EP1755629A1 - Extrait de ginkgo biloba et procede pour le produire - Google Patents

Extrait de ginkgo biloba et procede pour le produire

Info

Publication number
EP1755629A1
EP1755629A1 EP05759091A EP05759091A EP1755629A1 EP 1755629 A1 EP1755629 A1 EP 1755629A1 EP 05759091 A EP05759091 A EP 05759091A EP 05759091 A EP05759091 A EP 05759091A EP 1755629 A1 EP1755629 A1 EP 1755629A1
Authority
EP
European Patent Office
Prior art keywords
extract
weight
leaves
water
ginkgo biloba
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.)
Withdrawn
Application number
EP05759091A
Other languages
German (de)
English (en)
Inventor
Fu Yuanhui
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GOETECH GmbH
Original Assignee
GOETECH GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by GOETECH GmbH filed Critical GOETECH GmbH
Publication of EP1755629A1 publication Critical patent/EP1755629A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a ginkgo biloba extract and to processes for its production.
  • the invention relates to a ginkgo extract with an increased content of desired pharmaceutically active ingredients, and to methods in which only water or alcohol is used as the extractant.
  • Extracts from leaves of the Ginkgo biloba tree are the subject of extensive pharmacological studies and are used in medical and cosmetic fields.
  • Ginkgo extracts are primarily used in the medical field for the treatment of peripheral arterial circulatory disorders and vascular disorders, for the treatment of brain-related performance disorders such as memory and concentration disorders, headaches and ringing in the ears.
  • ginkgo leaves contain more than 70 different ingredients, such as flavone glycosides, quercetin, isorhamnetin, kaempferol, ginkgetin, isoginkgetin, ginkgolides A, B, C and J, bilobalide and others.
  • the pharmaceutical effect of ginkgo extracts is mainly attributed to the ingredients ginkgolflavone glycoside, ginkgolide and bilobalide.
  • ginkgo leaves also contain unwanted ingredients that can lead to severe allergic reactions. So is about allergic reactions after contact with gink
  • Ginkgo leaves could of course be used directly to achieve the desired pharmaceutical effect. However, this has the disadvantage that the undesirable allergenic ingredients are also administered. In addition, the contents of the leaf ingredients vary widely, so that no specifically dosed medical use is possible.
  • DE 21 17 429 proposes a process for the production of extracts from ginkgo leaves, in which ginkgo leaves are extracted with aqueous acetone, the extract thus obtained is extracted with carbon tetrachloride, butanone and ethanol and a precipitation reaction with lead hydroxide is carried out with the solution thus obtained. An extract is finally obtained through further process steps.
  • EP 0431 535 discloses a process in which dried Ginkgo biloba leaves are extracted with aqueous acetone, an aqueous alkanol or anhydrous methanol and further organic solvents such as methyl ethyl ketone are used in further process steps.
  • the international patent application WO 00/01397 describes an extraction process in which ginkgo leaves are extracted with alcoholic-aqueous or ketonic-aqueous solvents and the extracts obtained are subsequently subjected to ultrafiltration.
  • EP 0 431 535 reports an extract which contains at most 30% by weight of flavone glycosides, at most 4.5% by weight of ginkgolide and at most 4% by weight of bilobalide, the content of undesirable alkylphenol compounds being less than 10 ppm is.
  • This substance profile meets the requirements of the monograph "Ginkgo biloba dry extract" of Commission E of the former Federal Health Office of the Federal Republic of Germany.
  • Another object of the present invention is to provide a ginkgo biloba extract which has an increased content of desired ingredients, that is flavone glycosides, ginkgolides and or bilobalide, and at the same time low toxicologically acceptable levels of allergenic ingredients.
  • ginkgo leaves preferably organically grown leaves
  • an alkaline aqueous solution preferably with saturated lime water.
  • This treatment step in which ginkgo leaves are immersed in the alkaline aqueous solution, first removes surface impurities from the leaves and destroys their wax layer. there the leaves are rehydrated, which means that the cells of the leaves absorb water and swell.
  • the leaves are preferably immersed in water having a pH of approximately 8.5 over a period of approximately 4 hours. The water used for the treatment is then discarded and the remaining leaves are rinsed with water.
  • the leaves from step 1 are extracted with water, which can be normal tap water, but is preferably demineralized or distilled water.
  • the amount of water used is about 5-20 times, preferably 5-15 times and most preferably 8-10 times the dry weight of the leaves.
  • the extraction can take place at room temperature or slightly elevated temperatures between 40 and 70 ° C, lower temperatures being preferred in order to exclude hydrolysis.
  • the extraction can be carried out using conventional methods, such as. B. by simple immersion, diacolation, ultrasonic extraction or with mechanical stirring. Depending on the extraction method chosen, the extraction takes place over a period of 0.5-5 hours.
  • the extract obtained is then filtered to remove larger particles using conventional techniques and materials.
  • Filter paper or fabric, diatomite or the like can be used. The filtration can take place under normal pressure, increased pressure or reduced pressure.
  • the filtered extract is then subjected to ultrafiltration over several conventional ultrafiltration membranes.
  • the extract is preferably firstly via a membrane with an average pore size of approximately 10,000 daltons, then via a membrane with a pore size of approximately 6,000 daltons and then passed over a membrane with a pore size of approximately 2,000 daltons.
  • Commercial filters made of polyamide, polypropylene or other common materials are used. Ultrafiltration initially separates larger molecules such as wax components, proteins, tannins or polysaccharides through the coarser membranes and smaller molecules such as proteins, starches or Oligosacchari.de through the finer membranes.
  • the extract obtained after ultrafiltration is then subjected to reverse osmosis, using conventional semipermeable membranes and reverse osmosis devices.
  • reverse osmosis can be performed using a cellulose acetate membrane at a pressure of e.g. B. 4.5 MPa, the pressure can be adapted to the respective requirements.
  • the reverse osmosis separates heavy metal ions and smaller sugar molecules.
  • the extract obtained after the ultrafiltration is then passed through a chromatographic absorption column.
  • the column is filled with an absorption medium that contains allergenic substances such as.
  • allergenic substances such as.
  • ginkgolic acid can absorb and does not react with the desired ingredients of the extract.
  • Large-pore absorption resins or activated carbon in particular can be used as the immobile phase.
  • Coal produced from ginkgo nut shells activated carbon from charred ginkgo nut shells
  • Particularly preferred resins are the resins available under the trade names GARA 1 and GARA 2 from Woxun Bioengineering Ltd., Shanghai, China or Mitsubishi SP700.
  • Extracts obtained by the method described above can be dried by conventional methods, e.g. B. by distillation under reduced pressure if necessary or by freeze-drying.
  • the extracts obtained in this way have substance profiles that meet the requirements of the monograph "Ginkgo biloba dry extract” of Commission E of the former Federal Health Office of the Federal Republic of Germany.
  • the extracts typically contain 24-27% by weight flavone glycosides, 3.5-4% by weight ginkgolides and 2.4-2.6% by weight bilobalide, less than 10 ppm, even less than 2 ppm alkylphenol compounds and less than 10% by weight proanthocyanidins
  • the extracts have levels of heavy metals less than 0.12 mg / kg Lead, less than 0.1 mg / kg cadmium and less than 0.08 mg / kg mercury
  • the water solubility of the dry extracts obtained by the prescribed procedure is more than 1.2 g / 100 ml water.
  • the aqueous extract obtained after step 5 above may additionally be passed through a chromatographic column containing as stationary phase, an absorption resin, preferably based on cross-linked polystyrene, preferably under the designations Diaion ® and Sepabeads ® from Mitsubishi, particularly preferably Mitsubishi Diaion HP20, sold resins, contains. Extracts with variable substance profiles can be obtained by washing the loaded resin with water, then rinsing with an alcoholic-aqueous solution and finally eluting the extract containing the desired ingredients. Rinsing with an aqueous alcoholic solution can be carried out several times with increasing concentration of alcohol, the alcohol concentration preferably being between 10 and 25%.
  • washing can be carried out with 10% alcohol in a first step and with 20% alcohol in a second step in order to separate further undesirable ingredients.
  • the alcoholic aqueous solution used for rinsing contains up to 25%, preferably 10-20%, of a low molecular weight alcohol such as isopropanol, methanol or ethanol, ethanol being particularly preferred.
  • a low molecular weight alcohol such as isopropanol, methanol or ethanol, ethanol being particularly preferred.
  • an aqueous-alcoholic solution is used which contains at least 75% of an alcohol as described above, preferably ethanol.
  • extracts can be obtained with the following substance profiles:
  • Flavone glycosides 8.0-52% by weight ginkgolide A, B, C, J 2.8-41% by weight bilobalide 2.6-39% by weight proanthocyanidins 1-20% by weight alkylphenols less than 2, 0 ppm tannins less than 5% by weight
  • ginkgo biloba extracts with contents of desired ingredients (flavone glycosides, ginkgolides and bilobalids) which are significantly higher than known extracts, the contents of undesirable, allergenic substances not being significantly increased and the requirements of the monograph correspond.
  • desired ingredients flavone glycosides, ginkgolides and bilobalids
  • the extract obtained was then passed through a polypropylene ultrafiltration membrane with a pore size of 10,000 daltons, subsequently through an ultrafiltration membrane with a pore size of 6,000 daltons and finally through an ultrafiltration membrane with a pore size of 2,000 daltons.
  • the filtrate finally obtained was then subjected to reverse osmosis using a cellulose acetate membrane.
  • the salt permeation rate was at least 95% by weight, the water permeation rate 90-120 l / m 2 h at 4.5 MPa.
  • the filtrate thus obtained was then passed through a chromatographic column with a diameter of 30 cm and a height of 1.2 m, which was filled with charred ginkgo nut shells.
  • the chromatographic separation took place at ambient pressure and temperature.
  • the eluent was concentrated to a mass of less than 8 kg using a reverse osmosis membrane as described above and finally spray dried to obtain 1.4 kg of extract.
  • the extract obtained was analyzed by HPLC.
  • the total flavon content was 26.7% by weight
  • the content of ginkgolides A, B and C was 3.54% by weight
  • the content of bilobalide was 2.58% by weight
  • the content of ginkgolic acids 1 (a and b ) are 0.39 and 3.37 ppm
  • the content of ginkgolic acid 2 is less than 0.3 ppm
  • the content of heavy metals is less than 0.12 mg / kg lead, less than 0.1 mg / kg cadmium and less than 0.08 mg / kg mercury. (The percentages by weight in turn relate to the mass of the dry extract obtained).
  • the combined extracts were then centrifuged at 15,000 rpm and the solids and oil portions separated from the extract.
  • the extract obtained was then filtered using a Millipore Labscale TTF Pellicon XL ultrafiltration system using ultrafiltration membranes with pore sizes of 10,000 daltons, 8,000 daltons and 5,000 daltons. Filtration was subsequently carried out using membranes with a pore size of 3,000 Dalton and 1,000 Dalton. The filtrate thus obtained then became one Subjected to reverse osmosis using a cellulose acetate membrane.
  • the salt permeation rate was at least 95% by weight, the water permeation rate 90-120 l / m 2 h at 4.5 MPa.
  • the extract thus obtained was passed through a column packed with the Gara 1 resin. 5 g of the resin are used per 100 ml of extract. The chromatographic separation was carried out at ambient pressure.
  • the liquid obtained after the previous step was passed through a column packed with Diaion HP2MGL resin. 5 g of the resin were used per 100 ml of liquid. The chromatography was carried out at ambient temperature and ambient pressure.
  • the liquid thus obtained was then placed on a column packed with Mitsubishi Diaion HP20 resin; 2 g of the resin were used per 100 ml of liquid. As soon as any tea-colored parts leave the column, the process is stopped. The column is then washed with pure water and then with 10% aqueous ethanolic solution. The washing solutions are discarded. The column was then eluted with a 75% ethanolic aqueous solution and the liquid obtained was collected. The liquid obtained was dried at a low temperature to obtain the desired extract.
  • extracts with the following substance profiles were obtained: a) Composition of the extract: flavone glycosides 39% by weight ginkgolides A, B, C and J 2.9% by weight bilobalides 2.78% by weight proanthocyanidins 10.5% by weight alkylphenols ⁇ 0.7 ppm tannins ⁇ 5% by weight
  • the extracts according to the invention thus allow the production of pharmaceutical and cosmetic compositions with increased active substance contents. They can be processed without problems into conventional pharmaceutical compositions, preferably into tablets, solutions for injection and solutions for oral administration.
  • Ginkgo biloba extract 30.00 mg microcrystalline cellulose 100.00 mg lactose 60.00 mg Colloidal silica 20.00 mg

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne un extrait de Ginkgo biloba et un procédé pour le produire. L'invention concerne en particulier un extrait de Ginkgo ayant une teneur élevée en substances souhaitées ayant une action pharmaceutique, et un procédé au cours duquel de l'eau est utilisée comme agent d'extraction.
EP05759091A 2004-04-29 2005-04-29 Extrait de ginkgo biloba et procede pour le produire Withdrawn EP1755629A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004021276 2004-04-29
PCT/EP2005/004631 WO2005105122A1 (fr) 2004-04-29 2005-04-29 Extrait de ginkgo biloba et procede pour le produire

Publications (1)

Publication Number Publication Date
EP1755629A1 true EP1755629A1 (fr) 2007-02-28

Family

ID=34972164

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05759091A Withdrawn EP1755629A1 (fr) 2004-04-29 2005-04-29 Extrait de ginkgo biloba et procede pour le produire

Country Status (4)

Country Link
US (1) US20080050457A1 (fr)
EP (1) EP1755629A1 (fr)
CN (1) CN1946413A (fr)
WO (1) WO2005105122A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100462006C (zh) * 2006-02-21 2009-02-18 复旦大学 银杏酸在制备杀灭钉螺、防止血吸虫病的生物农药中的用途
ITMI20070408A1 (it) * 2007-03-01 2008-09-02 Pharmaval Srl Composizioni per la prevenzione e il trattamento della cefalea primaria e dell' emicrania
CN101559085B (zh) * 2008-04-16 2011-09-07 上海信谊百路达药业有限公司 一种提高银杏叶提取物中白果内酯含量的提取方法
CN101449805B (zh) * 2008-12-23 2012-08-08 浙江工业大学 一种从银杏叶中提取银杏提取物的方法
CN102091103B (zh) * 2011-01-25 2012-09-05 江苏九久环境科技有限公司 超声提取制备低酸值银杏提取物的方法
CN105053964A (zh) * 2015-07-07 2015-11-18 河南科技大学 一种银杏酱及其制备方法
CN106074631B (zh) * 2016-07-27 2019-11-15 晨光生物科技集团股份有限公司 一种低银杏酸低灰分银杏叶提取物的工业化生产方法
CN108743632B (zh) * 2018-04-27 2021-07-27 浙江工业大学 一种超声波辅助去除白果中银杏酸的方法
CN110327080B (zh) * 2019-07-05 2021-11-19 上海应用技术大学 金佛手精油和/或纯露的皮肤过敏性检测方法及应用
CN111084197A (zh) * 2019-12-30 2020-05-01 江苏腾龙生物药业有限公司 一种银杏酚可溶液剂的制备工艺
CN111714395B (zh) * 2020-07-20 2022-10-04 南京斯拜科生物科技股份有限公司 一种银杏提取物复配的多肽组合物及其应用
CN112697899B (zh) * 2020-12-07 2022-04-12 中国药科大学 一种银杏黄酮醇苷的检测方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053720A1 (fr) * 2003-11-24 2005-06-16 Indena S.P.A. Compositions pour traiter la dermatite atopique, les allergies cutanees et l'acne

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3940094A1 (de) * 1989-12-04 1991-06-06 Montana Ltd Wirkstoffkonzentrate und neue wirkstoff-kombinationen aus blaettern von ginkgo biloba, ein verfahren zu ihrer herstellung und die wirkstoff-konzentrate bzw. die wirkstoff-kombinationen enthaltenden arzneimittel
CN1048724C (zh) * 1995-11-15 2000-01-26 庚朋 一种从银杏叶中提取总黄酮的方法
ES2219259T3 (es) * 2000-06-16 2004-12-01 Linnea S.A. Complejo soluble en agua de un extracto de ginkgo biloba, procedimiento para su preparacion y composicion que lo comprende.
WO2004056792A1 (fr) * 2002-11-11 2004-07-08 Pro-Herb Gmbh Extrait organique de ginkgo, son procede de preparation et son utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053720A1 (fr) * 2003-11-24 2005-06-16 Indena S.P.A. Compositions pour traiter la dermatite atopique, les allergies cutanees et l'acne

Also Published As

Publication number Publication date
WO2005105122A1 (fr) 2005-11-10
US20080050457A1 (en) 2008-02-28
CN1946413A (zh) 2007-04-11

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