CN1265814C - 菊蒿提取物 - Google Patents
菊蒿提取物 Download PDFInfo
- Publication number
- CN1265814C CN1265814C CNB008082944A CN00808294A CN1265814C CN 1265814 C CN1265814 C CN 1265814C CN B008082944 A CNB008082944 A CN B008082944A CN 00808294 A CN00808294 A CN 00808294A CN 1265814 C CN1265814 C CN 1265814C
- Authority
- CN
- China
- Prior art keywords
- extract
- residue
- parthenolide
- resin
- gained
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940001448 feverfew extract Drugs 0.000 title claims description 9
- 239000000284 extract Substances 0.000 claims abstract description 48
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- KTEXNACQROZXEV-PVLRGYAZSA-N parthenolide Chemical compound C1CC(/C)=C/CC[C@@]2(C)O[C@@H]2[C@H]2OC(=O)C(=C)[C@@H]21 KTEXNACQROZXEV-PVLRGYAZSA-N 0.000 claims abstract description 16
- 229940069510 parthenolide Drugs 0.000 claims abstract description 16
- 239000011347 resin Substances 0.000 claims abstract description 16
- 229920005989 resin Polymers 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 9
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- 125000000457 gamma-lactone group Chemical group 0.000 claims description 8
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- 229930195733 hydrocarbon Natural products 0.000 claims description 6
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- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 claims description 4
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- AVFIYMSJDDGDBQ-UHFFFAOYSA-N Parthenium Chemical compound C1C=C(CCC(C)=O)C(C)CC2OC(=O)C(=C)C21 AVFIYMSJDDGDBQ-UHFFFAOYSA-N 0.000 description 2
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- MUROMQNYCWNWFJ-UHFFFAOYSA-N 3-Ketone-9beta-Hydroxy-4beta, 11alpha, 13, 15-tetrahydrozaluzanin C Natural products C1C(O)C(=C)C2CC(=O)C(C)C2C2OC(=O)C(C)C21 MUROMQNYCWNWFJ-UHFFFAOYSA-N 0.000 description 1
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- BBXAUSVGMAQCDJ-RCOKYBRUSA-N 3beta-hydroxyparthenolide Chemical compound C\C1=C/C[C@H](O)[C@@]2(C)O[C@@H]2[C@H]2OC(=O)C(=C)[C@@H]2CC1 BBXAUSVGMAQCDJ-RCOKYBRUSA-N 0.000 description 1
- KPUVIAXOGUUGET-UHFFFAOYSA-N 8alpha-hydroxyestafiatin Natural products CC12OC1CC3C2C4OC(=O)C(=C)C4C(O)CC3=C KPUVIAXOGUUGET-UHFFFAOYSA-N 0.000 description 1
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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Abstract
菊蒿的提取物，其中有低含量的α-不饱和γ-内酯，尤其是低含量的银胶菊内酯，可以通过在碱性树脂上洗脱而得到此提取物。本发明的提取物具有良好的药理学性质，并且发生变应性反应的危险显著降低。
Description
发明所属的技术领域
本发明涉及一种基本上不含α-不饱和γ-内酯的菊蒿(Tanacetumparthenium)提取物。
本发明还涉及制备此提取物及制备含有此基本上不含α-不饱和γ-内酯的菊蒿提取物的药物和化妆品组合物的方法。
技术背景
菊蒿，一种属于菊科的植物，也称为蒿(Artemisia)、菊(Chrysanthemum)、滨蒿(Leucanthemum)、短舌匹菊(Pyrethrumparthenium)，俗名为“小白菊、龙牙草、野甘菊”，其提取物习惯上用于治疗偏头痛、眩晕、关节炎、月经失调、发热、牙痛、胃痛和昆虫咬伤。除含有多种性质(单萜和倍半萜组分)的挥发油、黄酮类、鞣酸和除虫菊酯外，菊蒿的提取物还含有称为大根香叶内酯、愈创木内脂和桉叶内酯(eudesmanolides)的属于倍半萜内酯类的萜类化合物。这些化合物的特征是α-不饱和γ-内酯结构，并特别存在于称为银胶菊内酯(parthenolide)，3-β-羟基-银胶菊内酯，闭鞘姜酯，3-β-羟基-闭鞘姜酯，artemorin，8-α-羟基-estafiatin和野菊花宁(chrysanthemonin)的化合物中。
认为这些倍半萜内酯的存在是提取物的药理活性的基本条件。(《药物学与药理学杂志》1992，44：391-395)。
注意力曾特别集中于银胶菊内酯，认为它是此提取物的基本的活性成分，但也是用菊蒿提取物治疗后有时发生变应性反应的主要原因(见，例如，《皮肤病学文献》Fors ch.1975，251(3)：235-44；《皮肤病学文献》Fors ch.1976，255(2)：111-21；《接触性皮炎》，1988，38(4)：207-8；《美国接触性皮肤病学杂志》1998-9(1)：49-50；《英国皮肤病学杂志》1995，132(4)：543-7)。国际申请WO 94 06800、欧洲专利EP0553658、国际申请WO 92 11857、英国专利GB 2,166,952、欧洲专利EP 98041、国际申请WO 9839018公开了含有银胶菊内酯的菊蒿的提取物。
发明的公开
已发现基本不含α-不饱和γ-内酯，尤其不含银胶菊内酯的菊蒿提取物，具有令人感兴趣的药理学性质及发生变应性反应的危险显著降低。
因此本发明的提取物可以作为制备药物或口服化妆品组合物的适宜的活性成分。
本文“基本上不含α-不饱和γ-内酯”和“基本不含银胶菊内酯”意味着一种提取物中，银胶菊内酯的重量含量低于0.2％，优选低于0.1％，更优选低于0.09％，最优选低于0.07％。
能够通过包括以下步骤的方法得到本发明的提取物：
a)用丙酮、乙醇或这些溶剂与水的混合物提取植物(地上部分)；
b)用烃提取从步骤a)得到的物质；
c)用非极性溶剂提取非烃相；
d)用非极性溶剂处理提取物，蒸发溶剂并再溶解在水-醇溶液中，用一种强碱性树脂处理；
e)用醇洗脱树脂，并除去洗脱的溶液；
f)用酸的醇溶液或水-醇溶液处理树脂，浓缩溶液并用非极性溶剂提取所得残余物；
g)蒸发步骤f)的非极性溶剂，得到残余物，将其加入蒸发步骤b)的烃提取物后所得的残余物中，及步骤c)用非极性溶剂提取所得的丙酮或乙醇相中；
h)蒸发并干燥。
因为强碱性树脂意外地不引起公认对碱水解敏感的内酯环的开环，可以除去银胶菊内酯和其他相关的倍半萜内酯：树脂因而截留了含有酸性羟基的黄酮类成分，相反地能除去银胶菊内酯和相关的化合物。
以下列出了对于各种提取步骤优选的溶剂：
步骤a)：丙酮、甲醇、乙醇或它们与水的混合物；
步骤b)：己烷、正戊烷、石油醚、轻石油(ligroin)；
步骤c)：二氯甲烷、氯仿、乙酸乙酯，优选二氯甲烷；
步骤f)：乙酸乙酯。
在此处“醇性或水-醇性溶剂”指甲醇或甲醇与10-80％体积的水。
本发明可以使用的碱性树脂能够由市售得到，例如注册名称为Relite 2A、Relite 3A2、Dowex 2的商品。
或者可以从市售可得到的常规的提取物开始，用强碱性树脂处理而得到本发明的提取物，在此之前选择性地先用烃类溶剂提取会对树脂产生有害干扰的亲脂性的成分。
用HPLC法测定最终提取物中α-不饱和γ-内酯和银胶菊内酯的含量。
在附图中，显示了用上述方法得到的提取物的典型的HPLC曲线。
本发明的提取物具有良好的药理学性质，并且发生变应性反应的危险显著降低。考虑到最新的关于生物活性与已知的提取物的组成之间的关系的文献报道，令人惊奇的是虽然几乎全部除去了倍半萜内酯，但保留了常规的菊蒿提取物的药理学特性(《药物学与药理学杂志》1992，44：391-395.)。
特别地，基本不含银胶菊内酯的本发明的提取物，具有抗血小板、抗炎、止痛和抗偏头痛的活性。
本发明因此也涉及含有有效量的本发明的菊蒿提取物作为活性成分，并与适宜的载体形成混合物的药物组合物。
更特别地，本发明的组合物将含有约10-500mg提取物，每日给药3-4次，或按医师的处方给药。优选的给药途径是口服，但也可以采用其他的途径，如局部用药和胃肠外给药。
本发明的组合物特别用于治疗或预防偏头痛。
本发明的提取物也可以用作口服化妆品制剂的活性成分。
以下实施例更详细地记载了本发明。
例1 制备提取物
在50-60℃用20L 70％含水甲醇提取2公斤菊蒿。将提取物真空浓缩至约1升，并用等体积的甲醇稀释。所得溶液用正己烷萃取3次，每次2升。将正己烷提取物真空蒸发至干，得到约30g残余物(
提取 物H)。然后用二氯甲烷萃取水醇溶液2次，每次用二氯甲烷0.5升。在真空条件下将有机相蒸发至干，得到70g残余物(提取物DCM)。弃除水-甲醇相(提取物HM)。将DCM提取物溶解在0.6升90％甲醇中，在搅拌状态下用0.6升强碱树脂(Relite 2A)处理3-4小时。在真空条件下将混悬液过滤，用约2升90％甲醇洗涤树脂。除去含有银胶菊内酯及其同族物质的甲醇溶液。然后在搅拌下用0.6L含有65ml浓盐酸的甲醇处理碱性树脂约1小时。将树脂真空过滤并用另外2.5L甲醇洗涤。合并滤液和洗涤液，真空浓缩至约200mL，并用乙酸乙酯萃取3次，每次用乙酸乙酯200ml。含有黄酮类成分丹宁和同族物质的所得提取物(E.A.)，真空浓缩至干，得到4g残余物。提取物H和E.A.的残余物与提取物HM合并。将所得溶液真空蒸发至干，将固体残余物在50℃真空干燥至恒重。得到约490g已除去银胶菊内酯的菊蒿提取物，用HPLC分析(柱Zorbax SB C18；洗脱剂H2O+0.01％TFA；B：MeCN+0.01％TFA；洗脱剂梯度为A∶B＝90％-10％∶10％-90％；流速1ml/分钟)，其中所含的银胶菊内酯低于0.07％。
例2 药理学活性
使用《脑研究》1995，682：167-181；《脑研究》1995695，37-44和《神经药理学》1997，36(10)；1417-1424记载的大鼠硝酸甘油所致神经原兴奋的实验模型。
可以用硝酸甘油(通常用于治疗某些心血管的疾病的一种血管扩张剂)作为偏头痛的研究中的诊断剂，由于其给药会导致类似于自发的偏头痛发作。硝酸甘油导致的发病不是即刻发作的，而是延迟几小时，通常有伴随症状，如恶心和羞明。包括硝酸甘油的有机硝酸酯的血管舒张活性，是在其新陈代谢成含氮的氧化物时产生的，文献报道后者在SNC过程中也作为一种神经递质。神经原兴奋快速活化一些前致癌基因酶(proto-oncogenase)的转录，这些物质由于其快速而短暂的诱导效应，已被命名为即时早期基因。在这些物质中，c-fos是被最广泛研究的并被蛋白质编码的，Fos被异位成核心，在此它持续几小时并能通过免疫化学方法得以检测。
实验步骤
将25只雄性Sprague-Dawley大鼠分成5组。2组(对照组和硝酸甘油组)注射单纯的赋形剂(0.5％羧甲基纤维素，10ml/kg)，同时其它3组分别口服基本不合银胶菊内酯的菊蒿提取物(TPPDE)，剂量为100和200mg/kg，及等剂量的Tanaceutum parthenium常规提取物(TPRE)，共服用3天。
最后一次给药后1小时，除对照组外的所有动物皮下注射10ml/kg硝酸甘油。
硝酸甘油给药4小时后，用戊巴比妥钠使大鼠麻醉，并用定影剂灌注升主动脉。快速摘取脑组织，在同样的定影剂中固定过夜。用冰冻滑动切片机切制50μm厚度的通过全脑的切片。将切片连续收集在含有冷磷酸盐缓冲盐水(PBS)的6个样品池中，作为自由流动的部分(asfree-floating sections)进行免疫化学测定。
结果示于下表。
表：硝酸甘油给药4小时后下丘脑的室旁核(PVH)、蓝斑(LC)和臂旁
核(PBN)中免疫反应神经原的数目(平均±标准偏差)
| 治疗组 | PVH | LC | PBN |
| 对照组 | 95.4±43.1 | 47.0±21.2 | 27.3±15.2 |
| 硝酸甘油 | 574.2±298.5 | 334.3±61.4 | 231.3±89.4 |
| TPPDE(100)+硝酸甘油 | 378.5±182.9* | 200.5±43.4* | 140.7±64.6* |
| TPPDE(200)+硝酸甘油 | 123.4±74.5** | 87.5±24.5** | 71.6±28.6** |
| TPRE(200)+硝酸甘油 | 569.7±288.3 | 321.2±49.1 | 228.3±87.5 |
*P＜0.03 TPPDE(100)+硝酸甘油与硝酸甘油对照组比较
**P＜0.001 TPPDE(200)+硝酸甘油与硝酸甘油对照组比较
Claims (4)
1.一种α-不饱和γ-内酯的含量低于0.2％的菊蒿提取物，其特征在于是由包括以下步骤的方法获得的：
a)用丙酮、乙醇或这些溶剂与水的混合物提取植物地上部分；
b)用烃提取从步骤a)得到的物质；
c)用非极性溶剂提取非烃相；
d)用非极性溶剂处理提取物，先蒸发溶剂并再溶解在水-醇溶液中，用一种强碱性树脂处理；
e)用醇洗脱树脂，并除去洗脱的溶液；
f)用酸的醇溶液或水-醇溶液处理树脂，浓缩溶液并用非极性溶剂提取所得残余物；
g)蒸发步骤f)的非极性溶剂，得到残余物，将其加入蒸发步骤b)的烃提取物后所得的残余物中，及用步骤c)的非极性溶剂提取所得的丙酮或乙醇相中；
h)蒸发并干燥。
2.权利要求1所述的提取物，其中银胶菊内酯含量低于0.2％。
3.权利要求1或2所述的提取物，其中α-不饱和γ-内酯的含量低于0.1％。
4.一种口服化妆品组合物，其中含有权利要求1-3中任一项所述的提取物及适宜的载体。
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| ITMI99A001244 | 1999-06-03 |
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| US20030077343A1 (en) * | 2001-03-16 | 2003-04-24 | Martin Katharine M. | Composition containing feverfew extract and use thereof |
| EP1367993B1 (en) * | 2001-03-16 | 2007-05-16 | Johnson & Johnson Consumer Companies, Inc. | Use of a feverfew extract for regulating skin ageing factors |
| US20040086579A1 (en) * | 2002-11-05 | 2004-05-06 | Higgins James W. | Dietary supplement comprising parthenolide |
| US7192614B2 (en) | 2002-11-05 | 2007-03-20 | Gelstat Corporation | Compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| US20040247706A1 (en) * | 2003-06-06 | 2004-12-09 | Roberts Stephen C. | Transdermal dietary supplement comprising parthenolide |
| US20040247705A1 (en) * | 2003-06-06 | 2004-12-09 | Roberts Stephen C. | Transdermal compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| US7758903B2 (en) | 2003-09-12 | 2010-07-20 | Access Business Group International Llc | Cytokine modulators and related methods of use |
| WO2005025586A1 (en) * | 2003-09-12 | 2005-03-24 | Access Business Group International Llc | Cytokine modulators and related method of use |
| US7758902B2 (en) * | 2003-09-12 | 2010-07-20 | Access Business Group International Llc | Cytokine modulators and related methods of use |
| US20050186269A1 (en) * | 2004-02-25 | 2005-08-25 | Udell Ronald G. | Stabilized feverfew formulations |
| NZ607880A (en) * | 2006-02-21 | 2014-11-28 | Akzo Nobel Surface Chemistry Llc | Parthenolide free bioactive ingredients from feverfew (tanacetum parthenium) and processes for their production |
| AU2013201510B2 (en) * | 2006-02-21 | 2015-07-16 | Isp Investments Inc. | Parthenolide Free Bioactive Ingredients from Feverfew (Tanacetum Parthenium) and Processes for their Production |
| US20120089232A1 (en) | 2009-03-27 | 2012-04-12 | Jennifer Hagyoung Kang Choi | Medical devices with galvanic particulates |
| BR112012022106A2 (pt) | 2010-03-01 | 2016-10-25 | Johnson & Johnson Consumer | composição para tratamento de pele tendo uma cor desejável em volume |
| CN103524520B (zh) * | 2013-09-25 | 2015-12-09 | 中国人民解放军第四军医大学 | 一种从植物原料中提取小白菊内酯的方法 |
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| CA1270843A (en) * | 1982-05-19 | 1990-06-26 | Edward Stewart Johnson | Sesquiterpene lactones |
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| DE4202657C2 (de) * | 1992-01-31 | 1995-10-12 | Schaper & Bruemmer Gmbh | Pharmazeutisch wirksame Zusammensetzung aus Tanacetum parthenium sowie Verfahren zu deren Extraktion und mit der pharmazeutisch wirksamen Zusammensetzung hergestelltes Arzneimittel |
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