CN102670670B - Preparation method of ginkgo dipyridolum injection with high content of ginkgo terpene lactones - Google Patents
Preparation method of ginkgo dipyridolum injection with high content of ginkgo terpene lactones Download PDFInfo
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Abstract
The invention provides a preparation method of ginkgo dipyridolum injection with high content of ginkgo terpene lactones. The preparation method comprises the following steps: 1), collecting, processing, detecting and classifying ginkgo leaves; 2), extracting and preparing ginkgo terpene lactones extract from ginkgo leaves; 3), extracting ginkgo leaf flavonoid extract; 4), reflowing ginkgo leaf flavonoid extract and partial dipyridamole by adding water, and then filtering so as to be prepared into mixed liquor; 5), mixing the mixed liquor, ginkgo terpene lactones extract, the rest dipyridamole and auxiliary material to be prepared into ginkgo dipyridolum injection as per conventional preparation method; and in the ginkgo dipyridolum injection, the content of the total ginkgo leaf flavonoid and that of the dipyridamole conform to the conventional requirements, and the content of the ginkgo terpene lactones ranges from 0.5 to 1.2 mg/mL.
Description
Technical field
The present invention relates to a kind of preparation method of injection, specifically, relate to the preparation method of the higher Ginkgo Leaf Extract and Dipyridamole Injection of a kind of ginkalide A, ginkalide B, ginkalide C and content of bilobalide.
Background technology
Folium Ginkgo and dipyridamole are the main initiation materials of producing Ginkgo Leaf Extract and Dipyridamole Injection.Wherein, the dried leaves of Semen Ginkgo leaf system Ginkgoaceae plant Ginkgo biloba Ginkgo biloba L., have blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, astringe the lung and relieving asthma, change the function of turbid blood fat reducing, clinical in diseases such as obstruction of collaterals by blood stasis, obstruction of qi in the chest and cardialgia, apoplectic hemiplegia, cough and asthma due to lung deficiency and hyperlipidemia.The complex chemical composition of Folium Ginkgo mainly comprises flavone, lactone, terpenoid, phenolic acid, macromolecule, alkaloid, polysaccharide, aminoacid, trace element etc.The chemistry of dipyridamole (Dipyridamole) by name 2,2 ', 2 ", 2 " '-[4,8-dipiperidino pyrimido [5,4-d] pyrimidine-2,6-two bases] two nitrilo-s]-tetraethoxide, be yellow crystalline powder; 163 ℃ of fusing points; Be soluble in chloroform and diluted acid, be dissolved in ethanol, be slightly soluble in acetone, water-soluble hardly; Odorless, mildly bitter flavor.Clinically, dipyridamole is used for the treatment of angina pectoris and myocardial infarction mainly as coronary dilation agent and platelet aggregation inhibitor, the recurrence of prevention myocardial infarction and angina pectoris.Ginkgo Leaf Extract and Dipyridamole Injection is a compound injection product that is prepared from by Folium Ginkgo extract and chemical synthetic drug dipyridamole.
This pharmaceutical composition has the removing interior free yl, the not effect of receptor 1 activity radical damage of protection body.Clinically, Ginkgo Leaf Extract and Dipyridamole Injection is applicable to prevention and treats coronary heart disease, thrombotic disease, plays an important role in the anxious critical illness for the treatment of field.Contained Ginkgo total flavones has dilating coronary blood vessel, cerebrovascular in the Ginkgo Leaf Extract and Dipyridamole Injection, improve symptoms of cerebral ischemia and memory function, dipyridamole energy anticoagulant, high concentration can suppress platelet and discharge, and for acute and chronic ischemic cerebrovascular preferably preventive and therapeutic action is arranged all.Report according to clinical literature, Ginkgo Leaf Extract and Dipyridamole Injection all has good therapeutical effect to the acute and chronic ischemic cerebrovascular, and can significantly improve hemorheology index, reduces blood viscosity, promoting the recovery of function of nervous system, is one of ideal medicament for the treatment of acute cerebral infarction.In addition, Ginkgo Leaf Extract and Dipyridamole Injection transfers fat in addition, improve the effect that blood flow becomes and improves blood supply of cardiac muscle, be the treatment senile patients with coronary heart disease a kind of effectively and safe drugs also can be used for treating cardiovascular and cerebrovascular disease and merge hyperlipemia and high sticky blood.
Bilobalide has anticoagulation, prevents and treats atherosclerosis, protects many pharmacological actions such as ischemia damaged tissue, shock, antiinflammatory as the extract of Folium Ginkgo; can effectively suppress the platelet aggregation that multiple derivant is induced; and bilobalide has been considered to efficient special PAF antagonist, has Platelet Activating Factor-PAF and to the protective effect of myocardial ischemia, cerebral hypoxia ischemia.
But in the existing production technology of Ginkgo Leaf Extract and Dipyridamole Injection, most of techniques are only followed the tracks of the flavones content of sample, and fail the terpene lactone composition is monitored, in the existing production technology, all be that Folium Ginkgo is extracted with ethanol or water, then absorption, eluting for example obtains ginkgo biloba succi:
CN 1939357 discloses the Folium Ginkgo extraction process: after the present invention pulverizes Folium Ginkgo, and through alcohol reflux, thickening filtration, resin absorption, the technical finesses such as ethanol elution obtain ginkgo biloba succi.
CN 101947247B discloses the Folium Ginkgo extraction process, then adopts purified water extraction.
We have tested said method, and the terpene lactone component content is very low in the ginkgo biloba succi.
Terpene lactone constituents in the Folium Ginkgo mainly contains ginkalide A, ginkalide B, ginkalide C, bilobalide J and bilobalide, this constituents is subject to the restriction of the conditions such as the medical material place of production, collecting time, processing and storage, secondly, Different Extraction Method also has considerable influence to the content of terpene lactone.Therefore, a plurality of factors and the Index Influence terpene lactone contents in the Ginkgo Leaf Extract and Dipyridamole Injection if do not add attention, with having a strong impact on the curative effect of product, is finally brought security risks for clinical application.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of Ginkgo Leaf Extract and Dipyridamole Injection of high Folium Ginkgo terpene lactones content, the method can improve the content of ginkalide A, ginkalide B, ginkalide C and bilobalide in Folium Ginkgo extract and the Ginkgo Leaf Extract and Dipyridamole Injection significantly, improves clinical efficacy and the quality stability of Ginkgo Leaf Extract and Dipyridamole Injection.
In order to realize purpose of the present invention, the preparation method of Ginkgo Leaf Extract and Dipyridamole Injection of the present invention, it comprises the steps:
1) collection of Folium Ginkgo, processing, detection and classification;
2) from Folium Ginkgo, extract Folium Ginkgo terpene lactone extract;
3) extract the Folium Ginkgo flavone extract;
4) Folium Ginkgo flavone extract and the 2 gram dipyridamoles with composition containing ginkgo total flavones 10g add the rear filtration of water backflow, make mixed liquor 1;
5) Folium Ginkgo terpene lactone extract, 2 gram dipyridamoles and the adjuvant with above-mentioned full dose mixed liquor 1, the total lactone 5g of composition containing ginkgo mixes, formulation method is made Ginkgo Leaf Extract and Dipyridamole Injection routinely, in the described Ginkgo Leaf Extract and Dipyridamole Injection, the content of Ginkgo total flavones and dipyridamole is except should meeting conventional the requirement, and the content of Semen Ginkgo terpene lactone should be 0.5～1.2mg/mL.
Above-mentioned preparation method, step 1) be specially: be that late June is to late October the collection period of Folium Ginkgo, bright leaf at source in carrying out drying below 60 ℃, is selected the total content of ginkalide A, ginkalide B, ginkalide C and bilobalide to be higher than 0.35% Folium Ginkgo and extracted.
Above-mentioned preparation method, step 2) is specially: Folium Ginkgo is put in the extraction element, added 40～80% organic solvent of 7～15 times of amount medical material weight, heating and refluxing extraction, wherein, organic solvent can be selected any one in methanol, ethanol, acetone, the acetonitrile, extracts 1～3 hour, extract altogether 1～3 time, merge extractive liquid,, decompression and solvent recovery under the low temperature, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction.Crude extract adds ethyl acetate, filters after extracting, obtain filtrate and and ethyl acetate extraction after crude extract 2.Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 80～100% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, carry out eluting with 80～100% alcoholic solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract.
Above-mentioned preparation method, step 3) is specially: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 7～15 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 1～3 hour, extract altogether 1～3 time, merge extractive liquid,, be evaporated to 1/16～1/8 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the macroporous adsorptive resins of having handled well, wherein, can select macroporous adsorbent resin AB-8, ADS-17, D101, DM130, D201, HPD417, HPD600, HPD722, HZ803, HZ806, any among the HZ841, extracting solution is after fully adsorbing, purified water washing with 8～12 times of cylinder accumulated amounts, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 0.5～2 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract.
The concentration expressed in percentage by volume that adds 8～12 times of weight in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract.
Above-mentioned preparation method, step 4) is specially: get the Folium Ginkgo flavone extract of composition containing ginkgo total flavones 10g and the purified water of 2 gram dipyridamoles and 10～15 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5～1 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2mm, filtrate is again through the following ultrafilter membrane ultrafiltration of 100,000 dalton, the filtrate autoclave sterilization, let cool, namely get and make mixed liquor 1, low tempertaure storage.
Above-mentioned preparation method, it is characterized in that, step 5) is specially: with above-mentioned full dose mixed liquor 1, the Folium Ginkgo terpene lactone extract of the total lactone 5g of composition containing ginkgo, 2 gram dipyridamole and relevant auxiliary materials, dissolve fully with water for injection, wherein, adjuvant is propylene glycol, glycerol, Tween 80, sodium pyrosulfite, vitamin C, in calcium disodium edetate or the PEG400 one or more, adjust pH are 3.5～5.5, deepfreeze is placed, filter, depyrogenation makes the injection intermediate, through after the assay was approved, use the 0.22mm filtering with microporous membrane, filtrate fill, autoclave sterilization, namely get Ginkgo Leaf Extract and Dipyridamole Injection, low tempertaure storage.
The invention has the advantages that: the preparation method of Ginkgo Leaf Extract and Dipyridamole Injection of the present invention, feed intake by preferred high lactone content Folium Ginkgo raw material, carrying the certain density organic solvent of process using extracts, then adopt organic solvent, polyamide column and alumina column to carry out enrichment, improved the extraction ratio of Semen Ginkgo Folium Ginkgo terpene lactone, technique of the present invention and CN 1939357, the disclosed Folium Ginkgo extraction process of CN 101947247B compare, and the extraction ratio of its Semen Ginkgo Folium Ginkgo terpene lactone is much higher than the latter two techniques.Its beneficial effect is seen embodiment 5.
The present invention be advantageous in that: the Folium Ginkgo terpene lactone was added in the injection in the preparation stage, can effectively avoid strong acid and strong base destruction to the lactone composition in the long-time course of processing of intermediate.
Therefore, the finished product that makes is except the stable content of total flavones and dipyridamole is controlled, the content of the Semen Ginkgo terpene lactones such as ginkalide A, ginkalide B, ginkalide C, bilobalide also reached stablize controlled, improve stability and the controllability of Ginkgo Leaf Extract and Dipyridamole Injection quality, guaranteed the effectiveness of clinical application.Its beneficial effect is seen embodiment 8.
Description of drawings
The chromatogram of Fig. 1 Semen Ginkgo terpene lactone reference substance, among the figure, the 1-bilobalide; The 2-ginkalide C; The 3-ginkalide A; The 4-bilobalide;
The chromatogram of Fig. 2 Ginkgo Leaf Extract and Dipyridamole Injection terpene lactone, among the figure, the 1-bilobalide; The 2-ginkalide C; The 3-ginkalide A; The 4-bilobalide;
The chromatogram of Fig. 3 Semen Ginkgo extrac negative sample.
The specific embodiment
By the following specific examples further illustrate the invention, but be not used for limiting the scope of the invention.
Embodiment 1
1, Folium Ginkgo raw material: Folium Ginkgo picks up from the leaf of the Ginkgoaceae plant Ginkgo biloba of artificial growth, the age of tree is generally 6～15 years, be mid-June collection period, bright leaf is at source carried out forced air drying in about 60 ℃, moisture control is below 6%, store in aeration-drying place after packaging, the total content of measuring Ginkgolides in Ginkgo biloba L. Leaves A, ginkalide B, ginkalide C and bilobalide is 0.361%, and the content of measuring total flavones is 0.897%.
2, Folium Ginkgo terpene lactone extract: Folium Ginkgo is put in the extraction element, by feed intake 10 times of weight of medical material, adding concentration is 70% alcoholic solution, and heating and refluxing extraction was extracted 2 hours, extract altogether secondary, merge extractive liquid,, decompression and solvent recovery under the low temperature, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction.Crude extract adds the ethyl acetate of 3 times of amounts of crude extract, filters after extracting, obtain filtrate and and ethyl acetate extraction after crude extract 2.Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 80% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, carry out eluting with 80% alcoholic solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract.
3, Folium Ginkgo flavone extract: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 7 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 3 hours, extract altogether 3 times, merge extractive liquid,, be evaporated to 1/16 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the HZ841 macroporous adsorptive resins of having handled well, extracting solution is after fully adsorbing, with the purified water washing of 8 times of cylinder accumulated amounts, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 0.5 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract.
The concentration expressed in percentage by volume that adds 8 times of weight in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract.
4, the preparation of Ginkgo Leaf Extract and Dipyridamole Injection:
1) prescription forms
Annotate: by Ginkgo total flavones: 10g, show the content of the before measurement Folium Ginkgo flavone extract that feeds intake, the amount that contains the Folium Ginkgo flavone extract of 10g is inventory.
By Ginkgo total lactones: 5g, show the content of the before measurement Semen Ginkgo terpenoid lactone extract that feeds intake, the amount that contains the Semen Ginkgo terpenoid lactone extract of 5g is inventory.
2) preparation technology
A: make mixed liquor 1: get the Folium Ginkgo flavone extract (by Ginkgo total flavones: 10g), add the dipyridamole of extract weight 2g and the purified water of 10 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2mm, filtrate is again through the following ultrafilter membrane ultrafiltration of 100,000 dalton, the filtrate autoclave sterilization, let cool, namely get mixed liquor 1, low tempertaure storage;
B: with above-mentioned full dose mixed liquor 1, Folium Ginkgo terpene lactone extract (by Ginkgo total lactones: 5g), 2g dipyridamole and 20g Tween 80,50g vitamin C, 1000ml propylene glycol, the water for injection 8000ml of residue dosage stir fully dissolving, adjust pH is 3.5～5.5, deepfreeze is placed, filter, filtrate is supplied 10000ml, depyrogenation, make the injection intermediate, through after the assay was approved, use the 0.22mm filtering with microporous membrane, the filtrate fill, autoclave sterilization namely gets Ginkgo Leaf Extract and Dipyridamole Injection, low tempertaure storage.
Embodiment 2
1, Folium Ginkgo raw material: with embodiment 1.
2, Folium Ginkgo terpene lactone extract: Folium Ginkgo is put in the extraction element, by feed intake 7 times of weight of medical material, adding concentration is 80% methanol solution, and heating and refluxing extraction was extracted 3 hours, extract altogether 3 times, merge extractive liquid,, decompression and solvent recovery under the low temperature, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction.Crude extract adds the ethyl acetate of 4 times of amounts of crude extract, filters after extracting, obtain filtrate and and ethyl acetate extraction after crude extract 2.Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 90% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, carry out eluting with 90% alcoholic solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract.
3, Folium Ginkgo flavone extract: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 15 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 3 hours, extract altogether 3 times, merge extractive liquid,, be evaporated to 1/8 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the AB-8 macroporous adsorptive resins of having handled well, extracting solution is after fully adsorbing, with the purified water washing of 12 volumes, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 2 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract.
The concentration expressed in percentage by volume that adds 12 amounts in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract.
4, the preparation of Ginkgo Leaf Extract and Dipyridamole Injection:
1) prescription forms
2) preparation technology
A: make mixed liquor 1: get the Folium Ginkgo flavone extract (by Ginkgo total flavones: 10g), add the dipyridamole of extract weight 2g and the purified water of 10 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2mm, filtrate is again through the following ultrafilter membrane ultrafiltration of 100,000 dalton, the filtrate autoclave sterilization, let cool, namely get mixed liquor 1, low tempertaure storage;
B: with above-mentioned full dose mixed liquor 1, Folium Ginkgo terpene lactone extract (by Ginkgo total lactones: 5g), 2g dipyridamole and 20g Tween 80,50g vitamin C, 1000ml propylene glycol, the water for injection 8000ml of residue dosage stir fully dissolving, adjust pH is 3.5～5.5, deepfreeze is placed, filter, filtrate is supplied 10000ml, depyrogenation, make the injection intermediate, through after the assay was approved, use the 0.22mm filtering with microporous membrane, the filtrate fill, autoclave sterilization namely gets Ginkgo Leaf Extract and Dipyridamole Injection, low tempertaure storage.
1, Folium Ginkgo raw material: with embodiment 1.
2, Folium Ginkgo terpene lactone extract: Folium Ginkgo is put in the extraction element, by feed intake 15 times of weight of medical material, adding concentration is 40% acetone soln, and heating and refluxing extraction was extracted 2 hours, extract altogether secondary, merge extractive liquid,, decompression and solvent recovery under the low temperature, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction.Crude extract adds the ethyl acetate of 3 times of amounts of crude extract, filters after extracting, obtain filtrate and and ethyl acetate extraction after crude extract 2.Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 100% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, with identical (specifically what?) solution carries out eluting, collects effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract.
3, Folium Ginkgo flavone extract: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 10 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 3 hours, extract altogether 3 times, merge extractive liquid,, be evaporated to 1/12 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the HPD722 macroporous adsorptive resins of having handled well, extracting solution is after fully adsorbing, with the purified water washing of 10 times of cylinder accumulated amounts, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 1 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract.
The concentration expressed in percentage by volume that adds 10 times of weight in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract.
4, the preparation of Ginkgo Leaf Extract and Dipyridamole Injection:
1) prescription forms
2) preparation technology
A: make mixed liquor 1: get the Folium Ginkgo flavone extract (by Ginkgo total flavones: 10g), add the dipyridamole of extract weight 2g and the purified water of 10 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2mm, filtrate is again through the following ultrafilter membrane ultrafiltration of 100,000 dalton, the filtrate autoclave sterilization, let cool, namely get mixed liquor 1, low tempertaure storage;
B: with above-mentioned full dose mixed liquor 1, Folium Ginkgo terpene lactone extract (by Ginkgo total lactones: 5g), 2g dipyridamole and 20g Tween 80,50g vitamin C, 1000ml propylene glycol, the water for injection 8000ml of residue dosage stir fully dissolving, adjust pH is 3.5～5.5, deepfreeze is placed, filter, filtrate is supplied 10000ml, depyrogenation, make the injection intermediate, through after the assay was approved, use the 0.22mm filtering with microporous membrane, the filtrate fill, autoclave sterilization namely gets Ginkgo Leaf Extract and Dipyridamole Injection, low tempertaure storage.
Embodiment 4
1, Folium Ginkgo raw material: with embodiment 1.
2, Folium Ginkgo terpene lactone extract: Folium Ginkgo is put in the extraction element, by feed intake 10 times of weight of medical material, adding concentration is 70% acetonitrile solution, and heating and refluxing extraction was extracted 3 hours, extract altogether secondary, merge extractive liquid,, decompression and solvent recovery under the low temperature, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction.Crude extract adds the ethyl acetate of 3 times of amounts of crude extract, filters after extracting, obtain filtrate and and ethyl acetate extraction after crude extract 2.Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 90% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, carry out eluting with 90% alcoholic solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract.
3, Folium Ginkgo flavone extract: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 7 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 3 hours, extract altogether 3 times, merge extractive liquid,, be evaporated to 1/16 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the HZ803 macroporous adsorptive resins of having handled well, extracting solution is after fully adsorbing, with the purified water washing of 8 times of cylinder accumulated amounts, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 0.5 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract.
The concentration expressed in percentage by volume that adds 8 times of weight in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract.
4, the preparation of Ginkgo Leaf Extract and Dipyridamole Injection:
1) prescription forms
A: make mixed liquor 1: get the Folium Ginkgo flavone extract (by Ginkgo total flavones: 10g), add the dipyridamole of extract weight 2g and the purified water of 10 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2mm, filtrate is again through the following ultrafilter membrane ultrafiltration of 100,000 dalton, the filtrate autoclave sterilization, let cool, namely get mixed liquor 1, low tempertaure storage;
B: with above-mentioned full dose mixed liquor 1, Folium Ginkgo terpene lactone extract (by Ginkgo total lactones: 5g), 2g dipyridamole and 20g Tween 80,50g vitamin C, 1000ml propylene glycol, the water for injection 8000ml of residue dosage stir fully dissolving, adjust pH is 3.5～5.5, deepfreeze is placed, filter, filtrate is supplied 10000ml, depyrogenation, make the injection intermediate, through after the assay was approved, use the 0.22mm filtering with microporous membrane, the filtrate fill, autoclave sterilization namely gets Ginkgo Leaf Extract and Dipyridamole Injection, low tempertaure storage.
The comparison that embodiment 5 extracts Semen Ginkgo terpene lactone technique:
Technique A
1, Folium Ginkgo raw material: with embodiment 1,1 kilogram of inventory.
2, extract Semen Ginkgo terpene lactone technique with among the embodiment 12, extract-sample A.
Technique B
1, Folium Ginkgo raw material: with embodiment 1,1 kilogram of inventory.
2, extract Semen Ginkgo terpene lactone technique with CN 1939357, with after the Folium Ginkgo pulverizing, through alcohol reflux, thickening filtration, resin absorption, the technical finesses such as ethanol elution obtain ginkgo biloba succi-sample B
Technique C
1, Folium Ginkgo raw material: with embodiment 1,1 kilogram of inventory.
2, extract the same CN101947247B of Semen Ginkgo terpene lactone technique, Folium Ginkgo pulverized after, purified water reflux, extract,, thickening filtration, resin absorption, the technical finesses such as ethanol elution obtain ginkgo biloba succi-sample C.
The assay method of Semen Ginkgo terpene lactone is seen embodiment 6.
That extracts Semen Ginkgo terpene lactone technique relatively sees the following form 1:
Table 1: the measurement result of Folium Ginkgo terpene lactones
Conclusion: as can be seen from Table 1, technique of the present invention and CN 1939357, the disclosed Folium Ginkgo extraction process of CN 101947247B compare, and the extraction ratio of its Semen Ginkgo terpene lactone is much higher than the latter two techniques.
The mensuration of embodiment 6 Semen Ginkgo terpene lactones
One, instrument, medicine, reagent
Instrument: Agilent 1200 series of high efficiency chromatograph of liquid, Altech 2000ES evaporative light scattering detector; Reference substance: bilobalide (lot number 100865-200605), ginkalide A (lot number 100862-200608), ginkalide B (lot number 100863-200508), ginkalide C (lot number 100864-200906) all are purchased from Nat'l Pharmaceutical ﹠ Biological Products Control Institute; Reagent: acetonitrile (chromatographically pure), isopropyl alcohol (chromatographically pure), water (deionized water).
Two, assay method
2.1 the preparation of reference substance solution
Get ginkalide A, ginkalide B, ginkalide C and bilobalide reference substance, precision weighing adds methanol and makes every 1ml bilobalide-containing A 0.5mg, the mixed solution of ginkalide B, C and each 0.2mg of bilobalide, and get final product.
2.2 the preparation of need testing solution
Ginkgo Leaf Extract and Dipyridamole Injection, specification is 10ml, gets lot number and be 10 samples of 20100201, break glass into pieces, in the triangular flask of impouring 250ml, mix homogeneously, precision is drawn 30ml, places the separatory funnel of 100ml, and the hydrochloric acid solution with 2% is regulated about pH to 2.0, with ethyl acetate extraction 4 (30ml, 20ml, 20ml, 20ml), the combined ethyl acetate layer with 5% sodium acetate solution 20ml washing, divides and gets sodium acetate solution, use the 10ml ethyl acetate extraction, combined ethyl acetate, with the 20ml water washing, organic facies is concentrated into dried, residue adds acetone and is transferred in the 2ml volumetric flask, and be settled to scale with acetone, shake up, filter, and get final product.
2.3 chromatographic condition
Chromatographic column: Welch C
18Chromatographic column (250 * 4.6mm, 5mm); Mobile phase: methanol-isopropanol-water (9: 7.5: 83.5); Column temperature: 30 ℃; Flow velocity: 1.0ml/min; The drift tube temperature of evaporative light scattering detector: 105 ℃, flow rate of carrier gas: 3.0L/min; Number of theoretical plate must not be lower than 3000 by bilobalide.Fig. 1, Fig. 2 and Fig. 3 are respectively the chromatogram of Semen Ginkgo terpene lactone reference substance, Ginkgo Leaf Extract and Dipyridamole Injection and Semen Ginkgo extrac negative sample.
By Fig. 1, Fig. 2 and Fig. 3 as seen: the chromatogram of Ginkgo Leaf Extract and Dipyridamole Injection sample has corresponding chromatographic peak to occur in each retention time corresponding position of terpene lactone standard substance, and the Semen Ginkgo extrac negative sample does not disturb in corresponding position, illustrates that this chromatographic condition can be used for the content of the terpene lactone of analysis Ginkgo Leaf Extract and Dipyridamole Injection.
2.4 linear relationship
Chromatogram is measured and recorded to accurate reference substance 2,4,6,8,10, the 15mL injection liquid chromatography drawn by above-mentioned chromatographic condition.Respectively take the logarithm value of the quality of bilobalide, ginkalide A, ginkalide B and ginkalide C reference substance as abscissa, take the logarithm value of peak area as vertical coordinate, the drawing standard curve.Measurement result is as follows:
Ginkalide A:
Standard curve: the y=1.4511x+6.6004r=0.9992 range of linearity: 3.12ug～11.73ug
Ginkalide B:
Standard curve: the y=1.4253x+6.5094r=0.9991 range of linearity: 3.13ug～11.76ug
Ginkalide C:
Standard curve: the y=1.4146x+6.6309r=0.9985 range of linearity: 3.09ug～11.62ug
Bilobalide:
Standard curve: y=1.958x+2.7728r=0.9993 linear range: 0.96ug～14.40ug
Three, sample determination
Get the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation, parallel three parts, with reference to the preparation method of need testing solution, process respectively, make the Ginkgo Leaf Extract and Dipyridamole Injection sample that each is measured for the Semen Ginkgo terpene lactone contents.Precision absorbs reference substance solution 10ml, 20ml respectively, need testing solution 10～20ml, difference injection liquid chromatography, measure, calculate respectively the content of ginkalide A, ginkalide B, ginkalide C and bilobalide with external standard two-point method logarithmic equation, and get final product, each measured value is added and namely gets the total content of Semen Ginkgo terpene lactone.The sample determination of Ginkgo Leaf Extract and Dipyridamole Injection embodiment 1～4 the results are shown in following table.
The assay result of table 2 Ginkgo Leaf Extract and Dipyridamole Injection terpene lactone
From upper table as seen: the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation, the content of Folium Ginkgo terpene lactones is 0.5～1.2mg/ml, substantially can control by preparation technology the content of the Folium Ginkgo terpene lactones in the preparation finished product, illustrate preparation process and product quality substantially can reach stablize controlled.
The freezing-thawing test of embodiment 7 Ginkgo Leaf Extract and Dipyridamole Injection
The Ginkgo Leaf Extract and Dipyridamole Injection that embodiment 1～3 is prepared is placed on respectively below-20 ℃ and carries out freezing-thawing test, investigate respectively appearance character, pH, Ginkgo total flavones content, Semen Ginkgo terpene lactone contents and the dipyridamole content of each Ginkgo Leaf Extract and Dipyridamole Injection, the result is as shown in table 1.
Table 3 Ginkgo Leaf Extract and Dipyridamole Injection freezing-thawing test result
According to as seen from Table 2: in the preparation process of Ginkgo Leaf Extract and Dipyridamole Injection, no matter the terpene lactone composition of Semen Ginkgo is to be added in the extracting solution after organic solvent extraction is refining, or in the preparation process, add, prepared sample is all more stable, meets the requirements of injection, and sample is after the freezing again thawing of freezing, measure each index of correlation, sample is all more stable, particulate matter do not occur, illustrates that the sample of four case study on implementation preparations all can reach the correlated quality requirement.
The stability experiment research of embodiment 8 Ginkgo Leaf Extract and Dipyridamole Injection
1. accelerated test
This test objective is by accelerating chemistry or the physical change of medicine, inquiring into the stability of medicine, for drug packaging, transportation and storage provide necessary data.Experimental technique: the Ginkgo Leaf Extract and Dipyridamole Injection sample of getting embodiment 1～4 preparation, be to place 6 months under 75% ± 5% the condition in 40 ℃ ± 2 ℃, relative humidity, take a sample respectively 0,1,2,3 and 6 the end of month, the content of outward appearance, particulate matter, pH value, Semen Ginkgo terpene lactone, total flavones and dipyridamole is investigated.Result of the test sees the following form.
Table 4 accelerated test result
According to result of the test, the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation is packaged into 10ml/ by the commercially available prod specification and props up, and places 6 months under the condition of 40 ± 2 ℃ of temperature, relative humidity 75 ± 5%.Through sample analysis, analysis result and comparison in 0 month, the content of Semen Ginkgo terpene lactone, total flavones and dipyridamole descends a little, and other every detection indexs are without significant change, and quality is basicly stable.
2. influence factor's test
2.1 hot test
Get the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation, be to place 20 days in 60 ℃ the thermostatic drying chamber in temperature, in the 0th day, the 5th day, the 10th day and sampling in the 20th day, observe the outward appearance of Ginkgo Leaf Extract and Dipyridamole Injection and the situation of change of particulate matter, measure the content of each sample pH value, Semen Ginkgo terpene lactone, total flavones and dipyridamole.The results are shown in Table 5.
Table 5 hot test result
According to result of the test, the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation is packaged into 10ml/ by the commercially available prod specification and props up, and places 20 days under the condition of 60 ± 2 ℃ of temperature.Through sample analysis, analysis result and comparison in 0 day, the content of Semen Ginkgo terpene lactone, total flavones and dipyridamole descends a little, and other every detection indexs are without significant change, and quality is basicly stable.
2.2 strong illumination test
Get the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation, be to place 20 days under the condition of 4500lx ± 5001x in illumination, in the 0th day, the 5th day, the 10th day and sampling in the 20th day, observe the outward appearance of Ginkgo Leaf Extract and Dipyridamole Injection and the situation of change of particulate matter, the content of the pH value of working sample, Semen Ginkgo terpene lactone, total flavones and dipyridamole.The results are shown in Table 6.
Table 6 strong illumination result of the test
According to result of the test, the Ginkgo Leaf Extract and Dipyridamole Injection sample of embodiment 1～4 preparation is packaged into 10ml/ by the commercially available prod specification and props up, and in illumination is to place 20 days under the condition of 4500lx ± 500lx.Through sample analysis, analysis result and comparison in 0 day, the content decrease of Semen Ginkgo terpene lactone, total flavones and dipyridamole is obvious, and other every detection indexs are without significant change.Interpret sample preferably keeps in Dark Place.
Claims (3)
1. the preparation method of a Ginkgo Leaf Extract and Dipyridamole Injection, it comprises the steps:
Step (1): the collection of Folium Ginkgo, processing, detection and classification;
Step (2): from Folium Ginkgo, extract Folium Ginkgo terpene lactone extract; Be specially: Folium Ginkgo is put in the extraction element, the organic solvent that adds 40～80 % of 7～15 times of amount medical material weight, heating and refluxing extraction, wherein, organic solvent is selected any one in methanol, ethanol, acetone, the acetonitrile, extracted 1～3 hour, extract altogether merge extractive liquid,, decompression and solvent recovery under the low temperature 1～3 time, concentrate drying, make the organic solvent crude extract of Folium Ginkgo, stay the Folium Ginkgo medicinal residues after the extraction, crude extract adds ethyl acetate, filter after extracting, obtain the crude extract 2 behind filtrate and the ethyl acetate extraction; Merging filtrate, decompression filtrate is reclaimed ethyl acetate, adds 80～100% alcoholic solution, make abundant dissolving, filter, on the filtrate in the polyamide chromatographic column of having handled well, carry out eluting with 80～100% alcoholic solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, in alumina column, carry out eluting with dehydrated alcohol on the concentrated solution, collect effluent and the eluent of bilobalide-containing, concentrating under reduced pressure, crystallization is filtered, drying namely gets Folium Ginkgo terpene lactone extract;
Step (3): extract the Folium Ginkgo flavone extract; Be specially: with the Folium Ginkgo medicinal residues behind the organic solvent extraction and the crude extract 2 behind the ethyl acetate extraction, 7～15 times the purified water that adds medicinal residues and crude extract 2 gross weights, heating and refluxing extraction, extracted 1～3 hour, extract altogether 1～3 time, merge extractive liquid,, be evaporated to 1/16～1/8 of original volume, concentrated solution is placed, precipitation, centrifugal, filter, filtrate is upward adsorbed in the macroporous adsorptive resins of having handled well, wherein, can select macroporous adsorbent resin AB-8, ADS-17, D101, DM130, D201, HPD417, HPD600, HPD722, HZ803, HZ806, any among the HZ841, extracting solution is after fully adsorbing, with the purified water washing of 8～12 times of cylinder accumulated amounts, then use ethanol elution, collect the eluent of composition containing ginkgo flavone part, be concentrated into without the alcohol flavor, then the purified water that adds 0.5～2 times of Folium Ginkgo weight, leave standstill after stirring cooling, precipitation, centrifugal, filter, with the concentrated cream of receiving of filtrate, be dried to water content below 6%, pulverize, namely get the Semen Ginkgo water extract; The concentration expressed in percentage by volume that adds 8～12 times of weight in the Folium Ginkgo water extract is the ethanol more than 90%, be stirred to dissolving, filtration, filtrate are concentrated into without the alcohol flavor, then add the purified water of 10 times of concentrated rear medicine liquid volumes, leave standstill after stirring cooling, get supernatant, the concentrated cream of receiving after centrifugalize, vacuum drying to water content below 6%, pulverize, namely get the Folium Ginkgo flavone extract;
Step (4): Folium Ginkgo flavone extract and the 2 gram dipyridamoles of composition containing ginkgo total flavones 10 g are added the rear filtration of water backflow, make mixed liquor 1;
Step (5): Folium Ginkgo terpene lactone extract, 2 gram dipyridamoles and the adjuvant of above-mentioned full dose mixed liquor 1, total lactone 5 g of composition containing ginkgo are mixed, formulation method is made Ginkgo Leaf Extract and Dipyridamole Injection routinely, in the described Ginkgo Leaf Extract and Dipyridamole Injection, the content of Ginkgo total flavones and dipyridamole is except should meeting conventional the requirement, and the content of Semen Ginkgo terpene lactone should be 0.5～1.2 mg/mL.
2. preparation method according to claim 1, it is characterized in that, step (1) is specially: be that late June is to late October the collection period of Folium Ginkgo, at source in carrying out drying below 60 ℃, the Folium Ginkgo of selecting the total content of ginkalide A, ginkalide B, ginkalide C and bilobalide to be higher than 0.35 % extracts with bright leaf.
3. preparation method according to claim 1, it is characterized in that, step (4) is specially: get the Folium Ginkgo flavone extract of composition containing ginkgo total flavones 10 g and the purified water of 2 gram dipyridamoles and 10～15 times of weight of extract weight, fully stir, mix homogeneously, adjust pH to 3.5～5.5, reflux 0.5～1 hour is cooled to room temperature, readjustment pH value to 3.5～5.5, get supernatant, with the membrane filtration of 0.2 mm, filtrate is the ultrafilter membrane ultrafiltration below 100000 dalton again, the filtrate autoclave sterilization, let cool, namely get and make mixed liquor 1, low tempertaure storage.
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Address after: 037010 the first medical zone of Datong Economic and Technological Development Zone, Shanxi Patentee after: Shanxi Powerdone Pharmaceutics Co., Ltd. Address before: 037010 Datong economic and Technological Development Zone, Shanxi Patentee before: Shanxi Powerdone Pharmaceutical Co., Ltd. |