CN101301267A - Bilobalide B injection and preparation thereof - Google Patents
Bilobalide B injection and preparation thereof Download PDFInfo
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- CN101301267A CN101301267A CNA2008100242077A CN200810024207A CN101301267A CN 101301267 A CN101301267 A CN 101301267A CN A2008100242077 A CNA2008100242077 A CN A2008100242077A CN 200810024207 A CN200810024207 A CN 200810024207A CN 101301267 A CN101301267 A CN 101301267A
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- ginkalide
- bilobalide
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Abstract
The invention relates to a ginkgolide B injection and a method for making the same. The method comprises the following steps that: ginkgolide B is taken as a raw material and is added in ethanol, glycerol and PEG600, wherein the ratio between the ginkgolide B and the ethanol is between 1:25 and 1:200; the ratio between the ginkgolide B and the PEG600 is between 1:25 and 1:600; and the ratio between the ginkgolide B and the glycerol is between 1:12.5 and 1:50. The ginkgolide B injection has good stability and low cost, and each index of the injection meets the requirements of preparation; moreover, the making process of the injection has the characteristics of quick dissolution of a raw material and simple process, and is suitable for industrialized production.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, be specifically related to a kind of bilobalide B injection and preparation method thereof.
Technical background
Bilobalide is one of present strong specificity platelet activation factor (PAF) receptor blocking agent, Semen Ginkgo lactone B is the strongest to the paf receptor blocking effect in the bilobalide, but the caused platelet aggregation effect of the elimination PAF of dose dependent, thereby the formation of anti-tampon, and to not having effect by the inductive platelet aggregation of adenosine diphosphate (ADP), arachidonic acid, collagen and epinephrine.Up-to-date pharmacological research shows that ginkalide B has antiallergic, anti-inflammatory, Antishock function, and the rejection of ischemic injuries and organ transplantation is also had protective effect.
Ginkalide B content in Folium Ginkgo and Folium Ginkgo extract is very low, the Semen Ginkgo class preparation of Chu Xianing is an effective site with Ginkgo total lactones and total flavones mainly in the market, monomeric Semen Ginkgo class preparation does not appear as yet, monomeric the obtaining of ginkalide B mainly passed through liquid phase production at present, is difficult to form industrialization.Ginkalide B poorly soluble in water simultaneously, the span, tween 80 etc. that can be used for hydrotropy clearly are decided to be the adjuvant that causes the injection untoward reaction by the expert of State Bureau.At present, ginkalide B is made the injection difficulty, so be difficult to give full play to the advantage of its treatment.
Summary of the invention
The object of the present invention is to provide that a kind of cost is low, the bilobalide B injection of good stability.
Another object of the present invention is to provide the preparation technology of this bilobalide B injection.
A kind of bilobalide B injection is characterized in that with the ginkalide B being raw material, adds ethanol, glycerol and PEG600 (Macrogol 600); Wherein, ginkalide B is that 1: 25～200 (g/ml), ginkalide B are that 1: 25～600 (g/ml), bilobalide B raw material are 1: 12.5～50 (g/ml) with the ratio of glycerol with the ratio of PEG600 with the ratio of ethanol.
Described bilobalide B injection can be prepared by following steps:
Getting ginkalide B by above-mentioned formula proportion adds ethanol, glycerol and PEG600 and dissolves under 60 ℃ of conditions, adding water for injection to ginkalide B concentration again is that 0.5mg/ml～4mg/ml gets injection solution, by the active carbon that adds 0.1～1g in every 1L injection solution, be heated to 80～100 ℃ and fully stir 15～30min, take off charcoal, filtration, filtrate injection preparation method routinely obtains bilobalide B injection.
The preparation method of above-mentioned bilobalide B injection is characterized in that this method may further comprise the steps:
Getting ginkalide B according to the above ratio adds ethanol, glycerol and PEG600 and dissolves under 60 ℃ of conditions, adding water for injection to ginkalide B concentration again is that 0.5mg/ml～4mg/ml gets injection solution, by the active carbon that adds 0.1～1g in every 1L injection solution, be heated to 80～100 ℃ and fully stir 15～30min, take off charcoal, filtration, filtrate injection preparation method routinely obtains bilobalide B injection.
Ginkalide B injection of the present invention is used for the treatment of the thoracic obstruction, pained, the ischemia apoplexy that obstruction of collaterals by blood stasis causes.
The used ginkalide B of the present invention can be commercially available.
Beneficial effect of the present invention:
Ginkalide B is as lactone in, and its poorly soluble in water uses it to be still a difficult problem as injection.The preparation recipe that the present invention obtains by long-felt can be made ginkalide B the aqueous solution of stable in properties.It varies with temperature easily and separates out from solution after the ginkalide B dissolving, so add glycerol as stabilizing agent.Ethanol can with PEG600 as the ginkalide B cosolvent, ethanol has the advantage of quick dissolving ginkalide B, but it is volatile; Can increase the dissolving of ginkalide B by adding cosolvent PEG600, the ginkalide B solubilization-aid effect is weaker than ethanol, but remedy the volatile shortcoming of ethanol.It is fast that bilobalide B injection technology of the present invention has the dissolving raw material, the process characteristic of simple, and simultaneously stability of formulation is good, with low cost, and every index reaches all to the preparation requirement, is suitable for suitability for industrialized production.
Test example 1
Adopt different auxiliary material to make the comparing data table of bilobalide B injection stability:
| Adjuvant | Solution temperature | Dissolution time | Room temperature is preserved | After being injected into normal saline |
| Ethanol | 40℃ | 20min | Stable | Crystallize appears behind the 10min |
| Ethanol, glycerol | 40℃ | 25min | Stable | Crystallize appears behind the 20min |
| PEG600, ethanol, glycerol | 80℃ | 30min | Stable | 24h crystallize do not occur and occurs |
Annotate: the ginkalide B concentration of preparation is 20mg/10ml; Inject the 250ml normal saline.
The result: ginkalide B is intravenous drip in clinical use, so use after bilobalide injection will being added normal saline, product of the present invention crystallize do not occur in 24 hours, thereby has guaranteed normal clinical use.
Conclusion: PEG600 grease, avirulence can be wrapped in ginkalide B wherein, forms the stable microemulsion agent.In clinical use, need bilobalide B injection is injected normal saline, this moment, the concentration of ethanol and glycerol was diluted, the crystallize that can cause ginkalide B, and the injection that adds behind the PEG600 is a microemulsion, the process of injecting normal saline at bilobalide B injection has guaranteed that ginkalide B is dissolved in solution in good condition and does not have crystal and separate out, therefore ginkalide B injection of the present invention in use has more excellent stability, and with low cost.
Test example 2 ginkalide B injection pharmacodynamic studies
Place: Shandong University
1, to the influence of focal brain ischemia-reperfusion injury in rats model
Purpose: observe of the protective effect of ginkalide B injection, inquire into the curative effect of its treatment ischemic encephalopathy and cerebral thrombosis, for clinical experimental study provides reference to focal brain ischemia-reperfusion injury in rats.
Method: get healthy male Wistar rat, adaptability is tested after feeding a week.If sham operated rats, model group, the basic, normal, high dosage group of ginkalide B injection and Ginaton injection positive controls, totally 9 groups.Adopt bolt line blocked method (MCAO) preparation focal brain ischemia-reperfusion injury in rats model in improved Zea Longa ' the s middle cerebral artery, and behind ischemia 1.5h, pour into again.Each group is respectively at cerebral ischemia (iv) relative medicine of tail vein injection at once, and sham operated rats and model group give respective volume 0.9% sodium chloride injection, and basic, normal, high group of dosage of ginkalide B injection is respectively 1.5,3 and 6mgkg
-1, Ginaton injection positive controls dosage is 3mlkg
-1, the blank group gives equal-volume 0.9% sodium chloride injection.
After cerebral ischemia 1.5h poured into 24h again, each treated animal carried out neurologic check, got brain then and carried out TTC dyeing, and ischemia side cerebral infarction volume is measured in the back of taking pictures.In the experimentation, MCAO operative failure, the unsuccessful animal that reaches death in the 24h of modeling are all given it up, and not enough predetermined number person is according to the also modeling again of stochastic sampling principle polishing animal.
The influence (n=10) that table 1 ginkalide B injection changes the rat neuroethology
*P＜0.05,
*Compare with model control group P＜0.01;
△P＜0.05,
△ △Compare with the Ginaton group P＜0.01.
Table 2 ginkalide B injection is to the influence of rat cerebral infarction volume (n=10, x ± S)
*P＜0.05,
*Compare with model control group P＜0.01;
△P＜0.05,
△ △Compare with the Ginaton group P＜0.01.
The result:
(1) influence of neuroethology: after rat ischemia 1.5h poured into 24h again, sham operated rats did not have obvious neurologic impairment, and function of nervous system learns scoring and is 0.Neurologic impairment sign in various degree then appears in model group, and ginkalide B injection and Ginaton injection group neurologic impairment symptom have clear improvement.After ischemia 1.5h poured into 24h again, each medication group function of nervous system scoring was compared with model group, and the middle and high dosage group of ginkalide B injection has remarkable significant difference (P＜0.01), and the Ginaton injection group has obvious significant difference (P＜0.05).
(2) the brain general form learn to change: after rat ischemia 1.5h poured into 24h again, sham operated rats rat brain outward appearance was bright and clean, and color, form are normal, variations such as no pale, edema, hyperemia, bilateral cerebral tissue symmetrical configuration; The obvious edema of model group ischemia side cerebral hemisphere, volume obviously increases than offside, and center line is offset to the right.Ischemia side cerebral hemisphere top is the fat-like pale asphyxia, and cerebral tissue is softening frangible, the hyperemia of meningovascular height; Each medication group ischemia side cerebral hemisphere edema alleviates or obviously alleviates, and meningovascular hyperemia alleviates, and Infarction volume has obviously than model group and reduces.
The specific embodiment
By the following examples, the invention will be further described, and following embodiment to the present invention without limits.
Embodiment 1
1, bilobalide B injection preparation:
Prescription:
Ginkalide B 2g
Ethanol 150ml
PEG600 200ml
Glycerol 50ml
Water for injection 600ml
Method for making: the ginkalide B (the emerging biochemical company limited far away in Taiyuan) of getting above-mentioned recipe quantity, add ethanol 150ml, PEG600200ml, glycerol 50ml, be heated to 60 ℃ of stirrings, ginkalide B is fully dissolved, add water for injection 600ml again, be heated to 100 ℃ of stirring and evenly mixings, add the 0.3g active carbon, stir 15min, take off charcoal, filtration, embedding, sterilization, lamp inspection, packing, promptly obtain the ginkalide B liquid drugs injection.
Embodiment 2
1, the preparation of ginkalide B: take by weighing Folium Ginkgo 10kg, the hydrochloric acid digestion 30min that adds 500L1%, filter, obtain filtrate 480L, use the 480L n-butanol extraction, extract is concentrated in right amount, add an amount of 100～200 order silica gel, the mixing oven dry, last silicagel column (blade diameter length ratio is 1: 1, silica gel consumption 3kg), with ethyl acetate: acetone is 4: 6 ratio preparation mobile phase, control flow velocity 210ml/min, the 40L effluent of collection bilobalide-containing B concentrates the dried dried cream of 6g that obtains, add 180ml 95% alcohol crystal, obtain the 2.3g bilobalide B raw material, wherein, ginkalide B content is 91.5%.
2, bilobalide B injection preparation:
Prescription:
Ginkalide B 4g
Ethanol 400ml
PEG600 100ml
Glycerol 50ml
Water for injection 450ml
Method for making: the ginkalide B of getting recipe quantity, add ethanol 400ml, PEG600100ml, glycerol 50ml, be heated to 60 ℃ of stirring and evenly mixings, ginkalide B is fully dissolved, add water for injection 450ml again, stirring and evenly mixing, add the 0.5g active carbon, be heated to 80 ℃ and stir 30min, take off charcoal, filtration, embedding, sterilization, lamp inspection, packing, promptly obtain the ginkalide B liquid drugs injection.
Embodiment 3
1, the preparation of ginkalide B: take by weighing Folium Ginkgo extract and (meet " 2000 editions requirements of Chinese Pharmacopoeia, the emerging biochemical company limited far away in Taiyuan) 1kg, the hydrochloric acid digestion 30min that adds 5L0.1% filters, and obtains filtrate 4.8L, extract with the 4.8L acetoacetic ester, extract is concentrated in right amount, adds an amount of 100～200 order silica gel, the mixing oven dry, (blade diameter length ratio is 1: 1 to last silicagel column, silica gel consumption 2.5kg), with n-butyl alcohol: petroleum ether is 8: 2 a ratio preparation mobile phase, control flow velocity 360ml/min, collect the 35L effluent, concentrate the dried dried cream of 5g that obtains, add 150ml 95% alcohol crystal, obtain the 1.7g bilobalide B raw material, wherein, ginkalide B content is 90.7%.
2, bilobalide B injection preparation:
Prescription:
Ginkalide B 0.5g
Ethanol 100ml
PEG600 300ml
Glycerol 20ml
Water for injection 580ml
Method for making: the ginkalide B of getting recipe quantity, add ethanol 100ml, PEG600300ml, glycerol 20ml, be heated to 60 ℃ of stirrings, ginkalide B is fully dissolved, add water for injection 580ml again, stirring and evenly mixing, add the 0.1g active carbon, be heated to 90 ℃ and stir 20min, take off charcoal, filtration, embedding, sterilization, lamp inspection, packing, promptly obtain the ginkalide B liquid drugs injection.
Embodiment 4
The bilobalide B injection preparation:
Prescription:
Ginkalide B 4g
Ethanol 500ml
PEG600 200ml
Glycerol 80ml
Water for injection 220ml
Method for making: the ginkalide B of getting recipe quantity, add ethanol 500ml, PEG600 200ml, glycerol 80ml, be heated to 60 ℃ of stirrings, ginkalide B is fully dissolved, add water for injection 220ml again, stirring and evenly mixing, add the 0.5g active carbon, be heated to 80 ℃ and stir 15min, take off charcoal, filtration, embedding, sterilization, lamp inspection, packing, promptly obtain the ginkalide B liquid drugs injection.
Embodiment 5
The bilobalide B injection preparation:
Prescription:
Bilobalide B raw material 2g
Ethanol 50ml
PEG600 400ml
Glycerol 100ml
Water for injection 450ml
Method for making: the ginkalide B of getting recipe quantity, add ethanol 50ml, PEG600400ml, glycerol 100ml, be heated to 60 ℃ of stirrings, bilobalide B raw material is fully dissolved, add water for injection 450ml again, stirring and evenly mixing, add the 0.2g active carbon, be heated to 100 ℃ and stir 15min, take off charcoal, filtration, embedding, sterilization, lamp inspection, packing, promptly obtain the ginkalide B liquid drugs injection.
Claims (3)
1, a kind of bilobalide B injection is characterized in that with the ginkalide B being raw material, adds ethanol, glycerol and PEG600; Wherein, the ratio of ginkalide B and ethanol is 1: 25～200, the ratio of ginkalide B and PEG600 is 1: 25～600, ginkalide B is 1: 12.5～50 with the ratio of glycerol.
2, the preparation method of the described bilobalide B injection of a kind of claim 1 is characterized in that this method may further comprise the steps:
Getting ginkalide B, ethanol, glycerol and PEG600 by formula proportion dissolves under 60 ℃ of conditions, adding water for injection to ginkalide B concentration again is that 0.5mg/ml～4mg/ml gets injection solution, add the active carbon of 0.1～1g in every 1L injection solution, be heated to 80～100 ℃ and fully stir 15～30min, take off charcoal, filtration, filtrate injection preparation method routinely obtains bilobalide B injection.
3, the application of the described bilobalide B injection of claim 1 in the thoracic obstruction that causes of treatment obstruction of collaterals by blood stasis, pained, ischemia apoplexy.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100242077A CN101301267B (en) | 2008-05-21 | 2008-05-21 | Bilobalide B injection and preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100242077A CN101301267B (en) | 2008-05-21 | 2008-05-21 | Bilobalide B injection and preparation thereof |
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|---|---|
| CN101301267A true CN101301267A (en) | 2008-11-12 |
| CN101301267B CN101301267B (en) | 2011-07-13 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103142473A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Composition containing high purity bilobalide B and preparation method thereof |
| CN103142474A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Composition taking high-purity ginkgolide B as active ingredient and preparation method thereof |
| CN103142472A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Ginkgolide B composition and preparation method thereof |
| WO2013159411A1 (en) * | 2012-04-23 | 2013-10-31 | 成都百裕科技制药有限公司 | Ginkgolide injection and preparation method thereof |
| CN103877017A (en) * | 2014-04-18 | 2014-06-25 | 夏中宁 | Bilobalide B injection and preparation method thereof |
| CN104415044A (en) * | 2013-08-30 | 2015-03-18 | 陈震 | Pharmaceutical composition and preparation thereof for treating stroke and sequelae thereof |
| CN113484457A (en) * | 2021-06-29 | 2021-10-08 | 山东省中医药研究院 | Preparation method and application of test solution in thin-layer chromatography detection of traditional Chinese medicine compound preparation |
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2008
- 2008-05-21 CN CN2008100242077A patent/CN101301267B/en active Active
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| WO2013159411A1 (en) * | 2012-04-23 | 2013-10-31 | 成都百裕科技制药有限公司 | Ginkgolide injection and preparation method thereof |
| CN103142474B (en) * | 2013-03-26 | 2015-09-23 | 山东罗欣药业集团股份有限公司 | With the composition and method of making the same that high purity bilobalide B is active component |
| CN103142472A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Ginkgolide B composition and preparation method thereof |
| CN103142474A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Composition taking high-purity ginkgolide B as active ingredient and preparation method thereof |
| CN103142473A (en) * | 2013-03-26 | 2013-06-12 | 山东罗欣药业股份有限公司 | Composition containing high purity bilobalide B and preparation method thereof |
| CN103142473B (en) * | 2013-03-26 | 2015-09-23 | 山东罗欣药业集团股份有限公司 | A kind of composition and method of making the same containing high purity bilobalide B |
| CN103142472B (en) * | 2013-03-26 | 2016-05-11 | 山东罗欣药业集团股份有限公司 | A kind of ginkolide B composition and method of making the same |
| CN104415044A (en) * | 2013-08-30 | 2015-03-18 | 陈震 | Pharmaceutical composition and preparation thereof for treating stroke and sequelae thereof |
| CN104415044B (en) * | 2013-08-30 | 2018-10-16 | 陈震 | A kind of pharmaceutical composition and its preparation for treating apoplexy and its sequelae |
| CN103877017A (en) * | 2014-04-18 | 2014-06-25 | 夏中宁 | Bilobalide B injection and preparation method thereof |
| CN103877017B (en) * | 2014-04-18 | 2016-02-03 | 夏中宁 | A kind of Ginkgolide B injection and preparation method thereof |
| CN113484457A (en) * | 2021-06-29 | 2021-10-08 | 山东省中医药研究院 | Preparation method and application of test solution in thin-layer chromatography detection of traditional Chinese medicine compound preparation |
| CN113484457B (en) * | 2021-06-29 | 2023-10-24 | 山东省中医药研究院 | Preparation method and application of sample solution in thin-layer chromatography detection of traditional Chinese medicine compound preparation |
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| Publication number | Publication date |
|---|---|
| CN101301267B (en) | 2011-07-13 |
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