CN1513449A - Prepn. method for injection of ginkgolide - Google Patents
Prepn. method for injection of ginkgolide Download PDFInfo
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- CN1513449A CN1513449A CNA031377203A CN03137720A CN1513449A CN 1513449 A CN1513449 A CN 1513449A CN A031377203 A CNA031377203 A CN A031377203A CN 03137720 A CN03137720 A CN 03137720A CN 1513449 A CN1513449 A CN 1513449A
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Abstract
A ginkalide injection for treating cardiovascular and cerebrovascular diseases is prepared through dissolving the ginkalide in non-water solvent for injection (such as polyethanediol), adding absolute alcohol and surfactant or not, stirring or ultrasonic oscillating and post-processing. Its advantages are high curative effect and high stability.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical preparation, more particularly, relate to a kind of preparation method of injection of ginkgolide B.
Background technology
In the plurality of active ingredients of from Folium Ginkgo, extracting, bilobalide-like (A, B, C, etc.) be its important component; And at the bilobalide apoplexy due to endogenous wind, the strongest with ginkalide B (Ginkgolide B is hereinafter to be referred as GB) biological activity again, be about 2～3 times of ginkalide A, so extremely the people pays close attention to.But low and separation and purification is than reasons such as difficulties owing to GB content in Folium Ginkgo, thus with the mixing lactone (contain lactone A, B, C) injection is seen report, prepares the domestic of injection with the GB monomer and does not appear in the newspapers as yet.
Abroad in the document, see pharmacological research to GB more, rarely seen injection (code name: BN52021) that has French Beaufour-lpsen company to make with the GB monomer, treat the report that some disease relevant with platelet activating factor (PAF) antagonist (as the allosome repulsion of ulcer, allergy, asthma, some inflammation, organ transplantation etc.) carried out clinical trial, come out but still there is formal product at present.
Containing three lactonic rings in the chemical constitution of ginkalide B, is closed loop under neutrality or acid condition, and indissoluble is separated in water, and the preparation injection is difficulty; When under alkali condition, pH value is the open loop form 7.4～12, along with the increase of pH value, one, two and even three complete open loop salifies of lactone can be arranged.Lactone after the open loop is easily dissolving in water, be convenient to make injection, but chemical property also becomes not quite stable to heat, preserves use so must make lyophilized injection.The complicated special installation that needs of preparation also has bibliographical information to think that GB closed-loop structure pattern is its main active pattern, reduced activity after the open loop [US Patent, No.5798342].
" BN 52021 " are the GB lyophilized injectable powders of part open loop form preparation, and perhaps this be that its clinical effectiveness does not reach one of reason of expection [Brochet B, etal:J Neurology, Neurosurgery andPsychiatry.1995,58:360-362].Domestic Zhang Ping [Chinese patent: application number 02134223.7], Chen Zhongliang [Chinese patent: application number 00115134.7] etc. are equipped with Semen Ginkgo with the alkali open ring legal system to mix the lactone injection.
Be closed loop by extracting the pure product of gained in the Folium Ginkgo, stable in properties is insoluble in water.Once saw that useful propylene glycol etc. prepared [Chinese patent: application number 97107809.2] that Semen Ginkgo mixes the lactone injection for solvent, through inventor's test, it is not ideal enough to the dissolubility of GB.Therefore, seek the new method of development injection of ginkgolide B, become the task of top priority.
Summary of the invention
The objective of the invention is to remedy above-mentioned weak point of the prior art, and a kind of preparation method for preparing easy, effective injection of ginkgolide B is provided.
The objective of the invention is to realize by following measure.Selecting pure product GB (closed loop) is crude drug, is dissolved in the nonaqueous solvent-low-molecular-weight Polyethylene Glycol (PEG-400 or PEG-300) of injection, and Polyethylene Glycol can use separately, or uses with mixed solvent that dehydrated alcohol is formed; PEG and alcoholic acid ratio (by volume) can be 0.5: 0.5～0.9: 0.1 scopes, and be preferred more than 0.6: 0.4, and promptly the PEG proportion is big for well; Can add or not add the cosolvent surfactant in the mixed solvent, as Tweens (tween 80 etc.), GB by weight: tween=1: 1～1: 3 scope can make GB solution be difficult for separating out when the dilution injection for well, fully stirs or ultrasonic concussion, carries out post processing; Described post processing is meant filtration, embedding, sterilization, detection, promptly gets product, is diluted in before the use in an amount of isotonic sodium chloride injection, shakes up, injection for intravenous uses.
Injection of the present invention has following advantage compared to existing technology: preparation technology is easy, does not need freeze-drier, and be about to GB and add " solvent " dissolving of selecting for use, after filtration, embedding, sterilization, promptly.Every milliliter of sterile solution that contains 10-20 milligram GB.Face with before being diluted in an amount of isotonic sodium chloride injection, contain GB 4-40 milligram/100 milliliters, use for intravenous drip.
GB injection chemical property with this law preparation is stable, detects with high performance liquid chromatography behind the heat sterilization, does not up-to-standardly see that tangible catabolite is arranged, stability test proof stable in properties.Through pharmacodynamic experiment, be 4-8mg/kg/ day to rat MCAT model minimum effective dose, proving has therapeutical effect to cardiovascular and cerebrovascular disease.
Specific implementation method
Enumerate 5 embodiment below, the invention will be further described to reach the main pharmacodynamics experiment in conjunction with the embodiments.
Embodiment 1
GB 20,000mg
PEG-400 (or PEG-300) adds to 1000ml
Preparation: take by weighing GB and put in the container, add solvent PEG, stir or ultrasonic concussion dissolving, solubilizer is to full dose, mix homogeneously; After filtration, embedding, sterilization, promptly.
Face with before being diluted in an amount of isotonic sodium chloride injection (4-40 milligram/100 milliliter), intravenous drip.
Embodiment 2
GB 10,000mg
PEG-400 (or PEG-300) adds to 1000ml
Compound method is with embodiment 1.
Embodiment 3
GB 20,000mg
PEG-400 (or PEG-300) adds to 1000ml
(annotate: PEG-400: ethanol=0.5: 0.5～0.9: 0.1; PEG-300 replaces PEG-400)
Preparation: get GB and put in the container, add the mixed solvent that mixes by predetermined ratio in advance, the method by embodiment 1 makes product of the present invention then.
Embodiment 4
GB 10,000mg
Mixed solvent (PEG-400-ethanol) adds to 1000ml
(annotate: PEG-400: ethanol=0.9: 0.1; PEG-400 can replace with PEG-300)
Preparation: method is with embodiment 3.
Embodiment 5
GB 15,000mg
Tween 80 20,000mg
Mixed solvent (PEG-400-ethanol) adds to 1000ml
(annotate: PEG-400: ethanol=0.5: 0.5)
Preparation: take by weighing GB and put in the container, tween 80 is added in advance in the mixed solvent that mixes by predetermined ratio, again that the three is mixed mixed solvent adds among the GB, stirs or ultrasonicly in the ultrasonic wave concussion device makes dissolving, adds mixed solvent to full dose, mixing.After filtration, embedding, sterilization, promptly.
Face with before being diluted in (4-40 mg/ml) in an amount of isotonic sodium chloride injection, quiet.
Two kinds of solvents of ginkalide B injection are to the influence of MCAT rat cerebral infarction scope
Place: Beijing University of Chinese Medicine's pharmacology department
[test material]
One, medicine and reagent:
Be subjected to reagent ginkalide B injection (1): PLA General Hospital development department provides, and every 5ml, every milliliter of bilobalide-containing B10mg, solvent are solvent 1 (not containing tween 80), rat consumption 16,8,4mg/kg/ day.
Be subjected to reagent ginkalide B injection (2): PLA General Hospital development department provides, and every 5ml, every milliliter of bilobalide-containing B10mg, solvent are solvent 2 (containing tween 80), rat consumption 16,8,4mg/kg/ day.
Ginaton injection: Dr Willmar Schwabe's product, every 5ml, every milliliter contains flavonoid glycoside 0.84mg, lot number: 1060602, people's consumption is 20-40ml/ people/day, rat consumption 6.7ml/kg/ day.
Chemical reagent: FeCl
36H
2O (A.R.), the Beijing Chemical Plant produces, with the preparation of 1mol/L hydrochloric acid; Red tetrazolium (TTC), the Beijing Chemical Plant produces, lot number: 950221.
Two, animal: the SD rat, the male and female dual-purpose, body weight 190～210g is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., the quality certification number: SCXK 11-00-0008.
Three, instrument: the XTT stero microscope, Beijing electric light scientific instrument factory produces; Water bath with thermostatic control agitator SHZ-22 type, Da Cang medical apparatus and instruments factory in Jiangsu produces; Electronic analytical balance, the AEG-220 type, produce in a day island proper Tianjin.
[method and result]
One, the ginkalide B injection is to the influence of middle cerebral artery thrombus model (Middle Cerebral ArteryThrombosis MCAT) rat nervous symptoms
(1) grouping and administration: laboratory animal is divided into 11 groups at random, i.e. MCAT model group, 1 group of solvent, 2 groups of solvents, ginkalide B injection (1) 16,8,4mg/kg group, ginkalide B injection (2) 16,8,4mg/kg group, Ginaton injection 6.7ml/kg group, sham operated rats.Prevention administration two days (ip) before the modeling, once a day; After the modeling at once sublingual vein be administered once, the 4th administration (ip) drawn materials in back one hour.The administration group gives corresponding medicine; 1 group of solvent and solvent give corresponding solvent 1.6ml/kg body weight respectively for 2 groups; MCAT model group, sham operated rats give normal saline 1.6ml/kg body weight.
(2) implement the modeling operation: the anesthesia of rats by intraperitoneal injection 12% chloral hydrate solution (350mg/kg).Press method [the Tamura A of Tamura etc., Graham DI, McCulloch J et al.Focal Cerebral ischemia inthe rat.1.Description Of technique and early neuropathological consequences followingmiddle Cerebral artery occlusion.J Cereb Blood Flow Metab, 1981; 1:53], revise a little.The rat right arm reclining is fixed, make a curved incision at paropia and external auditory meatus line mid point, be about 1.5cm, the pinch off temporalis also cuts, expose temporal bone, make a diameter 2.5mm bone window at cheekbone and temporo squamosum joint to oral-lateral 1mm place with dental burr, the cleaning residue exposes middle cerebral artery (between tractus olfactorius and inferior cerebral vein).There is the small pieces quantitative filter paper of 50% ferric chloride solution (1mol/L hydrochloric acid), 10 μ l to apply on this section middle cerebral artery [Liu Xiaoguang, Xu Lina: a kind ofly can estimate thrombolytic medicine and anti-intraluminal middle cerebral artery occlusion in rats thrombus model of fastening medicine suction.Acta Pharmaceutica Sinica 1995,30:662], about 30min treats to take off filter paper after the blackening of blood vessel color, uses the normal saline flushing local organization, and layer-by-layer suture steams again and raises.
(3) behavior detects: different time (6h after surgery, 24h), press [Lundy EF.SolikBS such as Bederson, Frank RS et al Morphometric evaluation of brain infarcts in rats and gerbils.JPharamacol Method, 1986,16:201] method and improved, animal is carried out behavior scoring.1. carry the about chi of Mus tail built on stilts, observe forelimb flexing situation.Stretch to ground as two forelimb symmetries, be designated as 0 fen; As the flexing that shoulder flexing, elbow flexing, shoulder inward turning or existing wrist elbow appear in the offside forelimb of performing the operation has inward turning person again, is designated as 1 fen.2. animal is placed on the level and smooth ground, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and be designated as 0 fen effectively; As resistance descender when the operation offside promotes, be designated as 1 fen.3. animal two forelimbs are put on the wire netting, observed the muscular tension of two forelimbs.Bilateral muscular tension equity and strong person are 0 minute; Operation offside muscle of anterior limb tension force descends and is designated as 1 fen.4. carry the about chi of Mus tail built on stilts, animal has ceaselessly to operation offside revolver, is designated as 1 fen.According to above standard scoring, full marks are 4 minutes, and mark is high more, and the behavior disorder of animal is serious more.
(4) interpretation of result: to behavior detect the marking value organize between relatively, the t check.
The result shows that sham operated rats does not see that dystropy changes, and MCAT model group, 1,2 groups of rats of solvent are 6h after surgery, and hemiplegia sample symptom all appears in 24h, mainly show as in the operation offside forelimb and receive, and the shoulder inward turning, muscle of anterior limb tension force reduces, and the shoulder drag descends.The rat of each dosage group of ginkalide B injection (1) is 24h after surgery, and its nervous symptoms all has improvement in various degree, statistical procedures, significant difference (P＜0.05).
Two, the ginkalide B injection is rat modeling 24 hours to influencing behind the animal via last behavior scoring of MCAT rat cerebral infarction scope, and broken end is got brain.Remove olfactory bulb, cerebellum and low brain stem, residue partly is cut into 5 crown below 4 ℃.(every 5ml dye liquor contains 4%TTC 1.5ml, 1M K rapidly the brain sheet to be placed the TTC dye liquor
2HPO
40.1ml), 37 ℃ of lucifuge temperature were incubated 30 minutes, took out again, placed 10% formalin to keep in Dark Place.The non-ischemic region in dyed back is a rose, and infarct is white [seeing Lundy EF].White organized carefully to dig down weigh, the percentage ratio that accounts for total brain weight with blocking tissue's weight is as the cerebral infarction scope.Relatively, t checks the result between organizing.The results are shown in Table 1,2,3.
Table-1 ginkalide B injection is to the influence of MCAT rat cerebral tissue infarction size
Dosage example blocking tissue weight accounts for total brain
Group
Suppression ratio (%)
(mg/kg) count the percentage ratio (%) of weight
1 group-10 6.98 ± 1.91 of solvent
Ginkalide B injection (1) group 16 10 5.11 ± 1.51* 26.79
8 10 4.94±1.76* 29.23
4 10 4.86±1.40* 30.37
Ginaton injection group 6.7ml 9 4.42 ± 2.18* 36.68
Sham operated rats NS 11 0 ± 0** 100
Annotate: compare * P＜0.05 for 1 group with solvent, * * P＜0.01.
Table-2 ginkalide B injection are to the influence of MCAT rat cerebral tissue infarction size
Dosage example blocking tissue weight accounts for total brain
Group
Suppression ratio (%)
(mg/kg) count the percentage ratio (%) of weight
2 groups-10 5.53 ± 1.95 of solvents
Ginkalide B injection (2) group 16 9 3.75 ± 1.52** 32.19
8 10 4.64±0.85 16.09
4 10 4.07±1.65* 26.40
Ginaton injection group 6.7ml 9 4.42 ± 2.18 20.07
Sham operated rats NS 11 0 ± 0** 100
Annotate: compare * P＜0.05 for 2 groups with solvent, * * P＜0.01.
Table-3 ginkalide B injection are to the influence of MCAT rat cerebral tissue infarction size
Dosage example blocking tissue weight accounts for total brain
Group
(mg/kg) count the percentage ratio (%) of weight
MCAT model group NS 6 6.04 ± 1.97
1 group 1.6 10 6.98 ± 1.91 of solvent
2 group 1.6 10 5.53 ± 1.95 of solvent
Ginaton injection group 6.7 9 4.42 ± 2.18
Sham operated rats NS 11 0 ± 0**
Annotate: compare * * P＜0.01 with the MCAT model group.
The result shows, postoperative 24h, except that the sham operated rats no abnormality seen changed, the rat of MCAT model group, 1,2 groups of rats of solvent, each administration group had all in various degree that focus of infarct, ginkalide B injection (1) can obviously reduce the infraction degree, compares for 1 group with solvent to have significant difference (P＜0.05).Ginkalide B injection (1) 4mg/kg can obviously reduce the infraction degree, compares for 2 groups with solvent to have significant difference (P＜0.05).
The present invention shows that the ginkalide B injection can significantly reduce the infarction size of focal cerebral ischemia in rats.Two kinds of solvent effects show, the infarction size of 2 pairs of MCAT models of solvent has certain inhibitory action, so each dosage group of ginkalide B injection (2) and solvent 2 comparative statistics interrogatorys show, but stronger to the inhibitory action of the infarction size of focal cerebral ischemia in rats from infarction size size ginkalide B injection (2).
Claims (3)
1, a kind of preparation method of injection of ginkgolide B, it is characterized in that comprising following sequential steps: bilobalide B raw material is dissolved in the injection nonaqueous solvent Polyethylene Glycol, Polyethylene Glycol can use separately or be made into mixed solvent with dehydrated alcohol, by volume, Polyethylene Glycol: ethanol=0.5: 0.5～0.9: 0.1, can add or not add surfactant, fully stir or ultrasonic concussion, carry out post processing.
2, preparation method according to claim 1 is characterized in that, described injection nonaqueous solvent is low molecular poly PEG-400 or PEG-300.
3, preparation method according to claim 1 and 2 is characterized in that surfactant, is the tween 80 of Tweens, by weight, and GB: tween 80=1: 1～1: 3.
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| CN 03137720 CN1215841C (en) | 2003-06-20 | 2003-06-20 | Prepn. method for injection of ginkgolide |
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| CN 03137720 CN1215841C (en) | 2003-06-20 | 2003-06-20 | Prepn. method for injection of ginkgolide |
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| CN1215841C CN1215841C (en) | 2005-08-24 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100341502C (en) * | 2006-04-18 | 2007-10-10 | 张国清 | Vein administration ginkgolactone B powder injection and its preparation method |
| CN100349568C (en) * | 2006-04-18 | 2007-11-21 | 张国清 | Intravenous administered injection of ginkgolide B, its preparation method and application |
| CN100393313C (en) * | 2006-02-17 | 2008-06-11 | 夏中宁 | Bilobalide B powder injection and its preparing method |
| CN101036642B (en) * | 2007-04-24 | 2010-07-14 | 蔡海德 | Ginkgolide B nanometric liposomes medicine and the preparing method thereof |
| CN102058578A (en) * | 2011-01-07 | 2011-05-18 | 中国药科大学 | Preparation method of ginkgolide preparation |
| CN101491519B (en) * | 2008-01-22 | 2011-09-28 | 南京克温生物科技有限公司 | Bilobalide injector and preparation method thereof |
| CN103735543A (en) * | 2013-12-26 | 2014-04-23 | 哈尔滨誉衡药业股份有限公司 | Traditional Chinese medicine composition |
-
2003
- 2003-06-20 CN CN 03137720 patent/CN1215841C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393313C (en) * | 2006-02-17 | 2008-06-11 | 夏中宁 | Bilobalide B powder injection and its preparing method |
| CN100341502C (en) * | 2006-04-18 | 2007-10-10 | 张国清 | Vein administration ginkgolactone B powder injection and its preparation method |
| CN100349568C (en) * | 2006-04-18 | 2007-11-21 | 张国清 | Intravenous administered injection of ginkgolide B, its preparation method and application |
| CN101036642B (en) * | 2007-04-24 | 2010-07-14 | 蔡海德 | Ginkgolide B nanometric liposomes medicine and the preparing method thereof |
| CN101491519B (en) * | 2008-01-22 | 2011-09-28 | 南京克温生物科技有限公司 | Bilobalide injector and preparation method thereof |
| CN102058578A (en) * | 2011-01-07 | 2011-05-18 | 中国药科大学 | Preparation method of ginkgolide preparation |
| CN103735543A (en) * | 2013-12-26 | 2014-04-23 | 哈尔滨誉衡药业股份有限公司 | Traditional Chinese medicine composition |
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| CN1215841C (en) | 2005-08-24 |
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