CN1454596A - Compound medicine of ginkgo leaf extract and dipyridamole and preparing method thereof - Google Patents
Compound medicine of ginkgo leaf extract and dipyridamole and preparing method thereof Download PDFInfo
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- CN1454596A CN1454596A CN 03137926 CN03137926A CN1454596A CN 1454596 A CN1454596 A CN 1454596A CN 03137926 CN03137926 CN 03137926 CN 03137926 A CN03137926 A CN 03137926A CN 1454596 A CN1454596 A CN 1454596A
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Abstract
The invention is a manufacturing method for vein medicament of gingkgo leaves extraction materials and di-pyridine compound drug. It is based on that the stability of gingkgo flavone in low thickness aqueous solution is higher than in high thickness aqueous solution, the gingkgo leaves extraction materials and di-pyridine is dissolved at the same time, after the two are frozen and dried into even solid, the stability of gingko flavone is higher than the solid which is only frozen and dried from itself, and produces the infusion agent and powder pin agent. The manufacturing process doesn't use active carbon, but uses middle hole fiber film filtering new technology to wipe off impurities, enhances thep quality of the product. The method is simple, convenient, and good curative effect.
Description
Technical field
The present invention relates to a kind of medicine-Folium Ginkgo extract for the treatment of coronary heart disease, thrombotic disease and dipyridamole compound medicine and preparation method thereof.
Background technology
Folium Ginkgo, but only limits in the prescription or single proved recipe among the people of Chinese medicine as medicinal existing more than 5000 year history in China.With modern scientific method Folium Ginkgo is studied, found that the most important effective ingredient of Folium Ginkgo is bilobalide and flavonol.Bilobalide has the effect of opposing platelet activating factor, can improve blood circulation.Flavonol then has the function of eliminating free radical, except the effect that blood vessel dilating is arranged, also can prevent arteriosclerosis.Find that also Folium Ginkgo extract is influential to human memory's basic neural tuple, can improve memory, treat dizzy, tinnitus and cerebrovascular disease, effect is very remarkable.Because of the reason such as stable not good enough of Folium Ginkgo extract effective ingredient, gingko leaf preparation is mainly peroral dosage form but up to now.But the oral formulations onset is slow, bioavailability is low, can produce biodegradation through gastrointestinal absorption, makes some effective ingredient go to pot and affect the treatment.The Folium Ginkgo extract of commercially available clinical use and dipyridamole compound medicine then only are little aqueous injection (5 milliliters and 10 milliliters of two kinds of specifications), and have problems such as quality is stable inadequately, reduce at the easy variable color of lay up period, appearance precipitation and content.And can not be directly used in intravenous drip, need to add in glucose infusion liquid or the normal saline and just can carry out the intravenous drip administration.Not only use inconvenience, when opening little liquid drugs injection ampoule, medicinal liquid contacts with air, also causes secondary pollution easily, has increased safety of clinical administration hidden danger.
Summary of the invention
The present invention only has little liquid drugs injection dosage form at existing Folium Ginkgo extract and dipyridamole compound medicine exactly, the quality instability, use inconvenient, the defective that affects the treatment, a kind of good stability, Folium Ginkgo extract evident in efficacy and the intravenously administrable dosage form of dipyridamole compound medicine are provided, to improve drug quality, make things convenient for clinical practice.Pharmaceutical dosage form of the present invention is that (each basic packing unit is 50 milliliters to 500 milliliters for the infusion solution that contains Folium Ginkgo effective ingredient and dipyridamole of intravenously administrable, contain 4 milligrams to 30 milligrams of Semen Ginkgo total flavones, 1.5 milligrams to 15.0 milligrams of dipyridamoles) and intravenous drip with injectable powder (every contains 4 milligrams to 30 milligrams of Semen Ginkgo total flavones, 1.5 milligrams to 15.0 milligrams of dipyridamoles).Other active ingredient does not limit in the Folium Ginkgo extract.
Can contain one or more and EDTA disodium, EDTA calcium sodium or the two use in conjunction in sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, the vitamin C etc. in the infusion solution of the present invention as stabilizing agent; It is 3.5～7.5 that one or more pH value with the adjusting transfusion in the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid and each seed amino acid can also be arranged; In sodium chloride, potassium chloride, sodium lactate, xylitol, sorbitol, maltose, glucose, fructose, dextran or the glycine etc. one or more can be arranged simultaneously with as osmotic pressure regulator.
Injectable powder of the present invention can contain one or more in the alkali-metal phosphate of monovalence, acetate, carbonate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid and each seed amino acid, the pH value that every finished powder injection is added after the dissolving of 10 milliliters of waters for injection are 3.5～5.5) and mannitol, sorbitol and/or sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C in one or more, to play hydrotropy, dispersion or effect such as stable.
The used medicine material Folium Ginkgo active ingredient with the dipyridamole compatibility of the present invention can be that the Folium Ginkgo medical material is ethanol-aqueous extract, Folium Ginkgo extract, Ginkgo total flavones or the Ginkgo total flavones of initiation material and the mixture of bilobalide.
Infusion solution of the present invention has not only overcome Folium Ginkgo extract and the little liquid drugs injection of dipyridamole compound medicine as the awkward weakness of intravenous drip, and stability of drug is obviously strengthened.And injectable powder of the present invention, because of its two main component all is in homodisperse solid state, the increase of stability is more obvious, causes the chance of secondary pollution also to be lower than little aqueous injection during its clinical practice simultaneously, is easy to transportation and storage.
Innovative point of the present invention also has: 1. Ginkgo total flavones is higher than high concentration (by Ginkgo total flavones, being higher than 15mg among every 100ml) aqueous solution state in the stability of low concentration (by Ginkgo total flavones, being lower than 15mg among every 100ml) aqueous solution state; 2. Folium Ginkgo extract and dipyridamole dissolve jointly, after lyophilization becomes the two homodisperse solid, and the stability of the stability of its effective ingredient Ginkgo total flavones solid state after its independent lyophilizing.For reducing the absorption of active carbon to effective ingredient, preparation process is not used active carbon, and adopts mesopore fibrous membrane ultrafiltration new technique to remove impurity, improves the quality of products simultaneously.
Clinical proof already, the Ginkgo total flavones among the present invention in the Folium Ginkgo extract has dilating coronary blood vessel, cerebrovascular, improves symptom and memory function that cerebral ischemia produces.Dipyridamole anticoagulant, high concentration (50 mcg/ml) can suppress platelet and discharge.The two is in conjunction with can be used for prevention and treatment coronary heart disease, thrombotic disease.
The inventor finds that further Ginkgo total flavones is higher than high concentration (by Ginkgo total flavones, being higher than 15mg among every 100ml) aqueous solution state in the stability of low concentration (by Ginkgo total flavones, being lower than 15mg among every 100ml) aqueous solution state; Folium Ginkgo extract and dipyridamole dissolve jointly, after lyophilization becomes the two homodisperse solid, the stability of its effective ingredient Ginkgo total flavones is higher than two kinds of lyophilized powders and pulverizes the back by the blended stabilized with mixture of same ratio, the stability of solid state after the independent lyophilizing of Folium Ginkgo extract.
Table 1 is with the stable effective ingredients contrast when the variable concentrations of a collection of Folium Ginkgo extractum under the violent condition (50 ℃ constant temperature preserve).In view of the above this product is made infusion solution, not only can bring the convenience in the use, and stability is greatly strengthened, the effectiveness of medicine and safety are all strengthened.(mg/100ml) (moon) Ginkgo total flavones bilobalide of the situation of change extractum concentration outward appearance standing time active constituent content (mg/100ml) of effective ingredient during Folium Ginkgo extractum variable concentrations under the table 1.50 ℃ condition
0 solution is clear and bright, and it is muddy slightly not have precipitation 111.4 (100%) 27.8 (100%) 416.7 3 solution, does not have precipitation 91.3 (82.0%) 23.2 (83.5%)
6 solution muddinesses have precipitation 80.9 (72.6%) 20.8 (74.8%)
0 solution is clear and bright, and it is clear and bright not have precipitation 11.1 (100%) 2.78 (100%) 41.67 3 solution, does not have precipitation 10.3 (92.8%) 2.62 (94.24%)
6 solution are clear and bright, do not have precipitation 9.8 (88.3%) 2.54 (91.37%)
0 solution is clear and bright, and it is clear and bright not have precipitation 2.23 (100%) 0.56 (100%) 8.33 3 solution, does not have precipitation 2.12 (95.06%) 0.53 (94.64%)
6 solution are clear and bright, do not have precipitation 2.07 (92.83%) 0.51 (91.1%) and annotate: in the numerical value in () numeral for being equivalent to the percent of content when initial.
Table 2 be under the violent condition (50 ℃ constant temperature preserve) with the independent lyophilizing of a collection of Folium Ginkgo extractum make injectable powder, with dipyridamole by common dissolving, injectable powder is made in lyophilization, homodisperse and two kinds of lyophilized powders are pulverized the back is mixed and made into three kinds of situations of injectable powder by same ratio study on the stability result.As seen, Folium Ginkgo extract of the present invention and dipyridamole compound medicine injectable powder because of being the homogeneously dispersed state of molecular level between its effective ingredient and dipyridamole, and greatly improve stability.Therefore the present invention is strengthened the effectiveness and the safety of Folium Ginkgo extract and dipyridamole compound medicine.
Distinct methods prepares the situation of change preparation method outward appearance standing time active constituent content (mg/ props up) of injectable powder effective ingredient under the table 2.50 ℃ condition
The cold separately 3 pale brown toner ends 9.07 (88.57%) 2.43 (94.92%) of doing of (moon) Ginkgo total flavones bilobalide extract 0 sundown powder 10.24 (100%) 2.56 (100%)
6 brown ceramic powders, 7.87 (76.86%) 2.25 (87.89%) two compositions, 0 sundown powder, 10.57 (100%) 2.61 (100%) powder mixes, 3 pale brown toner ends 9.63 (91.11%) 2.45 (93.87%)
6 brown ceramic powders 8.71 (82.40%) 2.28 (87.36%)
0 sundown powder, 10.63 (100%) 2.64 (100%) the inventive method, 3 sundown powder 10.20 (95.95%) 2.51 (95.08%)
6 sundown powder 9.85 (92.66%) 2.48 (93.94%) are annotated: in the numerical value in () numeral for being equivalent to the percent of content when initial.
Table 3 is commercially available Folium Ginkgo extract and the little liquid drugs injection of dipyridamole and Folium Ginkgo extract of the present invention and the agent of dipyridamole compound infusion and injectable powder study on the stability result under violent condition.Show that effective ingredient Ginkgo total flavones in dipyridamole and the Folium Ginkgo extract and the stability of bilobalide in little liquid drugs injection, transfusion and injectable powder increase progressively.Illustrate that the present invention can obviously reduce the degraded of effective ingredient.And the degraded of effective ingredient not only reduces its effectiveness, and degradation product itself also may produce certain toxic and side effects, and therefore, the present invention has increased the safety and the effectiveness of this medicine.
The situation of change dosage form outward appearance standing time active constituent content of different situation injectable powder effective ingredient under the table 3.50 ℃ condition (milligram /)
The little liquid drugs injection 0 yellow extremely pale brown color clear liquid of (moon) Ginkgo total flavones bilobalide dipyridamole does not have precipitation 9.28 (100%) 2.17 (100%) 3.92 (100%)
3 pale brown color clear liquids do not have precipitation 8.08 (87.07%) 1.86 (85.71%) 3.45 (88.01%)
The turbid liquid of 6 pale brown color contaminations does not have precipitation 7.45 (80.28%) 1.73 (79.72%) 3.26 (83.16%)
9 brown turbid liquids have precipitation 6.50 (70.04%) 1.52 (70.05%) 2.98 (76.02%) transfusions 0 yellow clear liquid, do not have precipitation 10.16 (100%) 2.54 (100%) 4.06 (100%)
3 yellow clear liquids do not have precipitation 9.65 (94.98%) 2.39 (94.09%) 3.91 (96.31)
6 is yellow to pale brown color clear liquid, do not have precipitation 9.25 (91.04%) 2.33 (91.73%) 3.82 (94.09%)
9 pale brown color clear liquids do not have precipitation 8.74 (86.02%) 2.20 (86.6%) 3.69 (90.89%) powder pins 0 sundown powder 10.63 (100%) 2.64 (100%) 4.03 (100%)
3 sundown powder 10.20 (95.95%) 2.51 (95.08%) 3.91 (97.02%)
6 sundown powder 9.85 (92.66%) 2.48 (93.94%) 3.83 (95.04%)
Annotate at 9 pale brown toner ends 9.46 (88.99%) 2.37 (89.77%) 3.67 (91.07%): in the numerical value in () numeral for being equivalent to the percent of content when initial.
The preparation method of the infusion solution of Folium Ginkgo extract of the present invention of Ti Chuing and dipyridamole and injectable powder dosage form is in view of the above: the Folium Ginkgo extract that market is buied, add 5～15 times of water for injection dissolvings, centrifugation, supernatant is used filter paper successively, behind the membrane filtration, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution: the production procedure of 1. pressing infusion solution, in pure extracting solution, add dipyridamole (Ginkgo total flavones amount 40%), isoosmotic adjusting agent (transferring osmotic pressure and human body liquid phase etc.), acidity-basicity regulator (making the finished product pH value is 3.5～7.5) etc., and carry out ultrafiltration, dilution, fill, fill nitrogen, operations such as pressure sterilizing, the preparation infusion solution.2. pure extracting solution adds after dipyridamole (Ginkgo total flavones amount 40%), acidity-basicity regulator (making every finished powder pin add 10 milliliters of pH value after the waters for injection dissolving is 3.5～5.5) and other additives make dissolving, filter membrane degerming, fill, lyophilization get lyophilized injectable powder.
When the present invention prepared infusion solution, the isoosmotic adjusting agent of adding can be sodium chloride, potassium chloride, sodium lactate, xylitol, sorbitol, maltose, glucose, fructose, dextran or glycine etc.The additives that add can be stabilizing agent on the pharmaceutics such as antioxidant, complexing of metal ion agent, acidity-basicity regulator, and antioxidant can be that in sodium pyrosulfite (0.1%～0.2%), sodium sulfite (0.1%～0.2%), sodium thiosulfate (0.1%), cysteine hydrochloride (0.00015%～0.05%), TGA (0.005%), methionine (0.05%～0.1%), the vitamin C (0.2%) one or more are united use; The complexing of metal ion agent can be EDTA disodium, EDTA calcium sodium or the two use in conjunction; Acidity-basicity regulator can be that one or more mixing in the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid and each seed amino acid are used, and is 3.5～7.5 with the pH value of regulating transfusion.
When the present invention prepares injectable powder, before the filter membrane degerming, as in medicinal liquid, adding dispersant (as mannitol, sorbitol etc., the freeze-dried powder usual amounts), antioxidant is (as sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, in the vitamin C etc. one or more are united use, the same infusion solution of consumption) and pH regulator agent (the alkali-metal phosphate of monovalence, acetate, carbonate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, in phosphoric acid and each seed amino acid one or more mix use, the pH value that every finished powder pin is added after the dissolving of 10 milliliters of waters for injection are 3.5～5.5) etc. the additives on the pharmaceutics to play hydrotropy, stable or dispersion etc. done the time spent, and effect is better.Technological process also can be under aseptic condition, after the filter membrane degerming, uses the deep bid lyophilization earlier, is sub-packed in the cillin bottle after crushed.
The present invention also can use Folium Ginkgo to make raw material, extraction scheme is: get Folium Ginkgo, with its weight is that ethanol-water of 5～20 times (ratio is 1: 1～5) solution soaking of Folium Ginkgo is spent the night, twice of reflux, extract,, after extracting solution merges, filter, resin bed (the strong acid anion resin on average mixes with the highly basic cationic resin) decontamination, after being concentrated into nothing alcohol flavor, add kieselguhr and cyclodextrin to remove tannin, protein etc. filter, and filtrate is with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, press such scheme preparation transfusion or injectable powder again.
The present invention also can use the mixture of the pure product of commercially available ginkgetin or pure product of ginkgetin and the pure product of bilobalide to be raw material, with 10～30 times of (weight) water for injection dissolvings, behind the fine straining, use the hollow fiber ultrafiltration membrane ultrafiltration, get pure extracting solution, again by above-mentioned prepared infusion solution or injectable powder.
The intravenously administrable dosage form of Folium Ginkgo extract provided by the invention and dipyridamole compound medicine, preparation technology advanced person, be suitable for large-scale production, adopt the doughnut membrane ultrafiltration, remove active carbon absorption technology from, reduced the loss of effective ingredient ginkgetin etc., improved product quality, and stability strengthens, and is clinical easy to use, is easy to transportation and storage.Effective ingredient Ginkgo total flavones among the present invention has dilating coronary blood vessel, cerebrovascular, improves symptom and memory function that cerebral ischemia produces; Dipyridamole anticoagulant, high concentration (50 mcg/ml) can suppress platelet and discharge.The two combination is complemented each other, and can be used for treating coronary heart disease, thrombotic disease.Existing drug form is clinical easy to use, good effect.
The specific embodiment
Embodiment 1:
Get Folium Ginkgo extract 1kg, add the dissolving of 15kg water for injection, centrifugation, supernatant is used filter paper successively, after thin film (aperture≤0.45 μ m) filters, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, in pure extracting solution, add dipyridamole (for Ginkgo total flavones 40%), sodium chloride (final concentration at medicinal liquid is 0.9%), sodium pyrosulfite (final concentration at medicinal liquid is 0.1%) and EDTA disodium (final concentration at medicinal liquid is 0.008%), water for injection is diluted to total amount (content that makes the Ginkgo total flavones amount is 10mg/100ml), regulating pH value is 4.0, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, and fill is in 100 milliliters of infusion bottles, inflated with nitrogen, 121 ℃ of pressure sterilizings 20 minutes.Labeling is packed after the assay was approved.
Embodiment 2:
Get Folium Ginkgo extract 2.5kg, add the dissolving of 25kg water for injection.Centrifugation, supernatant with filter press after, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, the dipyridamole (be Ginkgo total flavones 40%) that in pure extracting solution, adds recipe quantity, sodium chloride (final concentration at medicinal liquid is 0.9%), sodium thiosulfate (final concentration at medicinal liquid is 0.1%) and EDTA calcium sodium (final concentration at medicinal liquid is 0.01%), water for injection is diluted to full dose (content that makes the Ginkgo total flavones amount is 25mg/500ml), regulating pH value is 4.0, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, fill is in 500 milliliters of infusion bottles, inflated with nitrogen, 115 ℃ of pressure sterilizings 30 minutes.Labeling is packed after the assay was approved.
Embodiment 3:
Get Folium Ginkgo 5kg, spend the night with 30kg ethanol-water (1: 1) solution soaking, twice of reflux, extract,, 9 hours for the first time, 7 hours for the second time, after extracting solution merges, filter press, resin bed (the strong acid anion resin on average mixes with the highly basic cationic resin) decontamination, after being concentrated into nothing alcohol flavor, add kieselguhr and cyclodextrin to remove tannin, protein etc., filter, filtrate is with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, the dipyridamole (be Ginkgo total flavones 40%) that in pure extracting solution, adds recipe quantity, glucose (final concentration at medicinal liquid is 5%), vitamin C (final concentration at medicinal liquid is 0.2%) and EDTA disodium (final concentration at medicinal liquid is 0.008%), water for injection is diluted to total amount (content that makes the Ginkgo total flavones amount is 30mg/250ml), regulating pH value is 4.0, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, fill in 250 milliliters of infusion bottles, inflated with nitrogen, 115 ℃ of pressure sterilizings 30 minutes.Labeling is packed after the assay was approved.
Embodiment 4:
Get Folium Ginkgo 3kg, spend the night with 60kg ethanol-water (1: 5) solution soaking, twice of reflux, extract,, 9 hours for the first time, 7 hours for the second time, after extracting solution merges, filter press, after being concentrated into nothing alcohol flavor, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution,, in pure extracting solution, add the dipyridamole (be Ginkgo total flavones 40%) of recipe quantity according to measurement result, glucose (final concentration at medicinal liquid is 10%), vitamin C (final concentration at medicinal liquid is 0.2%) and EDTA calcium sodium (final concentration at medicinal liquid is 0.01%), water for injection (logical nitrogen removes peroxide) is diluted to total amount (content that makes the Ginkgo total flavones amount is 4mg/50ml), regulating pH value is 4.5, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, and fill is in 50 milliliters of infusion bottles, inflated with nitrogen, 115 ℃ of pressure sterilizings 30 minutes.Labeling is packed after the assay was approved.
Embodiment 5:
Get Folium Ginkgo extract 1kg, add the dissolving of 5kg water for injection, centrifugation, supernatant with membrane filtration after, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, in pure extracting solution, add recipe quantity dipyridamole (for Ginkgo total flavones 40%) and vitamin C (account for total amount 0.02%) after, filter membrane degerming, fill (make every and contain Semen Ginkgo total flavones 10.0mg, dipyridamole 4.0mg), lyophilization get lyophilized injectable powder.
Embodiment 6:
Get Folium Ginkgo extract 2kg, add the dissolving of 10kg water for injection, centrifugation, after supernatant is used filter paper, membrane filtration successively, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, after in pure extracting solution, adding dipyridamole (be Ginkgo total flavones 40%), mannitol and the cysteine hydrochloride (0.006%) of recipe quantity, filter membrane degerming, fill (make every and contain Semen Ginkgo total flavones 10.0mg, dipyridamole 4.0mg), lyophilization get lyophilized injectable powder.
Embodiment 7:
Get Folium Ginkgo 50kg, with 500kg ethanol-water (1: 1) solution soaking, twice of reflux, extract,, 9 hours for the first time, 7 hours for the second time, after extracting solution merges, filter press, resin bed (the strong acid anion resin on average mixes with the highly basic cationic resin) decontamination, be concentrated into do not have the alcohol flavor after, add kieselguhr and cyclodextrin to remove tannin, protein etc., filter, filtrate gets pure extracting solution with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, measure Ginkgo total flavones content in this extracting solution, according to measurement result, in pure extracting solution, add the dipyridamole (be Ginkgo total flavones 40%) of recipe quantity, behind sorbitol and the sodium pyrosulfite (0.1%), the filter membrane degerming, the deep bid lyophilization, pulverize, packing (makes every to contain Semen Ginkgo total flavones 5.0mg, dipyridamole 2.0mg), get injectable powder.Labeling is packed after the assay was approved.
Embodiment 8:
Get Folium Ginkgo 15kg, spend the night with 100kg ethanol-water (1: 5) solution soaking, twice of reflux, extract,, after extracting solution merges, filter press, after being concentrated into nothing alcohol flavor, add kieselguhr and cyclodextrin to remove tannin, protein etc. filter, filtrate is with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, the dipyridamole (be Ginkgo total flavones 40%) that in pure extracting solution, adds recipe quantity, the filter membrane degerming, the filter membrane degerming, fill (make every and contain Semen Ginkgo total flavones 10.0mg, dipyridamole 4.0mg), lyophilization gets lyophilized injectable powder.Labeling is packed after the assay was approved.
Embodiment 9:
Get Ginkgo total flavones 200g, add the dissolving of 2kg water for injection, after solution meridian film (aperture≤0.45 μ m) filters, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, after in pure extracting solution, adding dipyridamole (be Ginkgo total flavones 40%), mannitol and the TGA (0.005%) of recipe quantity, filter membrane degerming, fill (make every to contain Semen Ginkgo total flavones 10mg, dipyridamole 4.0mg), lyophilization, lyophilized injectable powder.
Embodiment 10:
Get Ginkgo total flavones 200g and bilobalide 50g, add the dissolving of 7.5kg water for injection, after solution meridian film (aperture≤0.45 μ m) filters, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, the dipyridamole (be Ginkgo total flavones 40%) that in pure extracting solution, adds recipe quantity, glucose (final concentration at medicinal liquid is 10%), sodium pyrosulfite (final concentration at medicinal liquid is 0.1%) and EDTA calcium sodium (final concentration at medicinal liquid is 0.01%), water for injection (logical nitrogen removes peroxide) is diluted to total amount (content that makes the Ginkgo total flavones amount is 4mg/50ml), regulating pH value is 4.5, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, fill is in 50 milliliters of infusion bottles, inflated with nitrogen, 115 ℃ of pressure sterilizings 30 minutes.Labeling is packed after the assay was approved.
Embodiment 11:
Get Ginkgo total flavones 100g and bilobalide 25g, add the dissolving of 2.5kg water for injection, after solution meridian film (aperture≤0.45 μ m) filters, with hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, get pure extracting solution, measure Ginkgo total flavones content in this extracting solution, according to measurement result, the dipyridamole (be Ginkgo total flavones 40%) that in pure extracting solution, adds recipe quantity, sodium chloride (final concentration at medicinal liquid is 0.9%), sodium thiosulfate (final concentration at medicinal liquid is 0.1%) and EDTA calcium sodium (final concentration at medicinal liquid is 0.01%), water for injection is diluted to total amount (content that makes the Ginkgo total flavones amount is 30mg/100ml), regulating pH value is 5.0, hollow fiber ultrafiltration membrane (aperture is no more than 100,000) ultrafiltration, fill in 100 milliliters of infusion bottles, inflated with nitrogen, 115 ℃ of pressure sterilizings 30 minutes.Labeling is packed after the assay was approved.
Embodiment 12:
Ginkgo total flavones content is measured with the following method among the present invention:
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability experiment are filler with octadecylsilane chemically bonded silica; With 0.4% phosphoric acid solution-methanol (50: 50) is mobile phase; Flow velocity is 1.2ml/min; Detect wavelength 360nm.Number of theoretical plate calculates by the Quercetin peak should be not less than 1500, repeats 5 relative standard deviations of sample introduction (RSD) and should be not more than 2.0%.
Reference substance solution prepares precision and takes by weighing the about 12mg of Quercetin reference substance, puts in the 200ml measuring bottle, adds methanol and is diluted to scale, shakes up.
Need testing solution prepares precision, and to measure this product an amount of, adds sulfuric acid solution (5 → 100) 15ml, adds methanol 20ml, put in the water-bath and to reflux 4 hours, put coldly, move in the 100ml measuring bottle, add washed with methanol and, shake up, filter through filter membrane (aperture must not greater than 0.45 μ m) to scale.
The algoscopy precision is measured reference substance solution and each 20 μ l of need testing solution, inject high performance liquid chromatograph respectively, the record chromatogram, Zui Da three peaks wherein, be followed successively by Quercetin (Q), nimbecetin (K), isorhamnetin (I) by retention time, calculate Q, K, I with external standard method, be calculated as follows content of total flavone:
Q×2.50+K×2.59+I×2.44
Claims (9)
1, the compound medicine of a kind of Folium Ginkgo extract and dipyridamole is characterized in that said medicament is the infusion solution that contains Folium Ginkgo effective ingredient and dipyridamole or the intravenous drip injectable powder of intravenously administrable.
2, Folium Ginkgo extract according to claim 1 and dipyridamole compound medicine, each the basic packing unit that it is characterized in that said infusion solution is 50 milliliters to 500 milliliters, include 4 milligrams to 30 milligrams of Ginkgo total flavones, 1.5 milligrams to 15.0 milligrams of dipyridamoles; Every of said injectable powder contains 4 milligrams to 30 milligrams of Semen Ginkgo total flavones, 1.5 milligrams to 15.0 milligrams of dipyridamoles.
3, Folium Ginkgo extract according to claim 1 and dipyridamole compound medicine is characterized in that said Folium Ginkgo active ingredient with the dipyridamole compatibility is the mixture of Folium Ginkgo extract, Ginkgo total flavones or Ginkgo total flavones and bilobalide.
4, according to claim 2 or 3 described Folium Ginkgo extract and dipyridamole compound medicine, it is characterized in that also containing in the said infusion solution sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, in the vitamin C one or more and EDTA disodium and/or EDTA calcium sodium, the alkali-metal carbonate of monovalence also can be arranged, acetate, phosphate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, in phosphoric acid and the aminoacid one or more have sodium chloride simultaneously, potassium chloride, sodium lactate, xylitol, sorbitol, maltose, glucose, fructose, a kind of in dextran or the glycine or several.
5,, it is characterized in that in the said injectable powder also having in one or more and/or the alkali-metal phosphate of monovalence, acetate, carbonate or its aqueous solution and hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid and the aminoacid in mannitol, sorbitol and sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, the vitamin C one or more according to claim 2 or 3 described Folium Ginkgo extract and dipyridamole compound medicine.
6, the preparation method of claim 4 or 5 described Folium Ginkgo extract and dipyridamole compound medicine, it is characterized in that Folium Ginkgo extract is dissolved with 5～15 times of (weight) waters for injection, centrifugation, behind the first successively filter of supernatant, the fine straining, use the hollow fiber ultrafiltration membrane ultrafiltration, get pure extracting solution, press the production procedure of infusion solution, in pure extracting solution, add dipyridamole, isoosmotic adjusting agent and/or reach other additives, and carry out ultrafiltration, dilution, fill, fill operations such as nitrogen, pressure sterilizing, the preparation infusion solution; After pure extracting solution added dipyridamole and/or additives, filter membrane degerming, fill, lyophilization got lyophilized injectable powder.
7, preparation method according to described Folium Ginkgo extract of claim 6 and dipyridamole compound medicine, it is characterized in that with the Folium Ginkgo being initiation material, ethanol-water (1: 1～5) solution soaking with 5～20 times (weight) is spent the night, twice of reflux, extract,, after extracting solution merges, filter, resin bed (the strong acid anion resin on average mixes with the highly basic cationic resin) decontamination, after being concentrated into nothing alcohol flavor, add kieselguhr and cyclodextrin to remove tannin, protein etc. filter, and filtrate is used the hollow fiber ultrafiltration membrane ultrafiltration, get pure extracting solution, preparation infusion solution or injectable powder.
8, according to the preparation method of described Folium Ginkgo extract of claim 6 and dipyridamole compound medicine, it is characterized in that the mixture with Ginkgo total flavones or Ginkgo total flavones and bilobalide is an initiation material, with 1030 times of (weight) water for injection dissolvings, behind the fine straining, use the hollow fiber ultrafiltration membrane ultrafiltration, get pure extracting solution, preparation infusion solution or injectable powder.
9, according to the preparation method of claim 6 or 7 or 8 described Folium Ginkgo extract and dipyridamole compound medicine, when it is characterized in that making injectable powder, medicinal liquid through the deep bid lyophilization, after the pulverizing, is filled into cillin bottle again after the filter membrane degerming.
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| CN 03137926 CN1454596A (en) | 2003-05-30 | 2003-05-30 | Compound medicine of ginkgo leaf extract and dipyridamole and preparing method thereof |
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| CN 03137926 CN1454596A (en) | 2003-05-30 | 2003-05-30 | Compound medicine of ginkgo leaf extract and dipyridamole and preparing method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100352455C (en) * | 2005-11-08 | 2007-12-05 | 贵州益佰制药股份有限公司 | Ginkgo Damo freeze-drying prepn. and its prepn. method |
| CN1939357B (en) * | 2005-09-27 | 2010-12-15 | 博安兄弟制药（中国）有限公司 | Preparation of Ginkgo Damo injection |
| CN102813683A (en) * | 2011-06-09 | 2012-12-12 | 北京华夏众芳生物科技有限公司 | Gingko leaf extract capable of delaying senescence and preparation method and application thereof |
| EP2832348A4 (en) * | 2012-03-31 | 2015-09-02 | Kunming Pharmaceutical Corp | Method for dissolving flavonoid compound, carbon glycoside compound, or stilbene compound and method for preparing injection or powder for injection |
-
2003
- 2003-05-30 CN CN 03137926 patent/CN1454596A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939357B (en) * | 2005-09-27 | 2010-12-15 | 博安兄弟制药（中国）有限公司 | Preparation of Ginkgo Damo injection |
| CN100352455C (en) * | 2005-11-08 | 2007-12-05 | 贵州益佰制药股份有限公司 | Ginkgo Damo freeze-drying prepn. and its prepn. method |
| CN102813683A (en) * | 2011-06-09 | 2012-12-12 | 北京华夏众芳生物科技有限公司 | Gingko leaf extract capable of delaying senescence and preparation method and application thereof |
| CN102813683B (en) * | 2011-06-09 | 2013-12-04 | 北京华夏众芳生物科技有限公司 | Gingko leaf extract capable of delaying senescence and preparation method and application thereof |
| EP2832348A4 (en) * | 2012-03-31 | 2015-09-02 | Kunming Pharmaceutical Corp | Method for dissolving flavonoid compound, carbon glycoside compound, or stilbene compound and method for preparing injection or powder for injection |
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