min，7min)及贫血小板血浆(PPP，4000r/min，10min)。每次实验前将血小板聚集仪调至零点，并用PRP调至记录纸10格处，PPP调至记录纸80格处(记录纸纸格共100格)。取PRP 200μl于比浊管中，37℃温浴5min，加入5μmol的ADP 20μl，记录5min内的最大抑制率，并计算聚集抑制率。抑制率＝[(对照组最大聚集率—给药组最大聚集率)/对照组最大聚集率]×100％。实验结果见表7。
| 实验组 | 动物数(n) | 给药剂量(ml) | 收缩曲线振幅(±SD，ml/30s) | |
| 给药前 | 给药后 | |||
| 蒲黄总黄酮低剂量 | 10 | 0.5 | 2.78±0.58 | 4.12±0.64** |
| 蒲黄总黄酮高剂量 | 10 | 1.5 | 2.84±0.65 | 4.68±0.88*** |
| 钠盐衍生物 | 10 | 1.5 | 2.66±0.65 | 5.02±0.06*** |
| 铝络合物 | 10 | 1.5 | 2.92±0.65 | 4.15±0.56*** |
| 复方丹参注射液 | 10 | 1.5 | 2.86±0.51 | 3.78±0.74* |
| 组别 | ST段上移最大抑制率(％) | T波增高最大抑制率(％) |
| 生理盐水 | 2.70±1.50 | 1.02±0.24 |
| 复方丹参注射液 | 25.04±11.75** | 32.98±7.64** |
| 蒲黄总黄酮低剂量 | 22.14±5.89** | 26.94±7.70** |
| 蒲黄总黄酮高剂量 | 26.12±8.09** | 34.78±6.85* |
| 钠盐衍生物 | 27.33±4.18** | 36.53±4.065* |
| 铝络合物 | 24.78±6.34** | 28.65±3.35* |
表7.蒲黄总黄酮提取物对ADP诱导的家兔血小板聚集的影响
与对照组比较，**P＜0.01试验例6：对电刺激致家兔颈动脉血栓的影响取家兔60只，随机分为6组，生理盐水组、尿激酶组、蒲黄总黄酮低剂量组、高剂量组，钠盐衍生物组及铝络合物组，每组10只。家兔分别按体重耳缘静脉注射蒲黄总黄酮提取物低(1.0mg/kg)、高剂量(3.0mg/kg)、钠盐衍生物(3.0mg/kg)、铝络合物(3.0mg/kg)、尿激酶和生理盐水，给药后4h各组动物分别耳缘静脉注射戊巴比妥钠麻醉，背部固定，颈部正中切口，分离右颈总动脉1.5cm长，用一块小塑料布遮盖伤口附近的组织，然后用2根不锈钢电极将颈总动脉轻轻挑起，以1.5mA直流电刺激，以一半导体点式温度计固定接触动脉头端，连续测量动脉表面温度，记录从开始电流刺激到温度突降所需时间(occlusion time OT)，结果见表8。
| 组别 | 剂量(ml) | 血小板聚集率(％) | 抑制率(％) |
| 生理盐水 | - | 51.5±5.6 | - |
| 蒲黄总黄酮低剂量 | 1 | 28.8±6.8** | 44.1 |
| 蒲黄总黄酮高剂量 | 3 | 17.9±3.8** | 65.2 |
| 钠盐衍生物 | 3 | 16.7±2.3** | 67.6 |
| 铝络合物 | 3 | 18.5±4.2** | 64.1 |
表8.蒲黄总黄酮提取物对家兔颈动脉血栓的作用
*P＜0.05，**P＜0.01试验例7：对小鼠出、凝血时间的影响：小鼠随机分为空白对照组(ig等体积蒸馏水)；蒲黄总黄酮提取物低剂量组、高剂量组，钠盐衍生物组、铝络合物组及云南白药组，连续灌胃2周，于末次给药30min后玻璃法测定小鼠凝血时间。次日用剪尾法测定出血时间，结果见表9。
| 组别 | 剂量 | OT(min) |
| 生理盐水组 | - | 38.9±5.8 |
| 尿激酶组 | 20000U | 48.8±8.8* |
| 蒲黄总黄酮低剂量 | 1(mg/kg) | 58.1±9.8** |
| 蒲黄总黄酮高剂量 | 3(mg/kg) | 68.2±7.9** |
| 钠盐衍生物 | 3(mg/kg) | 70.4±6.5** |
| 铝络合物 | 3(mg/kg) | 64.4±5.8** |
表9.蒲黄总黄酮提取物对小鼠出凝血时间的影响
*P＞0.05，**P＜0.05，***P＜0.01
| 实验组 | 动物数(n) | 给药剂量(g/kg) | 凝血时间(s) | 出血时间(s) |
| 空白对照 | 10 | - | 250.16±40.20 | 451.34±178.40 |
| 云南白药 | 10 | 0.6 | 413.15±74.12*** | 584.90±176.45 |
| 蒲黄总黄酮低剂量 | 10 | 0.05 | 32.18±30.56* | 212.12±78.64*** |
| 蒲黄总黄酮高剂量 | 10 | 0.15 | 390.68±33.46** | 181.75±60.52*** |
| 钠盐衍生物 | 10 | 0.15 | 398.45±23.33** | 176.32±55.12*** |
| 铝络合物 | 10 | 0.15 | 366.23±34.33** | 189.55±34.89*** |
本发明还提出所述蒲黄总黄酮提取物的用途，它可以单独用于制备药物和功能性保健食品，也可以与其它任何中西药物或食物，尤其是与某些具有活血化瘀和(或)保护心脑血管疾病的中药配伍，用于制备药物和功能性保健食品。
单独由本发明的提取物制备的药物和功能性保健食品，或由该提取物与其它中西药物或食物组成的复方药物和功能性保健食品，均具有降血脂、抗动脉粥样硬化、增加冠脉流量、提高心脑组织对缺氧缺血的耐受性、抗血小板凝集、抗血栓、止血等药理活性，可用于：(1)预防和治疗心脑血管疾病，如高血脂症、动脉粥样硬化、冠心病、心肌梗塞、脑血栓，脑中风及脑中风后遗症等；(2)预防和治疗各种血瘀所致的胸痛、胃脘疼痛、跌打损伤，妇女产后瘀痛及痛经等症；(3)用于预防和治疗各种出血病症，如咯血、衄血、吐血、便血、尿血、崩漏、皮下出血、紫癜及创伤性出血等。
当该提取物，或包含该提取物的药物和食物组合，用于上述医疗和保健目的时，可以采用本专业人员所熟知的方法和技术，直接和添加必要的辅料，制成胶囊剂、片剂、注射剂、颗粒剂、口服液、糖浆、药膏、酒剂、饮料、果汁、速溶茶、糖果等多种制剂成品。当本发明的提取物被制成片剂时，它含有的赋型剂有：稀释剂，如淀粉、糊精、乳糖等；润湿剂或粘合剂，如：水、乙醇、淀粉浆、糊精、明胶浆、低取代羟丙基纤维素、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂，如：干燥淀粉、泡腾崩解剂、表面活性剂等；润滑剂，如滑石粉、硬脂酸镁、液体石蜡、聚乙二醇6000或4000等。当本发明提取物被制成胶囊剂时，它含有的赋型剂有：稀释剂，如：淀粉、糊精、乳糖、氧化镁、碳酸镁等；润湿剂或粘合剂，如：水、乙醇、淀粉浆、糊精浆、明胶浆、低取代羟丙基纤维素、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂，如：干燥淀粉、泡腾崩解剂、表面活性剂等；并选用明胶硬胶囊壳或软胶囊壳。当本发明药物组合物被制成注射剂时，它含有的赋型剂有：增溶剂，如：吐温-80、甘油等；混悬剂，如：羟甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素等；抗氧化剂，如：亚硫酸钠、焦亚硫酸钠、硫代硫酸钠等：渗透压调节剂，如氯化钠或葡萄糖等；减轻疼痛的附加剂，如：苯甲醇、盐酸普鲁卡因等。当本发明药物组合物被制成糖浆剂或饮料时，它含有的赋型剂有：蔗糖水溶液、矫味剂；助悬剂，如羟甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素等；防腐剂，如尼伯金乙酯或尼伯金甲酯、丙二醇、苯甲酸、山梨醇等。
具体实施方式
以下以实施例和实验例更具体地说明本发明。实施例1：蒲黄总黄酮的制备工艺
生蒲黄1kg，置于10L的圆底烧瓶中，加70％的乙醇7kg，充分搅拌均匀，在水浴中加热回流提取2小时，趁热过滤，残渣再用70％乙醇5kg回流加热提取1小时，趁热过滤，合并滤液。滤液用旋转蒸发仪减压回收至1.1～1.2比重的稠浸膏，按1∶10的比例加入10％的乙醇液，同时按总体积1％的比例加入壳聚糖澄清剂，静置，放至室温后离心过滤。将该滤液经过预先处理好的1kg HZ-802大孔吸附树脂(上海华震科技贸易公司生产)柱床进行吸附，待全部滤液通过后，先用8～10升去离子水冲洗柱床至澄清，再改用10～12升30％乙醇冲洗至色淡，最后，用8～10升80％乙醇洗脱，收集80％洗脱液，洗脱液用旋转蒸发仪减压回收至稠浸膏，然后将稠浸膏置于真空干燥器中充分干燥。干燥物粉碎，即得蒲黄总黄酮提取物125g。经测定，总黄酮含量为62.5％。实施例2：蒲黄总黄酮的制备工艺
生蒲黄1kg，置于10L的圆底烧瓶中，加70％的乙醇7kg，充分搅拌均匀，在水浴中加热回流提取2小时，趁热过滤，残渣再用70％乙醇5kg回流加热提取1小时，趁热过滤，合并滤液。滤液用旋转蒸发仪减压回收至3L(比重约为1.05)，加入500ml饱和醋酸铅水溶液，充分搅拌，静置沉淀。离心滤取沉淀物。将该沉淀物混悬于2.5L 95％乙醇中，通入H2S进行复分解，离心除去硫化铅沉淀，滤液回收乙醇后，真空干燥，粉碎，即得蒲黄总黄酮提取物143g。经测定，总黄酮含量为54.2％。实施例3：高纯度蒲黄总黄酮的制备工艺
取上述实施例1或实施例2所获得的蒲黄总黄酮提取物5g，用甲醇适量溶解，溶液上500g Sephadex-LH20柱层析，以甲醇进行洗脱，分别收集主要色带，回收溶剂至干，分别得到异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙1.25g，及异鼠李素-3-O-新橙皮糖甙0.98g。经测定，前一成分的含量为96.4％；后一成分的含量为98.5％。实施例4：钠盐衍生物的制备工艺
取上述实施例1或实施例2所获得的蒲黄总黄酮提取物100g，溶于500ml水中，加0.5N的碳酸氢钠溶液至pH～8，充分搅拌后离心(8000转/分)除去不溶物，溶液经减压浓缩、真空干燥即得蒲黄总黄酮钠盐，计89g。含量为58.0～65.5％。实施例5：铝络合物的制备工艺
取上述实施例1或实施例2所获得的蒲黄总黄酮提取物100g，溶于500ml水中，加入10％的三氯化铝溶液100ml，充分搅拌并于90℃加热1小时，放冷后离心(8000转/分)除去不溶物，溶液经减压浓缩、真空干燥即得蒲黄总黄酮铝络合物，计95g。含量为54.3～62.5％。实施例6：蒲黄总黄酮片的制备蒲黄总黄酮提取物 100g淀粉 100g上述组分混合均匀，装入硬明胶胶囊中，共1000粒胶囊。实施例7：蒲黄总黄酮复方制剂的制备蒲黄总黄酮提取物 50g五灵脂水提醇沉提取物 50g冰片 20g淀粉 80g上述组分混合均匀，装入硬明胶胶囊中，共1000粒胶囊。
Claims (20)
1、一种蒲黄总黄酮提取物，其特征在于，该提取物由中药蒲黄中提取获得，并含有以下黄酮类成分：
(1)异鼠李素；
(2)异鼠李素-3-O-新橙皮糖甙；
(3)异鼠李素-3-O-芸香糖甙；
(4)异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；
(5)异鼠李素-3-芸香糖-7-鼠李糖甙。
(6)山柰酚；
(7)山柰酚-3-O-新橙皮糖甙；
(8)山柰酚-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；
(9)山柰酚-3-芸香糖-7-鼠李糖甙；
(10)槲皮素；
(11)槲皮素-3-O-新橙皮糖甙；
(12)槲皮素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙；
(13)槲皮素-3-芸香糖-7-鼠李糖甙；
2、根据权利要求1所述的总黄酮提取物，其特征在于蒲黄为香蒲科香蒲属任一一种植物的全部植株或其任何部位：花粉、花序、茎、叶、果实、根及根茎，其中优选的是成熟花粉。
3、根据权利要求1所述的总黄酮提取物，其特征在于蒲黄包括未经炮制的生蒲黄，也包括炒蒲黄、蒲黄炭、酒制蒲黄、醋制蒲黄炮制品。
4、根据权利要求1所述的总黄酮提取物，其特征在于上述各黄酮类成分的含量总和为5-100％(w/w)，较优的含量为50-100％(w/w)，最优的含量为95-100％(w/w)。
5、根据权利要求4所述的总黄酮提取物，其特征在于各黄酮类成份中异鼠李素-3-O-(2G-α-L-鼠李糖基)-芸香糖甙和/或异鼠李素-3-O-新橙皮糖甙的含量占黄酮类成分含量的20-100％(w/w)，较优的含量为50-100％(w/w)，最优的含量为95-100％(w/w)。
6、根据权利要求1所述的总黄酮提取物，其特征在于上述黄酮类成分，还包括因加热或在酸、碱及酶的作用下发生降解所形成的降解产物。
7、根据权利要求1所述的总黄酮提取物，其特征在于上述黄酮类成分，还包括其与钠盐、钾盐形成的金属盐衍生物。
8、根据权利要求1所述的总黄酮提取物，其特征在于上述黄酮类成分，也包括其与锌、镁、鉻、铁、铝、铜、钙、钴、钡、锶、锆金属离子形成的金属络合物。
9、一种如权利要求1～8所述总黄酮提取物的提取方法，其特征在于，采用以下任一方法，或这些方法的任意组合：(1)溶剂萃取法，(2)大孔吸附树脂法，(3)铅盐沉淀法，(4)超临界CO2萃取法，(5)柱层析法，(6)液—液逆流分配层析法，其中优选方法为大孔吸附树脂法和/或柱层析法。
10、根据权利要求9所述的提取方法，其特征在于，在使用这些方法进行制备时，包括以下几个步骤：
(1)提取：所用溶剂可以是水或任一一种醇类、酮类及酯类溶剂，或由这些溶剂按一定比例配成的混合溶剂，或由这些溶剂与酸、碱配成的酸性或碱性溶剂，其中优选结果为70％的乙醇，提取方法可以是加热回流、冷浸渗漉、超声提取、微波提取或高压提取等；
(2)过滤：包括离心、抽滤、压滤、超滤几个步骤，使用或不使用以下任一种澄清剂或其组合：醇沉剂、明胶、活性炭、硅藻土、高岭土、各种树脂、聚乙二醇、聚乙三醇、壳聚糖以及天然澄清剂成品；
(3)浓缩：包括常压或减压条件下的薄膜蒸发、旋转蒸发及煎煮浓缩等；
(4)干燥：包括真空干燥、喷雾干燥、冷冻干燥等方法。
11、根据权利要求9所述的提取方法，其特征在于，当采用溶剂萃取法时，是先将提取物混悬于水中，接着用低极性的酯类、烷类或醚类溶剂萃取除去脂溶性杂质，然后用合适极性的溶剂：正丁醇、异丙醇、氯仿，或这些溶剂的组合物，萃取获得其中的总黄酮成分。
12、根据权利要求9所述的提取方法，其特征在于，当采用大孔吸附树脂法时，所用的大孔吸附树脂可以是非极性、弱极性，中等极性，弱碱性和弱酸性任何一种类型，其中优选的是非极性大孔吸附树脂，所用的洗脱剂是水及含水的乙醇、甲醇、丙酮，其中优选的是0～100％的乙醇。
13、根据权利要求9所述的提取方法，其特征在于，当采用铅盐沉淀法时，所用的铅盐试剂是醋酸铅或碱式醋酸铅，所有的脱盐剂为H2S、磷酸盐及硫酸盐。
14、根据权利要求9所述的提取方法，其特征在于，当采用柱层析法时，其处理的对象可以是上述提取步骤所获得的产物，也可以是经上述溶剂萃取法、大孔吸附树脂法、铅盐沉淀法或超临界CO2萃取法初步纯化后的产物，所用的固定相可以是硅胶、聚酰胺、氧化铝、葡聚糖、C-8、C-18、活性炭、纤维素；所用的洗脱液是由水、甲醇、乙醇、丙酮、氯仿、乙酸乙酯组成的混合溶剂。
15、根据权利要求9所述的提取方法，其特征在于，当采用液—液逆流萃取法时，其处理的对象可以是上述提取步骤所获得的产物，也可以是经上述溶剂萃取法、大孔吸附树脂法、铅盐沉淀法或超临界CO2萃取法初步纯化后的产物，具体是先将提取物混悬于水中，接着用低极性的酯类、烷类或醚类溶剂萃取除去脂溶性杂质，然后用合适极性的溶剂：正丁醇、异丙醇、氯仿，或这些溶剂的组合物，萃取获得其中的总黄酮成分，其中优选的萃取溶剂是正丁醇。
16、一种如权利要求1、6、7、8所述的提取物的应用，其特征在于，该提取物可以单独或与其它任何中西药物或食物配伍，用于制备药物和功能性保健食品。
17、根据权利要求16所述的提取物的应用，其特征在于，所说的药物和保健食品主要用于预防和治疗心脑血管疾病。
18、根据权利要求16所述的提取物的应用，其特征在于，所说的药物和保健食品还可用于预防和治疗各种血瘀所致的胸痛、胃脘疼痛、跌打损伤，妇女产后瘀痛及痛经病症。
19、根据权利要求16所述的提取物的应用，其特征在于，所说的药物和保健食品还可用于预防和治疗各种出血病症。
20、根据权利要求16所述的提取物的应用，其特征在于，该提取物或包含该提取物的药物和食物组合，可以制成胶囊剂、片剂、注射剂、颗粒剂、口服液、糖浆、药膏、酒剂、冲剂及饮料。
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| US10/621,426 US20040018261A1 (en) | 2002-07-19 | 2003-07-16 | Method and use of extract of a member of Typhaceae's family |
| AU2003257364A AU2003257364A1 (en) | 2002-07-19 | 2003-07-18 | An extract of a typhae pollen and its manufacture and use |
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| CN1315856C (zh) * | 2004-12-24 | 2007-05-16 | 北京中医药大学 | 蒲黄中香蒲新苷的提取分离方法 |
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2003
- 2003-07-16 US US10/621,426 patent/US20040018261A1/en not_active Abandoned
- 2003-07-18 WO PCT/CN2003/000577 patent/WO2004009575A1/en not_active Application Discontinuation
- 2003-07-18 AU AU2003257364A patent/AU2003257364A1/en not_active Abandoned
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Also Published As
| Publication number | Publication date |
|---|---|
| US20040018261A1 (en) | 2004-01-29 |
| WO2004009575A1 (en) | 2004-01-29 |
| AU2003257364A1 (en) | 2004-02-09 |
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