CN1698599A - Bilobalide injection and preparation method thereof - Google Patents
Bilobalide injection and preparation method thereof Download PDFInfo
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- CN1698599A CN1698599A CN 200510072466 CN200510072466A CN1698599A CN 1698599 A CN1698599 A CN 1698599A CN 200510072466 CN200510072466 CN 200510072466 CN 200510072466 A CN200510072466 A CN 200510072466A CN 1698599 A CN1698599 A CN 1698599A
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Abstract
The invention relates to a bilobalide injection and preparation process, wherein the preparation process comprises charging hydroxypropyl-beta-cyclodextrin into water for injection, stirring to dissolve, charging bilobalide, stirring and heating to dissolve, charging chelating agent, stirring and dissolving, charging activated charcoal and straining, charging water for injection for constant volume, refining and split charging, hot-pressed sterilization.
Description
The application is one and divides an application, and the applying date of original application is that June 30, application number in 2004 are 200410041120.2, invention and created name is " bilobalide extraction process and bilobalide injection and preparation method thereof ".
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, particularly relate to a kind of bilobalide extraction process and bilobalide injection and preparation method thereof.
Background technology
Sought potent PAF (platelet activating factor) antagonist and be one of great direction of new drug research since the eighties in last century.PAF participates in many pathophysiological processes in vivo, acts on widely, and activity is very big, has found that PAF plays an important role in the pathological processes such as shock that thrombosis, asthma, organ-graft refection, acute inflammation, heart allergy, endotoxin cause.In the research of PAF antagonist, the ginkgolide compound that screens from natural product is that activity is the strongest, estimate maximum natural products, pharmacology and clinical research also show, ginkgolide compound is state-of-the-art PAF antagonist, and wherein the selectivity of ginkalide B antagonism paf receptor and activity are the strongest.Bilobalide is as highly narrow spectrum paf receptor blocker, its active strong and weak IC
50Be respectively: ginkalide B 0.25Mm＞ginkalide A 0.74Mm＞ginkalide C 7.1Mm.Bilobalide acts on mainly showing as to the central nervous system and can stop the damage that causes after the cerebral ischemia, can obviously improve cerebral ischemic condition, and cerebral edema, electrolyte disturbance, inflammatory cell infiltration that ischemia is caused have remarkable inhibitory action.Bilobalide can anticoagulant, and blood viscosity lowering improves ischemia patient's microcirculation, reduces thrombosis; The bilobalide stabilizing cell membrane reduces the osmosis of angiotensin; Have antiallergic, antiinflammatory, Antishock function, the rejection of ischemic injuries and organ transplantation is also had protective effect.In addition, all right SOD activity improving of bilobalide is eliminated free radical, slow down aging.But present bilobalide extraction process cost height, yield is low, active substance content is few, and because bilobalide dissolubility in water is low, is difficult for making the injection of high concentration, has limited its effective application.
Summary of the invention
The extraction process that the purpose of this invention is to provide the bilobalide that a kind of cost is low, yield is high.
Another object of the present invention provides the bilobalide injection of a kind of concentration height, Heat stability is good.
A further object of the invention provides the preparation method of above-mentioned bilobalide injection.
Extraction solvent used in the bilobalide extraction process of the present invention is rare acetone solution, ethyl acetate, in the technology with petroleum ether and sodium acetate solution remove impurity; Use ethyl alcohol recrystallization.This process using solvent method.
The present invention has selected the solubilizing agent of HP-as bilobalide for use, can improve the dissolubility of bilobalide in water greatly, can make transfusion and use, solve the heavy dose of use problem of bilobalide, also make the heat stability of bilobalide in water obtain bigger raising simultaneously.Adding an amount of isoosmotic adjusting agent in transfusion makes with blood etc. and oozes.For improving the long-term stability of placing of transfusion, can also add an amount of chelating agen.
The present invention is realized by following scheme:
A kind of extraction process of bilobalide is characterized in that comprising the following step:
Take by weighing a certain amount of Folium Ginkgo, pulverize, the rare acetone solution warm macerating that adds the several times amount extracts, and uses the remove impurity of remove impurity solvent behind the recovery acetone, the ethyl acetate extraction purification, and sodium acetate is remove impurity again, reclaims ethyl acetate, and recrystallization in ethanol or the methanol filters cold drying.
Described extraction process, the rare acetone extraction of Folium Ginkgo wherein, its concentration is 20%～70%, and the warm macerating temperature is 30～55 ℃, and the acetone consumption is 2～10 times of crude drug.
Described extraction process, the remove impurity solvent can be normal hexane, cyclohexane extraction, chloroform, petroleum ether (30～120 ℃) in its extraction process.
Described extraction process, the abstraction purification solvent is ethyl acetate, 2-15% sodium acetate solution or sodium bicarbonate solution in its extraction process.
Described extraction process, the bilobalide recrystallization solvent is 40～95% ethanol or methanol in its extraction process, and is dry under the 40-80 ℃ of temperature.
A kind of bilobalide injection, it is the aqueous solution that adopts the HP-solubilising to make to bilobalide.
Described bilobalide injection, it also contains chelating agen.
Described bilobalide injection, wherein chelating agen can be disodiumedetate or calcium disodium chelate.
Described bilobalide injection, it also contains isoosmotic adjusting agent.
Described bilobalide injection, wherein isoosmotic adjusting agent can be sodium chloride or glucose.
Above-mentioned arbitrary bilobalide injection contains in every 100ml preparation:
Bilobalide 0.001-0.1g HP-0.01-10g isoosmotic adjusting agent 0.5-5g chelating agen 0.01-0.05g.
The preparation method of described bilobalide injection, comprise dissolving, charcoal treatment, coarse filtration, standardize solution, fine straining, packing, sterilization process, it is characterized in that HP-is added in the water for injection, after the stirring and dissolving, add bilobalide again, stir and be heated to dissolving, add isoosmotic adjusting agent and chelating agen stirring and dissolving then, add coarse filtration after the charcoal treatment, add fine straining behind the injection water standardize solution, packing, pressure sterilizing.
Advantage of the present invention:
Adopt this law production bilobalide advantage as follows:
1, this law adopts solvent method to extract bilobalide, cuts off domestic resin column commonly used at present and other adsorbents and produces bilobalide.This law is simple to operate, pollute less, cost is low.
2, this law is extracted the bilobalide yield up to more than 0.1%, and only is about 0.07% with other extracting method bilobalide yield.
3, this law extraction bilobalide content reaches more than 90%, and wherein ginkalide B content reaches 50%, and ginkalide B content can only reach about 30% in the like product.
4, major impurity separating Ginkgo phenolic acids content is less than 5ppm in this law extraction bilobalide, and phenolic acids content is higher than 100ppm in the bilobalide of additive method production.
5, HP-is a beta-cyclodextrin derivative, and good water solubility is nontoxic non-stimulated, can be used as the used for intravenous injection adjuvant, and multiple medicine is had solubilising and clathration.The present invention utilizes HP-to the bilobalide solubilising, not only solved the water solublity problem of bilobalide under non-alkali condition, make bilobalide dissolubility maximum under non-alkali condition can reach 1mg/ml, and can improve the heat stability of bilobalide aqueous solution, make the injection pressure sterilizing become possibility, the injection of preparation is safer, more stable, helps clinical application.
Bilobalide injection of the present invention is according to clinical needs, solved the heavy dose of problem of using of bilobalide, simplified operation, easy to use, avoided extracting the intermediate link of injecting sodium chloride or glucose infusion liquid by little envelope pin, stop the cross-contamination in the medication process, improved medicine quality, ensured drug safety.Bilobalide transfusion of the present invention can be made all size, directly selects for use for the clinician.
This transfusion appearance colorless is clear and bright, and every index all meets " Chinese Pharmacopoeia version (second one) in 2000 " appendix IB pertinent regulations.
6, the preparation method cost of bilobalide injection of the present invention is low, simple.
The specific embodiment
The invention will be further elaborated by the following examples.
Embodiment 1
The extraction process of bilobalide: take by weighing Folium Ginkgo 100g and pulverize, the 70% acetone solution warm macerating that adds 4 times of amounts extracts, and temperature is 30 ℃, and lixiviate 5 hours was stirred once every 10 minutes, filtered, and got filtrate I.Medicinal residues continue to add the 70% acetone solution warm macerating extraction of 4 times of amounts, and temperature is 30 ℃, and lixiviate 1 hour is filtered, and gets filtrate II.Medicinal residues continue to add 3 times of amount 70% acetone solution warm macerating and extract, and temperature is 30 ℃, and lixiviate 1 hour is filtered, and gets filtrate II I, and medicinal residues discard.Merge three times extracting solution, reclaim 1/4 amount of acetone, place to about cumulative volume.Filter above-mentioned concentrated solution and use petroleum ether (30 ℃, consumption is 2: 1) remove impurity 4 times, water extracts 3 times with ethyl acetate (consumption is 2: 1); Ethyl acetate liquid reclaims ethyl acetate with 8% sodium acetate solution (consumption is 2: 1) washing, and residue 70% dissolve with ethanol is placed crystallize, filtration, 70 ℃ of vacuum dryings (0.07～0.08MPa), promptly.
Embodiment 2
The extraction process of bilobalide: take by weighing Folium Ginkgo 200g and pulverize, the 50% acetone solution warm macerating that adds 7 times of amounts extracts, and temperature is 40 ℃, and lixiviate 6 hours was stirred once every 10 minutes, filtered, and got filtrate I.Medicinal residues continue to add the 50% acetone solution warm macerating extraction of 5 times of amounts, and temperature is 40 ℃, and lixiviate 1 hour is filtered, and gets filtrate II.Medicinal residues continue to add 3 times of amount 50% acetone solution warm macerating and extract, and temperature is 40 ℃, and lixiviate 1 hour is filtered, and gets filtrate II I, and medicinal residues discard.Merge three times extracting solution, reclaim 1/4 amount of acetone, place to about cumulative volume.Filter above-mentioned concentrated solution and use petroleum ether (120 ℃, consumption is 3: 1) remove impurity 5 times, water extracts 4 times with ethyl acetate (consumption is 3: 1); Ethyl acetate liquid reclaims ethyl acetate with 10% sodium acetate solution (consumption is 3: 1) washing, and residue 50% dissolve with ethanol is placed crystallize, filtration, 40 ℃ of vacuum dryings (0.07～0.08MPa), promptly.
Embodiment 3
The extraction process of bilobalide: take by weighing Folium Ginkgo 200g and pulverize, the 60% acetone solution warm macerating that adds 5 times of amounts extracts, and temperature is 50 ℃, and lixiviate 8 hours was stirred once every 10 minutes, filtered, and got filtrate I.Medicinal residues continue to add the 60% acetone solution warm macerating extraction of 5 times of amounts, and temperature is 50 ℃, and lixiviate 2 hours is filtered, and gets filtrate II.Medicinal residues continue to add 4 times of amount 60% acetone solution warm macerating and extract, and temperature is 50 ℃, and lixiviate 2 hours is filtered, and gets filtrate II I, and medicinal residues discard.Merge three times extracting solution, reclaim 1/4 amount of acetone, place to about cumulative volume.Filter above-mentioned concentrated solution also with cyclohexane extraction (consumption is 3: 1) remove impurity 3 times, water extracts 2 times with ethyl acetate (consumption is 3: 1); Ethyl acetate liquid reclaims ethyl acetate with 15% sodium acetate solution (consumption is 3: 1) washing, and residue 95% dissolve with ethanol is placed crystallize, filtration, 50 ℃ of vacuum dryings (0.07～0.08MPa), promptly.
Embodiment 4
The extraction process of bilobalide: take by weighing Folium Ginkgo 200g and pulverize, the 20% acetone solution warm macerating that adds 10 times of amounts extracts, and temperature is 55 ℃, and lixiviate 6 hours was stirred once every 10 minutes, filtered, and got filtrate I.Medicinal residues continue to add the 20% acetone solution warm macerating extraction of 8 times of amounts, and temperature is 55 ℃, and lixiviate 1 hour is filtered, and gets filtrate II.Medicinal residues continue to add 6 times of amount 20% acetone solution warm macerating and extract, and temperature is 55 ℃, and lixiviate 1 hour is filtered, and gets filtrate II I, and medicinal residues discard.Merge three times extracting solution, reclaim 1/6 amount of acetone, place to about cumulative volume.Filter above-mentioned concentrated solution also with chloroform (consumption is 4: 1) remove impurity 6 times, water extracts 6 times with ethyl acetate (consumption is 4: 1); Ethyl acetate liquid reclaims ethyl acetate with 2% sodium acetate solution (consumption is 4: 1) washing, and residue 40% dissolve with ethanol is placed crystallize, filtration, 80 ℃ of vacuum dryings (0.07～0.08MPa), promptly.
Embodiment 5
Bilobalide sodium chloride injection and preparation method: take by weighing HP-50g and add in the 5000ml water for injection, after the stirring and dissolving, add bilobalide 2.5g according to specification, stir and be heated to dissolving, add sodium chloride 89g and calcium disodium chelate 1g stirring and dissolving, add active carbon 2.5g, 80 ℃ of insulations were also stirred 10 minutes, and the coarse filtration carbon removal adds the injection water to 10000ml, mixing, with 0.22 μ m filtering with microporous membrane, gained solution is sub-packed in the 100ml infusion bottle, and every bottle contains bilobalide 25mg, sterilized 30 minutes for 115 ℃, promptly get the bilobalide transfusion.
Embodiment 6
Bilobalide glucose injection and preparation method: production technology changes sodium chloride 89g among the embodiment 5 into glucose 494g with embodiment 5.
Embodiment 7
Bilobalide sodium chloride injection and preparation method: take by weighing HP-500g and add in the 5000ml water for injection, after the stirring and dissolving, add bilobalide 5g according to specification, stir and be heated to dissolving, add sodium chloride 89g and disodiumedetate 1g stirring and dissolving, add active carbon 2.5g, 80 ℃ of insulations were also stirred 10 minutes, and the coarse filtration carbon removal adds the injection water to 10000ml, mixing, with 0.22 μ m filtering with microporous membrane, gained solution is sub-packed in the 100ml infusion bottle, and every bottle contains bilobalide 50mg, sterilized 30 minutes for 115 ℃, promptly get the bilobalide transfusion.
Embodiment 8
Bilobalide glucose injection and preparation method: production technology changes sodium chloride 89g among the embodiment 7 into glucose 494g with embodiment 7.
Embodiment 9
Bilobalide sodium chloride injection and preparation method: take by weighing HP-800g and add in the 5000ml water for injection, after the stirring and dissolving, add bilobalide 8g according to specification, stir and be heated to dissolving, add sodium chloride 89g and calcium disodium chelate 1g stirring and dissolving, add active carbon 2.5g, 80 ℃ of insulations were also stirred 10 minutes, and the coarse filtration carbon removal adds the injection water to 10000ml, mixing, with 0.22 μ m filtering with microporous membrane, gained solution is sub-packed in the 100ml infusion bottle, and every bottle contains bilobalide 80mg, sterilized 30 minutes for 115 ℃, promptly get the bilobalide transfusion.
Embodiment 10
Bilobalide glucose injection and preparation method: production technology changes sodium chloride 89g among the embodiment 9 into glucose 494g with embodiment 9.
Embodiment 11
Bilobalide sodium chloride injection and preparation method: take by weighing HP-1000g and add in the 5000ml water for injection, after the stirring and dissolving, add bilobalide 10g according to specification, stir and be heated to dissolving, add sodium chloride 89g and calcium disodium chelate 1g stirring and dissolving, add active carbon 2.5g, 80 ℃ of insulations were also stirred 10 minutes, and the coarse filtration carbon removal adds the injection water to 10000ml, mixing, with 0.22 μ m filtering with microporous membrane, gained solution is sub-packed in the 100ml infusion bottle, and every bottle contains bilobalide 100mg, sterilized 30 minutes for 115 ℃, promptly get the bilobalide transfusion.
Embodiment 12
Bilobalide glucose injection and preparation method: production technology changes sodium chloride 89g among the embodiment 11 into glucose 494g with embodiment 11.
Claims (7)
1, a kind of bilobalide injection is characterized in that it is the aqueous solution that adopts the HP-solubilising to make to bilobalide.
2, bilobalide injection according to claim 1 is characterized in that also containing chelating agen.
3, bilobalide injection according to claim 2 is characterized in that chelating agen can be disodiumedetate or calcium disodium chelate.
4, bilobalide injection according to claim 1 is characterized in that also containing isoosmotic adjusting agent.
5, bilobalide injection according to claim 4 is characterized in that isoosmotic adjusting agent can be sodium chloride or glucose.
6,, it is characterized in that containing in every 100ml preparation according to the arbitrary described bilobalide injection of claim 1～5:
Bilobalide 0.001-0.1g HP-0.01-10g isoosmotic adjusting agent 0.5-5g chelating agen 0.01-0.05g.
7, the preparation method of the arbitrary described bilobalide injection of claim 1～6, comprise dissolving, charcoal treatment, coarse filtration, standardize solution, fine straining, packing, sterilization process, it is characterized in that HP-is added in the water for injection, after the stirring and dissolving, add bilobalide again, stir and be heated to dissolving, add isoosmotic adjusting agent and chelating agen stirring and dissolving then, add coarse filtration after the charcoal treatment, add fine straining behind the injection water standardize solution, packing, pressure sterilizing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510072466 CN1698599A (en) | 2004-06-30 | 2004-06-30 | Bilobalide injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510072466 CN1698599A (en) | 2004-06-30 | 2004-06-30 | Bilobalide injection and preparation method thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410041120 Division CN1263763C (en) | 2004-06-30 | 2004-06-30 | Process for extracting ginkgolide, ginkgolide injection and process for preparing same |
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| CN1698599A true CN1698599A (en) | 2005-11-23 |
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| CN 200510072466 Pending CN1698599A (en) | 2004-06-30 | 2004-06-30 | Bilobalide injection and preparation method thereof |
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