CN1813782B - Composition of ginkgo leaf extract and dipyridamole, medicine containing same and preparing method thereof - Google Patents
Composition of ginkgo leaf extract and dipyridamole, medicine containing same and preparing method thereof Download PDFInfo
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- CN1813782B CN1813782B CN 200510125674 CN200510125674A CN1813782B CN 1813782 B CN1813782 B CN 1813782B CN 200510125674 CN200510125674 CN 200510125674 CN 200510125674 A CN200510125674 A CN 200510125674A CN 1813782 B CN1813782 B CN 1813782B
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Abstract
The present invention discloses a new ginkgodamole composition, medicine composition prepared hy using it, in particular, injection and their preparation method. Said ginkgodamole composition mainly contains the following components: (by wt%) 18-65% of ginkgo total flavone glycoside, 6-32% of dipyridamole, 4-25% of ginkgo total lactone and the heavy metal content is less than 9.4 ppm (weight), in which the ginkgo total lactone is formed from bilobalide, ginkgolide A, ginkgolide B and ginkgolide C according to the weight ratio of 4-40:7-40:3-30:3-40. Said medicine preparation, specially injection have obvious therapeutic effect for curing angiocardiopathy and cerebrovascular diseases.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation method thereof, relate in particular to a kind of ginkgo bilobate extract compositions that contains Ginkgo total flavones alcohol glycosides, dipyridamole, Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C), by this pharmaceutical composition prepared preparation and preparation method thereof, belong to the field of Chinese medicines.
Background technology
Folium Ginkgo has the cardiovascular and cerebrovascular circulation of improvement, and memory is provided, and removes oxygen-derived free radicals, function in delaying senility, the double effects that has treatment and keep healthy.Injection by the Folium Ginkgo preparation uses for many years in clinical, has obtained good effect.Its main active is Ginkgo total flavones alcohol glycosides and Ginkgo total lactones, Ginkgo total lactones mainly comprises ginkalide A, B, C, M and J and bilobalide etc., active in the highest with ginkalide B in ginkalide A, B and C, ginkalide A has synergism with it.And YINXINGYE ZHUSHEYE of the prior art is only controlled the content of Ginkgo total flavones, do not control the wherein content of bilobalide, especially do not control the ratio of bilobalide, ginkalide A, B and C, and the ratio of they and total flavonoids, therefore when the treatment disease, be difficult to obtain gratifying curative effect.In addition, in recent years, the also listing successively of compound preparation that Folium Ginkgo extract and dipyridamole are prepared into, for example CN1454596A discloses a kind of Folium Ginkgo extract and dipyridamole compound recipe intravenous drip liquid, contain 4 to 30 milligrams of Ginkgo total flavones in wherein per 50 to 500 milliliters of intravenous drip liquids, 1.5 to 15 milligrams of dipyridamoles, because bilobalide and total flavonoids content are not high in this intravenous drip liquid, and do not control the ratio between each composition of bilobalide, so this compound preparation is difficult to obtain gratifying curative effect, using value is not high clinically.Same problem also is present in the lyophilized injectable powder of disclosed Folium Ginkgo extract of CN1176656C and dipyridamole, because active constituent content is relatively low, be difficult to obtain gratifying curative effect too, and impurity (ginkgoic acid, heavy metal etc.) equal size is not effectively controlled in the said preparation, gained pharmaceutical preparation safety and stability are all relatively poor, because impurity content is higher, toxic and side effects is bigger, and untoward reaction such as allergy, injection pain take place during injection easily.
Therefore, need always to prepare that curative effect is higher, stability and safety be better, the Semen Ginkgo dipyridamole compound preparation that toxic and side effects is little.
Summary of the invention
The inventor is through further investigation, final bilobalide, ginkalide A, ginkalide B, the ginkalide C of different proportion found has different effects when the treatment disease, especially after they and Ginkgo total flavones alcohol glycosides is mixed with compositions in varing proportions, has visibly different therapeutic effect, and the compositions of finding some special ratios has and makes us unexpected outstanding beneficial effect, not only can improve therapeutic effect greatly, and its toxic and side effects also has significant reduction, finished the present invention on the basis of this discovery.
First technical problem to be solved by this invention is to overcome the deficiencies in the prior art, a kind of new ginkgo bilobate extract compositions is provided, this ginkgo bilobate extract compositions is Ginkgo total flavones alcohol glycosides content of material height not only, and the content of dipyridamole, Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) is also high.
First technical problem to be solved by this invention realizes by following technological approaches:
A kind of ginkgo bilobate extract compositions contains each component of following percentage by weight: Ginkgo total flavones alcohol glycosides 18～65%, dipyridamole 6～32%, Ginkgo total lactones 4～25% in the said composition; Wherein, described Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 4～40: 7～40: 3～30: 3～40 part by weight is formed; The content of beary metal of said composition is lower than 9.4ppm.
Preferably, the percentage by weight of each component is: Ginkgo total flavones alcohol glycosides 20～40%, dipyridamole 8～18%, Ginkgo total lactones 7～20%; Wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 8～40: 7～30: 4～20: 5～28 part by weight is formed.
Further preferred, the percentage by weight of each component is: Ginkgo total flavones alcohol glycosides 22～36%, dipyridamole 9～16%, Ginkgo total lactones 8～18%.
Further preferred again, the percentage by weight of each component is: Ginkgo total flavones alcohol glycosides 24～32%, dipyridamole 10～15%, Ginkgo total lactones 8～13%, wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 10～40: 7～25: 4～18: 5～26 part by weight is formed.
Preferred, the percentage by weight of each component is: Ginkgo total flavones alcohol glycosides 26～32%, dipyridamole 10～12%, Ginkgo total lactones 8～12%, wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 10～35: 10～20: 4～15: 5～25 part by weight is formed.
Most preferred, the percentage by weight of each component is: Ginkgo total flavones alcohol glycosides 28～32%, dipyridamole 10～12%, Ginkgo total lactones 8～12%; Wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 20～32: 12～20: 4～10: 6～24 part by weight is formed.
In addition, impurity separating Ginkgo phenolic acids material (for example ginkgoic acid), protein, tannin, heat source substance equal size are lower than 20ppm in the present composition, its curative effect has unexpected significant raising than existing Folium Ginkgo extract and ginkgo bilobate extract compound preparation, and since the content of controlling content of beary metal wherein and other impurity (ginkgoic acid, protein etc.) in ppm level level, the stability and the safety of the present composition improve greatly, during injection injection pain and anaphylaxis can not take place, be convenient to clinical use, therefore finished the present invention.
Total flavonoids among the present invention mainly is meant the Quercetin glycosides, Rhizoma Kaempferiae phenolic glycoside and isorhamnetin glycosides, and its assay method carries out according to the high performance liquid chromatography of Chinese Pharmacopoeia version in 2000.Equally, the content of bilobalide also is to carry out according to the high performance liquid chromatography of Chinese Pharmacopoeia version in 2000.Ginkgo total lactones among the present invention also is Semen Ginkgo terpene lactone or bilobalide, the total terpene lactone of Semen Ginkgo.
Second technical problem to be solved by this invention provides the above-mentioned ginkgo bilobate extract method for compositions of a kind of preparation.
Second technical problem to be solved by this invention realizes by following technological approaches:
The above-mentioned ginkgo bilobate extract method for compositions of a kind of preparation comprises: take by weighing each component according to following percentage by weight: Ginkgo total flavones alcohol glycosides 18～65%, dipyridamole 6～32%, Ginkgo total lactones 4～25%; Wherein, described Ginkgo total lactones is by bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10) and ginkalide C (C
20H
24O
11) according to 4～40: 7～40: 3～30: 3～40 part by weight is formed; With above-mentioned each component mix homogeneously promptly.
Each component in the compositions can commercially availablely obtain, and also can prepare by known method.Can after fully being mixed by said ratio, each commercially available component prepare described compositions.When prepare each component with known method; during especially from Folium Ginkgo extraction Ginkgo total flavones alcohol glycosides and bilobalide; in the Semen Ginkgo extrac except that ginkgetin alcohol glycosides that contains aforementioned proportion and bilobalide; also may contain other effective ingredient that extraction obtains from Semen Ginkgo; glycosides million for example; kaempferol etc.; these effective ingredient can not influence effect of the present invention; at this moment in the compositions owing to also contain other composition; therefore the content sum of above-mentioned three kinds of compositions is lower than 100%, but these compositionss are also in protection scope of the present invention.
The preparation method of relevant Folium Ginkgo extract can be carried out in the first to file disclosed method according to the inventor, is that disclosed method prepares Ginkgo total flavones alcohol glycosides, bilobalide (C among the CN1193753C according to publication number for example
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) etc.Also can prepare the Folium Ginkgo extract that contains Ginkgo total flavones alcohol glycosides and Ginkgo total lactones by following method, then with Folium Ginkgo extract with obtain described ginkgo bilobate extract compositions after dipyridamole mixes.
As a reference, above-mentioned Folium Ginkgo extract can be prepared from accordance with the following methods:
1) after, Folium Ginkgo is pulverized, add 60～95% alcohol reflux 1-5 time, each reflux extracting time 1-3 hour, the 5-10 that each amount of alcohol that adds is a Folium Ginkgo weight doubly, filtration is concentrated into 0.3～0.8 times of Folium Ginkgo weight, cold preservation 3～24 hours with filtrate;
2), scrape off oil slick, with the oil slick that scrapes, add 0.03～0.1 times water for injection of Folium Ginkgo weight, agitator treating 1～5 time at every turn, after cleaning mixture and concentrated solution merging, add injection water 1～3 times to Folium Ginkgo weight, cold preservation 16～84 hours is filtered, filtrate decompression is concentrated into 0.2～0.5 times of Folium Ginkgo weight, put to room temperature, add 85%～95% ethanol, make to contain alcohol to 80%;
3), the solution behind the precipitate with ethanol is carried out successively cold preservation, filtration and concentrate and repeat 1～5 time;
4), the filtrate after concentrating is with cationic resin absorption 2～8 times, control pH value to 1～3, reuse resin anion (R.A.) absorption 1～5 time, control pH value to 2～5, adsorption liquid is filtered and is evaporated to Folium Ginkgo weight 0.2～0.5 times, put to room temperature, adding 85%～95% ethanol makes and contains alcohol amount to 80%～84%, cold preservation 16～84 hours, the filtration decompression recycling ethanol is concentrated into 0.1～0.5 times of Folium Ginkgo weight, puts to room temperature, adds water to 0.6～2 times of Folium Ginkgo weight, cold preservation 16-48 hour, filter standby;
5), separate water layer and organic layer, organic layer reclaims solvent, water layer promptly gets Folium Ginkgo extract after concentrating.
The 3rd technical problem to be solved by this invention provides a kind of ginkgo bilobate extract pharmaceutical composition.
The 3rd technical problem to be solved by this invention realizes by following technological approaches:
A kind of ginkgo bilobate extract pharmaceutical composition, form by above-mentioned ginkgo bilobate extract compositions and pharmaceutical carrier or diluent, total flavonoids (the preferred 20-40% that contains (by weight) 18～65% in this pharmaceutical composition, more preferably 22～36%, further preferred 26～32%, most preferably 28～32%), 6～32% dipyridamole (preferred 8～18%, more preferably 9～16%, further preferred 10～15%, most preferably 10～12%), 4～25% Ginkgo total lactones (preferred 7～20%, more preferably 8～18%, further preferred 8～13%, most preferably 8～12%), and Ginkgo total lactones is by the bilobalide of following weight ratio, ginkalide A, ginkalide B and ginkalide C are formed: 4～40: 7～40: 3～30: 3～40 (preferred 8～40: 7～30: 4～20: 5～28, more preferably 10～40: 7～25: 4～18: 5～26, further preferred 10～35: 10～20: 4～15: 5～25, most preferably 20～32: 12～20: 4～10: 6～24), surplus is pharmaceutical carrier or diluent; Content of beary metal is lower than 9.4ppm in this pharmaceutical composition.
Above-mentioned ginkgo bilobate extract pharmaceutical composition can be preferably injection for injection, lyophilized injectable powder, infusion solutions, tablet, capsule, granule, drink form.
Pharmaceutical carrier in the aforementioned pharmaceutical compositions or diluent can be as required from the Chinese Pharmacopoeia regulation can be medicinal carrier, excipient select.For example can be tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, Oleum Ricini, polyvinylpyrrolidone, methylcellulose, hydroxy methocel, poloxamer, Pulvis Talci, starch, the mixture of one or more in the HP-etc.
When aforementioned pharmaceutical compositions is the injection form, can also contain sodium pyrosulfite, sodium sulfite, cysteine hydrochloride, TGA, methionine in the aforementioned pharmaceutical compositions, vitamin C, sodium thiosulfate, EDTA and slaine thereof, alkali carbonates such as sodium carbonate, acids such as phosphoric acid and each seed amino acid etc.Simultaneously can also contain sodium chloride, potassium chloride, sodium lactate, xylitol, sorbitol, maltose, fructose, dextran isosmoticity regulator.Can also contain cosolvent in this injection in addition, dispersant, pH regulator agent etc.
In addition, can as required Semen Ginkgo dipyridamole preparation of pharmaceutical compositions of the present invention be become slow releasing preparation.For example, can use hydroxypropyl methylcellulose as the hydrophilic framework material effective component of ginkgo leaf and dipyridamole, lactose, dextrin are as diluent, ethanol is as binding agent, Pulvis Talci is made label as lubricant, carry out coating with gelatin and simple syrup then, carry out film coating at last again and make slow releasing preparation, as slow releasing tablet etc.
On the basis of the above, the inventor has further finished following goal of the invention: by the injection of above-mentioned ginkgo bilobate extract preparation of pharmaceutical compositions.
Particularly, the present invention also provides a kind of ginkgo bilobate extract injection, it is characterized in that it is 0.70～2.275mg (preferred 0.7～1.4mg that this injection of every 1m1 contains Ginkgo total flavones alcohol glycosides, more preferably 0.77～1.26mg, 0.84～1.12mg more preferably, be preferably 0.91～1.12mg again, most preferably be 1.07mg), dipyridamole is that 0.21～1.12mg (is preferably 0.28～0.63mg, 0.315～0.56mg more preferably, more preferably 0.35～0.525mg is preferably 0.36～0.44mg again, most preferably be 0.42mg), Ginkgo total lactones is that 0.14～0.875mg (is preferably 0.245～0.70mg, more preferably 0.28～0.63mg, more preferably 0.28～0.455mg, preferred again 0.28～0.42mg most preferably is 0.31mg); , wherein Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 4～40: 7～40: 3～30: 3～40 (preferred 8～40: 7～30: 4～20: 5～28; More preferably 10～40: 7～25: 4～18: 5～26; Further preferred 10～35: 10～20: 4～15: 5～25; Preferred again 20～32: 12～20: 4～10: 6～24; Most preferably 25: 13: 7: weight ratio 6) was formed; This injection content of beary metal is lower than 9.4ppm.
The pH value of Semen Ginkgo dipyridamole of the present invention is 3.5～7.5, is preferably 4.0～7.0, most preferably is 4.5～5.5.
Injection of the present invention is preferably lyophilized injectable powder.
The present invention relates to a kind of method for preparing the ginkgo bilobate extract injection, comprising: in ginkgo bilobate extract compositions and/or pharmaceutical carrier, add water for injection to requirement, make wherein that each component ratio reaches described content, fill, sterilization is made.
The invention still further relates to the purposes of ginkgo bilobate extract compositions in preparation treatment cardiovascular and cerebrovascular diseases medicament.
Ginkgo bilobate extract compositions of the present invention not only total flavonoids and Ginkgo total lactones (Ginkgo total lactones is by bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10) and ginkalide C (C
20H
24O
11) form) the content height, and contain Western medicine dipyridamole composition; And contain impurity such as ginkgol, protein, tannin and be lower than 20ppm, content of beary metal is lower than 9.4ppm, being very beneficial for being prepared into pharmaceutical preparation uses, especially be suitable for preparing and require high injection, since the active constituent content height, impure low (impurity such as contained Semen Ginkgo aldehydes matter (for example ginkgoic acid), protein, tannin, heat source substance are lower than 20ppm), the injection determined curative effect for preparing thus, injection pain can be do not caused, heat source response can be do not caused yet.
The ratio of bilobalide, ginkalide A, B and C directly has influence on clinical therapeutic efficacy (seeing Table 3) in the ginkgo bilobate extract compositions, the ratio of the bilobalide of ginkgo bilobate extract compositions of the present invention, ginkalide A, B and C is 4～40: 7～40: 3～30: 3～40, in this proportion, the synergism of each effective ingredient can perform to the best, has better clinical effect thereby make the prepared injection of Folium Ginkgo extract of the present invention compare with the positive control medicine.
The ginkgo bilobate extract compositions for preparing by the inventive method: not only total flavonoids and Ginkgo total lactones content height, contain Western medicine dipyridamole composition, and the weight ratio of bilobalide, ginkalide A, B and C is 4～40: 7～40: 3～30: 3～40; Contain impurity such as Semen Ginkgo aldehydes matter (for example ginkgoic acid), protein, tannin, heat source substance and be lower than 20ppm, content of beary metal is no more than 9.4ppm (checking according to 2000 editions standards of Chinese Pharmacopoeia).The pharmaceutical preparation for preparing thus is particularly conducive to clinical use, and Zhi Bei injection can not cause injection pain, heat source response etc. in clinical use especially thus.
In addition, ginkgo bilobate extract composition injection of the present invention can be prepared into the lyophilized injectable powder form, and this freeze-dried powder is at water for injection, can be instant in glucose injection and the sodium chloride injection equal solvent, do not need to use special solvent or cosolvent, and the solution clarification, do not precipitate.And good stability, effect duration is long, stores convenient transportation.
Product of the present invention is carried out study on the stability, and the result is through after 1 year, and product effective ingredient of the present invention does not reduce, and various inspections all meet national drug standards requirement.
(Fructus Pruni fourth injection: lot number 20021104, manufacturer: the curative effect of treatment cardiovascular disease Guizhou benefit one hundred pharmacy) has been carried out relative analysis, and it the results are shown in Table 1 with injection of the present invention and commercially available Ginkgo Leaf Extract and Dipyridamole Injection.Result of the test explanation, the general curative effect of ginkgo bilobate extract composite injection of the present invention will be apparently higher than the general curative effects of commercially available YINXINGYE ZHUSHEYE, and do not find obvious adverse reaction, and its safety also obviously is better than commercially available YINXINGYE ZHUSHEYE.
The clinical trial result contrast of table 1 ginkgo bilobate extract composite injection of the present invention and control sample (commercially available Ginkgo Leaf Extract and Dipyridamole Injection)
| The ginkgo bilobate extract composite injection that the present invention produces | Control sample | |
| Clinical in-service evaluation | Total effective rate 85.8% | Total effective rate 67.6% |
| Clinical adverse is estimated | Do not find obvious adverse reaction | Obvious adverse reaction incidence rate 1.83% |
Product of the present invention proves anaphylaxis is not appearred in the blood vessel nonirritant yet through animal experiment.Little through animal acute toxicity test proof toxicity, be very beneficial for clinical use.
Further describe beneficial effect of the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
The specific embodiment
Embodiment 1 ginkgo bilobate extract preparation of compositions method
Get dry Folium Ginkgo 10kg, be ground into coarse powder with pulverizer, add 90% ethanol 6000ml reflux, extract, 6 hours, filter, residue used the same method extract 2 times again, filter, merging filtrate adds sodium bicarbonate aqueous solution and transfers pH to 10, left standstill 6 hours, filter, filtrate adds dilute hydrochloric acid and transfers pH to 5, and filtrate is concentrated, in concentrate, add the 1500ml distilled water and be heated to 75 ℃, kept 10 minutes in this temperature under stirring, water extract cold preservation (0～4 ℃) is spent the night, filter, filtrate is gone up macroporous adsorbent resin, the control flow velocity to current to the greatest extent after, colourless with 30～50% ethanol gradient elutions to effluent, with 50% alcoholic acid eluent normal hexane: twice of acetone (38: 1) mixed extractant solvent, separate water layer and organic layer, organic layer reclaims solvent, and concentrate drying promptly gets Folium Ginkgo extract 300g.Desired proportions adds dipyridamole 41g, adds ethanol, and is evenly moistening, reinstalls in the percolator, and ethanol adds to and exceeds the medicine face, carries out percolation after placement a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets ginkgo bilobate extract compositions 320g.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 30.2%, dipyridamole 12% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 10.4% (part by weight of bilobalide, ginkalide A, B and C is 25: 13: 7: 6), and content of beary metal 8.8ppm.
Embodiment 2 ginkgo bilobate extract preparation of compositions
Get fresh Folium Ginkgo 10kg, be ground into paste with beater, add 5000ml 75% alcohol reflux 5 hours, filter, residue used the same method extract 3 times again, filter, merging filtrate adds saturated limewater and transfers pH to 9, left standstill 6 hours, filter, filtrate adds dilute hydrochloric acid and transfers pH to 5.5, and filtrate is concentrated, in concentrate, add entry and be heated to 70 ℃, kept 30 minutes in this temperature under stirring, water extract cold preservation (0～4 ℃) is spent the night, filter, filtrate is gone up macroporous adsorbent resin, the control flow velocity to current to the greatest extent after, colourless with 30～50% ethanol gradient elutions to effluent, with 50% alcoholic acid eluent normal hexane: twice of acetone (35: 1) mixed extractant solvent, separate water layer and organic layer, organic layer reclaims solvent, and concentrate drying promptly gets Folium Ginkgo extract 500g.Desired proportions adds dipyridamole 70g, adds ethanol, and is evenly moistening, reinstalls in the percolator, and ethanol adds to and exceeds the medicine face, carries out percolation after placement a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets ginkgo bilobate extract compositions 530g.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 42.2%, dipyridamole 12.3% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 18.4% (part by weight of bilobalide, ginkalide A, B and C is 23: 14: 16: 37), and content of beary metal 8.8ppm.
Embodiment 3 ginkgo bilobate extract preparation of compositions
Folium Ginkgo extract (available from Hainan to journey medicine trade Co., Ltd) (containing Semen Ginkgo total flavonoids 33%, Ginkgo total lactones 11%) 900g, dipyridamole 100g.
Accurately take by weighing above weight raw material, pulverizing, mixing, adding ethanol, evenly moistening, reinstall in the percolator, ethanol adds to and exceeds the medicine face, carries out percolation after placement a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets the ginkgo bilobate extract compositions.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 29.7%, dipyridamole 10% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 9.9% (part by weight of bilobalide, ginkalide A, B and C is 6: 12: 7: 6), and content of beary metal 8.8ppm.
Embodiment 4 ginkgo bilobate extract preparation of compositions
Folium Ginkgo extract (available from Hainan to journey medicine trade Co., Ltd) (wherein containing Semen Ginkgo total flavonoids 30%, Ginkgo total lactones 12%) 900g, dipyridamole 100g.
Accurately take by weighing above weight raw material, pulverizing, mixing, adding ethanol, evenly moistening, reinstall in the percolator, ethanol adds to and exceeds the medicine face, carries out percolation after placement a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets the ginkgo bilobate extract compositions.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 27%, dipyridamole 10% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 10.8% (part by weight of bilobalide, ginkalide A, B and C is 4: 9: 6: 6), and content of beary metal 8.8ppm.
Embodiment 5 ginkgo bilobate extract preparation of compositions
Ginkgo total flavones alcohol glycosides 0.55kg
Dipyridamole 0.20kg
Ginkgo total lactones 025g[wherein contains bilobalide (C
15H
18O
8) 0.067kg, ginkalide A (C
20H
24O
9) 0.066kg, ginkalide B (C
20H
24O
10) 0.050kg, ginkalide C (C
20H
24O
11) 0.067kg];
Accurately take by weighing above weight raw material (above-mentioned raw materials all available from Hainan to journey medicine trade Co., Ltd), pulverizing, mixing, adding ethanol, evenly moistening, reinstall in the percolator, ethanol adds to and exceeds the medicine face, carries out percolation after placing a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets ginkgo bilobate extract compositions 0.98kg.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 55%, dipyridamole 20% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 25% (part by weight of bilobalide, ginkalide A, B and C is 40: 40: 30: 40), and content of beary metal 8.6ppm.
Embodiment 6 ginkgo bilobate extract preparation of compositions
Ginkgo total flavones alcohol glycosides 0.60kg
Dipyridamole 0.32kg
Ginkgo total lactones 0.08kg[wherein contains bilobalide (C
15H
18O
8) 0.019kg, ginkalide A (C
20H
24O
9) 0.033kg, ginkalide B (C
20H
24O
10) 0.014kg, ginkalide C (C
20H
24O
11) 0.014kg];
Accurately take by weighing above weight raw material (above-mentioned raw materials all available from Hainan to journey medicine trade Co., Ltd), pulverizing, mixing, adding ethanol, evenly moistening, reinstall in the percolator, ethanol adds to and exceeds the medicine face, carries out percolation after placing a period of time.Collect percolate, concentrate under reduced pressure at low temperature continues to be concentrated into aequum to the thick shape of cream.It is dry that the cream thick liquid is put into drying baker, and the airtight storage of shading container is put in dehydration, promptly gets ginkgo bilobate extract compositions 0.98kg.
After testing, the weight percentage of each composition is as follows in the prepared ginkgo bilobate extract compositions of present embodiment: total flavonoids 60%, dipyridamole 32% Ginkgo total lactones (in the total amount of bilobalide, ginkalide A, ginkalide B, ginkalide C) 8% (part by weight of bilobalide, ginkalide A, B and C is 4: 7: 3: 3), and content of beary metal 8.6ppm.
The preparation method of embodiment 7 ginkgo bilobate extract composite injections
Get the ginkgo bilobate extract compositions 220g of embodiment 1, put into agitator, add water for injection, stirring and dissolving is added water for injection and is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides be 1.05mg, and dipyridamole is 0.42mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.36mg, (part by weight of bilobalide, ginkalide A, B and C is 25: 13: 7: 6).Dissolving is 5 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The testing result of each component content of injection that present embodiment is prepared sees Table 2.
The testing result of table 2 each component content of injection of the present invention
| Composition or inspection item | The ginkgo bilobate extract composite injection that the embodiment of the invention 7 is prepared | The ginkgo bilobate extract composite injection that the embodiment of the invention 8 is prepared | The ginkgo bilobate extract composition freeze-drying injection that the embodiment of the invention 9 is prepared |
| Total flavonoids (mg/ml) | 1.05 | 1.925 | 1.05 |
| Dipyridamole (mg/ml) | 0.42 | 0.70 | 0.42 |
| Ginkgo total lactones (mg/ml) | 0.36 | 0.875 | 0.36 |
| The part by weight of bilobalide, ginkalide A, B and C | 25∶13∶7∶6 | 40∶40∶30∶40 | 24∶13∶15∶37 |
| Protein is checked | Haze-free | Haze-free | Haze-free |
| Tannin is checked | Haze-free, do not precipitate | Haze-free, do not precipitate | Haze-free, do not precipitate |
| Ginkgol is checked | The relevant position immaculate | The relevant position immaculate | The relevant position immaculate |
| Heavy metal (ppm) | 8.8 | 8.6 | 8.6 |
The preparation of embodiment 8 ginkgo bilobate extract composite injections
Get the ginkgo bilobate extract compositions 500g of embodiment 5, put into agitator, add the chloride injection water, stirring and dissolving, add water for injection and be diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides be 1.925mg, dipyridamole is 0.70mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.875mg, (part by weight of bilobalide, ginkalide A, B and C is 40: 40: 30: 40).Dissolving is 5 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The testing result of each component content of injection that present embodiment is prepared sees Table 2.
The preparation of embodiment 9 ginkgo bilobate extract composite freeze-dried powder agent
Get the ginkgo bilobate extract compositions 200g of embodiment 1, put into agitator, add water for injection, stirring and dissolving is complete, adds water for injection and is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides be 1.05mg, and dipyridamole is 0.42mg, and Ginkgo total lactones is with bilobalide (C
15H
19O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.36mg.Add mannitol, regulating pH value with meglumine is 5, filters concentrating under reduced pressure, and aseptic filtration, fill are in glass ampoule bottles, and cool drying promptly gets the agent of ginkgo bilobate extract composite freeze-dried powder.
The testing result of each component content of injection that present embodiment is prepared sees Table 2.
The preparation of embodiment 10 ginkgo bilobate extract injections
The ginkgo bilobate extract compositions of getting embodiment 5 preparations (contains Semen Ginkgo total flavonoids 55%, dipyridamole 20%, Ginkgo total lactones 25% (bilobalide, ginkalide A, B and C ratio are 40: 40: 30: 40)) 100g, put into agitator, add the chloride injection water, stirring and dissolving, adding water for injection is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides is 1.925mg, dipyridamole is 0.70mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.875mg, (part by weight of bilobalide, ginkalide A, B and C is 40: 40: 30: 40).Dissolving is 5 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The preparation of embodiment 11 ginkgo bilobate extract injections
The ginkgo bilobate extract compositions of getting embodiment 4 preparations (contains Semen Ginkgo total flavonoids 27%, dipyridamole 10%, Ginkgo total lactones 10.8% (bilobalide, ginkalide A, B and C ratio are 4: 9: 6: 6)) 100g, put into agitator, add the chloride injection water, stirring and dissolving, adding water for injection is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides is 0.945mg, dipyridamole is 0.35mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.378mg, (part by weight of bilobalide, ginkalide A, B and C is 4: 9: 6: 6).Dissolving is 6 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The preparation of embodiment 12 ginkgo bilobate extract injections
The ginkgo bilobate extract compositions of getting embodiment 1 preparation (contains Semen Ginkgo total flavonoids 30.2%, dipyridamole 12%, Ginkgo total lactones 10.4% (bilobalide, ginkalide A, B and C ratio are 25: 13: 7: 6)) 100g, put into agitator, add the chloride injection water, stirring and dissolving, adding water for injection is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides is 1.057mg, dipyridamole is 0.42mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.364mg, (part by weight of bilobalide, ginkalide A, B and C is 25: 13: 7: 6).Dissolving is 7 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The preparation of embodiment 13 ginkgo bilobate extract injections
The ginkgo bilobate extract compositions of getting embodiment 6 preparations (contains Semen Ginkgo total flavonoids 60%, dipyridamole 32%, Ginkgo total lactones 8% (bilobalide, ginkalide A, B and C ratio are 4: 7: 3: 3)) 100g, put into agitator, add the chloride injection water, stirring and dissolving, adding water for injection is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides is 2.1mg, dipyridamole is 1.12mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.28mg, (part by weight of bilobalide, ginkalide A, B and C is 4: 7: 3: 3).Dissolving is 5.5 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection.
The preparation of embodiment 14 ginkgo bilobate extract injections
The ginkgo bilobate extract compositions of getting embodiment 2 preparations (contains Semen Ginkgo total flavonoids 42.2%, dipyridamole 12.3%, Ginkgo total lactones 18.4% (bilobalide, ginkalide A, B and C ratio are 23: 14: 16: 37)) 100g, put into agitator, add the chloride injection water, stirring and dissolving, adding water for injection is diluted to every 1ml to contain Ginkgo total flavones alcohol glycosides is 1.477mg, dipyridamole is 0.4305mg, and Ginkgo total lactones is with bilobalide (C
15H
18O
8), ginkalide A (C
20H
24O
9), ginkalide B (C
20H
24O
10), ginkalide C (C
20H
24O
11) total amount count 0.644mg, (part by weight of bilobalide, ginkalide A, B and C is 23: 14: 16: 37).Dissolving is 6.5 with meglumine adjusting pH value fully, filters, and in the fill ampoule bottle, sterilization promptly gets the ginkgo bilobate extract composite injection
Test the pharmacodynamics test of routine ginkgo bilobate extract composite injection of the present invention
One, test material
1, for test agent: for test agent 1: the prepared ginkgo bilobate extract injection of the embodiment of the invention 10 [contain Semen Ginkgo total flavonoids 55%, dipyridamole 20%, Ginkgo total lactones 25% (bilobalide, ginkalide A, B and C ratio are 40: 40: 30: 40)]; For test agent 2: the prepared ginkgo bilobate extract injection of the embodiment of the invention 11 [contain Semen Ginkgo total flavonoids 27%, dipyridamole 10%, Ginkgo total lactones 10.8% (bilobalide, ginkalide A, B and C ratio are 4: 9: 6: 6)]; For test agent 3: the prepared ginkgo bilobate extract injection of the embodiment of the invention 12 [contain Semen Ginkgo total flavonoids 30.2%, dipyridamole 12%, (bilobalide, ginkalide A, B and C ratio are (25: 13: 7: 6)) to Ginkgo total lactones 10.4%; For test agent 4: the prepared ginkgo bilobate extract injection of the embodiment of the invention 13 [contain Semen Ginkgo total flavonoids 60%, dipyridamole 32%, Ginkgo total lactones 8% (bilobalide, ginkalide A, B and C ratio are 4: 7: 3: 3)]; For test agent 5: the prepared ginkgo bilobate extract injection of the embodiment of the invention 14 [contain Semen Ginkgo total flavonoids 42.2%, dipyridamole 12.3%, Ginkgo total lactones 18.4% (bilobalide, ginkalide A, B and C ratio are 23: 14: 16: 37)].
2, control sample: according to application number is the freeze dried injection of 03104645 Chinese patent application description embodiment, 1 disclosed method preparation.
Two, content of the test
1, chooses 30 of healthy rats, be divided into 6 groups at random, 6 groups of rats are anaesthetized, cervical region overlaps a tourniquet, is forced into 80-93 kPa, reduces cerebral blood flow, make it to cause the cerebrum ischemia symptom, injection is treated for test agent 1-5 and control sample, respectively brain wave is carried out quantitative analysis then, found that can significantly strengthen each ripple of cerebrum ischemia rat brain electrograph for test agent recovers.This description of test Ginkgo Leaf Extract and Dipyridamole Injection of the present invention has remarkable effect (the results are shown in Table 3) to the damage that alleviates cerebrum ischemia and cause.
2,30 healthy rats are divided into 6 groups at random, 5 every group.Feeding adds the feedstuff of cholesterol with modeling.After the modeling success, with treating, get capable tectology of aorta and electron microscopic examination after 10 weeks respectively, measure soluble thrombomodulin (sTM) level with elisa for test agent 1-5 and control sample.The result adopts for the rat triglyceride of test agent 1-5 treatment and low-density lipoprotein cholesterol level and is starkly lower than the rat triglyceride and the low-density lipoprotein cholesterol level for the treatment of with control sample.A large amount of monocyte infiltrations are arranged under the tunica intima of control sample group, but obviously less for the test agent group.There is tangible disintegration phenomenon in the vascular endothelial cell of control sample group, and slight for the damage of test agent group.For test agent group sTM less than to group in the same old way.The result show Ginkgo Leaf Extract and Dipyridamole Injection of the present invention effectively the blood fat reducing level, alleviate the partial inflammatory reaction of atherosclerotic plaque, the protection vascular endothelial cell and bring into play the control atherosclerotic effect (the results are shown in Table 3).
3, choose 30 of healthy rats, be divided into 6 groups at random, all manually urge always, make it bring out acute lung injury by the intravenous injection lipopolysaccharide with the D-galactose, and respectively with treating for test agent 1-5 and control sample.Found that the D-galactose causes superoxide dismutase (SOD) and all significantly reductions of lung tissue activity in the normal rat serum of old and feeble rat, raises and lactic acid dehydrogenase (LDH) is active in the blood.Just formed acute lung injury behind the old and feeble rat injection lipopolysaccharide in two hours, light microscopic is observed in interstitial lung and the alveolar down more inflammatory cell, protein content and lung permeation index increase in the bronchoalveolar lavage fluid, in the blood in lactic acid, malonaldehyde, nitric oxide, endothelin-1, levels of tnf-alpha and LDH activity and the lung tissue activity of myeloperoxidase all significantly raise, and SOD activity and lung tissue activity all descend in the blood.Except that SOD, supply above-mentioned other index of the old and feeble rat of test agent 1-5 treatment to treat in advance with control sample, remarkable alleviation is all arranged.Above-mentioned test proves absolutely that Ginkgo Leaf Extract and Dipyridamole Injection of the present invention can be removed free radical, protects vascular endothelial cell, improves the gas exchange of lung, and acute lung injury (the results are shown in Table 3) finally can be effectively alleviated in the release of inflammation-inhibiting medium.
Table 3 Ginkgo Leaf Extract and Dipyridamole Injection contains the animal experiment contrast of bilobalide, ginkalide A, B and C different proportion
| Alleviate the damage that cerebrum ischemia causes | Atherosclerotic control and rehabilitation | Alleviate acute lung injury | |
| For test agent 1 | Total effective rate 91.60% | Total effective rate 86.64% | Total effective rate 83.60% |
| For test agent 2 | Total effective rate 92.66% | Total effective rate 86.82% | Total effective rate 85.62% |
| For test agent 3 | Total effective rate 93.18% | Total effective rate 88.36% | Total effective rate 86.32% |
| For test agent 4 | Total effective rate 95.26% | Total effective rate 89.38% | Total effective rate 88.24% |
| For test agent 5 | Total effective rate 83.30% | Total effective rate 82.68% | Total effective rate 80.32% |
| Control sample | Total effective rate 56.87% | Total effective rate 62.32% | Total effective rate 61.17% |
Claims (8)
1. a ginkgo bilobate extract compositions is characterized in that said composition contains each composition of following percentage by weight: Ginkgo total flavones alcohol glycosides 20～40%, dipyridamole 8～18%, Ginkgo total lactones 7～20%; Wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 20～32: 12～20: 4～10: 6～24 part by weight is formed; The content of beary metal of said composition is lower than 9.4ppm.
2. a ginkgo bilobate extract pharmaceutical composition is characterized in that being made up of with pharmaceutical carrier or diluent the ginkgo bilobate extract compositions of effective dose in the described treatment of claim 1.
3. according to the ginkgo bilobate extract pharmaceutical composition of claim 2, it is characterized in that being prepared into injection, tablet, capsule, granule, oral liquid or slow releasing preparation according to the pharmaceutical preparation conventional method.
4. according to the ginkgo bilobate extract pharmaceutical composition of claim 3, it is characterized in that described preparation is an injection.
5. according to the ginkgo bilobate extract pharmaceutical composition of claim 4, it is characterized in that this injection of every 1ml contains Ginkgo total flavones alcohol glycosides 0.77～1.26mg, dipyridamole 0.315～0.56mg, Ginkgo total lactones 0.28～0.63mg, this injection content of beary metal is lower than 9.4ppm; PH value is 3.5～7.5; Wherein Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 20～32: 12～20: 4～10: 6～24 part by weight is formed.
6. one kind prepares claim 1 ginkgo bilobate extract method for compositions, comprising: take by weighing each component according to following percentage by weight: Ginkgo total flavones alcohol glycosides 20～40%, dipyridamole 8～18%, Ginkgo total lactones 7～20%; Wherein, Ginkgo total lactones by bilobalide, ginkalide A, ginkalide B and ginkalide C according to 20～32: 12～20: 4～10: 6～24 part by weight is formed; The content of beary metal of said composition is lower than 9.4ppm; With above-mentioned each component mix homogeneously promptly.
7. method for preparing claim 4 or 5 described ginkgo bilobate extract pharmaceutical compositions comprises: in the ginkgo bilobate extract compositions, adds water for injection, makes wherein that each component ratio reaches described content, and fill, sterilization is made.
8. the ginkgo bilobate extract compositions of claim 1 is preparing the purposes for the treatment of in the cardiovascular and cerebrovascular diseases medicament.
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| CN107468725A (en) * | 2017-08-16 | 2017-12-15 | 朗致集团江西医药有限公司 | A kind of Chinese medicine composition and its application with function of reducing blood sugar and the parenteral solution being made from it |
| CN107625757A (en) * | 2017-08-16 | 2018-01-26 | 朗致集团万荣药业有限公司 | A kind of Chinese medicine composition and its application with blood fat reducing function and the parenteral solution being made from it |
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