CN102397281A - Ginsenoside composition for treating cardiovascular and cerebrovascular diseases - Google Patents
Ginsenoside composition for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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- CN102397281A CN102397281A CN2010102802723A CN201010280272A CN102397281A CN 102397281 A CN102397281 A CN 102397281A CN 2010102802723 A CN2010102802723 A CN 2010102802723A CN 201010280272 A CN201010280272 A CN 201010280272A CN 102397281 A CN102397281 A CN 102397281A
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Abstract
The present invention relates to the field of medicine, and discloses a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, wherein the pharmaceutical composition comprises a ginsenoside monomer Rg1 and a ginsenoside monomer Rb1, a weight ratio of the Rg1 to the Rb1 is 1:4-4:1. The ginsenoside composition of the present invention has the following advantages that: the pharmaceutical composition of the present invention has effects of blood activating and stasis removing, blood circulation promoting and collateral activating, and can be applicable for obstruction of collaterals by blood stasis, apoplectic hemiplegia, chest stuffiness and pains, and central retinal vein occlusion; the efficacy of the pharmaceutical composition is definite; the adverse reaction rate is significantly reduced; when the weight ratio of the Rg1 to the Rb1 is 1:4, the LD50 of the ginsenoside composition is more than 1000 mg/kg, and is significantly higher than the LD50 of panax notoginsenosidum; the ginsenoside composition provides the significant inhibition effect for thrombosis, and the anticoagulant effect so as to essentially improve various damages of ischemic cardiovascular and cerebrovascular disease patients due to ischemia.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1The pharmaceutical composition of the treatment cardiovascular and cerebrovascular disease of forming.
Background technology
Cardiovascular and cerebrovascular disease is the primary disease that threatens human health; Be to cause dead and maximum disease that disables; Regarded as harm humans healthy " No.1 killer " by The World Health Organization (WHO), the whole world has 1,500 ten thousand people to die from cardiovascular and cerebrovascular disease every year approximately, accounts for more than 50% of death toll.China has 4,000,000 people to die from this disease every year approximately, just has a people to die from this disease in per 24 seconds, accounts for 40% of the total cause of the death of China with regard to there being a people therefore to disable in per 13 seconds.According to World Health Organization's prediction, to the year two thousand twenty, noninfectious will account for 79% of China's cause of death, and wherein cardiovascular disease accounts for the first place.Cardiovascular and cerebrovascular disease has the low characteristics of three-hypers one: sickness rate is high, disability rate is high, mortality rate is high, cure rate is low.Cardiovascular and cerebrovascular disease sickness rate the highest countries and regions in the whole world are just in China, and China is high region of disease with the north.The family that causes thus, medical treatment and financial burden have become the social problem that can not despise.
The cardiovascular and cerebrovascular diseases medicine that how evident in efficacy society need is more, safe.The diseases of cardiovascular and cerebrovascular systems medication is the focus of drug development research in the world wide, production application always.Therefore, Development and Production diseases of cardiovascular and cerebrovascular systems medication and realize that industrialization has extremely important social meaning and economic implications.
Radix Notoginseng total arasaponins has blood circulation promoting and blood stasis dispelling; The active effect of promoting blood circulation; At present Radix Notoginseng total arasaponins and preparation XUESAITONG series of products thereof are widely used in apoplectic hemiplegia, obstruction of collaterals by blood stasis and sequal of cerebrovascular diseases, obstruction of qi in the chest and cardialgia clinically, central retinal vein occlusion belongs to blood-stasis syndrome person.Complicated component in the Radix Notoginseng total arasaponins; At present known and mainly contain ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd and arasaponin R1 as the composition of quality control index; Other rare saponin are lower because of content; Be difficult to measure its content, and the different of in various degree difference and ratio are all arranged because of the difference of pseudo-ginseng and each preparation technology's of producer difference causes ginsenoside Rg1 in the different batches Radix Notoginseng total arasaponins, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd, arasaponin R1 and other rare saponin contents.Because of adverse reaction rate is rising year by year, along with consumption constantly increases and enlarges, safety issue has become important problem in the clinical application process.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition of safer treatment cardiovascular and cerebrovascular disease, it is definite to have drug effect, safe, the advantage that untoward reaction is low.
The pharmaceutical composition of treatment cardiovascular and cerebrovascular disease provided by the invention comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1, Rg wherein
1With Rb
1Part by weight is 1: 4～4: 1.
As preferably, said pharmaceutical composition is by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1Form, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1; Said cardiovascular and cerebrovascular disease is hemorrhage or ischemic diseases.
More preferably, Rg in the said pharmaceutical composition
1With Rb
1Part by weight is 1: 4.
The present invention also provides a kind of pharmaceutical preparation of treating cardiovascular and cerebrovascular disease, comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1And acceptable accessories, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1.
More preferably, Rg in the said pharmaceutical preparation
1With Rb
1Part by weight is 1: 4.
As preferably, said pharmaceutical preparation is injection, freeze-dried powder injection or oral formulations.
Bibliographical information is arranged, and ginsenoside Rb1, ginsenoside Rg1 are at expeirmental myocardial ischemia, similar with Radix Notoginseng total arasaponins to aspects such as vascular smooth muscle effects, and the both is the effective ingredient of blood vessel dilating smooth muscle.Therefore in early-stage Study, the inventor utilizes the cardiovascular and cerebrovascular disease model, the proportioning combination that the repeated screening checking is made up of ginsenoside Rg1 and ginsenoside Rb1.Along with going deep into of research, the inventor in the cardiovascular and cerebrovascular disease model that with antiplatelet aggregation, antithrombotic and anti-anoxia enduring is index, has found to have more the ginsenoside Rg1 of therapeutic activity and ginsenoside Rb1's proportioning makes up.Ginsenoside Rg1 in the tradition Radix Notoginseng: about 1: 1 of ginsenoside Rb1's proportioning; Traditional knowledge thinks that Rg1 is the main component of activating blood circulation to dissipate blood stasis, the activity of Rb1 blood circulation promoting and blood stasis dispelling very a little less than, therefore; The ginsenoside Rg1 conforms to traditional Radix Notoginseng with ginsenoside Rb1's proportioning in the prior art; The ginsenoside Rg1: about 1: 1 of ginsenoside Rb1's proportioning, and think that the ginsenoside Rg1 has stronger haemolysis in the Radix Notoginseng, the ginsenoside Rb1 does not then have haemolysis.
In arasaponin injection standard, hemolytic test is the important indicator of safety evaluatio always.The inventor furthers investigate unexpected discovery, and new proportioning ginsenoside Rg1's ratio according to the invention significantly reduces, and ginsenoside Rb1's ratio raises, Rg
1With Rb
1Part by weight is 1: 4, and its safety is more excellent than Radix Notoginseng and Radix Notoginseng total arasaponins preparation.
According to the present invention, said pharmaceutical composition has significant antiplatelet aggregative activity, can prevent thrombosis; The said pharmaceutical composition of specificity cardiac muscle anoxia enduring models show has the patient flesh anoxia functions of highly significant, and the time-to-live Rg1 of mice: Rb1 (1: 4) group exceeds nearly 10% than the Radix Notoginseng total arasaponins group.
Collagen protein-epinephrine is brought out the influence research demonstration that the mice thrombus in vivo forms; The protective effect (P＜0.01) of pharmaceutical composition group tool highly significant according to the invention; And Rg1: Rb1 (1: 4) group and Rg1: Rb1 (1: 1) group compare mortality rate far below the Radix Notoginseng total arasaponins group with the Radix Notoginseng total arasaponins group; Point out other composition influences in the possibility Radix Notoginseng total arasaponins and cause mortality rate to raise, and the ability that makes its antagonism collagen protein-epinephrine bring out the mice thrombus in vivo that increases of Rb1 ratio is strengthened.
Influence research to the cerebral ischemia of head-breaking chmice acute shows; But panting the time of pharmaceutical composition significant prolongation decapitated mice according to the invention; The rate elongation of Rg1: Rb1 (1: 4,1: 5) group is than the Radix Notoginseng total arasaponins group leader, and the rate elongation of Rg1: Rb1 (1: 4) group is high than the rate elongation of Rg1: Rb1 (1: 5) group.
Pharmaceutical composition according to the invention can obviously prolong the clotting time of mice, and wherein, the rate elongation of Rg1: Rb1 (1: 4) group is high by 20% than the Radix Notoginseng total arasaponins group.
Hemolytic experiment shows that the Rg1 of same concentrations: Rb1 (1: 4) group, Rg1: Rb1 (1: 1) group and Rg1: Rb1 (4: 1) group are later than Rg1: Rb1 (5: 1) group and Radix Notoginseng total arasaponins group generation hemolytic reaction.
Ginsenoside Rg in the pharmaceutical composition according to the invention
1Or Rb
1Derive from crude drug Radix Notoginseng, Radix Ginseng, Radix Panacis Quinquefolii or semi-synthetic, can buy from market, purity requirement is more than 90%.
Pharmaceutical composition according to the invention has blood circulation promoting and blood stasis dispelling, and the active effect of promoting blood circulation is used for obstruction of collaterals by blood stasis; Apoplectic hemiplegia, obstruction of qi in the chest and cardialgia and central retinal vein occlusion disease, drug effect is definite; Adverse reaction rate obviously reduces, and Rg1 and Rb1 part by weight are 1: 4 o'clock, its LD
50Greater than 1000mg/kg, be significantly higher than the LD of Radix Notoginseng total arasaponins
50(455mg/kg); Can obviously suppress thrombosis effect and anticoagulation, can be from improve the various damages that ischemic cardio-cerebral diseases patient produces because of ischemia at all.
Pharmaceutical composition according to the invention has tangible antithrombotic, antiplatelet aggregation and anti-resisting oxygen lack, and discovers that through the proportioning test of different proportion its pharmacologically active is strong than the Radix Notoginseng total arasaponins effect.Tradition thinks that the ginsenoside Rg1 is the main component of invigorating blood circulation in the Radix Notoginseng; And have stronger haemolysis, and a little less than ginsenoside Rb1's effect of invigorating blood circulation, but the present invention confirms when compound recipe; Tradition thinks that the composition Rg1 proportion of invigorating blood circulation is few, has the effect of better invigorating blood circulation on the contrary.And see that from acute toxicity test and hemolytic test the present invention improves significantly aspect safety, the present invention compares with Radix Notoginseng total arasaponins, and hemolytic obviously reduces, thereby more can ensure the safety of preparation.
The specific embodiment
The invention discloses a kind of pharmaceutical composition that comprises ginsenoside monomer Rg1 and ginsenoside monomer Rb1 of treating cardiovascular and cerebrovascular disease, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention and application are described through preferred embodiment; The related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
The ginsenoside monomer Rg1 that the present invention treats cardiovascular and cerebrovascular disease and ginsenoside monomer Rb1 compositions are compared advantages such as to have drug effect suitable, and it is fixing to become to distinguish one from the other, quality controllable with other Radix Notoginseng total arasaponins ejection preparations, prove through following pharmacodynamic experiment.
Further details of the present invention can find in an embodiment, rather than protection domain is restricted to this embodiment.
Below in conjunction with embodiment, further set forth the present invention:
Test specimen
The ginsenoside Rg1, Kunming Medicine Group Stock Co., Ltd provides, purity 99.3%, lot number 20091011; The ginsenoside Rb1, Kunming Medicine Group Stock Co., Ltd provides, purity 98.6%, lot number 20091109; Radix Notoginseng total arasaponins, Kunming Medicine Group Stock Co., Ltd provides, content 93%, lot number 20080115.
Embodiment 1, ginsenoside Rg1, ginsenoside Rb1 and proportioning thereof are induced the influence of rabbit extracorporeal platelet aggregation to ADP
1 medicine
1.1 receiving the reagent thing prepares
Use distilled water to be mixed with high concentration before the experiment and be the solution of 0.8925mg/ml as final concentration as 3.5700mg/ml, middle concentration as 1.7850mg/ml, low concentration, the ginsenoside Rg1 all forms by the different volumes proportioning mixing of ginsenoside Rg1 and the above-mentioned concentration of ginsenoside Rb1 with ginsenoside Rb1's different proportioning solution preparations.The normal control group is selected normal saline for use, wherein each dosage receive in reagent thing and the normal saline add tween 30 μ l among every 10ml.More than receive the reagent thing before treated in vitro, all to be mixed with clear and bright solution.
1.2 reagent
Adenosine diphosphate (ADP) (ADP): Sigma Company products; Sodium citrate: Tianjin chemical reagent three factories, lot number: 061107; Sodium chloride injection: Kuming Nanjiang Pharmacy Co., Ltd, lot number: A08070412; Chloral hydrate (analytical pure): the special chemicals company limited in Rui Jin, Tianjin, lot number: 20060917; Tween 80 (chemical pure CP): Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20050324.
2 animals
Healthy rabbits; ♀
dual-purpose; Body weight 2-2.5kg; Sichuan Province medical scientific institute zooscopy provides product batch number: Dossy-2009-10.
3 instruments
LBY-NJ2 blood pool appearance: Pulisheng Instruments Co., Ltd., Beijing; LG10-2.4A high speed centrifuge: Beijing high speed centrifuge factory.
4 statistical method
Measurement data is used one factor analysis of variance, relatively adopts the Dunnett check between many groups.
Test method
1 test principle
(platelet rich plasma PRP) has certain turbidity to platelet rich plasma, and platelets contained number directly has influence on the turbidity height among the PRP.After derivant added PRP, under stirring condition, platelet aggregation became aggregation, and the PRP turbidity descends, and light transmittance increases, and therefore changed through the turbidity of measuring PRP and represented hematoblastic aggregation extent.Be changed to the electric signal variation because the electro-optical system in the platelet aggregation instrument can change the turbidity of PRP dress, and trace with monitor.
2 drug level setting and foundations
2.1 ginsenoside Rg1 and ginsenoside Rb1 and Radix Notoginseng total arasaponins: the high concentration final concentration is that 3.57mg/ml is provided with.This is tested the setting of high, medium and low concentration group dosage and is set to by geometric progression: (1) A medicine ginsenoside Rg1, B medicine ginsenoside Rb1 and Radix Notoginseng total arasaponins high dose group: 3.5700mg/ml; (2) concentration group: 1.7850mg/ml in ginsenoside Rg1 and ginsenoside Rb1 and the Radix Notoginseng total arasaponins; (3) ginsenoside Rg1 and ginsenoside Rb1 and Radix Notoginseng total arasaponins low concentration group: 0.8925mg/ml.
2.2 route of administration
Each medicine is external giving.
2.3 observation index
Platelet maximum agglutination rate and platelet aggregation inhibition rate.
3 test procedures
3.1 get blood
Chloral hydrate intraperitoneal injection of anesthesia rabbit with 10% is got blood from common carotid artery, is collected in the disposable plastic tube, adopts 3.2% sodium citrate anticoagulant, and blood and anticoagulant volumetric ratio are 9: 1, puts upside down mixing (can not firmly rock) after getting immediately.
3.2 platelet rich plasma (platelet rich plasma, PRP) and platelet poor plasma (platelet poorplasma, preparation PPP)
Blood adopts the centrifugal 6min of 800r/min respectively in room temperature, and the gained upper plasma is different rotating speeds PRP.Residue blood is again with the centrifugal 15min of 3000r/min, and upper strata liquid is PPP.In the process of the test, the platelet count among the PRP is controlled at and is about 500,000 mm-3.。
3.3 the mensuration of platelet maximum agglutination rate (MaxRate)
Adopt platelet aggregation instrument to measure by BornShi turbidimetry principle.Get different rotating speeds PPP300 μ l respectively in than zeroing in the turbid cup, get PRP 270 μ l and add solvent or receive reagent liquid 30 μ l, incubation 5min in 37 ℃ of preheating gates in than turbid cup in another.During mensuration the PPP cup is inserted in the instrument connection and returns to zero; Take out the PPP cup and insert the PRP cup, and in PRP, add stirrer, under the instrumentation prompting, adding final concentration then is the derivant ADP 10 μ l of 15 μ mol/L; Induced platelet is assembled, and measures platelet maximum agglutination rate in the 5min.Platelet aggregation inhibition rate is calculated as follows: assemble suppression ratio (%)=(1-administration group PAR/matched group PAR) * 100%.
4 result of the tests
Ginsenoside Rg1 and each concentration of ginsenoside Rb1's Radix Notoginseng total arasaponins and ginsenoside Rg1, each proportioning of ginsenoside Rb1 are induced the influence of rabbit extracorporeal platelet aggregation effect to ADP; The result sees table 1; Can find out from table 1: compare with the normal control group; Ginsenoside Rg1, ginsenoside Rb1's height, middle dose groups and the high, medium and low dose groups of Radix Notoginseng total arasaponins and normal control group compare, and difference all has significance meaning (P＜0.05, P＜0.01 or P＜0.001); Rg1: Rb1=1: 1,4: 1,1: 4,2: 1,1: 2 high concentration and Rg1: Rb1=1: 4 middle concentration and normal control group compare, and difference all has significance meaning (P＜0.05, P＜0.01 or P＜0.001).
5. conclusion
The ginsenoside Rg1, ginsenoside Rb1's height, middle concentration and the high, medium and low concentration of Radix Notoginseng total arasaponins, and Rg1: Rb1=1: 1,4: 1,1: 4,2: 1,1: 2 high concentration and Rg1: Rb1=1: 4 middle concentration has significant antiplatelet aggregative activity.Experimental result is visible when senior middle school's dosage, Rg1: Rb1=1: the 4 pairs of hematoblastic suppression ratio are identical with Radix Notoginseng total arasaponins, point out this proportioning that the prophylaxis of thrombosis effect is arranged.
Table 1A, B medicine and the different proportionings of Radix Notoginseng total arasaponins and A: B are induced the influence (
n=6) of rabbit extracorporeal platelet aggregation rate to ADP
Annotate: A is the ginsenoside Rg1, and B is the ginsenoside Rb1.Compare with the normal control group:
*P＜0.05;
*P＜0.01;
* *P＜0.001
Embodiment 2 ginsenoside Rgs
1With Rb
1Different proportionings are to the influence of specificity cardiac muscle anoxia enduring model
1, test material:
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare Rg1: Rb1=1 respectively: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1
Reagent and equipment: isoproterenol hydrochloride inj (2ml:1mg Shanghai Hefeng Pharmaceutical Co., Ltd.), 250ml ground wide mouthed bottle, timer, sodica calx vaseline etc.
Laboratory animal: SPF level ICR mice; ♀
dual-purpose; W:18～22g; Laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods:
Mice is divided into 8 groups at random: Rg1: Rb1 (5: 1) group, Rg1: Rb1 (4: 1) group, Rg1: Rb1 (1: 1), Rg1: Rb1 (1: 4), Rg1: Rb1 (1: 5) group, Radix Notoginseng total arasaponins group, model group and blank control group; Every group 10; Below respectively organize intraperitoneal injection 120mg/kg every day, administration volume 0.1ml/10g; Model group and blank control group all give isometric normal saline, continuous 5 days.Each group is respectively at behind the last tail iv administration 10min; Ip isoproterenol injection 0.4ml/10g (blank control group is not given); Behind the 15min mice is put into the ground wide mouthed bottle that fills the 20g sodica calx, timing immediately is the index observing mice time-to-live to cease breathing.
3 result of the tests:
The influence
of table 2 pair specificity myocardial ischemia mice time-to-live
| Group | Dosage (mg/kg) | Time-to-live (min) |
| Blank control group | - | 22.31±3.59 |
| Model group | - | 18.23±2.45 ΔΔ |
| Rg1∶Rb1(5∶1) | 120 | 19.36±3.54* |
| Rg1∶Rb1(4∶1) | 120 | 19.87±4.22* |
| Rg1∶Rb1(1∶1) | 120 | 20.18±2.66* |
| Rg1∶Rb1(1∶4) | 120 | 22.08±4.27** |
| Rg1∶Rb1(1∶5) | 120 | 21.44±4.31* |
| Radix Notoginseng total arasaponins | 120 | 20.77±4.21* |
The Δ ΔP＜0.01, model group and blank control group relatively have significant differences;
*P＜0.01, administration group and model group relatively have significant differences;
*P＜0.05, administration group and model group relatively have significant difference;
Can be known Rg1 by table 2: Rb1 (1: 4) group has the patient flesh anoxia functions (p＜0.01) of highly significant, and the Radix Notoginseng total arasaponins group has significant patient flesh anoxia functions (p＜0.05).See that from result of the test under same dosage condition, the time-to-live Rg1 of mice: Rb1 (1: 4) group exceeds nearly 10% than the Radix Notoginseng total arasaponins group.And the time-to-live of Rg1: Rb1 (1: 1) group is compared no significant difference with the Radix Notoginseng total arasaponins group, explains that the main component of the anti-myocardial ischemia of Radix Notoginseng total arasaponins is ginsenoside Rg1 and ginsenoside Rb1.
Embodiment 3: collagen protein-epinephrine is brought out the influence that the mice thrombus in vivo forms
1 test material
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare Rg1: Rb1=1 respectively: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1Visit aspirin, U.S. Beyer Co., Ltd produces.
Reagent: collagen protein, epinephrine etc.
Laboratory animal: SPF level ICR mice; ♀
dual-purpose; W:18～22g; Laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods:
Get 60 of mices; Be divided into 8 groups at random: Rg1: Rb1 (5: 1) group, Rg1: Rb1 (4: 1) group, Rg1: Rb1 (1: 1), Rg1: Rb1 (1: 4), Rg1: Rb1 (1: 5) group, Radix Notoginseng total arasaponins group, positive group and blank control group; Every group 10; Below respectively organize intraperitoneal injection 120mg/kg every day, administration volume 0.1ml/10g; Positive group is irritated stomach and is visitd aspirin 20mg/kg; Blank control group is irritated stomach and is given isometric normal saline, continuous 5 days.15min after the last administration (positive group and blank control group be 45min after the administration) gives derivant by tail iv, observes and write down dead mouse number in 5 minutes or the recovery number of mice hemiplegia in 15 minutes, calculates each medicine to mouse brain thrombosis protective rate, and the result sees table 3.
Table 3 pair collagen protein-epinephrine brings out the influence that the mice thrombus in vivo forms
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows; Whole hemiplegia in 5 minutes behind the blank treated animal injection derivant; Dead in 15 minutes; The positive controls aspirin has the protective effect (P＜0.01) of highly significant, and Rg1: Rb1 (1: 1) group and Rg1: Rb1 (1: 4,1: 5) organize also has a protective effect (P＜0.01) of highly significant, Rg1: Rb1 (1: 4) group and Radix Notoginseng total arasaponins group relatively mortality rate far below the Radix Notoginseng total arasaponins group.And Rg1: Rb1 (1: 1) group mortality rate is low than the Radix Notoginseng total arasaponins group, prompting maybe Radix Notoginseng total arasaponins in other composition influences and cause mortality rate to raise, and the ability that makes its antagonism collagen protein-epinephrine bring out the mice thrombus in vivo that increases of Rb1 ratio is strengthened.
Embodiment 4: to the influence of head-breaking chmice acute cerebral ischemia
1 test material
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare Rg1: Rb1=1 respectively: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h1.NAODESHENG capsule, (97) are defended the accurate word Z-121 of medicine number, the 0.28g/ grain, and the refreshing really pharmaceutcal corporation, Ltd in Guizhou produces lot number 20081201.
Laboratory animal: SPF level ICR mice; ♀
dual-purpose; W:19～22g; Laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
Get 72 of mices, male and female half and half are divided into 8 groups at random by table 4,12 every group.Each treated animal according to dosage in every day intraperitoneal administration once, the blank group is irritated stomach and is given sodium chloride injection 20ml/kg, positive controls is irritated stomach and is given NAODESHENG 1.68g/kg, continuous 7 times.30min after the last administration cuts after mouse ear broken end fast with profit, and record is from the broken end once snorting to the end time of beginning.The result sees table 4.
The influence
of table 4. pair head-breaking chmice acute cerebral ischemia
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows, but administration group significant prolongation decapitated mice pant the time Rg1: the rate elongation of Rb1 (1: 4,1: 5) group is than the Radix Notoginseng total arasaponins group leader, and the rate elongation of Rg1: Rb1 (1: 4) group is high than the rate elongation of Rg1: Rb1 (1: 5) group.
Embodiment 5: to the influence of clotting time of mice
1 test material
Medicine: ginsenoside Rg1 and ginsenoside Rb1 prepare Rg1: Rb1=1 respectively: 4,1: 5,5: 1,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1Visit aspirin, U.S. Beyer Co., Ltd produces.
Laboratory animal: SPF level ICR mice; ♀
dual-purpose; W:18～20g; Laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
Get 60 of mices, male and female half and half are pressed table 5 and are divided into groups immediately, 10 every group.Each treated animal according to dosage in every day intraperitoneal administration once, the blank group is irritated stomach and is given sodium chloride injection 20ml/kg, positive controls is irritated stomach and is given aspirin 20g/kg, continuous 7 days.30min after the last administration plucks eyeball and gets blood, and slide method is measured the clotting time of respectively organizing mice.The result sees table 5.
The influence of table 5 pair clotting time of mice
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows that the administration group all can obviously prolong the clotting time of mice, and wherein, the rate elongation of Rg1: Rb1 (1: 4) group is high by 20% than the Radix Notoginseng total arasaponins group.
Embodiment 6: compositions according to the invention and the comparative study of Radix Notoginseng total arasaponins toxicity
With reference to version in 2005 " Chinese pharmacopoeia undue toxicity's inspection technique and the present invention and relevant Radix Notoginseng total arasaponins are carried out toxicity test relatively with reference to the acute toxicity test method.
Table 6. The acute toxicity tests (LD
50)
Embodiment 7: compositions according to the invention and the comparative study of Radix Notoginseng total arasaponins ejection preparation hemolytic test
As the saponins Chinese medicine, hemolytic test is the important indicator as its safety evaluation always, dissolves according to the test method of " Chinese medicine, natural drug zest and hemolytic investigative technique guideline "
Blood test is observed the present invention and haemolysis and the cohesion situation of Radix Notoginseng total arasaponins under variable concentrations.
1 test material
Medicine: ginsenoside Rg1 and ginsenoside Rb1 prepare Rg1: Rb1=1: 4 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1
Laboratory animal: regular grade large ear rabbit; ♀
dual-purpose; Provide by unming Medical College's Experimental Animal Center; Laboratory animal production licence card SCXK (Yunnan) 2005-2008, occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
The preparation of 2% red blood cell suspension: get Sanguis Leporis seu oryctolagi 20～30ml, remove Fibrinogen, add the about 10 times of amount washings of chlorination sodium injection; The centrifugal 15min of 1500r/min abandons supernatant, repeats 2～3 times; Till supernatant does not show redness; Abandon supernatant, the gained erythrocyte is prepared 2% red blood cell suspension with sodium chloride injection, be for experiment.
The preparation of test liquid: precision takes by weighing these article, adds the chlorination sodium injection and is dissolved as solution that every 1ml contains 15mg and 25mg as test liquid.
The method of inspection:
Get 7 in test tube respectively, wherein 1～No. 5 pipe is for receiving the reagent property management, manages negative control tube No. 6, manages positive control tube No. 7.Add 2% red cell suspension, sodium chloride injection, distilled water shown in the according to the form below, place 37 ℃ ± 0.5 ℃ thermostatic water tank to carry out incubation behind the mixing immediately.Beginning is every to be observed once at a distance from 15 minutes, behind the 1h interval 1 h observation once, continuous 24 hours.
Solution as in the test is clear and bright redness, and the pipe end is acellular residual or have a small amount of erythrocyte residual, and showing has haemolysis to take place; All sink like erythrocyte, the supernatant achromatism and clarity shows that no haemolysis takes place.
If in the solution brownish red or rufous flocculent deposit are arranged, do not disperse after the jolting, showing has red blood cell condensation to take place.If any the phenomenon of red blood cell condensation, can further judge it is cohesion or pseudo agglutination by purgation.If condensation product again can homodisperse after test tube vibration; Or condensation product placed on the microscope slide, drip 2 sodium chloride injections at the microscope slide edge, put microscopically and observe; The cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken diffusing or on slide, is not cohesion by the person of breaking up.
The result judges:
Do not take place with cohesion when the negative control pipe has haemolysis, when the positive control pipe had haemolysis to take place, if haemolysis and cohesion did not take place in 3 hours the solution in test sample the 3rd pipe (0.3ml), it was up to specification to declare test sample; If haemolysis and cohesion took place in 3 hours the solution in test sample pipe the 3rd pipe (0.3ml), it is against regulation to declare test sample.
3 result of the tests:
Rg1: Rb1 (1: 4) group is when concentration reaches 25mg/ml, and haemolysis and cohesion did not take place in 5 hours the solution in the 3rd pipe (0.3ml), and the 5th pipe (0.5ml) began to take place hemolytic reaction in 4 hours, and the 4th pipe (0.4ml) began to take place hemolytic reaction in 6 hours; Hemolytic reaction does not take place under the 15mg/ml concentration.Rg1: Rb1 (1: 5) group is when concentration reaches 25mg/ml, and haemolysis and cohesion did not take place in 5 hours the solution in the 3rd pipe (0.3ml), and the 5th pipe (0.5ml) began to take place hemolytic reaction in 4 hours, and the 4th pipe (0.4ml) began to take place hemolytic reaction in 5 hours; Hemolytic reaction does not take place under the 15mg/ml concentration.Rg1: Rb1 (4: 1) group is when concentration reaches 15mg/ml, and hemolytic reaction did not take place at 3 hours the solution in the 3rd pipe (0.3ml).Rg1: Rb1 (5: 1) group is when concentration reaches 15mg/ml, and hemolytic reaction took place at 3 hours the solution in the 3rd pipe (0.3ml).Rg1: Rb1 (1: 1) group is when concentration reaches 25mg/ml concentration; Haemolysis and cohesion did not take place in the solution in the 3rd pipe (0.3ml) in 3 hours; The 4th pipe (0.4ml) began to take place hemolytic reaction in 5 hours; The 5th pipe (0.5ml) began to take place hemolytic reaction in 4 hours, under the 15mg/ml concentration hemolytic reaction did not take place.When the Radix Notoginseng total arasaponins group reached 15mg/ml concentration in concentration, hemolytic reaction took place in solution in the 3rd pipe (0.3ml) at 3 hours.
Embodiment 8: the preparation of medicine composition injection of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 by weight being to carry out proportioning at 1: 4, add an amount of water for injection dissolving, ultrafiltration, fill, the injection injection is processed in sterilization.
Embodiment 9: the preparation of lyophilized injection of pharmaceutical composition of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 by weight being to carry out proportioning at 4: 1, add an amount of water for injection dissolving, filter, fill, freeze-dried powder injection is processed in lyophilization.
Embodiment 10: the preparation of pharmaceutical composition tablet of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 by weight being to carry out proportioning at 1: 4, be prepared into tablet according to the conventional formulation method.
Embodiment 11: the preparation of medicament composition capsule agent of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 by weight being to carry out proportioning at 1: 4, prepare capsule in blocks according to the conventional formulation method.
Embodiment 12: the preparation of medicament composition granule agent of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 by weight being to carry out proportioning at 1: 4, prepare granule in blocks according to the conventional formulation method.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (8)
1. a pharmaceutical composition of treating cardiovascular and cerebrovascular disease comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1, Rg wherein
1With Rb
1Part by weight is 1: 4～4: 1.
2. pharmaceutical composition according to claim 1 is characterized in that, by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1Form, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1.
3. pharmaceutical composition according to claim 1 and 2 is characterized in that, wherein Rg
1With Rb
1Part by weight is 1: 4.
4. pharmaceutical composition according to claim 3 is characterized in that, said cardiovascular and cerebrovascular disease is hemorrhage or ischemic diseases.
5. a pharmaceutical preparation of treating cardiovascular and cerebrovascular disease comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1And acceptable accessories, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1.
6. pharmaceutical preparation according to claim 5 is characterized in that Rg
1With Rb
1Part by weight is 1: 4.
7. pharmaceutical preparation according to claim 5 is characterized in that, it is injection or freeze-dried powder injection.
8. according to the said pharmaceutical preparation of claim 5, it is characterized in that it is an oral formulations.
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| CN105287614A (en) * | 2015-11-19 | 2016-02-03 | 昆药集团股份有限公司 | Dengyin naotong pharmaceutical composition and preparation method thereof, preparation and application thereof |
| CN106501472A (en) * | 2016-11-29 | 2017-03-15 | 昆明理工大学 | A kind of method that pseudo-ginseng blood-circulation-invigovating effect is evaluated based on anticoagulation biochemical index |
| CN108670972A (en) * | 2018-07-19 | 2018-10-19 | 昆明龙津药业股份有限公司 | Pharmaceutical composition and purposes for preventing/treating ischemic angiocardiopathy and cerebrovascular disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105287614A (en) * | 2015-11-19 | 2016-02-03 | 昆药集团股份有限公司 | Dengyin naotong pharmaceutical composition and preparation method thereof, preparation and application thereof |
| CN105287614B (en) * | 2015-11-19 | 2018-04-13 | 昆药集团股份有限公司 | A kind of Dengyin naotong pharmaceutical composition and preparation method thereof, preparation and application |
| CN106501472A (en) * | 2016-11-29 | 2017-03-15 | 昆明理工大学 | A kind of method that pseudo-ginseng blood-circulation-invigovating effect is evaluated based on anticoagulation biochemical index |
| CN108670972A (en) * | 2018-07-19 | 2018-10-19 | 昆明龙津药业股份有限公司 | Pharmaceutical composition and purposes for preventing/treating ischemic angiocardiopathy and cerebrovascular disease |
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| CN102397281B (en) | 2013-04-10 |
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