CN101518553A - Oral medicinal preparation of ginkgo leaf total flavonoid aglycone, preparation method and an application thereof - Google Patents
Oral medicinal preparation of ginkgo leaf total flavonoid aglycone, preparation method and an application thereof Download PDFInfo
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Abstract
The invention discloses an oral preparation of ginkgo leaf total flavonoid aglycone, a preparation method and an application thereof, pertaining to the field of traditional Chinese medicine. Total flavonoid glycosides extracted from ginkgo leaves are hydrolyzed to obtain ginkgo leaf total flavonoid aglycone which is then added with special auxiliary materials for preparing a highly efficient preparation, thereby greatly increasing the bioavailability of the ginkgo leaf total flavonoid aglycone. The preparation has significant curative effects in the treatment of coronary disease, hyperpiesis, cerebral thrombosis, cerebral infarction, apoplexy, dizziness, psychosis, nephritis, bronchitis, Parkinson's disease, diabetes, tumor, leukemia and other diseases.
Description
Technical field
The present invention relates to a kind of Chinese medicine Folium Ginkgo extract, especially a kind of extract of Folium Ginkgo total flavonoid aglycone, and the medicinal usage of this extract.Belong to the field of Chinese medicines.
Background technology
Folium Ginkgo is the leaf of Ginkgoaceae Ginkgo plant Ginkgo biloba (Ginkgo biloba L.).Semen Ginkgo originates in China, is present in ground such as the Tian Mu Shan Mountain, China Zhejiang, Dabie Mountain with wild species.Because sill keeps the ecological characteristic of fourth before 1.5 hundred million years, claim " living fossil " plant again.Folium Ginkgo sweet-bitter flavor, puckery. property is flat.But Fructus Alpiniae Oxyphyllae is prolonged life, skin Caring is taken care of hair, astringe the lung relieving asthma, the astringent therapy leukorrhagia stopping.Cure mainly old age with weakness of spirit, pained, uncomfortable in chest, QI rising in reverse order is breathed with cough, leucorrhea, clear rare etc.The Folium Ginkgo flavone class has unique physiological action, clinical treatment and health care and is worth, the effect of blood vessel dilating is not only arranged, thereby increase the heart and brain blood flow, also have functions such as antiinflammatory, analgesia, defying age, blood fat reducing, antitumor, leukemia, endocrine regulation.
Have a lot relevant for the Folium Ginkgo flavone report, Geng Xiufang etc. are at " Folium Ginkgo total flavones recent research progress " (" CHINA JOURNAL OF CHINESE MATERIA MEDICA ", in June, 2003, the 28th the 6th phase of volume), Hao Difei is in " development and use of Semen Ginkgo and ginkgetin and prospect " (" Biology Teaching ", 2007 the 27th the 9th phases of volume), rowlands etc. are at " gingkgo flavonoids extraction separation and analytical method progress " (" Laiyang Agricultural College journal ", 2003 the 20th the 4th phases of volume), Qi Lixia etc. are at " comparative study of Folium Ginkgo total flavones extracting method " (" Jiangxi agricultural journal ", 2007 the 19th the 1st phases of volume) show in the research, contained flavones ingredient in the Folium Ginkgo, has the expansion blood vessel, antiinflammatory, analgesia, free radical resisting, blood fat reducing, effect such as antitumor and leukemia has a wide range of applications clinically; And also provide the multiple method for preparing Folium Ginkgo total flavones and folk prescription or compound preparation in patent publication us such as CN95118737.6, CN200510036774.0, CN200510039105.9, CN200610046070.6.As seen in technical field of Chinese medicines, the total flavonoid glycoside constituents is the focus that is studied always in the Folium Ginkgo.Simultaneously at Zhong Weifang etc. at " the orthogonal experiment research of ginkgetin alcohol glycosides hydrolysising condition " (" Heilungkiang medical science ", in October, 2006, the 29th the 5th phase of volume), the Du An congruence is at " the HPLC method of Folium Ginkgo total flavones glycosides is analyzed hydrolysising condition " (" Anhui medicine ", calendar year 2001 JIUYUE, the 5th the 3rd phase of volume), Wu is superfine at " Folium Ginkgo extract is produced the enzymolysis process research of flavone aglycone " (" food and machinery ", in November, 2005, the 21st the 6th phase of volume), the preparation method of the flavone aglycone in the Folium Ginkgo is studied among the patent CN03153489.9.As seen flavonoid glycoside in the Folium Ginkgo and aglycon thereof have become the focus of research.
But existing technology has all been ignored the research to Folium Ginkgo total flavonoid aglycone curative effect, preparation, and its effect and applicable cases are in space state always.
Summary of the invention
It is the oral drugs of active component with the Folium Ginkgo total flavonoid aglycone that first purpose of the present invention is to provide a kind of.
Second purpose provides the dosage form of this medicine, particularly a kind of high-efficiency preparation;
The 3rd purpose provides the preparation method of this medicine high-efficiency preparation.
Provide the application of this medicine in treatment coronary heart disease, hypertension, cerebral thrombosis, cerebral infarction, apoplexy, dizzy, psychosis, nephritis, bronchitis, parkinson, diabetes, tumor, leukemia at last.
The object of the invention first purpose is achieved in that
The inventor provides a kind of oral medicine, and this medicine is active component with the Folium Ginkgo total flavonoid aglycone.
The inventor finds, the glycoside material is the lower chemical compound of biological activity that produces in plant in fact, as on chemical compound, adding polar group, the aglycon of biologically active and sugar combined form the lower glycoside of physiologically active and stored, make it easier and excrete.Equally, these glycosides compounds are also lower in the intravital bioavailability of people, oral glycosides compound is difficult to absorb in intestinal, bioavailability is low, majority is metabolism and incomplete in vivo, that have even external with prototype (glycoside form) eliminating fully, have only a spot of glycosides compound after intestinal bacteria, enzyme are decomposed into aglycon, just to give play to curative effect; Non-oral glycosides compound, the glycosides that is absorbed by the body also need to be transported to liver through blood, and again by the liver sausage circulation, glycosides is hydrolyzed to aglycon is absorbed into blood again and brings into play curative effect, but because step is more, so can not bring into play curative effect rapidly.
Thereby at the medical value of Folium Ginkgo, the inventor proposes a kind of new medical substance, i.e. Folium Ginkgo total flavonoid aglycone.It is to extract from the Folium Ginkgo medical material by prior art to obtain the Folium Ginkgo total flavones glycosides, and this effective site is hydrolyzed, and makes glycoside material wherein slough glycosyl, generates to have more bioactive aglycon, promptly becomes Folium Ginkgo total flavonoid aglycone provided by the present invention.The inventor confirms that after deliberation glycoside material gained aglycon after hydrolysis has not had glycosyl, and its lipotropy strengthens greatly, thereby aglycon is absorbed than the easier intestinal mucosa that sees through of glycosides; Simultaneously, the molecule of medicine is more little also easy more to be absorbed, the glycosides hydrolysis fall with glycan molecule become aglycon after, molecular change gets littler, also can easier absorption.In addition, directly as medical substance, overcome in the past glycoside material long operational time, factor such as transformation efficiency is low, conversion results is uncertain in vivo, improved the bioavailability of medicine greatly, saved drug resource with aglycon.
In medicine provided by the invention, Folium Ginkgo total flavonoid aglycone can use separately, also can unite use with the other drug composition, that is: in active constituents of medicine, can have only the pure product of Folium Ginkgo total flavonoid aglycone, also can be the Folium Ginkgo total flavonoid aglycone crude product, can also be the mixture of Folium Ginkgo total flavonoid aglycone and other drug.The present invention preferably uses the Folium Ginkgo total flavonoid aglycone crude product, promptly extracts the Folium Ginkgo total flavones glycosides from medical material, hydrolysis in a suitable manner again, and make with extra care as required, obtain required purity.
Above-mentioned method for hydrolysis has comprised acid hydrolysis, enzyme hydrolysis or microbial hydrolysis, and the inventor is through screening, and following several concrete method for hydrolysis is provided respectively: acid hydrolysis can be hydrolyzed with hydrochloric acid, sulphuric acid, acetic acid and the formic acid etc. of 1～10mol/L; Enzyme hydrolysis can be hydrolyzed with emulsin, maltase, conversion carbohydrase, hesperidinase etc.; Microorganism can be hydrolyzed with escherichia coli, enterococcus, lactobacillus, clostridium, lopsided thalline, bifidus bacillus and human body intestinal canal normal flora etc.
Second purpose of the present invention provides the pharmaceutical preparation of above-mentioned Folium Ginkgo total flavonoid aglycone, especially a kind of high-efficiency preparation.Owing to solved the absorption problem of medicine in first purpose of the present invention,, be prepared into various conventional formulations so those skilled in the art can cooperate Folium Ginkgo total flavonoid aglycone of the present invention with suitable adjuvant easily.But the inventor is also noted that another problem, and promptly because aglycon fat-soluble stronger relatively, thereby after its preparation was applied to human body, aglycon composition wherein was difficult for wetted and stripping, if can not address this problem, also can influence the absorption of aglycon.So at this problem, the inventor provides a kind of new solution, can guarantee Folium Ginkgo total flavonoid aglycone is made high-efficiency preparation, this technical scheme is:
Scheme one: a kind of is the efficient pharmaceutical preparation of active component with Folium Ginkgo total flavonoid aglycone of the present invention, contain bio-adhesive agent and wetting agent in its adjuvant, can also contain the conventional adjuvant on dispersant and other pharmaceuticss, and oral formulations such as the sheet that is made into, capsule, granule, powder, ball.
The core of this technical scheme is Folium Ginkgo total flavonoid aglycone is used for pharmaceutical preparation, and guarantees the efficient utilization of Folium Ginkgo total flavonoid aglycone by special adjuvant.Thereby; embody in the concrete pharmaceutical preparation; can have only Folium Ginkgo total flavonoid aglycone of the present invention in its active constituents of medicine; also can be used with other medicinal or non-medical substances; as long as its objective is contained Folium Ginkgo total flavonoid aglycone is utilized bio-adhesive agent and wetting agent, can also utilize dispersant, carry out moistening, dispersion; to make oral high-efficiency preparation, all should be in the scope of the present patent application protection.In like manner, technical solution of the present invention is selected bio-adhesive agent and wetting agent for use, can also be with dispersant as main adjuvant, and purpose is to make Folium Ginkgo total flavonoid aglycone to be able to fully, to disperse uniformly, is beneficial to absorption; In actual applications; can also add other conventional adjuvants and molding adjuvant as required; as starch, little product cellulose, carboxymethylstach sodium, citric acid, sodium bicarbonate, low-substituted hydroxypropyl methylcellulose, lactose, mannitol, citric acid, Aspartane, dextrin, magnesium stearate etc.; these all should be considered as the work finished on the basis of the technology of the present invention, also should be subjected to the protection of the present patent application.
In this technical scheme, the bio-adhesive agent is preferably chitosan, carbomer, polyvinylpyrrolidone or the mixture between them; Wetting agent is preferably lecithin, poloxamer or its mixture; Dispersant is preferably micropowder silica gel, cyclodextrin or its mixture.
Wherein, chitosan, carbomer have the bio-adhesive performance as the bio-adhesive agent, but prolong drug significantly improves bioavailability of medicament in the gastrointestinal holdup time.Surfactant such as lecithin, poloxamer has the effect of moistened surface to Folium Ginkgo total flavonoid aglycone, reduces surface tension, increases the dissolubility of fat-soluble Folium Ginkgo total flavonoid aglycone, promotes it to absorb rapidly, is beneficial to rapid performance curative effect.Micropowder silica gel, cyclodextrin be as dispersant, and itself possess hydrophilic property is beneficial to moistening, the dispersion of aglycon, strengthens stability of drug.Folium Ginkgo total flavonoid aglycone of the present invention and above-mentioned adjuvant are used, and fully mix homogeneously can strengthen wherein dispersibility, the wettability of Folium Ginkgo total flavonoid aglycone, improves its bioavailability.
In the preferred case, each composition proportion is preferably active component 20～60% in the medicine of the present invention, bio-adhesive agent 1～10%, wetting agent 5～20%, dispersant 0～30%, other adjuvants 0～50%.Other adjuvants wherein are meant other adjuvants of preparation some in forming process, as: starch, microcrystalline Cellulose, carboxymethylstach sodium, citric acid, sodium bicarbonate, low-substituted hydroxypropyl methylcellulose, lactose, mannitol, citric acid, Aspartane, dextrin, magnesium stearate etc.
Technique scheme is mainly used in oral formulations, and optimum dosage form is tablet, capsule, granule, powder and pill.
Scheme two: a kind of is the efficient pharmaceutical preparation of active component with Folium Ginkgo total flavonoid aglycone of the present invention, contain dispersant and wetting agent in its adjuvant, can also contain the conventional adjuvant on bio-adhesive agent and other pharmaceuticss, and oral formulations such as the soft capsule that is made into, liquid hard capsule, drop pill.
The core of this technical scheme is Folium Ginkgo total flavonoid aglycone is used for pharmaceutical preparation, and guarantees the efficient utilization of Folium Ginkgo total flavonoid aglycone by special adjuvant.Thereby; embody in the concrete pharmaceutical preparation; can have only Folium Ginkgo total flavonoid aglycone of the present invention in its active constituents of medicine; also can be used with other medicinal or non-medical substances; as long as its objective is contained Folium Ginkgo total flavonoid aglycone is utilized dispersant and wetting agent, can also utilize the bio-adhesive agent, carry out moistening, dispersion; to make oral high-efficiency preparation, all should be in the scope of the present patent application protection.In like manner, technical solution of the present invention is selected dispersant and wetting agent for use, can also be with the bio-adhesive agent as main adjuvant, and purpose is to make Folium Ginkgo total flavonoid aglycone to be able to fully, to disperse uniformly, is beneficial to absorption; In actual applications; can also add other conventional adjuvants and molding adjuvant as required; as glycerol, glycine, citric acid, ethyl hydroxybenzoate, Cera Flava etc., these all should be considered as the work finished on the basis of the technology of the present invention, also should be subjected to the protection of the present patent application.
In this technical scheme, dispersant is preferably vegetable oil or Polyethylene Glycol; Wetting agent is preferably lecithin, poloxamer, propylene glycol or the mixture between them; The bio-adhesive agent is preferably chitosan, carbomer or its mixture.
Wherein, surfactants such as lecithin, poloxamer, propylene glycol have the effect of moistened surface to Folium Ginkgo total flavonoid aglycone, reduce surface tension, increase the dissolubility of fat-soluble Folium Ginkgo total flavonoid aglycone, promote it to absorb rapidly, be beneficial to rapid performance curative effect.Vegetable oil, Polyethylene Glycol can be uniformly dispersed Folium Ginkgo total flavonoid aglycone as dispersant.Chitosan, carbomer have the bio-adhesive performance as the bio-adhesive agent, but prolong drug significantly improves bioavailability of medicament in the gastrointestinal holdup time.Folium Ginkgo total flavonoid aglycone of the present invention and above-mentioned adjuvant are used, and fully mix homogeneously can strengthen wherein dispersibility, the wettability of Folium Ginkgo total flavonoid aglycone, improves its bioavailability.
In the preferred case, each composition proportion is preferably active component 10～40% in the medicine of the present invention, bio-adhesive agent 0～10%, wetting agent 5～20%, dispersant 50～80%, other adjuvants 0～20%.Other adjuvants wherein are meant other adjuvants of preparation some in forming process, as: glycerol, glycine, citric acid, ethyl hydroxybenzoate, Cera Flava etc.
Technique scheme is mainly used in oral formulations, and optimum dosage form is liquid hard capsule, soft capsule and drop pill.
The 3rd purpose of the present invention provides the preparation method of above-mentioned high-efficiency preparation, core technology wherein is with behind Folium Ginkgo total flavonoid aglycone and any method mix homogeneously during required adjuvant mixes by fusion, dissolving, stirring, grinding or micronizing, add required conventional formulation adjuvant again, technology is made preparation routinely.And the blended method of the preferred vibromill micronizing of the mixed method here.
Have only by effective hybrid mode, could guarantee that contained Folium Ginkgo total flavonoid aglycone and special adjuvant fully are uniformly dispersed in the extract, moistening rapidly, stripping, absorption when being applied to human body, performance is effect efficiently.Through inventor's checking, modes such as fusion, dissolving, stirring, grinding or micronizing mixing can both realize the object of the invention, and micronizing mode effect wherein are the most outstanding.
Though superfine communication technique occurs already, the application in technical field of Chinese medicines stays in the conceptive of " pulverizing " always, do not break through all the time, thereby its scope is limited to very much.The inventor finds in practice, superfine communication technique has been not only crushing technology, a kind of especially high efficient mixed technology, it can make aglycon be subjected to intensive forward extrusion power and the tangentially effect of shearing force with adjuvant, utilization at a high speed, high-energy is pulverized, mix, resulting powder medium particle diameter is reduced to below the 10 μ m by 75 original μ m, the granularity exquisiteness, evenly, surface area increases, porosity increases, drug particle is fully contacted with the adjuvant particle, mix, both improved the dispersion of drug particle, guaranteed its rapid moistening and stripping again, improved the absorbance and the bioavailability of medicine greatly, its advantage is that present conventional mixed method is incomparable.At this wherein, vibromill micronizing mode is to realize the best approach of the object of the invention.
Beneficial effect
Folium Ginkgo total flavonoid aglycone of the present invention, have effects such as expanding blood vessel, antiinflammatory, analgesia, free radical resisting, blood fat reducing, antitumor and leukemia, can be used for treating diseases such as coronary heart disease, hypertension, cerebral thrombosis, cerebral infarction, apoplexy, dizzy, psychosis, nephritis, bronchitis, parkinson, diabetes, tumor, leukemia.Cooperate high-efficiency preparation means of the present invention, more can give full play to its effect.The inventor illustrates outstanding effect of the present invention by following zoopery.
Experiment 1: the effect of Chinese People's Anti-Japanese Military and Political College's Mus venous thrombosis
1 experiment material
1.1 50 of animal Wister rats, male and female half and half, body weight 200 ± 20g.Provide by Military Medical Science Institute's Experimental Animal Center.
1.2 medicine
Folium Ginkgo 6kg is got in preparation for test agent, and coarse pulverization decocts with water three times, each 2 hours, filter merging filtrate, being evaporated to relative density is 1.10～1.15 (60 ℃), add ethanol and make and contain alcohol amount and reach 70%, left standstill 12 hours, filter, filtrate recycling ethanol, extract three times with water-saturated n-butanol, merge n-butyl alcohol liquid, reclaim n-butyl alcohol, surplus liquid adds 6 times of water gaging dissolvings, be added on the D101 macroporous adsorptive resins, respectively with water, 10% ethanol, 70% ethanol elution is collected 70% ethanol elution, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepares the Folium Ginkgo total flavones glycosides formulation; The alcoholic acid water liquid of all the other recovery of 3/4 was with 2mol/L hydrochloric acid hydrolysis 3 hours, it is an amount of that hydrolyzed solution adds calcium oxide, filter, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, 1/3 dry thing prepares the general preparation of Folium Ginkgo total flavonoid aglycone, and 2/3 dry thing prepares the Folium Ginkgo total flavonoid aglycone high-efficiency preparation in addition.
Folium Ginkgo total flavones glycosides group test sample: get the dry thing of Folium Ginkgo total flavones glycosides, add chitosan 2.5g, poloxamer 10g, cyclodextrin 40g, and add carboxymethylstach sodium to 200g, micronizing was mixed 80 minutes, and getting wherein, 60g is suspended to 100ml with water;
Folium Ginkgo total flavonoid aglycone is generally organized test sample: gets the dry thing of 1/3 Folium Ginkgo total flavonoid aglycone, adds starch to 200g, and mixing, getting wherein, 60g is suspended to 100ml with water;
Folium Ginkgo total flavonoid aglycone is efficiently organized test sample: get the dry thing of 2/3 Folium Ginkgo total flavonoid aglycone, add chitosan 5g, poloxamer 20g, cyclodextrin 80g, and add carboxymethylstach sodium to 400g, micronizing was mixed 80 minutes.Getting wherein 60g is suspended to 100ml with water and efficiently organizes as aglycon.
2 experimental techniques and result
Get 40 of Wistar rats, male and female half and half, body weight 200 ± 20g, be divided into 4 groups at random, every group 10: Folium Ginkgo total flavonoid aglycone is efficiently organized, Folium Ginkgo total flavones glycosides group, Folium Ginkgo total flavonoid aglycone are generally organized, and gastric infusion every day 1 time, dosage is respectively 10ml/kg, the blank group is irritated stomach and is given with the volume normal saline continuous 10 days.1h after the last administration, each treated animal lumbar injection 3.5% pentobarbital sodium anesthesia, the separation postcava of cutting open the belly is worn a silk thread ligation postcava pipe under left renal vein, cause congestion, closes the abdominal cavity.Behind the 6h, be that the capillary glass tube of 1mm inserts Mus angular vein clump and gets blood, reach 5cm to the capillary blood post,, check to have or not clotting strands to occur, calculate capillary tube and take a blood sample to and the blood clotting silk time occurs, be clotting time every fracture one section in capillary tube of 30s with internal diameter.Open the abdominal cavity once more, folder closes blood vessel in 2cm place, ligation below, and stringer is cut open, removal of thromboses, and the record thrombosis has or not and weighs.The results are shown in Table 1.
The thrombotic influence of table 1 pair rat vein (X ± S)
Compare (t check) with the blank group,
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Above result of the test shows that Folium Ginkgo total flavonoid aglycone high-efficiency preparation group can obviously prolong clotting time, relatively has significant difference with the blank group; Simultaneously, the general preparation group of Folium Ginkgo total flavonoid aglycone is also effective than Folium Ginkgo total flavones glycosides group.
Experiment 2: to the influence of hemorheology of rat
1 experiment material
1.1 animal
40 of Wister rats, male and female half and half, body weight 200 ± 20g.Provide by Military Medical Science Institute's Experimental Animal Center.
1.2 for test agent (with experiment 1)
1.3 instrument
LBY-N6A self-cleaning rotary viscosimeter Beijing Puli gives birth to medical apparatus and instruments science and technology company limited
2 experimental techniques and result
Get rat, be divided into 4 groups at random, 10 every group.Press the gastric infusion of dosage shown in the table 2, every day 1 time, continuous 14 days, matched group was irritated with equal-volume water every day.1h after the last administration, after each was organized rat and anaesthetizes successively with 3% pentobarbital sodium, through the ventral aorta blood sampling, anticoagulant heparin was put on LBY-N6A self-cleaning rotary viscosimeter, measures whole blood viscosity and plasma viscosity.The results are shown in Table 2.
Influence (the mpaS of table 2 pair normal hemorheology of rat; X ± SD)
Compare (t check) with the blank group,
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Above result of the test shows, efficient group of whole blood viscosity that can reduce rat of Folium Ginkgo total flavonoid aglycone is remarkable with the matched group comparing difference; Simultaneously, the general group of Folium Ginkgo total flavonoid aglycone is also effective than Folium Ginkgo total flavones glycosides group.Little to the plasma viscosity influence.
Experiment 3: the influence of xylol induced mice ear swelling
1 material
1.1 animal
Animal: Kunming mouse, male, body weight 22-24g, Mus 10-11 in age week.Provide by Military Medical Science Institute's Experimental Animal Center.
1.2 for test agent
Folium Ginkgo 6kg is got in preparation for test agent, and coarse pulverization adds 60% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, water liquid is added on the D101 macroporous adsorptive resins, with water, 20% ethanol, 70% ethanol elution, collects 70% ethanol elution respectively, decompression recycling ethanol, get 1/4 the alcoholic acid water liquid of recovery, drying under reduced pressure, dry thing prepares the Folium Ginkgo total flavones glycosides formulation; The alcoholic acid water liquid of all the other recovery of 3/4 was with 2mol/L sulphuric acid hydrolysis 4 hours, it is an amount of that hydrolyzed solution adds calcium oxide, filter, and with an amount of washing with alcohol precipitation, filter, merge water liquid and ethanol washing liquid, decompression recycling ethanol, drying under reduced pressure, 1/3 dry thing prepares the general preparation of Folium Ginkgo total flavonoid aglycone, and 2/3 dry thing prepares the Folium Ginkgo total flavonoid aglycone high-efficiency preparation in addition.
Folium Ginkgo total flavones glycosides group test sample: get the dry thing of Folium Ginkgo total flavones glycosides, add chitosan 5g, lecithin 5g, micropowder silica gel 25g, and add microcrystalline Cellulose to 200g, micronizing was mixed 50 minutes, and getting wherein, 60g is suspended to 100ml with water;
Folium Ginkgo total flavonoid aglycone is generally organized test sample: gets the dry thing of 1/3 Folium Ginkgo total flavonoid aglycone, adds starch to 200g, and mixing, getting wherein, 60g is suspended to 100ml with water;
Folium Ginkgo total flavonoid aglycone is efficiently organized test sample: get the dry thing of 2/3 Folium Ginkgo total flavonoid aglycone, add chitosan 10g, lecithin 10g, micropowder silica gel 50g, and add microcrystalline Cellulose to 400g, micronizing was mixed 50 minutes.Getting wherein 60g is suspended to 100ml with water and efficiently organizes as aglycon.
1.3 positive control drug
Dexamethasone acetate tablets, Tianjin pharmaceutcal corporation, Ltd produces
2 experimental techniques and result
Choose 50 Kunming mouses, male, body weight 22-24g in Mus 10-11 in age week, is divided into 5 groups by body weight, 10 every group at random.Press listed medicine of table 3 and dosage, gastric infusion is 1 time/day respectively, continuous 4 days.60min after the last administration, each treated animal is applied to auricle two sides, a mice left side with dimethylbenzene 50ul and causes inflammation, cuts ears after causing scorching 30min, and hammer is got ears same area auricle, weighs, and is calculated as follows swelling degree and inhibitory rate of intumesce.The results are shown in Table 3.
Swelling degree=cause inflammation pick up the ears sheet heavy-it is non-that to cause the inflammation sheet of picking up the ears heavy
Inhibitory rate of intumesce=(matched group swelling degree-administration group swelling degree)/matched group swelling degree
The influence of table 3 xylol induced mice ear swelling
Annotate: each administration group and matched group are relatively.
*P<0.05，
**P<0.01。
Above result of the test shows that Folium Ginkgo total flavonoid aglycone can reduce dimethylbenzene induced mice ear thickness for efficient group, and is remarkable with the matched group comparing difference; Simultaneously, the general group of Folium Ginkgo total flavonoid aglycone is also effective than Folium Ginkgo total flavones glycosides group.
Experiment 4: paratartaric acid antimony potassium causes the influence of mouse writhing reaction
1 material
1.1 the animal Kunming mouse is provided by Military Medical Science Institute's Experimental Animal Center.
1.2 for test agent (with experiment 3)
1.3 reagent
Antimony potassium tartrate, chemical reagent three factories in Tianjin produce.
2 methods and result
Get 40 of mices, male and female half and half, body weight 20 ± 2g, evenly be divided into 4 groups at random, promptly blank group, Folium Ginkgo total flavonoid aglycone are efficiently organized, Folium Ginkgo total flavonoid aglycone is generally organized, Folium Ginkgo total flavones glycosides group, experimental group gastric infusion dosage is 10ml/kg, blank group filling stomach gives the normal saline with volume, administration every day 1 time, successive administration 3 days, 1h after last 1 administration, the antimony potassium tartrate liquid of the new preparation of every Mus lumbar injection is observed incubation period and the interior mouse writhing generation number of 10min that writhing response appears in mice first immediately.The results are shown in Table 4.
The influence of table 4 paratartaric acid antimony potassium induced mice writhing response (X ± S)
Annotate: with blank group ratio,
*P＜0.05;
*P＜0.01.
Above result of the test shows that Folium Ginkgo total flavonoid aglycone can obviously prolong the incubation period that mice is turned round body first for efficient group, reduces the mouse writhing number of times, relatively has significant difference with the blank group; Simultaneously, the general group of Folium Ginkgo total flavonoid aglycone is also effective than Folium Ginkgo total flavones glycosides group.
Experiment 5: to the influence of MCAT rat cerebral infarction scope
1 experiment material
1.1 animal
The Wistar rat, body weight 260-300g.Provide by Military Medical Science Institute's Experimental Animal Center.
1.2 for test agent
Preparation for test agent is got Folium Ginkgo 3kg for the preparation of test agent, and coarse pulverization adds 70% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, water liquid extracts three times with water-saturated n-butanol, and n-butyl alcohol liquid evaporate to dryness is got 1/3 dry thing and prepared glycosides formulation; All the other dry things of 2/3 are dissolved in water, 115 ℃ of sterilization 20min, with lactic acid bacteria culturers hydrolysis fermentation 72 hours, hydrolyzed solution is added on the D101 macroporous adsorptive resins, with water, 30% ethanol, 80% ethanol elution, collect 80% ethanol elution, decompression recycling ethanol respectively, drying under reduced pressure, dry thing is standby.
Folium Ginkgo total flavones glycosides group test sample: get the dry thing of glycosides, add carbomer 4g, interior glycol 10g, poloxamer 5g, and add Polyethylene Glycol 400 to 200g, micronizing was mixed 80 minutes, and getting wherein, 60g is suspended to 100ml with water;
Folium Ginkgo total flavonoid aglycone is efficiently organized test sample: get the dry thing of aglycon, add carbomer 8g, propylene glycol 20g, poloxamer 10g, and add Polyethylene Glycol 400 to 400g, micronizing was mixed 80 minutes, got wherein 60g and was suspended to 100ml with water and efficiently organizes as aglycon.
1.3 reagent and instrument
FeCI
3(A.R.), lot number: 20020128, chemical plant, Gansu Province, west, the hilltop, Guangdong city
Red tetrazolium (TTC), A.R., Beijing chemical reagents corporation
The AO optical microscope, U.S.'s product;
Angry tepidarium, HH.W21.Cu600, the Shanghai medical apparatus and instruments factory of making a leapleap forward;
Electronic balance, JUPITER S2 160A type, Japan produces.
2 experimental techniques
2.1 grouping and administration
Get 40 of Wistar rats, be divided into 4 groups (they being sham operated rats, MCAT model group, Folium Ginkgo total flavonoid aglycone group, Folium Ginkgo total flavones glycosides group), and 10 every group, male and female half and half.Experimental group gastric infusion dosage is 10ml/kg, and sham operated rats, MCAT model group filling stomach give the normal saline with volume, administration every day 1 time, successive administration 5 days.Modeling, modeling success back experimental group gastric infusion dosage is 10ml/kg, and sham operated rats, MCAT model group filling stomach give the normal saline with volume, administration every day 1 time, successive administration 5 days.
2.2 experimental technique
Rats by intraperitoneal injection 3% amobarbital 0.1ml/100g anesthesia.Press the Tamura method, improve a little.The rat right arm reclining is fixed, make a curved incision at paropia and auditory meatus line mid point, be about 1.5cm, pinch off temporalis and excision, expose temporal bone, make a diameter 2.5mm bone window at cheekbone and temporal bone joint near oral-lateral 1mm place with dental burr, the cleaning residue exposes middle cerebral artery (between tractus olfactorius and inferior cerebral vein).Put small pieces plastic sheeting protection blood vessel surrounding tissue.Have the small pieces quantitative filter paper of 50% liquor ferri trichloridi, 10 μ l to apply on this section middle cerebral artery suction, take off filter paper behind the 30min, use the normal saline flushing local organization, layer-by-layer suture steams again and raises.The sham operated rats rat is except that not dripping the liquor ferri trichloridi the same model group of all the other operating procedures.
2.3 the cerebral infarction scope is measured
Last administration is after 12 hours, and broken end is got brain.Remove olfactory bulb, cerebellum and low brain stem, remainder is cut into 5 crown below 4 ℃.(every 5ml dyestuff contains 4% TTC 1.5ml, 1M K rapidly the brain sheet to be placed the TTC dye liquor
2HPO
40.1ml), 37 ℃ of lucifuge temperature are incubated 30min, take out again, place formaldehyde to keep in Dark Place.The non-ischemic region in dyed back is the rare redness of Min, and infarct is a white.White organized carefully to dig down weigh, the percentage ratio that accounts for total brain weight with blocking tissue's weight is as the cerebral infarction scope.
3 experimental results
Relatively, the t check the results are shown in Table 5 to result of the test between organizing.
The influence of table 5 pair MCAT rat cerebral tissue infarction size (X ± SD)
Compare with model group,
*P＜0.05,
*P＜0.01.
The result shows that except that the sham operated rats no abnormality seen changed, thrombus model group rat and each administration group rat all had focus of infarct in various degree.The Folium Ginkgo total flavonoid aglycone group all can obviously reduce the infraction degree, and relatively there were significant differences with model group, effective than Folium Ginkgo total flavones glycosides group.
The specific embodiment
Enumerate embodiment below, further specify the present invention, each embodiment only is used to illustrate the present invention, does not limit the present invention:
Embodiment 1
Get Folium Ginkgo total flavonoid aglycone 100g, add chitosan 20g, polyvinylpyrrolidone 20g, carbomer 10g, poloxamer 50g, lecithin 50g, micropowder silica gel 50g, betacyclodextrin 100g, starch 100g, the vibromill micronizing was mixed 30 minutes, and powder is made in packing.
Embodiment 2
Get Folium Ginkgo total flavonoid aglycone 70g, Radix Puerariae Lobatae total flavonoid glycoside 10g, add chitosan 5g, carbomer 5g, poloxamer 14g, lecithin 10g, micropowder silica gel 10g, betacyclodextrin 20g, carboxymethylstach sodium 6g, microcrystalline Cellulose 50g, the weight formula was ground ultra micro machine micronizing 30 minutes, added 70% ethanol and closed and stick together 10 minutes, pill bar, gradation and round, dry, polishing, pill is made in packing.
Embodiment 3
Get Folium Ginkgo total flavonoid aglycone 80g, Folium Ginkgo total lactones 40g, add chitosan 2g, lecithin 10g, add dextrin 66g, Aspartane 2g again, stir, dry-pressing is granulated, and granule is made in packing.
Embodiment 4
Get Folium Ginkgo total flavonoid aglycone 60g, add chitosan 10g, polyvinylpyrrolidone 2g, poloxamer 8g, betacyclodextrin 20g, starch 100g, the mix homogeneously that sieves is granulated, and the dress enteric coated capsule is made capsule.
Embodiment 5
Get Folium Ginkgo total flavonoid aglycone 80g, Radix Paeoniae Rubra total glycosides 20g, add polyvinylpyrrolidone 10g, poloxamer 20g, lecithin 10g, micropowder silica gel 10g, betacyclodextrin 50g, the vibromill micronizing was mixed 50 minutes, granulate, and tabletting, coating is made tablet.
Embodiment 6
Get Folium Ginkgo total flavonoid aglycone 20g, add propylene glycol 10g, poloxamer 10g, lecithin 20g, chitosan 10g, carbomer 10g, add the 120g PEG400, vibromill micronizing 20 minutes makes mix homogeneously, makes liquid hard capsule, promptly.
Embodiment 7
Get Folium Ginkgo total flavonoid aglycone 30g, add lecithin 10g, glycine 10g, glycerol 30g adds the 120g Macrogol 600 again, and vibromill ultra micro 30 minutes makes mix homogeneously, is pressed into soft capsule, promptly.
Embodiment 8
Get Folium Ginkgo total flavonoid aglycone 50g, add chitosan 10g, lecithin 20g, poloxamer 4g, ethyl hydroxybenzoate 1g, Cera Flava 5g, and add soybean oil 110g, and stirring, the mixing that sieves is pressed into soft capsule, promptly.
Embodiment 9
Get 50g polyethylene glycol 6000 and 50g Macrogol 4000, add Folium Ginkgo total flavonoid aglycone 80g, propylene glycol 10g, glycerol 10g, vibromill ultra micro 50 minutes makes mix homogeneously, drips and makes drop pill, promptly.
Embodiment 10
Get Folium Ginkgo total flavonoid aglycone 100g, lecithin 25g, ethyl hydroxybenzoate 2.5g, Cera Flava 47.5g, and add soybean oil 325g, vibromill ultra micro 40 minutes makes mix homogeneously, is pressed into soft capsule, makes 1000, promptly.
Embodiment 11
Get Folium Ginkgo 2kg, coarse pulverization decocts with water three times, each 2 hours, filter merging filtrate, being evaporated to relative density is the clear paste of 1.10～1.15 (60 ℃), adds ethanol, makes to contain the alcohol amount and reach 70%, left standstill 12 hours, filter, decompression filtrate recycling ethanol, water liquid are added on the D101 macroporous adsorptive resins, respectively with water, 20% ethanol, 70% ethanol elution, collect 70% ethanol elution, decompression recycling ethanol, surplus water liquid add sulphuric acid makes acid content reach 2mol/L, heating hydrolysis 3 hours, put coldly, filter, residue with water washing near neutral, drying under reduced pressure, obtain Folium Ginkgo total flavonoid aglycone 160g (contain the Folium Ginkgo total-flavonoid aglycone more than 30%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add carbomer 15g, chitosan 5g, lecithin 10g, poloxamer 10g, propylene glycol 30g, and adding 450g Macrogol 600, vibromill ultra micro 80 minutes makes mix homogeneously, makes liquid hard capsule, make 1000, promptly.
Embodiment 12
Get Folium Ginkgo 4kg, pulverize, add 60% alcohol reflux three times, each 1.5 hours, filter, filtrate recycling ethanol, surplus water liquid is added on the D101 macroporous adsorptive resins, the difference water, 70% ethanol elution, collect 70% ethanol elution, reclaim ethanol, surplus water liquid adds hydrochloric acid makes acid content reach 2mol/L, heating hydrolysis 4 hours, hydro-oxidation sodium is regulated pH to neutral, is added on the D101 macroporous adsorptive resins, respectively water, 20% ethanol, 80% ethanol elution, collect 80% ethanol elution, reclaim ethanol, drying under reduced pressure obtains Folium Ginkgo total flavonoid aglycone 150g and (contains the Folium Ginkgo total-flavonoid aglycone more than 60%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add propylene glycol 30g, glycerol 10g, ethyl hydroxybenzoate 1g, and add 200g PEG400, stirring and evenly mixing, be pressed into soft capsule, promptly.
Embodiment 13
Get Folium Ginkgo 3kg, coarse pulverization decocts with water three times, each 2 hours, filter, merging filtrate, being evaporated to relative density is the clear paste of 1.10～1.15 (60 ℃), adds ethanol, make and contain alcohol amount and reach 60%, left standstill 12 hours, and filtered decompression filtrate recycling ethanol, water liquid extracts three times with water-saturated n-butanol, n-butyl alcohol liquid evaporate to dryness, dry thing is dissolved in water, 115 ℃ of sterilization 20min, with bifidus bacillus strain fermentation hydrolysis 72 hours, concentrating under reduced pressure, drying under reduced pressure obtains Folium Ginkgo total flavonoid aglycone 112g and (contains the Folium Ginkgo total-flavonoid aglycone more than 40%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add the 100g polyethylene glycol 6000, the 250g Macrogol 4000, Folium Ginkgo total lactones 20g, carbomer 5g, propylene glycol 40g, lecithin 5g, poloxamer 5g, vibromill ultra micro 35 minutes, heating and melting, make mix homogeneously, drip and make drop pill, promptly.
Embodiment 14
Get Folium Ginkgo medical material 2.5kg, pulverize, add 10 times of water gagings and decoct 3 times, each 1 hour, filter, merging filtrate concentrates, 70% ethanol precipitation, reclaim ethanol, n-butyl alcohol liquid is reclaimed in n-butanol extraction 3 times of water liquid, 115 ℃ of sterilizations of surplus water liquid 15-20min, the escherichia coli strain is mixed with every milliliter with sterilized water and contains 10
8Individual conidial suspension is that the ratio of 3-10% inserts culture medium with the form of spore suspension in V/W,, shakes incubation time 72-96h under the condition of shaking speed 140-220rpm in 26-30 ℃; After stopping fermentation, filter, filter cake is measured 80% alcohol reflux 2 times with 5 times, and each 30 minutes, merging filtrate, decompression recycling ethanol, surplus water liquid is crossed the D101 macroporous resin column, respectively water, 70% ethanol elution is collected 70% ethanol elution, reclaim ethanol, concentrate, drying obtains Folium Ginkgo total flavonoid aglycone 91g and (contains the Folium Ginkgo total-flavonoid aglycone more than 55%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add carbomer 5g, lecithin 25g, betacyclodextrin 25g, starch 105g, the vibromill micronizing was mixed 20 minutes, granulated, encapsulated, make capsule.
Embodiment 15
Get Folium Ginkgo medical material 5kg, coarse pulverization adds 70% alcohol reflux three times, each 1.5 hours, filter merging filtrate, decompression recycling ethanol, surplus water liquid merge n-butyl alcohol liquid with n-butanol extraction three times, water bath method, residue are added on the D101 macroporous adsorptive resins with water dissolution, earlier with water, 30% ethanol elution discards eluent, again with 70% ethanol elution, eluent reclaims ethanol, surplus liquid adds hydrochloric acid makes acid content reach 1mol/L, and hydrolysis 3 hours is put cold, with in the sodium hydroxide and remaining acid, drying, dry thing alcohol reflux, gained ethanol liquid reclaims ethanol, dry, obtain Folium Ginkgo total flavonoid aglycone 128g (contain the Folium Ginkgo total-flavonoid aglycone more than 65%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 25g, poloxamer 45g, micropowder silica gel 30g, betacyclodextrin 30g, carboxymethylstach sodium 10g, the vibromill micronizing was mixed 80 minutes, granulate tabletting, coating, make 1000, promptly.
Embodiment 16
Get Folium Ginkgo medical material 3kg, pulverize, add 60% alcohol reflux 3 times, each 1 hour, filter merging filtrate, reclaim ethanol, surplus water liquid is crossed the D101 macroporous resin column, respectively water, 65% ethanol elution is collected 65% ethanol elution, reclaim ethanol, water liquid adds hydrochloric acid 300ml, heating hydrolysis 4 hours, the neutralization of hydrolyzed solution hydro-oxidation sodium, cross the AB-8 macroporous resin column, the difference water, 65% ethanol elution is collected 65% ethanol elution, reclaims ethanol, spray drying, obtain Folium Ginkgo total flavonoid aglycone 70g (contain the Folium Ginkgo total-flavonoid aglycone more than 70%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add Radix Puerariae Lobatae total flavonoid glycoside 20g, chitosan 5g, carbomer 5g, poloxamer 5g, lecithin 15g, starch 50g, the vibromill micronizing was mixed 40 minutes, granulate, encapsulated, make capsule.
Embodiment 17
Get Folium Ginkgo medical material 3.5kg, pulverize, adding 70% ethanol percolation extracts, percolate, reclaim ethanol, water liquid adds 0.5% activated carbon decolorizing, filters, filtrate is crossed the D101 macroporous resin column, the difference water, 20% ethanol, 60% ethanol elution is collected 60% ethanol elution, reclaims ethanol, use the maltoside enzyme, amygdaloside enzyme hydrolysis 24 hours, hydrolyzed solution is crossed the D101 macroporous resin column, respectively water, 70% ethanol elution is collected 70% ethanol elution, reclaim ethanol, drying obtains Folium Ginkgo total flavonoid aglycone 101g (contain the Folium Ginkgo total-flavonoid aglycone more than 60%, all the other are unhydrolysed glycosides and the not secondary completely glycosides of hydrolysis and other by-products), add chitosan 5g, polyvinylpyrrolidone 10g, carbomer 5g, poloxamer 15g, lecithin 15g, starch 150g, carboxymethylstach sodium 5g, the vibromill micronizing was mixed 40 minutes, granulated tabletting, enteric coated, make tablet.
Embodiment 18
Get embodiment 13 made drop pill and treat 32 routine coronary atherosclerotic heart disease patients.Therapeutic scheme: every day 3 times, each 0.5g, logotype 3 months, effective percentage 69%.Subjective symptoms as uncomfortable in chest, cardiopalmus, angina pectoris and electrocardiogram etc., all has improvement in various degree.
Embodiment 19
Get embodiment 12 made soft capsules and treat 28 routine chronic bronchitis patients.Therapeutic scheme: every day 3 times, each 2, logotype 1 month, effective percentage 71%.
Embodiment 20
Get the incomplete comprehensive patient of embodiment 3 made granule therapy 36 routine brain functions.Therapeutic scheme: every day 2 times, each 5g.12 weeks of logotype.Have 25 examples (69%) significantly to improve according to doctor's evaluation, the conscious improver of patient has 30 examples (83%).
Claims (18)
1, a kind of is the oral drugs of active component with the Folium Ginkgo total flavonoid aglycone.
2, medicine according to claim 1 is characterized in that can having only Folium Ginkgo total flavonoid aglycone in the described active component, also can be that Folium Ginkgo total flavonoid aglycone and other drug composition are united use.
3, medicine according to claim 2 is characterized in that described Folium Ginkgo total flavonoid aglycone obtains by hydrolysis Folium Ginkgo total flavones glycosides.
4, medicine according to claim 3 is characterized in that method for hydrolysis is acid hydrolysis, enzyme hydrolysis or microbial hydrolysis.
5, according to each described medicine in the claim 1 to 4, it is characterized in that acceptable auxiliary is used on active constituents of medicine and the pharmaceutics.
6, medicine according to claim 5 is characterized in that containing in the adjuvant bio-adhesive agent and wetting agent.
7, medicine according to claim 6 is characterized in that also can containing dispersant in the adjuvant.
8, medicine according to claim 7 is characterized in that bio-adhesive agent in the adjuvant is meant any or the compositions more than two kinds in chitosan, carbomer, the polyvinylpyrrolidone; Wetting agent is meant lecithin and/or poloxamer; Dispersant is meant micropowder silica gel and/or cyclodextrin.
9, medicine according to claim 8 is characterized in that the proportion of composing of active constituents of medicine and adjuvant is:
Active component 20～60%,
Bio-adhesive agent 1～10%,
Wetting agent 5～20%,
Dispersant 0～30%,
Other adjuvants 0～50%.
10, medicine according to claim 9 is characterized in that being made into tablet, capsule, granule or pill.
11, medicine according to claim 5 is characterized in that containing in the adjuvant wetting agent and dispersant.
12, medicine according to claim 11 is characterized in that also can containing the bio-adhesive agent in the adjuvant.
13, medicine according to claim 12 is characterized in that wetting agent in the adjuvant is meant any or the compositions more than two kinds in propylene glycol, lecithin, the poloxamer; Dispersant is meant Polyethylene Glycol or vegetable oil; The bio-adhesive agent is meant chitosan and/or carbomer.
14, medicine according to claim 13 is characterized in that the proportion of composing of active constituents of medicine and adjuvant is:
Active component 10～40%,
Bio-adhesive agent 0～10%,
Wetting agent 5～20%,
Dispersant 50～80%,
Other adjuvants 0～20%.
15, medicine according to claim 14 is characterized in that being made into soft capsule, liquid hard capsule or drop pill.
16, the method for preparing each described medicine in the claim 6 to 15, it is characterized in that behind active constituents of medicine and any method mix homogeneously during required adjuvant mixes by fusion, dissolving, stirring, grinding or micronizing, add required conventional formulation adjuvant again, technology is made preparation routinely.
17, preparation method according to claim 16 is characterized in that active constituents of medicine is mixed by the vibromill superfine grinding method with required adjuvant.
18, each described medicine is used for the treatment of application in coronary heart disease, hypertension, cerebral thrombosis, cerebral infarction, apoplexy, dizzy, psychosis, nephritis, bronchitis, parkinson, diabetes, tumor or the leukemic medicine in preparation in the claim 1 to 4.
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| CN101780030A (en) * | 2010-03-09 | 2010-07-21 | 贵州大学 | Ginkgo flavone aglycone solid dispersion and preparation method thereof |
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| CN101780030A (en) * | 2010-03-09 | 2010-07-21 | 贵州大学 | Ginkgo flavone aglycone solid dispersion and preparation method thereof |
| CN104138601A (en) * | 2014-07-21 | 2014-11-12 | 江苏天晟药业有限公司 | Oral puerarin compound and preparing method thereof |
| CN107693577A (en) * | 2017-11-06 | 2018-02-16 | 威海松龄诺可佳中药饮片股份有限公司 | A kind of composition of plant extracts and its preparation method and application |
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| CN110522772B (en) * | 2019-09-09 | 2021-11-30 | 江苏飞马药业有限公司 | Ginkgo leaf composition and preparation method thereof |
| CN114410550A (en) * | 2022-03-15 | 2022-04-29 | 中南大学 | Microbial functional flora for increasing flavonoid glycoside content in ginkgo leaves and preparation and application thereof |
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