CN1552319A - Ginkgo ketonic ester dripping pill - Google Patents
Ginkgo ketonic ester dripping pill Download PDFInfo
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- CN1552319A CN1552319A CNA031364853A CN03136485A CN1552319A CN 1552319 A CN1552319 A CN 1552319A CN A031364853 A CNA031364853 A CN A031364853A CN 03136485 A CN03136485 A CN 03136485A CN 1552319 A CN1552319 A CN 1552319A
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- dropping pills
- lactone
- bilobanone ester
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- ginkgo
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Abstract
The invention relates to a new ginkgo ketone ester dripping pill preparation, which is prepared by adopting an advanced solid dispersion technology, wherein the total flavone content in the product is more than or equal to 44 percent, and the ginkgo total lactone content in the product is more than or equal to 6 percent. The product quality and the curative effect are improved compared with the prior dosage form, and the preparation has the advantages of quick effect, convenient use, high content of effective components, small dosage and the like.
Description
The present invention relates to a kind of bilobanone ester dropping pills preparation.
Folium Ginkgo is the leaf of Ginkgoaceae plant Ginkgo biloba (Ginkgo biloba L), and since the 1970's, Chinese scholars has been carried out omnibearing research to the chemistry of Folium Ginkgo, pharmacological preparation etc.States such as Japan, the U.S. and West Europe have dropped into great amount of manpower and material resources, to development product, obtain patented technology.China is the native place of Semen Ginkgo, and the distributed pole of Semen Ginkgo is wide, and north is to Liaoning, all plants to Guangxi in south.Particularly about 500,000 mu of area is cultivated now for concentrating the producing region in Central China, North China, produces ton surplus the Semen Ginkgo cured leaf 1.5 ten thousand per year, and this valuable resource needs our development and use of further tackling key problems.According to the interrelated data analysis-by-synthesis, about 5,000,000,000 dollars of the total sales volume of global Folium Ginkgo extract goods, wherein American market is about 2,000,000,000 dollars, 2,000,000,000 dollars of European market, about 1,000,000,000 dollars of other country, wherein Korea S is 1.3 hundred million dollars, and China is estimated as 8,500 ten thousand dollars (being roughly equal to 700,000,000 yuan of RMB).At present, ginkgo agent both domestic and external mostly is confined to dosage forms such as tablet, capsule, pill, and the bilobanone ester dropping pills agent still belongs to blank.
The object of the present invention is to provide a kind of new bilobanone ester dropping pills preparation, this dosage form has advantages such as quick-acting, easy to use, that active constituent content is high, dose is few.
Bilobanone ester dropping pills is the inventor with motherland's traditional medicine and high-tech means in conjunction with the cardiovascular and cerebrovascular vessel protective agent of developing of new generation; wherein main composition ginkgo flavone and lactone contains total flavones 〉=44%, Ginkgo total lactones 〉=6%; the expansion cerebrovascular is arranged; promote cerebral blood circulation; strengthen cerebral blood flow; improve the cerebrum metabolism vigor, effects such as memory reinforcing.No matter be product quality, or curative effect, all more improve that this can obtain demonstration from following experiment than prior dosage form.
The test of animal pharmacodynamics shows, the myocardial ischemia effect of having clear improvement that bilobanone ester dropping pills causes because of the injection lobus posterior hypophyseos rat; But acute myocardial infarction that the rat coronary ligation is caused and compensatory heart rate are accelerated decreased heart rate; Rat peripheral blood vessel microcirculation is improved significantly, and have antithrombotic to form, improve effects such as hemorheology and raising hypoxia-bearing capability.Its mechanism of action may be: 1. ginkgetin class composition has the effect of Citrin sample, can improve the permeability and the vascular fragility of blood capillary, increases coronary flow, reduces myocardial oxygen consumption.Platelet activating factor (PAF) be so far known to the strongest inducer of platelet activation, it can cause platelet aggregation and thrombosis, shrink coronary artery, reduce coronary flow, in myocardial ischemia pathology and physiological process, also play an important role, and bilobalide is considered to have most at present the natural paf receptor antagonists of potential applicability in clinical practice, has the effect of selectivity antagonism PAF.Therefore, bilobalide has caused platelet aggregation of antagonism platelet activating factor and thrombotic effect as strong PAF antagonist, has the regulation of blood vessels agent, and antithrombotic agent is for functions such as reinforcing agents.
Toxicologic study shows, bilobanone ester dropping pills acute toxicity mice LD
50＞7.2g/kg (calculating) with ginkgo flavone and lactone; Long term toxicity test, continuous 3 months of rat oral administration, 1080mg/kg, 360mg/kg, 108mg/kg (all calculating with ginkgo flavone and lactone) do not have obvious influence to the weight of animals, appetite, activity situation, routine blood test, blood biochemical; Pathologic finding, naked eyes and microscopically do not see that main organs such as the heart, liver, spleen, lung, kidney, testis, ovary have the variation of infringement property, and stomach and duodenum anatomic observation do not see that infringement is arranged yet.
The present invention seeks to realize like this:
The prescription proportioning of bilobanone ester dropping pills of the present invention is:
Ginkgo flavone and lactone 1-6 part PEG-6000 1-25 part
Its preparation method is: ginkgo flavone and lactone is made fine powder sieve, take by weighing ginkgo flavone and lactone fine powder and PEG-6000 according to the above ratio, get PEG-6000 and place 50-150 ℃ of water-bath heat fused, after the fusing, adding the ginkgo flavone and lactone fine powder below 90 ℃, the limit edged stirs, mixing time is 5 minutes-5 hours, make its abundant mixing, under 70-90 ℃ of heat-retaining condition, splash in the condensed fluid again, drip and make ball.
In the present invention, ginkgo flavone and lactone can extract by known conventional method and obtain, and meets each pertinent regulations under National Drug Administration of People's Republic of China (PRC) standard (trying) (WS-227 (Z-028)-2000) the ginkgo flavone and lactone item.This product contains total flavones in rutin (C27H80O6), must not be lower than 44%, and bilobalide-containing A, B, C and bilobalide BB are that the Ginkgo total lactones amount must not be less than 6.0% in this product.That is, contain total flavones 〉=44%, total lactone＞6% in the preferred ginkgo flavone and lactone.
Wherein, the proportion optimization of ginkgo flavone and lactone and PEG-6000 1: 4,1: 8, more preferably 1: 15,1: 20.
Preparation the preferred 90-110 of bath temperature ℃ during drop pill; Mixing time preferred 30 minutes-2 hours, more preferably 1 hour.
Condensed fluid among the present invention is preparation drop pill condensed fluid commonly used, preferred liquid paraffin, more preferably 10-25 ℃ of liquid paraffin.
Show through pilot scale research: the bilobanone ester dropping pills that this technology is made, hardness is moderate, thermostability and mobile phase are all better, the coefficient of variation that ball is heavy is 3.82%～4.58%, the molten diffusing time limit, presentation quality was better, is evenly distributed through assay active component ginkgo flavone and lactone in 7.6～10.5min scope, drug release is rapid, the onset piece.
Bilobanone ester dropping pills is compared with other dosage form of ginkgo flavone and lactone, has the active constituent content height, and dose is little, and medication dosing is accurate, the characteristics that drug release is fast.And the advantage of have production, transport, use, carry, keeping is convenient is the very ideal dosage form of bilobanone.
Below in conjunction with embodiment the present invention is further specified:
Embodiment 1
Get ginkgo flavone and lactone 50g, PEG-6000 200g, ginkgo flavone and lactone is made fine powder sieve, get PEG-6000 and put heat fused in 90 ℃ of water-baths, add the ginkgo flavone and lactone fine powder at 80 ℃, the limit edged stirs, stirred 30 minutes, and made it full and uniform, 85 ℃ of insulations splash in 12 ℃ of liquid paraffin, drip and make ball, promptly.
Embodiment 2
Get ginkgo flavone and lactone 100g, PEG-6000 1500g, ginkgo flavone and lactone is made fine powder sieve, get PEG-6000 and put heat fused in 110 ℃ of water-baths, add the ginkgo flavone and lactone fine powder at 60 ℃, the limit edged stirs, stirred 1 hour, and made it full and uniform, 75 ℃ of insulations splash in 20 ℃ of liquid paraffin, drip and make ball, promptly.
Embodiment 3
Get ginkgo flavone and lactone 200g, PEG-6000 1600g, ginkgo flavone and lactone is made fine powder sieve, get PEG-6000 and put heat fused in 120 ℃ of water-baths, add the ginkgo flavone and lactone fine powder at 50 ℃, the limit edged stirs, stirred 2 hours, and made it full and uniform, 80 ℃ of insulations splash in the vegetable oil condensed fluid, drip and make ball, promptly.
Development purpose of the present invention: ginkgo flavone and lactone (we are selected from National Drug Administration of People's Republic of China (PRC) standard (trying) XINGLING KELI) function is a blood circulation promoting and blood stasis dispelling, and what be used for that the blood stasis type thoracic obstruction (angina pectoris) and the slight cerebral arteriosclerosis of blood stasis type cause is dizzy.In order to make it reach the quick-acting purpose of treatment, we adopt solid dispersion technology, have developed bilobanone ester dropping pills.
Experimental result is as follows:
One, the comparison of bilobanone ester dropping pills and Folium Ginkgo disintegration
What gingko leaf preparation was commonly used clinically is tablet, has compared the disintegration of two kinds of dosage forms for this reason.Adopt " one one of Chinese pharmacopoeia.Appendix X IIA.Disintegration, inspection technique was checked, be 24.3 ± 6.2min the disintegration of Folium Ginkgo, and be 8.5 ± 2.3min the disintegration of bilobanone ester dropping pills, and the disintegration of visible bilobanone ester dropping pills is good than tablet.
Two, instructions of taking and dose are relatively
But bilobanone ester dropping pills not only can oral but also sublingual administration, and Semen Ginkgo tablet and XINGLING KELI are oral only, and needed water; This delays the state of an illness sometimes for the anxious blood stasis type thoracic obstruction (angina pectoris) of morbidity.So drop pill has a clear superiority in than other dosage forms.
Bilobanone ester dropping pills is more refining, and active constituent content height, drop pill are once only obeyed 0.2g, and granule is once taken 1.0g, and tablet is once taken 0.5g.Ginkgo flavone and lactone content is 20% in the drop pill, and the content of ginkgo flavone and lactone is 4% in the granule, and ginkgo flavone and lactone content is 8% in the tablet.
Three, be beneficial to environmental protection
The drop pill process for producing is simple, and is with short production cycle, three-waste free pollution, and the Semen Ginkgo tablet can produce part waste residue, waste liquid in process of production.
Therefore, other dosage forms of bilobanone ester dropping pills and Folium Ginkgo relatively have the disintegration time weak point, absorb soon, and the active constituent content height, dose is little, and drug dose is accurate, taking convenience, rapid-action characteristics.And produce, transport, carry, the advantage of taking convenience, be very ideal dosage form.
It below is the relevant experimentation of the application's bilobanone ester dropping pills.
I. bilobanone ester dropping pills and the Folium Ginkgo treatment coronary heart disease heart than the pain curative effect relatively
Bilobanone ester dropping pills, Folium Ginkgo are treated coronary heart disease 141 examples respectively, 52 examples, the angina pectoris total effective rate is respectively 96.7%, 85.4%, to ischemic ECG change total effective rate is 86% and 73.1%, and drop pill and tablet be the obvious hypercholesterolemia reducing of energy, triglyceride and high density lipoprotein increasing cholesterol all.Curative effect to bilobanone ester dropping pills treatment coronary heart disease angina cordis is carried out clinical research, observes simultaneously the hyperlipidemia influence, and uses the Folium Ginkgo do contrast at random that Yangtze River, Jiangsu Pharmaceutical is produced.The result is reported as follows:
1. clinical data
1.1 the angina pectoris diagnostic criteria is according to national internal medicine academic conference in 1980 " about the suggestion of coronary heart disease name and diagnostic criteria ".
" the clinical research guideline of the treatment by Chinese herbs thoracic obstruction " selects following 3 kinds of patients 1.2 the treatment object of observation is defended the medicine word No. 32 with reference to Ministry of Public Health (87): (1) classical angina, electrocardiogram has the ischemic change or the exercise test positive at ordinary times or during angina pectoris attacks.(2) though angina pectoris is not true to type the clear and definite person of electrocardiographic diagnosis.(3) the angina pectoris attacks typical case person though electrocardiogram is normal
[1]Divide 2 groups of observations:
(1) drop pill group 141 examples classical angina 104 examples wherein, angina pectoris is not true to type and clear and definite person's 39 examples of electrocardiographic diagnosis, male 82 examples, women 59 examples, 60.1 years old mean age.
(2) tablet group 52 routine classical angina 41 examples, angina pectoris is not true to type and clear and definite person's 11 examples of electrocardiographic diagnosis, male 28 examples, women 24 examples, 57.2 years old mean age.
2. observational technique
Be bilobanone ester dropping pills 2.1 control group, matched group is a Folium Ginkgo at random.Dosage, tablet are 1 day 3 times.1 time 2, drop pill is 1 day 3 times, 1 time 8 ball; Be 1 month the course of treatment.Interview medical history before the treatment, health check-up is had a blood test, urine, stool for routine, and liver, renal function, blood fat, blood glucose, the 12 complete rest electrocardiogram that leads is all stopped using antianginal and 2 weeks of fat-reducing medicament.After the administration, follow up a case by regular visits to weekly 1 time, the course of treatment is when finishing, comprehensive review.
2.2 the angina pectoris efficacy assessment standard is formulated standard according to national therapy of combining Chinese and Western medicine angina pectoris in 1979 and arrhythmia forum
[1]Own control before and after the blood fat reducing curative effect is taken medicine with hyperlipemia.
3. result
Following column data is handled by 28M AST 386 computer for analysis, and statistical method adopts paired t-test, X
2Check.
Concrete outcome is as follows:
3.1 bilobanone ester dropping pills, Folium Ginkgo treatment angina pectoris curative effect are relatively, see Table 1
Table 1. bilobanone ester dropping pills, Folium Ginkgo treatment angina pectoris curative effect are relatively
Group example digital display is imitated the enabledisable total effective rate
Drop pill 107 73 (68.2%) * * 26 (24.3%) 8 (7.5%) 79 (92.5%) *
Tablet 37 17 (45.9%) 12 (32.4%) 8 (21.6%) 29 (78.4%) *
* compare with tablet, total effective rate does not have significant difference * * to be compared with tablet, produce effects (P＜0.05)
As seen from Table 1, drop pill treatment angina pectoris obvious effective rate is apparently higher than tablet (P＜0.05), but each group of total effective rate does not relatively have significant difference.
3.2 bilobanone ester dropping pills, Folium Ginkgo see Table 2 to ischemic ECG change curative effect situation.
Table 2 bilobanone ester dropping pills, Folium Ginkgo are to ischemic ECG change curative effect relatively
Group example digital display is imitated the enabledisable total effective rate
Drop pill 132 55 (42.7%) 60 (45.5%) 17 (12.9%) 115 (88.2%) * *
Tablet 50 15 (30.0%) 21 (42.0%) 14 (28.0%) 19 (72.0%)
* compares with tablet, P＜0.05
As seen from Table 2, ischemic electrocardiogram total effective rate drop pill is higher than tablet, P＜0.05.
3.3 bilobanone ester dropping pills, Folium Ginkgo see Table 3 to the influence of hyperlipemia blood fat.
Blood fat reducing curative effect comparison before and after table 3 bilobanone ester dropping pills, Folium Ginkgo are taken medicine (X ± S)
TG(mmol/L) TC(mmol/L) HDL-C(mg/dL)
Dosage form
After preceding treatment is treated in the treatment back before treating after the treatment before the treatment
5.80± 3.992**± 3.10± 2.56**± 30.9± 41.5**±
Drop pill
2.14(70) 1.79(70) 0.50(23) 0.59(23) 4.8(49) 5.1(49)
5.62± 3.8**± 2.69± 2.18*± 34.9± 42.3*±
Tablet
1.92(12) 1.24(12) 0.34(3) 0.32(3) 2.2(10) 3.7(10)
* preceding more preceding with treatment with treatment than P＜0.01 than P＜0.05**
As seen from Table 3, clothes drop pill or tablet are after course of treatment, and hypercalcinuria patient TG and TC meansigma methods obviously descend, P＜0.001 and 0.01, and HDL-C obviously raises, P＜0.001.
4. discuss
4.1 as seen from last, bilobanone ester dropping pills, Folium Ginkgo improve the ischemic ECG change to the treatment angina pectoris, curative effect is sure, and the curative effect of drop pill is significantly better than tablet.
4.2 Folium Ginkgo treatment coronary heart disease mechanism of action, Chinese scholars is studied it, finds that its main effective ingredient is flavonoid glycoside and bilobalide.Flavonoid glycoside has the effect of the oxygen-derived free radicals of removing, bilobalide tool antagonism platelet activating factor (PAF) effect, and the two is collaborative mutually, brings into play therapeutical effect from different links.PAF be so far known to the strongest inducer of platelet activation, coronary artery is shunk, reduce coronary flow, also can stimulate leukocyte, endotheliocyte produces oxygen-derived free radicals, injury of myocardium cell.And gingko leaf preparation has antagonism PAF effect, in addition, also has the raising mouse core, the tolerance of cerebral anoxia, protection ischemic myocardium
[2]
Bilobanone ester dropping pills and Folium Ginkgo have obvious reduction TG, TC and rising HHL-C function, and this helps preventing and treating coronary heart disease, but its mechanism of action it be unclear that, and remain to be continued research.
II. bilobanone ester dropping pills is to the hemorheology influence of experimental cerebral ischemia rat
1. materials and methods
1.1 animal model: healthy wistar rat, body weight 150～170g, the male and female dual-purpose, Henan medical experiment animal center provides.The preparation of rat unilateral cerebral ischemia model: after the rat 3% sodium pentobarbital 30mg/kgip anesthesia, lie on the back on operating-table, cut rat right side skin of neck, passivity is separated common carotid artery, with medical operation silk thread ligation common carotid artery, skin suture.
1.2 experiment grouping: (every day is irritated stomach 1 in rat operation back to be divided into sham operated rats, normal saline matched group at random, the 5ml normal saline, put to death on 7th), drop pill group (began medication the same day from operation, dosage is respectively 24,12,6mg/kg/ days, successive administration 7 days).
1.3 experimental index
1.3.1 brain water content is measured: the blood-letting of every treated animal ventral aorta causes death, and the complete fast right side brain 20mg tissue that takes off adopts weight method
[2]Measure brain water content.
1.3.2 hemorheology index determining: STEELLEX R
20Blood viscosity instrument is measured whole blood viscosity and plasma viscosity, and WB-A type blood capillary hematid specific volume instrument is measured hematocrit, and Fibrinogen and prothrombin time adopt the method for national visiting rule of operation.
2 results
2.1 medication group brain water content is compared remarkable reduction (P＜0.05) than the saline control group, the results are shown in Table 1.
Table 1 bilobanone ester dropping pills to the influence of rat cerebral ischemia side brain water content (± s)
Grouping dosage (mg/kg) sample size n brain water content (%)
Sham operated rats-8 77.3 ± 0.7
Normal saline group-8 80.2 ± 1.4
△
Drop pill group 12 8 77.7 ± 1.1
*
36 8 78.9±1.5
*
108 8 78.9±0.7
*
Annotate: compare △ P＜0.05 with sham operated rats, compare with the normal saline group
*P＜0.05
2.2 the packed cell volume of medication group and whole blood be low to be cut viscosity and be starkly lower than saline control group (P＜0.01), thrombinogen and Fibrinogen and normal saline group do not have relatively that significant difference the results are shown in Table 2, table 3.
Table 2 bilobanone ester dropping pills is to the influence of rat cerebral ischemia blood viscosity and packed cell volume (n=8, x ± s)
Grouping dosage viscosity (mPaa) packed cell volume
(mg/kg) whole blood blood plasma (%)
Sham operated rats-25.7 ± 5.2 3.2 ± 1.1 36.9 ± 4.7
Normal saline group-29.7 ± 4.7 ▲ 4.8 ± 2.2 ▲ 38.7 ± 3.4 ▲
Bilobanone ester dropping pills 108 26.8 ± 3.5
*3.5 ± 1.1
*36.5 ± 1.7
*
36 27.7±8.4
* 3.8±0.4
* 37.8±2.3
*
12 28.2±1.2
* 4.1±0.7
* 38.0±1.4
*
Annotate:, compare with the normal saline group with sham operated rats comparison ▲ P＜0.05
*P＜0.05
Table 3 bilobanone ester dropping pills is to the influence of rat cerebral ischemia fibrin and prothrombin time (n=8, x ± S)
Grouping dosage (mg/kg) Fibrinogen prothrombin time
(g/L) (s)
Sham operated rats-2.74 ± 0.69 15.75 ± 1.26
Normal saline group-2.45 ± 0.51 14.14 ± 2.34
Bilobanone ester dropping pills 108 2.57 ± 0.61 15.55 ± 1.96
36.0 2.48±0.58 15.40±2.07
12 2.59±0.68 15.60±1.89
3 conclusions
Bilobanone ester dropping pills can reduce the packed cell volume of rats with cerebral ischemia and whole blood is low cuts viscosity, improves the blood circulation of ischemic tissue of brain, and cerebral ischemia is had certain prevention and therapeutical effect.
III. bilobanone ester dropping pills is to the protective effect of isolated rat heart ischemical reperfusion injury
1 experiment material
1.1 (the He'nan University institute of materia medica provides for medicine and reagent bilobanone ester dropping pills, lot number 20010901), sodium pentobarbital (Shanghai reagent packing factory), nadide (Shanghai Inst. of Biochemistry, Chinese Academy of Sciences), Sodium Pyruvate (Shanghai Cao Yang chemical reagent work), MDA, SOD measures test kit (biological study institute is built up in Nanjing).
1.2 equipment 721 type spectrophotometers (Shanghai analytical tool factory), LMS-2B type two road physiology monitors (Chengdu Electronic Instruments Plant), thermostatic water-circulator bath (Chongqing test apparatus instrument factory).
1.3 (x ± s), the male and female dual-purpose is provided by Zunyi Medical College's Experimental Animal Center animal health Wistar rat body weight 250 ± 15g.
2 methods and result
Get 24 of rats, be divided into 4 groups at random: the ischemia filling group again that normal control group, ischemia filling group again and big low dose of drop pill are handled.Rat is used sodium pentobarbital (40mgkg
-1, ip) after the anesthesia, through tongue ivl% heparin 0.2ml anticoagulant.Open breast behind the 1min, take out heart rapidly, immerse in the oxygen-saturated cold K-H balance liquid,, carry out non-circulating type Langendorff perfusion through aorta retrograde catheterization, fixing.Regulate the arteria coronaria discharge and be about 7mlmin
-137 ± 0.5 ℃ of perfusate temperature continue to feed 95%O
2+ 5%CO
2Mist, pH7.4, heart promptly begins to beat behind the perfusion.The apex intubate is connected with LMS-2B two road physiology monitors through pressure transducer to left ventricle, and record left indoor pressure (LVP) is swept note myocardial contraction (ST) simultaneously, heart rate (HR), and every 5min collects arteria coronaria discharge (CBF).Matched group Chang Su (7mlmin
-1); Ischemia filling group again: the normal fast perfusion 15min of elder generation, low speed (1mlmin
-1) irritate ischemia 40min after, recover normal fast perfusion 30min again; Drop pill administration group: contain Semen Ginkgo ketone ester 10mgL respectively in the perfusate during perfusion again behind the low speed 40min
-1And 20mgL
-1Outward, surplus with ischemia filling group again, experimental result is judged significance with the t check.
2.1 bilobanone ester dropping pills is to the influence of ischemic reperfusion rat heart
Isolated rat heart balance 15min reaches the variation (table 1) of irritating ST, LVP, HR and the CBF of back 5,10,15,20,25 and 30min again before the record ischemia.Behind the ischemic reperfusion, myocardial contraction descends, and left indoor pressure significantly reduces (P＜0.05), and does not relatively have significant change before administration group These parameters and the ischemia, shows ginkgo flavone and lactone 10mgL
-1, 20mgL
-1Reduction to myocardial contraction due to the ischemia-reperfusion and left indoor pressure has protective effect.
Table 1 bilobanone ester dropping pills is to ischemic reperfusion rat heart muscle contractility (ST, to be 100% before the ischemia), and left indoor pressure (LVP, mmHg), heart rate (HR, beatmin
-1), arteria coronaria discharge (CBF, ml5min
-1) influence.(x±s，n＝6)
Dosage is the perfusion time (min) again
Before the group index ischemia
(mg·L
-1) 5 10 15 20 25 30
Ischemia
1.0±0.00 0.6±0.10* 0.7±0.24** 0.6±0.16** 0.6±0.19** 0.6±0.14** 0.6±0.12**
Filling group again
Drop pill 1 10 1.0 ± 0.00 0.8 ± 0.24 0.8 ± 0.20 0.7 ± 0.29 0.7 ± 0.23 0.7 ± 0.24 0.7 ± 0.28
Drop pill 2 20 ST 1.0 ± 0.00 0.9 ± 0.09 1.0 ± 0.05 1.0 ± 0.05 1.0 ± 0.08 0.9 ± 0.08 0.9 ± 0.08
Ischemia 130 ± 12 79 ± 11*, 79 ± 22*, 81 ± 15**, 86 ± 19**, 86 ± 19**, 87 ± 21**
Filling group again
Drop pill 1 10 138 ± 23 110 ± 23 110 ± 22 101 ± 33 112 ± 26 101 ± 38 105 ± 38
Drop pill 2 20 LVP 132 ± 19 130 ± 23 129 ± 18 116 ± 37 135 ± 31 128 ± 30 131 ± 31
Ischemia
132±25 111±331 99±36 116±39 116±33 109±29 111±30
Filling group again
Drop pill 1 10 138 ± 16.8 131 ± 22 137 ± 27 110 ± 36 111 ± 36 112 ± 29 115 ± 30
Drop pill 2 20 HR 113 ± 59.4 137 ± 18 131 ± 16 129 ± 16 123 ± 27 123 ± 26 126 ± 22
Ischemia
31±2.7 29.52.1 29±4.9 28±4.6 27±4.1 27±4.6 28±4.4
Filling group again
Drop pill 1 10 30 ± 2.7 29.2 ± 3.2 30 ± 2.2 31 ± 3.3 31 ± 4.2 31 ± 4.7 31 ± 3.3
Drop pill 2 20 CBF 29 ± 2.6 29.6 ± 41 30 ± 4.4 31 ± 5.4 31 ± 5.1 30 ± 7.5 30 ± 8.3
With comparison * P＜0.05**P＜0.01 before the ischemia
2.2 bilobanone ester dropping pills is irritated the influence of LDH content in the rat arteria coronaria effluent again to ischemia
Collect and respectively to organize before the ischemia and arteria coronaria effluent in 5～30min behind the perfusion again,, the results are shown in (table 2) with photoelectricity colorimetric method for determining LDH changes of contents.LDH obviously raises in the ischemia filling group again heart arteria coronaria effluent, and rises with the perfusion time; The administration group obviously reduces (P＜0.05) with ischemia group comparison LDH behind the perfusion again, shows that bilobanone ester dropping pills can reduce myocardium LDH burst size, increases the dosage effect and further strengthens (P＜0.01 sees Table 2).
Table 2 bilobanone ester dropping pills is to LDH activity (U100ml in the ischemic reperfusion rat arteria coronaria effluent
-1) influence (x ± s, n=6)
Dosage is the perfusion time (min) again
Before the group ischemia
(mg·L
-1) 5 10 15 20 25 30
Ischemia filling group again 2.49 ± 4.0 7 ± 9.3 29 ± 2.5 511 ± 2.5 51 ± 2.6 60 ± 23.3 66 ± 24.0
Administration group 1 10 2.36 ± 5.7 12 ± 4.8 29 ± 7.6 30 ± 8.2*, 36 ± 9.1*, 36 ± 7.9*, 40 ± 8.4*
Administration group 2 20 2.39 ± 5.5 12 ± 11.5 12 ± 9.5**, 25 ± 6.4**, 28 ± 8.4**, 26 ± 3.6**, 30 ± 4.1**
Compare * P＜0.05**P＜0.01 with ischemia filling group again
2.3 ginkgetin is irritated the influence of rat heart muscle MDA content, SOD vigor again to ischemia
Perfusion finishes, and cuts left ventricular wall myocardium rapidly, and the back of weighing adds normal saline in 10: 1 ratios, makes 10% myocardium homogenate, presses TBA colorimetry principle, measures lipid peroxidation product MDA content in the kit measurement cardiac muscular tissue with MDA.Getting above-mentioned myocardium homogenate dilution is 1%, measures test kit with SOD, and xanthine oxidase is measured the SOD vigor.The result shows that ischemia filling group again MDA content is apparently higher than normal hemoperfusion group; The SOD vigor obviously reduces (P＜0.05).Show that ischemic reperfusion makes that MDA obviously increases in the cardiac muscular tissue, the SOD vigor reduces.Bilobanone ester dropping pills obviously reduces MDA content in the cardiac muscular tissue, reduces the reduction of SOD vigor, and relevant with dosage (table 3).
Table 3 bilobanone ester dropping pills is irritated rat heart muscle to ischemia third and is organized MDA content, and the influence of SOD vigor (x ± s, n=6)
Dosage guideline
Group
(mg·L
-1) MDA(nmol/g) SOD(U/g)
Matched group 77 ± 38.4** 456 ± 60.5*
Ischemia filling group again 206 ± 64.9 320 ± 35.4
Administration group 1 10 109 ± 36.2 368 ± 81.8
Administration group 2 20 92 ± 21.9** 444 ± 86.9**
Compare * P＜0.05**P＜0.01 with ischemia filling group again
3. conclusion
Bilobanone ester dropping pills has protective effect to the isolated heart ischemia-reperfusion.
IV. bilobanone ester dropping pills is to the protective effect of mice and rat cerebral ischemia
1 experiment material
1.1 medicine and reagent bilobanone ester dropping pills, every ball 200mg, (Ginkgo total flavones 〉=17.6mg, bilobalide 〉=2.4mg), the He'nan University institute of materia medica provides, lot number: 20010901 to contain Semen Ginkgo ketone ester 40mg.Nimodipine, Shandong Xinhua Pharmaceutical Factory provides; Triphenyltetrazolium chloride (2,3,5 triphenyltetrazoliumchloride, TTC), Beijing chemical pharmaceutical factory produces, the distilled water preparation, the lucifuge low tempertaure storage is standby; All the other are commercially available analytical reagent.
1.2 instrument CY-2 type oxygen analyser, Shanghai China light instrument and meter factory product; PYX DHS water isolation type constant incubator, the Shanghai City medical apparatus and instruments one factory's product of making a leapleap forward; TE II type Olympus Tokyo stero microscope, OlympusOptical Co.ctd product.
1.3 the animal Kunming mouse, the Wistar rat is all available from Henan medical experiment animal center
2 experimental techniques
2.1 mice normal pressure airtight anoxia experiment
Get body weight 18～22g, 50 of ♀ ♂ half and half mices are divided into 5 groups (as shown in table 1) at random.Gastric infusion 8d, 30min measures behind the last medicine.Mice is placed in the 150ml wide mouthed bottle, and an amount of sodica calx of interior Sheng, bottleneck connect rubber closure and link to each other with CY-2 type oxygen analyser.Measure the oxygen content O in the per minute bottle
2% (keto consumpting speed) and mice time-to-live.
2.2 chmice acute cerebral ischemia experiment
Get body weight 18～22g, 120 of ♂ mices are divided into 6 groups (as shown in table 2) at random.Gastric infusion 8d, 30min behind the last medicine, etherization separates left and right sides common carotid artery and (is with vagus nerve, BCCA-VNL), heart end is pricked with toe-in, head end is clamped with bulldog clamp, in the centre common carotid artery is cut off the death time of record animal then, surpass 2h death person, its death time is designated as 120min.
2.3 focal cerebral ischemia in rats experiment
Get body weight 280～320g, the ♂ rat is divided into 6 groups (as shown in table 3) at random.Gastric infusion 7d, the capable MCAO art of d8, undertaken by method shown in the document and collection of illustrative plates, promptly at the mid point incision skin of left eye outer canthus to left external ear line, separate muscle bundle, before cheekbone and squamosal bone before the associating in 2mm place hole and open cranium, electricly be positioned at the about 2mm of tractus olfactorius with fixed attention to one section middle cerebral artery between great cerebral vein, sew up wound notes making the insulation of postoperative animal.Adopt blind method scoring in postoperative 6,24h, broken end is got brain then, remove olfactory bulb, cerebellum and low brain stem, remainder along vowing that the centre joint is divided into two, is got operation homonymy cerebral hemisphere, it is cut to five, in the TTC dye liquor, hatch 30min for 37 ℃, normal structure is rose, and blocking tissue is white in color.The percentage ratio of the shared gross area of ischemic areas of 8 faces of counting under stero microscope.Counting finishes, the preparation pathological section, and HE dyeing is carried out histology's paired observation to each group section under the light microscopic.
2.4 the statistical procedures experimental result adopts x ± s to represent, during the significance of statistical discrepancy, and enumeration data x
2Check, measurement data is checked with t.
3 experimental results
3.1 influence to mice airtight anoxia tolerance
The result shows that each dosage of bilobanone ester dropping pills does not have obvious influence to the keto consumpting speed of mice under the airtight anoxia state, to the not prolongation effect of time-to-live of mice.
Table 1 bilobanone ester dropping pills and nimodipine to the influence of mice anoxia enduring and time-to-live (x ± s, n=10)
Group dosage (mg/kg) body weight (g) time-to-live (min) remaining O
2(%)
Solvent group-21.5 ± 1.62 17.49 ± 2.62 6.13 ± 0.84
Nimodipine group 10 21.3 ± 0.75 19.69 ± 1.64
*6.21 ± 0.50
Bilobanone ester dropping pills 12 21.2 ± 0.98 17.45 ± 0.79 6.18 ± 0.65
Bilobanone ester dropping pills 36 21.1 ± 1.04 17.67 ± 1.42 6.23 ± 0.77
Bilobanone ester dropping pills 108 21.1 ± 0.77 17.51 ± 0.83 6.17 ± 0.52
Compare * P＜0.05 with vehicle group
3.2 influence to the mortality rate death time in the acute cerebral ischemia mice 2h
The results are shown in Table 2, compare with the solvent matched group, bilobanone ester dropping pills can reduce the mortality rate in the acute cerebral ischemia mice 120min, prolongs the death time of animal.
Table 2 bilobanone ester dropping pills to the influence of acute cerebral ischemia mortality of mice and time-to-live (x ± s, n=20)
Group dosage (mg/kg) mortality rate (%) time-to-live (min)
Blank-95 10.35 ± 26.01
Solvent contrast-95 15.77 ± 31.16
Bilobanone ester dropping pills 12 95 13.18 ± 28.31
Bilobanone ester dropping pills 36 90 17.26 ± 35.30
Bilobanone ester dropping pills 108 65* 54.63 ± 52.92
*
Compare * P＜0.05**P＜0.01 with the solvent matched group
3.3 influence to focal cerebral ischemia in rats
3.3.1 influence to the rat behavior obstacle
After the middle cerebral artery blocking-up, neuromotor dysfunction in various degree appears in all animals, and model group is particularly evident.Mainly show as: carry that tail is received in the right fore when unsettled, the shoulder inward turning, right fore tension force reduces, and changes to a side ring during severe patient walking.The behavior disorder of rats with cerebral ischemia had improvement in various degree when each dosage of bilobanone ester dropping pills all can make operation back 6,24h, the results are shown in Table 3.
3.3.2 influence to the rat cerebral infarction area
As shown in table 3, to compare with the solvent matched group, each dosage of bilobanone ester dropping pills can dwindle the cerebral infarct size of focal cerebral ischemia rat.
3.3.3 influence to rat cerebral tissue's pathological state
Encephalopathy reason section shows that control rats ischemia side cerebral tissue has the downright bad center of major injury and the ischemic penumbra of light moderate lesion, shows as a large amount of neuron peripheral clearances and enlarges, have be dispersed in secretly dye neuron, shrinkage in various degree appears in neurocyte.Each medication group rat has alleviating in various degree.
Table 3 bilobanone ester dropping pills is to the influence of focal rats with cerebral ischemia cerebral infarct size (x ± s)
Number of animals
Group dosage (mg/kg) infarct size (%) slip (%)
(only)
Solvent contrast-10 23.2 ± 1.9-
Bilobanone ester dropping pills 12 8 20.3 ± 3.7** 12.50
Bilobanone ester dropping pills 36 9 17.8 ± 1.7** 23.28
Bilobanone ester dropping pills 108 10 16.7 ± 1.9** 28.02
Nim 2 10 20.4±0.4** 12.07
Annotate * P＜0.05**P＜0.01
4 conclusions
Bilobanone ester dropping pills has treating cerebral ischemia.
V. bilobanone ester dropping pills is to the influence of physiological function
The 1 pair of rat's pial and the microcirculatory influence of mesentery
Selecting for use 10 of healthy SD rats to be used for arteriole bore, 10 is used for the open number of blood capillary, 30 and is used for the experiment of pia mater encephali arteriole blood fluidised form.It is 50ug/ml (low concentration), 100ug/ml (middle concentration), three kinds of different concentration of 200ug/ml (high concentration) that bilobanone ester dropping pills is made into the ginkgo flavone and lactone amount respectively with normal saline (NS), drop on rat's pial and the mesentery, and be contrast with norepinephrine (NE).Observe under the OLYMPUS universal research microscope, videotape with PANSONLC board WV-CL320/G stylus, colour is looked machine and is shown, observes respectively and measures the influence of bilobanone ester dropping pills to rat arteriole bore, the open number of blood capillary, arteriole blood vessel fluidised form.
1.1 influence (seeing Table 1) to the arteriole bore
Table 1 bilobanone ester dropping pills is to the influence of arteriole bore (x ± SD)
Time pia mater encephali fine motion CUN KOU mesentery arteriole
ACSF
(min) directly (um) bore (um)
Contrast 27 ± 3 30 ± 5 29 ± 3 before the medicine
Drip behind the EN 10 19 ± 5 16 ± 6 21 ± 6
Drip low concentration 1 23 ± 4
*17 ± 6 25 ± 5
*
Ginkgo flavone and lactone
3 35±5
** 20±7 39±5
**
Behind the drop pill
5 26±4
* 20±7 32±5
*
50 26±3
* 23±5 30±4
*
100 27±3
* 28±5
* 29±3
*
200 27±3
* 30±5
* 29±3
*
Concentration 1 25 ± 4 in dripping
*27 ± 5
*
Ginkgo flavone and lactone
3 41±2
** 43±3
**
Behind the drop pill
5 31±3
** 43±4
**
50 29±3
* 32±3
*
100 28±3
* 30±3
*
200 28±3
* 29±3
*
Drip high concentration 1 24 ± 4
*26 ± 4
*
Ginkgo flavone and lactone
3 36±5
** 39±5
**
Behind the drop pill
5 28±3
* 31±4
*
50 28±3
* 30±3
*
100 27±3
* 29±3
*
200 27±3
* 29±3
*
Annotate: * P＜0.05, * * P＜0.01
Shown in the table 1, (1) pia mater encephali is compared with the EGB that drips three kinds of concentration again after dripping NE10min, low high two kinds of concentration 1,3min, middle concentration has significant differences (P＜0.01) 1,3, during 5min; Low high concentration 5,10,20,30min, middle concentration has significant difference (P＜0.05) 10,20, during 30min.(2) pia mater encephali is dripped artificial cerebrospinal fluid (ACSF) and is compared with the bilobanone ester dropping pills that drips three kinds of variable concentrations, find three kinds of concentration all 20, significant difference (P＜0.05) arranged during 30min.The above results shows that bilobanone ester dropping pills can resist the microcirculation disturbance that NE causes, rat's pial and mesentery arteriole bore are significantly expanded.
1.2 bilobanone ester dropping pills is to the influence (seeing Table 2) of the open number of rat blood capillary.
Table 2 bilobanone ester dropping pills is to the influence of the open number of blood capillary (x ± SD)
Pia mater encephali blood capillary mesentery blood capillary
Group
Standard-sized sheet is put the open % standard-sized sheet of number and is put the open % of number
Contrast 6 ± 2 60 60 ± 1 60 before the medicine
Drip NE 0000
Drip the low concentration ginkgo flavone and lactone
** 8±1 80 9±1
** 90
Drop pill
Drip NE 2 ± 2 20 2 ± 2 20
Concentration ginkgo flavone and lactone in dripping
** 10±1 100 10±1
** 100
Drop pill
Drip NE 3 ± 1 30 3 ± 2 30
Drip the high concentration ginkgo flavone and lactone
** 10±1 100 10±1
** 100
Drop pill
Annotate: * * P＜0.01
Table 2 shows, compares with the bilobanone ester dropping pills of the three kinds of variable concentrations that instil again behind (1) pia mater encephali blood capillary instillation NE, and the open number average of blood capillary has the difference (P＜0.01) of highly significant.(2) experiment of mesentery blood capillary also obtains identical result (P＜0.01).Illustrate that bilobanone ester dropping pills can make pia mater encephali and the open quantity of mesentery blood capillary significantly increase, and is improved in-house blood supply effectively.
1.3 influence (seeing Table 3) to rat's pial arteriole blood vessel fluidised form.
Table 3 bilobanone ester dropping pills is to the influence of pia mater encephali arteriole blood vessel fluidised form (x ± SD)
The number of animals blood flow stops
Three grades of scorings of group recover normal
(only) time (min)
Matched group 8 5.89 ± 0.75 7.57 ± 4.72 1
Post drips the low concentration bilobanone
7 3.93±1.73* 2.87±4.24* 3*
The ester drop pill
Post drips middle concentration bilobanone
8 1.89±1.80** 1.53±3.13** 7**
The ester drop pill
Post drips the high concentration bilobanone
7 2.77±1.91** 1.79±2.52** 7**
The ester drop pill
Annotate: * P＜0.05, * * P＜0.01
Table 3 explanation, (1) in three grades of evaluation experiments of fluidised form of microcirculation disturbance, low concentration group has significant difference (P＜0.05), and middle and high concentration group has significant differences (P＜0.01).(2) it is identical to recover in the experiment of other binomial three grades of evaluations of its result and fluidised form in blood flow dwell time and blood flow attitude.Explanation is using in advance NE obstacle liquid to make that bilobanone ester dropping pills can make its blood flow rate accelerate under the situation that the arteriole blood flow slows down, and the blood flow dwell time shortens, and the tremulous pulse bar number that recovers normal condition increases.
Bilobanone ester dropping pills can effectively resist the microcirculation disturbance that NE causes to rat's pial and mesentery microcirculation influence research prompting bilobanone ester dropping pills, and the arteriole bore is significantly expanded, and the open number of blood capillary increases, and arteriole blood flow degree is accelerated.
The influence of 2 pairs of blood systems
Select 30 of SD rats for use, be divided into 1 group and 2 groups totally 3 groups of matched group, experiment at random, test 1 group of every day every animal and irritate stomach with the bilobanone ester dropping pills of body weight 10.8mg/Kg, 2 groups of 36mg/Kg, matched group is then irritated distilled water, adopt tail blood after irritating stomach 10d simultaneously for three groups, do erythrocyte sum (RBC), content of hemoglobin (Hb), RBC diameter, total white blood cells (WBC) and classification immediately, and the detection of blood plasma total protein (SR), albumin (A), globulin aspects such as (G).
2.1 influence (seeing Table 4) to rat RBC and Hb
Table 4 bilobanone ester dropping pills is to the influence of rat RBC and Hb (x ± SD)
Group RBC (1,000,000/mm
3) Hb (g/100ml blood) unicellular Hb (mg)
Matched group 8.6 ± 1 15 ± 1 15 ± 2
Test group 1 8.8 ± 2*** 16.5 ± 1* 17 ± 1.5*
Test group 2 10.9 ± 1* 19.5 ± 1* 19 ± 1.5**
Annotate: * P＜0.05, * * P＜0.01, * * * P＞0.05
Table 4 shows, though test 1 group the RBC sum do not had significance influence (P＞0.05), and the content of Hb total amount and unicellular Hb is had significance influence (P＜0.05).Testing 2 groups has significance influence (P＜0.05) to the RBC sum, and the content of Hb total amount and unicellular Hb is had highly significant influence (P＜0.01).
2.2 influence (seeing Table 5) to rat RBC diameter.
Table 5 bilobanone ester dropping pills is to the influence of rat RBC diameter (x ± SD)
Group is measured number of cells RBC diameter (μ)
Matched group 60 6.5 ± 0.3
Test group 1 60 8.0 ± 0.6*
Test group 2 60 8.8 ± 0.2**
Annotate: * P＜0.05, * * P＜0.01
Table 5 explanation is tested 1 group and can be made the RBC diameter obviously increase (P＜0.05), tests 2 groups than experiment 1 group of better effects if (P＜0.01).
2.3 influence (seeing Table 6) to rat WBC sum and classification.
Table 6 bilobanone ester dropping pills is to the influence of rat WBC sum and classification (x ± SD)
The project matched group is tested 1 group and is tested 2 groups
WBC number (thousand/mm
2) 14.5 ± 5 15.6 ± 4*, 16.7 ± 3**
Neutrophilia WBC 3.5 ± 1 3.5 ± 2*, 3.6 ± 2***
Acidophilia WBC 0.3 ± 0.1 0.3 ± 0.1***, 0.35 ± 0.1***
Basophilia WBC 0.15 ± 0.01 0.2 ± 0.01***, 0.2 ± 0.02***
Lymphocyte 10.4 ± 3 11.2 ± 2*, 12.2 ± 1**
Mononuclear cell 0.35 ± 0.1 0.36 ± 0.05***, 0.36 ± 0.1***
Annotate: * P＜0.05, * * P＜0.01, * * * P＞0.05
As seen from Table 6, though two experimental grouies are influential to neutrophilia, acidophilia, basophilia WBC and mononuclear cell, but do not have statistical significance (P＞0.05), testing 1 group has significant difference (P＜0.05) to WBC sum and lymphocyte number, and testing 2 groups has significant differences (P＜0.01)
2.4 influence (seeing Table 7) to rat SP, A, G.
Table 7 bilobanone ester dropping pills is to the influence of rat SP, A, the G (g/100ml of x ± SD)
Group SP A G A/G
Matched group 7.3 ± 0.4 3.1 ± 0.5 3.9 ± 0.6 0.79
Test group 1 8.4 ± 0.2* 3.6 ± 0.4* 4.6 ± 1* 0.78
Test group 2 10.6 ± 0.1** 4.5 ± 0.2** 5.9 ± 1** 0.76
Annotate: * P＜0.05, * * P＜0.01
Table 7 shows, testing 1 group all has significance influence (P＜0.05) to SP, A, G, and testing 2 groups has highly significant influence (P＜0.01), and from A/G ratio, experimental group and matched group do not have much difference.
Above result shows: bilobanone ester dropping pills can significantly improve blood circulation.
Claims (10)
1, a kind of bilobanone ester dropping pills is characterized in that it makes as follows:
Ginkgo flavone and lactone 1-6 part PEG-6000 1-25 part
Ginkgo flavone and lactone is sieved, take by weighing ginkgo flavone and lactone fine powder and PEG-6000 according to the above ratio, get PEG-6000 and place 50-150 ℃ of water-bath heat fused, after the fusing, adding the ginkgo flavone and lactone fine powder below 90 ℃, the limit edged stirs, mixing time is 5 minutes-5 hours, make its abundant mixing, under 70-90 ℃ of heat-retaining condition, splash in the condensed fluid again, drip and make ball.
2, bilobanone ester dropping pills according to claim 1 is characterized in that total flavones 〉=44% in the ginkgo flavone and lactone, total lactone＞6%.
3 bilobanone ester dropping pills according to claim 1, the proportioning that it is characterized in that ginkgo flavone and lactone and PEG-6000 is 1: 4.
4, bilobanone ester dropping pills according to claim 1, the proportioning that it is characterized in that ginkgo flavone and lactone and PEG-6000 is 1: 8.
5, bilobanone ester dropping pills according to claim 1, the proportioning that it is characterized in that ginkgo flavone and lactone and PEG-6000 is 1: 15.
6, bilobanone ester dropping pills according to claim 1, the proportioning that it is characterized in that ginkgo flavone and lactone and PEG-6000 is 1: 20.
7, bilobanone ester dropping pills according to claim 1 is characterized in that bath temperature is 90-110 ℃.
8, bilobanone ester dropping pills according to claim 1 is characterized in that mixing time is 30 minutes-2 hours.
9, bilobanone ester dropping pills according to claim 1 is characterized in that mixing time is 1 hour.
10, bilobanone ester dropping pills according to claim 1 is characterized in that condensed fluid is a 10-25 ℃ of liquid paraffin.
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| CN104997742B (en) * | 2015-07-01 | 2018-05-29 | 北京汉典制药有限公司 | Bilobanone ester dropping pills and preparation method thereof |
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