CN1124275C - Method of preparing ginkalide A and B as medicine from ginkgo leaf or its extract - Google Patents
Method of preparing ginkalide A and B as medicine from ginkgo leaf or its extract Download PDFInfo
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- CN1124275C CN1124275C CN 00117758 CN00117758A CN1124275C CN 1124275 C CN1124275 C CN 1124275C CN 00117758 CN00117758 CN 00117758 CN 00117758 A CN00117758 A CN 00117758A CN 1124275 C CN1124275 C CN 1124275C
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- ginkgolide
- ginkgo leaf
- ginkalide
- medicinal extract
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Abstract
The present invention discloses a method for preparing medicine (ginkalide A and ginkalide B) from ginkgo leaves or ginkgo leaf extractum, which comprises: a leaching agent, such as ethanol, etc., is added to ginkgo leaves or extractum thereof; the obtained leaching liquid is treated with filtration and delamination, and organic phases are taken out for removing impurities; after the leaching liquid is concentrated and dried, enriched ginkalide A and enriched ginkalide B are obtained; then the ginkalide A and the ginkalide B are separated by adopting preparation-type liquid chromatography. The present invention is characterized in that the leaching liquid and chloride saltingout agents are simultaneously added to the raw material; in the process of impurity removal, potassium salts or sodium salts are added. The mixed liquid of ethyl acetate and ligarine is used as a mobile phase of a separating column of the liquid chromatography, and silica gel is used as an immobile phase. The present invention has the advantages of simple preparation process and low cost.
Description
The present invention relates to a kind of method for preparing medicine Ginkgolide A, B by Ginkgo Leaf or Ginkgo Leaf medicinal extract.It is the technology of preparing that belongs to natural ginkgo lactone single component.
Bilobalide is a material exclusive in the Ginkgo Leaf, and it comprises Ginkgolide A, B, C, M and J, and they are platelet-activating factor antagonist, and wherein the physiologically active with Ginkgolide B is the strongest.Bilobalide-like substances is the medicine that application prospect is arranged in the present natural platelet-activating factor antagonist most.The pure product Ginkgolide B of injection has been used for treatment of conditions such as transplant rejection, apoplexy, hemodialysis and shock in clinical trial, also may and treat allergic asthma for prevention provides a class new medicine.Ginkgolide A has synergy.
The content of bilobalide-like substances in Ginkgo Leaf is very low, and changes along with changes of seasons, only is 0.5% during content at most according to statistics.For Ginkgolide B, then still less.The source of bilobalide mainly contains three kinds; (1) chemosynthesis; (2) culture plant cell; (3) extracted form natural plant.Wherein the research of chemosynthesis and culture plant cell all is in initial stage, and the production technology difficulty is big, the production cost height, can't with compete mutually from the approach of artificial culture economic forest natural extract.
Existing ginkgo class medicine is mainly ginkgo agent (mixture that contains multiple components), and ginkgo agent is raw materials used to be Ginkgo Leaf medicinal extract Egb
761, its quality standard is: flavonoid glycoside is more than 24%, and more than 6%, ginkgolic acid is below 0.0005% for terpene lactones (summation of bilobalide and bilobalide).Be mainly used in treatment coronary heart disease, stenocardia, senile dementia and hypermnesis function etc.The ginkgo agent medicine of listing mainly contains: the TEBONIN (Ginaton) of German Schwabe drugmaker, the TANAKAN (Da Nakang) of France Bo Fu-beneficial general life (Beaufour-Ipsen) drugmaker, taponin (Zhejiang Kang Enbei), Ginkgo Biloba Leaf Preparation (sea, Shenzhen king's medicine company), 999 puerarins (magnificent pharmacy is stood by Three-nine Group), ginkgo oral liquid (Zunhua, Hebei pharmaceutical factory), Gingkocapsule (the Shanxi heart grinds institute) etc.
The preparation method of the relevant ginkgo medicinal ingredients of now having reported only limits to Ginkgo Leaf medicinal extract Egb
761With bilobalide preparation process of mixture two classes,, adopt organic solvent extraction and ion exchange method to make the Ginkgo Leaf medicinal extract Egb that contains ginkgolic flavone glycoside and bilobalide as pointing out in patent " DE3,940, the 092 " report
761Point out in patent " US Patent5,089, the 636 " report, repeatedly extract the mixture that also crystallization obtains Ginkgolide A, B, C, J and M with organic solvent; Point out in patent " CN1195665A " report, by Ginkgo Leaf or Cortex Ginkgo, through poach, adsorbents adsorb and desorption, crystallization and recrystallization process make the mixture that is rich in bilobalide.At present, still have nothing to do in bilobalide single component preparation method's report.
Purpose of the present invention is to provide a kind of method that is prepared medicine Ginkgolide A, B by Ginkgo Leaf or Ginkgo Leaf medicinal extract.This method has that technological process is simple, cost is low, power consumption less, characteristics that goods purity is high.
For achieving the above object, the present invention is realized by following concrete scheme.With Ginkgo Leaf or Ginkgo Leaf medicinal extract is raw material, add ethanol or methyl alcohol or acetone or butanone or ethyl acetate organic solvent soaking extraction, leaching liquid after filtration, standing demix, the organic layer liquid that obtains carries out decon to be handled, and then the organic layer liquid that standing demix obtains is through the enriched material that concentrates, drying obtains enrichment Ginkgolide A and B, adopt preparative liquid chromatography that the enriched material that contains Ginkgolide A and B is separated, aftertreatment, obtain Ginkgolide A and Ginkgolide B, it is characterized in that: when adding leaching agent, add the muriate agent of saltouing; The impurity elimination process is organic layer liquid adding sylvite or the sodium salt to leaching liquid; The moving phase of the separator column of preparative liquid chromatography is to adopt the mixed solution of ethyl acetate and sherwood oil, and stationary phase adopts silica gel.
The agent of saltouing of above-mentioned muriate is the aqueous solution of Repone K or calcium chloride or bariumchloride or sodium-chlor, and its add-on is 0.5～3 times of raw material weight.
Above-mentioned sylvite or sodium salt are the aqueous solution of sodium-acetate or Potassium ethanoate or yellow soda ash or sodium bicarbonate or salt of wormwood or saleratus, and when strength of solution was 1mol/l, its add-on was 0.1～0.7 times of organic liquor volume.
The above-mentioned ethyl acetate and the optimum mixture ratio of sherwood oil are 7: 1～9: 1.
Below the present invention is described in detail.
Ginkgo Leaf or Ginkgo Leaf medicinal extract are dipped in methyl alcohol or ethanol or acetone or butanone or the ethyl acetate organic solvent, also to add aqueous chloride solution simultaneously and make salting-out agent, the add-on GPRS of salting-out agent is suitable, too much be unfavorable for the down separation in step, very fewly be unfavorable for separating out of bilobalide again.After soaking certain hour, filter out soak solution, heated and stirred, refilter, standing demix takes out organic layer liquid, adds sylvite or sodium salt again in solution, sylvite or sodium salt are selected from carbonate and acetate, they are sodium-acetate or Potassium ethanoate or yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, add in the organic layer liquid add-on with their aqueous solution, when concentration is 1mol/l, be long-pending 0.1～0.7 times of organic layer liquid.It is crucial that this process is selected the kind and the add-on of sylvite or sodium salt, that they are determined is good, bad direct relation the yield height of goods.After adding sylvite or sodium-salt aqueous solution, through stirring, standing demix, obtain the more shallow organic liquid layer of color, this liquid layer is the concentrated solution of enrichment Ginkgolide A and B, this concentrated solution is sent to preparative liquid chromatography and is separated, and the stationary phase of chromatographic column adopts silica gel, and moving phase adopts the mixed solution of ethyl acetate and sherwood oil, collect effluent from the post mouth, just can obtain the concentrated solution of Ginkgolide A and Ginkgolide B.The concentrated solution that obtains is carried out concentrating under reduced pressure, crystallization, the goods of acquisition Ginkgolide A and Ginkgolide B.
With embodiment the present invention is further specified again below.
Embodiment one
Get the ground Ginkgo Leaf of 2kg, with 5L anhydrous methanol leaching twice, filter with B then respectively, remove residue, collect filtrate, merge filtrate with film Rotary Evaporators evaporate to dryness and collect resistates 46g.Resistates is dissolved in the 500ml dehydrated alcohol, 40 ℃ are stirred 1h down, add the aqueous solution of Repone K simultaneously, and consumption is 60g Repone K/100ml water, the elimination insolubles, the filtrate standing demix takes out organic layer, adds aqueous sodium carbonate (concentration is 1mol/l) 100ml, standing demix behind the stirring 10min, take out organic layer, behind the recovery ethanol, drying obtains the 0.96g enriched material.Getting this enriched material of 200mg dissolves with 5ml moving phase (ethyl acetate is 7: 3 with the sherwood oil ratio), the flow velocity of preparative chromatography moving phase is 25ml/min, sample size is 5ml, adopt light scattering detector to carry out online detection, collect successively effusive Ginkgolide A, Ginkgolide B according to the color atlas that detects, concentrating under reduced pressure, drying obtain enriched material 87.39mg Ginkgolide A and 56.61mg Ginkgolide B.In methyl alcohol and water ratio are 3: 7 system, respectively Ginkgolide A, Ginkgolide B are carried out recrystallization, at last pure product Ginkgolide A is 70.38mg, purity reaches 95.7%, Ginkgolide B is 43.24mg, purity reaches 96.3%.
Embodiment two
Get the Ginkgo Leaf medicinal extract of 40g, add 700ml acetone, 60 ℃ are stirred 1h down, the aqueous solution that adds sodium-chlor simultaneously, consumption is 50g sodium-chlor/100ml water, elimination insolubles, filtrate standing demix, take out organic layer, add sodium acetate aqueous solution (concentration is 1mol/l) 80ml, standing demix behind the stirring 10min takes out organic layer, after reclaiming acetone, drying obtains the 1.0247g enriched material.Getting this enriched material of 100mg dissolves with 5ml moving phase (ethyl acetate is 8: 2 with the sherwood oil ratio), the flow velocity of preparative chromatography moving phase is 25ml/min, sample size is 5ml, adopt light scattering detector to carry out online detection, collect successively effusive Ginkgolide A, Ginkgolide B according to the color atlas that detects, concentrating under reduced pressure, drying obtain enriched material 50.13mg Ginkgolide A and 29.43mg Ginkgolide B.In methyl alcohol and water ratio are 35: 65 system, respectively Ginkgolide A, Ginkgolide B are carried out recrystallization, at last pure product Ginkgolide A is 38.25mg, purity reaches 96.1%, Ginkgolide B is 20.18mg, purity reaches 96.2%.
Embodiment three
Get the Ginkgo Leaf medicinal extract of 40g, add the 600ml ethyl acetate, 50 ℃ are stirred 1h down, the aqueous solution that adds calcium chloride simultaneously, consumption is 70g calcium chloride/100ml water, elimination insolubles, filtrate standing demix, take out organic layer, add sodium bicarbonate aqueous solution (concentration is 1mol/l) 60ml, standing demix behind the stirring 10min takes out organic layer, after reclaiming ethyl acetate, drying obtains the 1.4274g enriched material.Getting this enriched material of 200mg dissolves with 5ml moving phase (ethyl acetate is 8: 2 with the sherwood oil ratio), the flow velocity of preparative chromatography moving phase is 25ml/min, sample size is 5ml, adopt light scattering detector to carry out online detection, collect successively effusive Ginkgolide A, Ginkgolide B according to the color atlas that detects, concentrating under reduced pressure, drying obtain enriched material 101.7mg Ginkgolide A and 67.82mg Ginkgolide B.In methyl alcohol and water ratio are 40: 60 system, respectively Ginkgolide A and Ginkgolide B are carried out recrystallization, at last pure product Ginkgolide A is 87.16mg, purity reaches 96.4%, Ginkgolide B is 56.93mg, purity reaches 96.2%.
It is simple that the present invention has technical process, and preparation cost is low, the high characteristics of main goods purity.
Claims (4)
1, a kind ofly prepare the medicine Ginkgolide A by Ginkgo Leaf or Ginkgo Leaf medicinal extract, the method of B, it is to be raw material with Ginkgo Leaf or Ginkgo Leaf medicinal extract, through adding ethanol, or methyl alcohol, or acetone, or butanone, or ethyl acetate organic solvent soaking extraction, leaching liquid after filtration, standing demix, the organic phase that obtains is carried out decon and is handled, the organic phase that obtains of standing demix is through concentrating again, drying obtains the enriched material of enrichment Ginkgolide A and B, adopt preparative liquid chromatography that the enriched material that contains Ginkgolide A and B is separated, aftertreatment, obtain Ginkgolide A and Ginkgolide B, it is characterized in that: when adding leaching agent, add the muriate agent of saltouing; The decon process is organic layer liquid adding sylvite or the sodium salt to leaching liquid; The moving phase of the separator column of preparative liquid chromatography is to adopt the mixed solution of ethyl acetate and sherwood oil, and stationary phase adopts silica gel.
2, by the said method for preparing medicine Ginkgolide A, B by Ginkgo Leaf or Ginkgo Leaf medicinal extract of claim 1, it is characterized in that: the muriate agent of saltouing is the aqueous solution of Repone K or calcium chloride or bariumchloride or sodium-chlor, and its add-on is 0.5～3 times of raw material weight.
3, by the said method for preparing medicine Ginkgolide A, B by Ginkgo Leaf or Ginkgo Leaf medicinal extract of claim 1, it is characterized in that: sylvite or sodium salt are the aqueous solution of sodium-acetate or Potassium ethanoate or yellow soda ash or sodium bicarbonate or salt of wormwood or saleratus, when strength of solution was 1mol/l, add-on was 0.1～7 times of organic liquor volume.
4, prepare the method for medicine Ginkgolide A, B by claim 1 is said by Ginkgo Leaf or Ginkgo Leaf medicinal extract, it is characterized in that: the optimum mixture ratio of ethyl acetate and sherwood oil is 7: 3～9: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00117758 CN1124275C (en) | 2000-06-02 | 2000-06-02 | Method of preparing ginkalide A and B as medicine from ginkgo leaf or its extract |
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| CN 00117758 CN1124275C (en) | 2000-06-02 | 2000-06-02 | Method of preparing ginkalide A and B as medicine from ginkgo leaf or its extract |
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| CN1287121A CN1287121A (en) | 2001-03-14 |
| CN1124275C true CN1124275C (en) | 2003-10-15 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2823116B1 (en) * | 2001-04-10 | 2004-11-19 | Sod Conseils Rech Applic | PROCESS FOR THE PREPARATION OF A HIGHLY ENRICHED GINKGO BILOBA LEAF EXTRACT IN ACTIVE INGREDIENTS |
| CN100413869C (en) * | 2004-05-10 | 2008-08-27 | 潘见 | Method for ligand chromatography separation purification of bilobalide |
| CN100367963C (en) * | 2005-10-28 | 2008-02-13 | 阿尔贝拉医药(中国)有限公司 | Medicinal composition containing bilobalide B and its preparation process and usage |
| CN101392000B (en) * | 2008-09-25 | 2010-12-22 | 成都普思生物科技有限公司 | High efficiency separation purification method of ginkgolide A, B, C, J and bilobalide monomer |
| CN103159780B (en) * | 2013-03-27 | 2015-10-21 | 徐州工业职业技术学院 | The method of bilobalide is extracted from Cortex Ginkgo |
| CN103588785B (en) * | 2013-11-28 | 2016-04-20 | 上海信谊百路达药业有限公司 | The process for purification of a kind of Ginkgolide A and Ginkgolide B |
| CN106234418A (en) * | 2016-08-18 | 2016-12-21 | 江苏绿洲园艺绿化有限公司 | A kind of method utilizing gingko episperm to prepare flowering cherry insecticide |
| CN107129505B (en) * | 2017-06-01 | 2019-03-29 | 陕西理工大学 | The industrial production process of lactone element monomers in a kind of ginkgo leaf purification |
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