CN101185669B - Medicine composition for treating cardiovascular and cerebrovascular diseases - Google Patents
Medicine composition for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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- CN101185669B CN101185669B CN2007101937191A CN200710193719A CN101185669B CN 101185669 B CN101185669 B CN 101185669B CN 2007101937191 A CN2007101937191 A CN 2007101937191A CN 200710193719 A CN200710193719 A CN 200710193719A CN 101185669 B CN101185669 B CN 101185669B
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Abstract
The invention discloses a medicine composition for treating cardiovascular diseases. The composition uses the effective part of radix, radix total saponin, and the effective part of kudzuvine root, kudzuvine root total flavonoids as active components, and has significant effects of anti-cerebral ischemia and myocardial ischemia. The therapeutic effect is much superior to using radix total saponin or kudzuvine root total flavonoids alone; the invention provides a compound recipe or preparation with better therapeutic effect and convenient usage.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, specifically the present invention relates to treat the pharmaceutical composition of cardiovascular and cerebrovascular disease, said composition is an active component with the effective site Radix Notoginseng total arasaponins of Radix Notoginseng and the effective site Radix Puerariae total flavones of Radix Puerariae.
Background technology
Cardiovascular disease such as coronary heart disease, angina pectoris is serious threat human life and healthy commonly encountered diseases, frequently-occurring disease.At its prevalence height of developed country, the disability rate height is the adult's of most developed countries and many developing countries a major causes of death, also is the modal cause of death in the world wide.According to the numeral of World Health Organization (WHO) issue, last year, the whole world was about 1,700 ten thousand because of the number of cardiovascular disease death, account for the whole world dead 1/3rd, in other words, it is cardiovascular disease that every dead 3 people in the whole world just have 1 people.The cardiovascular diseases accounts for population of China cause of the death first place.Along with the growth of the average life span, the affluence of material conditions and the variation of life culture mode, cardiovascular disease, particularly Incidence of CHD and mortality rate are increasing year by year, and the trend of rejuvenation is arranged.Thereby protection heart, prevention and treatment cardiovascular disease are more and more paid attention to by people and are paid close attention to.Though the cardiovascular drug species is more at present, the cardiovascular drugs of research and development highly effective and safe is still the task of top priority.
In the medicine of cardiovascular and cerebrovascular disease, the application of Chinese medicine and western medicine emphasizes particularly on different fields, and Chinese medicine also occupies the bigger market share with the little advantage of its side effect.In the Chinese patent medicine of present numerous treatment cardiovascular and cerebrovascular diseases, be that the Chinese patent medicine of main active such as Radix Notoginseng total arasaponins, Radix Salviae Miltiorrhizae total phenolic acids, Ginkgo total flavones, puerarin, breviscapine etc. more and more is subject to people's attention with effective site.The effect of the various effective ingredient in Chinese of treatment cardiovascular and cerebrovascular disease is had nothing in common with each other and is stressed, and therefore, has the great demand of drug combination clinically.At present injection such as XUESAITONG, XUESHUANTONG and the effective ingredient injection such as the puerarin injection etc. of the kind, particularly effective site of each single effective site and effective ingredient are difficult to satisfy the demand of clinical drug combination.In addition, Chinese medicine is mixed use simply, will emit huge risk, might cause unpredictable untoward reaction, sharply increase, heating, anaphylaxis or the like as blood pressure without the approval of national drug food Surveillance Authority.Therefore, provide convenient effective effective ingredient in Chinese compound preparation to have important clinical meaning and important social value.
Radix Puerariae total flavones is the effective site in the Chinese medicine Radix Puerariae, and wherein contained puerarin is one of its effective ingredient, and the test of pesticide effectiveness shows that both all can increase brain and crown vascular flow amount, the corresponding reduction of vascular resistance improves cerebral circulation, can make the peripheral blood vessel expansion, coronary artery dilator blood vessel particularly, increase the coronary artery blood flow, improve the blood flow of ischemic region, reduce myocardial oxygen consumption, reduce the generation of ischemic myocardium lactic acid, improve blood high viscosity syndrome, anticoagulant, microcirculation improvement; And receptor retardation and demulcent blood pressure lowering are widely arranged and improve brain and the effect of peripheral circulation.Untoward reaction to puerarin has report more clinically, as heating, allergic rash, anaphylactic shock, digestive tract hemorrhage, hemolytic anemia etc. but in recent years.
Radix Notoginseng total arasaponins has function of promoting blood circulation to disperse blood clots preferably, cerebrovascular circulates to improving, the cerebral blood flow increasing amount has obvious effects, it is effective preparation of treatment cerebral infarction, in recent years find, this product also has good dilating effect to cardiovascular, can reduce Peripheral resistance, reduce myocardial oxygen consumption, promote collateral circulation, suppress platelet aggregation, angina pectoris is had curative effect preferably.Existing Radix Notoginseng total arasaponins injection has function of promoting blood circulation to disperse blood clots preferably.
At present, above-mentioned two kinds of active component all have been used to treat cardiovascular and cerebrovascular disease, the patent application CN03121958.6 of Shengtai Pharmaceutical Co., ltd., Harbin for example, denomination of invention is " in a kind of pharmaceutical composition for the treatment of cerebrovascular disease ", wherein disclose in a kind of pharmaceutical composition that is used for the treatment of cerebrovascular disease, said composition contains Radix Notoginseng total arasaponins, Radix Puerariae total flavones and total panaquilon.
In No. 03121958.6 patent application, described compositions comprises three kinds of compositions, composition is comparatively complicated, for the preparation of Chinese medicine ingredients, increase a kind of composition and bring very big inconvenience all can for production technology, quality control standard, for example for injection, increase stability, the safety that a kind of composition means product and all can receive very big challenge, and total panaquilon is that raw material obtains with the Radix Panacis Quinquefolii, also increased the treatment cost of production cost and consumer.Therefore, treatment wish to obtain during cardiovascular and cerebrovascular disease to form simple, effect is good and lower-cost drug regimen.
The present inventor finds, use a certain proportion of Radix Notoginseng total arasaponins and Radix Puerariae total flavones administering drug combinations can obtain beyond thought synergy, not only better than the Radix Puerariae total flavones or the Radix Notoginseng total arasaponins effect more of independent use Isodose, and in the suitable effect of effect of removing No. 03121958.6 patented product that still can reach suitable under a kind of situation of composition one total panaquilon with accumulated dose, but, compare with the compositions in No. 03121958.6 patent application, compositions of the present invention is formed more simple, cost reduces, more be applicable to large-scale commercial production, thereby finished the present invention.
Still find no in the prior art about using a certain proportion of Radix Notoginseng total arasaponins and Radix Puerariae total flavones to have synergistic instruction, therefore, pharmaceutical composition of the present invention has novelty and the creativeness on the patent meaning.
Summary of the invention
Purpose of the present invention just provides a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, this pharmaceutical composition energy blood circulation promoting and blood stasis dispelling, generation synergism, raising evident in efficacy, can significantly reduce the puerarin consumption again, thereby reduce the probability that untoward reaction clinically takes place, overcome simultaneously the deficiency that single effective ingredient in Chinese is difficult to satisfy the demand for the treatment of the cardiovascular and cerebrovascular disease drug combination clinically again, avoid medicine simply to mix the side reaction that use may cause, a kind of better efficacy clinically, convenient effective ingredient in Chinese compound and preparation thereof are provided.
Compared with prior art, the invention has the beneficial effects as follows: this pharmaceutical composition contains Radix Notoginseng total arasaponins and Radix Puerariae total flavones, energy blood circulation promoting and blood stasis dispelling, generation synergism, than singly using with the dosage Radix Notoginseng total arasaponins or singly using with the dosage Radix Puerariae total flavones or singly use with dosage puerarin effect and all improve greatly, prove that through pharmacodynamics test it is evident in efficacy.Can significantly reduce the puerarin consumption again, thereby reduce the probability that untoward reaction clinically takes place.
The purpose of this invention is to provide a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, said composition contains Radix Notoginseng total arasaponins and Radix Puerariae total flavones as active component, and conventional pharmaceutical carrier.
In the pharmaceutical composition of above-mentioned treatment cardiovascular and cerebrovascular disease, the purity of described Radix Puerariae total flavones is more than 50%, preferably more than 80%.
The present invention treats in the pharmaceutical composition of cardiovascular and cerebrovascular disease, and the purity of described Radix Notoginseng total arasaponins is more than 80%, and is preferred more than 90%.
Treat in the pharmaceutical composition of cardiovascular and cerebrovascular disease in the present invention, described Radix Notoginseng total arasaponins is extracted by Radix Notoginseng, and described Radix Puerariae total flavones is extracted by Radix Puerariae; In the wherein said Radix Notoginseng extract in the content of Radix Notoginseng total arasaponins and the Radix Puerariae extract content of Radix Puerariae total flavones meet above-mentioned requirements.
In aforementioned pharmaceutical compositions of the present invention, the weight ratio of two kinds of active component is: 1 part of Radix Notoginseng total arasaponins, Radix Puerariae total flavones 0.1-10 part.Preferably, the weight ratio of two kinds of active component is in the pharmaceutical composition of the present invention: 1 part of Radix Notoginseng total arasaponins, Radix Puerariae total flavones 1-5 part.Preferred, the weight ratio of two kinds of active component is in the pharmaceutical composition of the present invention: 1 part of Radix Notoginseng total arasaponins, Radix Puerariae total flavones 1.5-2.5 part.Most preferred, the weight ratio of two kinds of active component is in the pharmaceutical composition of the present invention: Radix Notoginseng total arasaponins and Radix Puerariae total flavones are 3: 7 or 4: 6.
One of active component in said composition Radix Puerariae total flavones can be by buying on the market, and also available conventional method is prepared by Radix Puerariae.For example, can adopt following method preparation:
Described Radix Puerariae total flavones also can prepare according to following method: get Radix Puerariae medical material 10Kg, measure 70% alcohol reflux three times, each 2h, filtration with 10 times, merge three times ethanol extract, reclaim ethanol, be concentrated into about 20L, add water to about 100L, leave standstill 12h, centrifugal; Supernatant is with the wet AB-8 macroporous resin adsorption of 20L, washes with water to effluent colourlessly earlier, and reuse 30% concentration ethanol 80L desorption is collected 30% ethanol elution, reclaims ethanol, and drying under reduced pressure promptly gets Radix Puerariae total flavones.
(1) content of puerarin is measured (high performance liquid chromatography) in the above-mentioned Radix Puerariae total flavones
Chromatographic condition and system suitability test: closing silica gel with the octadecylsilane chain is filler; Methanol-1.0% acetic acid (25: 75) is mobile phase; The detection wavelength is 250nm.Number of theoretical plate calculates by puerarin peak, should be not less than 3000.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the puerarin reference substance, makes the solution that every ml contains 0.1mg with 30% ethanol.
The preparation of need testing solution: precision takes by weighing the about 10mg of this product, puts in the 10ml measuring bottle, adds 30% dissolve with ethanol and is diluted to scale, shakes up; Precision is measured 1ml and is put in the 10ml measuring bottle,, shakes up to scale with 30% ethanol dilution, promptly.
Algoscopy: accurate respectively reference substance and each 10ul of need testing solution of drawing, inject chromatograph of liquid and measure, its HPLC finger printing is seen Fig. 1.
Adopting in the total fingerprint peaks the bigger and metastable total peak puerarin of peak area as the reference peak, is basic calculation relative retention time and relative peak area with the reference peak.The finger printing of above-mentioned Radix Puerariae total flavones should have 4-7 total peak, is generally 5 total peaks.The relative retention time at 5 total peaks is followed successively by 0.52-0.65 (3 '-hydroxyl puerarin peak), 1.0 (puerarin peak is promptly with reference to peak S), 1.10-1.20 (3 '-methoxy puerarin peak), 1.40-1.55,1.70-1.85.In the total peak unimodal area account for total peak area greater than 20% have only puerarin peak (promptly with reference to the peak), the peak area of puerarin peak accounts for the 45%-90% of total peak area, its relative peak area is 1; Relative retention time is that total peak (the 3 '-methoxy puerarin peak) peak area of 1.10-1.20 accounts for the 3%-18% of total peak area, and its relative peak area is 0.03-0.25.The non-total peak gross area is not more than 5% of total peak area.
(2) mensuration of above-mentioned Radix Puerariae total flavones total flavones (ultraviolet visible spectrophotometry)
The preparation of reference substance solution: it is an amount of that precision takes by weighing the puerarin reference substance, makes the solution that every ml contains 10ug with 30% ethanol, promptly.
The preparation of need testing solution: precision takes by weighing the about 10mg of this product, puts in the 10ml measuring bottle, with 30% dissolve with ethanol and be diluted to scale, shakes up, and precision is measured 1ml, puts in the 100ml measuring bottle, adds 30% ethanol dilution to scale, shakes up, promptly.
Algoscopy: getting reference substance and need testing solution respectively, is blank with 30% ethanol, according to ultraviolet one visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005)), measure trap at 250nm wavelength place, calculate, promptly.
Another active component Radix Notoginseng total arasaponins in the present composition can be by buying on the market, the product of buying must meet the regulation of national ministry standard WS3-B-3590-2001 (Z) or WS3-B-3829-98 "; also can adopt following method from Radix Notoginseng, to extract: to get pseudo-ginseng; water or ethanol extraction; to collect extracting solution; the extracting solution that concentrates or reclaim behind the ethanol is crossed macroporous adsorbent resin; the low-concentration ethanol eluting of first water or 5-20%, remove the impurity that is dissolved in polar solvent, discard, the high concentration ethanol eluting of reuse 30-95% is collected this high concentration ethanol eluent, eluent drying with behind the recovery ethanol promptly gets Radix Notoginseng total arasaponins.
(1) arasaponin R1, ginsenoside Rg1, ginsenoside Rb1's assay (high performance liquid chromatography) in the above-mentioned Radix Notoginseng total arasaponins
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Flow velocity: 1.0ml/min; The detection wavelength is 203nm; Column temperature: 35 ℃; Mobile phase A is an acetonitrile, and B is a water, and gradient is as follows:
| Time (minute) | A (acetonitrile) | B (water) |
| 0 | 20 | 80 |
| 13 | 40 | 60 |
| 19 | 20 | 80 |
| 30 | 20 | 80 |
The preparation of reference substance solution: it is an amount of that precision takes by weighing arasaponin R1, ginsenoside Rg1 and ginsenoside Rb1's reference substance, add methanol and make the solution that every ml contains the 0.2mg arasaponin R1 respectively, every ml contains 0.4mg ginsenoside Rg1's solution, and every ml contains 0.4mg ginsenoside Rb1's solution.
The preparation of need testing solution: precision takes by weighing the about 15mg of this product, puts in the 10ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up, promptly.
Algoscopy: accurate respectively reference substance solution and each 10ul of need testing solution of drawing, inject chromatograph of liquid, measure, promptly get the HPLC finger printing, see Fig. 2.
Adopting in the total fingerprint peaks the bigger and metastable total peak ginsenoside Rg1 of peak area as the reference peak, is basic calculation relative retention time and relative peak area with the reference peak.The finger printing of above-mentioned Radix Notoginseng extract should have 8-12 total peak, is generally 11 total peaks.The HPLC finger printing of described Radix Notoginseng extract has 11 total peaks, the relative retention time at 11 total peaks is followed successively by 0.80-0.90 (Radix Notoginseng total arasaponins R1 peak), 1 (the bitter Rg1 of Radix Ginseng soap peak is promptly with reference to the peak), 1.65-1.75,1.80-1.85,1.90-2.10,2.20-2.30 (ginsenoside Rb1 peak), 2.45-2.51,2.53-2.59, (2.70-2.80 ginsenoside Rd peak), 3.45-3.63,3.65-3.82.In the total peak unimodal area account for total peak area greater than 20% ginsenoside Rg1 peak and ginsenoside Rb1 peak arranged.The peak area at ginsenoside Rg1 peak (promptly with reference to the peak) accounts for the 30%-50% of total peak area, its relative peak area is 1.0, the peak area at ginsenoside Rb1 peak accounts for the 20%-50% of total peak area, its relative peak area is 0.85-2.50: the honeybee area at Radix Notoginseng total arasaponins R1 peak accounts for the 2%-10% of total peak area, and its relative peak area is 0.06-0.40.The non-total peak gross area is not more than 5% of total peak area.
(2) mensuration (ultraviolet visible spectrophotometry) of total saponins in the above-mentioned Radix Notoginseng total arasaponins
The preparation of standard curve: it is an amount of that precision takes by weighing the ginsenoside Rg1, adds methanol and make every milliliter of solution that contains ginsenoside Rg 125ug, shakes up.Accurate contrast liquid 0.5,1.0,1.5,2.0,2.5, the 3.0ml of drawing, put respectively in the tool plug test tube, solvent is flung in water-bath, put coldly, accurate freshly prepared 5% vanillin glacial acetic acid solution 0.2ml and the perchloric acid 0.8ml of adding heats 15min in 60 ℃ of water-baths, the ice bath cooling, the accurate respectively acetic acid 5ml that adds, mixing is placed 10min.And get blank solution work blank under the similarity condition, measure absorbance, drawing standard curve at 550nm wavelength place.
The preparation of need testing solution and mensuration: precision takes by weighing this product 30mg, put in the conical flask, after adding a small amount of moistening of water, add water saturated n-butyl alcohol reflux, extract, three times, solvent load is respectively 30,20,15ml, each 1 hour, merge n-butyl alcohol liquid, add the saturated water of n-butyl alcohol and wash on a small quantity, discard water liquid, be diluted to 100ml with water saturated n-butyl alcohol, shake up.The accurate 10ml that draws puts in the 50ml measuring bottle, adds water saturated n-butyl alcohol and is diluted to scale, shake up, the accurate 0.5ml that draws, water bath method is put cold, accurate freshly prepared 5% vanillin glacial acetic acid solution 0.2ml and the perchloric acid 0.8ml of adding, in 60 ℃ of water-baths, heat 15min, ice bath cooling, the accurate respectively acetic acid 5ml that adds, mixing is placed 10min.Measure trap at 550nm wavelength place, calculate total saponin content according to standard curve.
Another object of the present invention has provided preparation of drug combination method of the present invention, and this method can adopt the conventional method of pharmaceutical field, uses conventional pharmaceutical carrier to carry out.After for example adopting conventional method with Radix Notoginseng total arasaponins and Radix Puerariae total flavones uniform mixing, mix, make various required dosage forms then with carrier or the adjuvant used always on any or more than one pharmaceuticss.Described carrier is excipient, filler, diluent, lubricant, wetting agent, disintegrating agent, surfactant, antiseptic, sweeting agent, aromatic etc. for example.Concrete, described carrier is starch, dextrin, lactose, microcrystalline Cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, magnesium stearate, micropowder silica gel, glucose, mannitol, xylitol, glycine etc. for example.
As required, pharmaceutical composition of the present invention can be made into the preparation that is suitable for various approach medications, particularly is suitable for dosage form oral and injection.Described to be suitable for oral dosage form can be to be selected from following arbitrary dosage form: tablet, capsule, soft capsule, granule, drop pill, dispersible tablet, slow releasing tablet, controlled release tablet or oral cavity quick disintegrating slice.The described dosage form that is suitable for injecting can be injection, transfusion or powder injection formulation.
When pharmaceutical composition of the present invention was made into the dosage form that is suitable for injecting such as injection or injectable powder, wherein general flavone content was more than 80% in the Radix Puerariae total flavones, and total saponin content is more than 80% in the Radix Notoginseng extract.
Another object of the present invention has provided the application of pharmaceutical composition of the present invention aspect the treatment cardiovascular and cerebrovascular disease, and described cardiovascular and cerebrovascular disease mainly comprises cerebral thrombosis, cerebral ischemia, coronary heart disease, angina pectoris, myocardial ischemia, heart failure, arrhythmia etc.
When being used for the treatment of cardiovascular and cerebrovascular disease, can adopt oral and the injecting pathway medication according to the needs of the state of an illness, described injecting drug use comprises the form of for example intravenous injection or instillation.Dosage can be according to the weight of the state of an illness, and factors such as patient's body constitution, age, sex, body weight are determined.In general, adult's oral dose is 360-600mg, but single administration or multiple dosing; During with the injection form administration, daily dose can be at 200-400mg.
Chinese medicine composition raw material sources of the present invention are easy to get, be easy to industrialization, can make various dosage forms as required, for clinical provide convenient, more effectively, the more controlled modern Chinese medicine of quality, for the patient brings more benefits, thereby produce the huge social benefit.
Description of drawings
Fig. 1 is the HPLC finger printing of Radix Puerariae total flavones; With
Fig. 2 is the HPLC finger printing of Radix Notoginseng total arasaponins.
The specific embodiment
The present invention is described in further detail below in conjunction with the specific embodiment, and the embodiment that provides is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Embodiment 1Raw material is prepared
(1) Radix Puerariae total flavones
Get Radix Puerariae medical material 10Kg, with 10 times of amount 70% alcohol reflux three times, each 2h filters, and merges three times ethanol extract, and recovery ethanol is concentrated into about 20L, adds water to about 100L, leaves standstill 12h, and is centrifugal; Supernatant is with the wet AB-8 macroporous resin adsorption of 20L, washes with water to effluent colourlessly earlier, and reuse 30% concentration ethanol 80L desorption is collected 30% ethanol elution, reclaims ethanol, and drying under reduced pressure promptly gets Radix Puerariae total flavones ".Wherein puerarin content is 45.2%, and general flavone content is 86.7%, and its HPLC finger printing as shown in Figure 1.
(2) Radix Notoginseng total arasaponins
Available from Yunnan Plant Pharmaceutical Industry Co., Ltd., wherein arasaponin R1, ginsenoside Rg1 and ginsenoside Rb1's summation is 68.55%, and total saponin content is 82.7%, and its HPLC finger printing as shown in Figure 2.
Embodiment 2The injectable powder type of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 2g, Radix Notoginseng total arasaponins 8g, mannitol 5g and 500ml water for injection.
Preparation:
The Radix Notoginseng total arasaponins 8g of embodiment 1 described purchase, Radix Puerariae total flavones 2g that embodiment 1 makes and mannitol 5g are mixed and be dissolved in the 500ml water for injection, filter, sterilization, spray drying, aseptic subpackaged, make the pharmaceutical composition of the injectable powder type that contains 1 part of Radix Puerariae total flavones and 4 parts of Radix Notoginseng total arasaponinss.
Embodiment 3The injectable powder type of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 5g, Radix Notoginseng total arasaponins 5g, mannitol 5g and 1000ml water for injection.
Preparation:
The Radix Notoginseng total arasaponins 5g of embodiment 1 described purchase, Radix Puerariae total flavones 5g that embodiment 1 makes and mannitol 5g are mixed and be dissolved in the 1000ml water for injection, filter, sterilization, aseptic subpackaged, lyophilization makes the pharmaceutical composition of the injectable powder type that contains 1 part of Radix Puerariae total flavones and 1 part of Radix Notoginseng total arasaponins.
Embodiment 4The injectable powder type of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 8g, Radix Notoginseng total arasaponins 2g, mannitol 10g and 2000ml water for injection.
Preparation:
Adopt the method identical, make the pharmaceutical composition of the injectable powder type that contains 4 parts of Radix Puerariae total flavoness and 1 part of Radix Notoginseng total arasaponins according to above-mentioned prescription with embodiment 3.
Embodiment 5The injection of pharmaceutical composition of the present invention or transfusion dosage form
Prescription:
Radix Puerariae total flavones 3g, Radix Notoginseng total arasaponins 7g, 0.05g EDTA-Na and 200ml 50% propylene glycol.
Preparation:
Adopt conventional process for preparation of injection, the raw material with embodiment 1 is provided makes injection or the transfusion forms of pharmaceutical compositions that contains 3 parts of Radix Puerariae total flavoness and 7 parts of Radix Notoginseng total arasaponinss according to above-mentioned prescription.
Embodiment 6The injection of pharmaceutical composition of the present invention or transfusion dosage form
Prescription:
Radix Puerariae total flavones 4g, Radix Notoginseng total arasaponins 6g, 0.05g EDTA-Na and 100ml 50% propylene glycol.
Preparation:
Adopt conventional process for preparation of injection, the raw material with embodiment 1 is provided makes injection or the transfusion forms of pharmaceutical compositions that contains 2 parts of Radix Puerariae total flavoness and 3 parts of Radix Notoginseng total arasaponinss according to above-mentioned prescription.
Embodiment 7The drops of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 1g and Radix Notoginseng total arasaponins 10g.
Preparation:
Adopt the technology of conventional preparation drop pill, the raw material with embodiment 1 is provided makes the drop pill that contains 1 part of Radix Puerariae total flavones and 10 parts of Radix Notoginseng total arasaponinss according to above-mentioned prescription.
The soft capsule dosage form of embodiment 8 pharmaceutical compositions of the present invention
Prescription:
Radix Puerariae total flavones 10g, Radix Notoginseng total arasaponins 1g and vegetable oil 25g.
Preparation:
Adopt the technology of conventional preparation soft capsule,, get Radix Puerariae total flavones 10g with the raw material that embodiment 1 is provided, Radix Notoginseng total arasaponins 1g, vegetable oil 25g, mixing, make capsule casing material with gelatin, be pressed into soft capsule, make the soft capsule that contains 1 part of Radix Puerariae total flavones and 0.1 part of Radix Notoginseng total arasaponins.
Embodiment 9The capsule formulation of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 10g, Radix Notoginseng total arasaponins 2g and starch 100g.
Preparation:
Adopt the technology of conventional preparation capsule, with the raw material that embodiment 1 is provided, get Radix Puerariae total flavones 10g, Radix Notoginseng total arasaponins 2g and starch 100g mixing incapsulate shell, make capsule.Make the capsule that contains 1 part of Radix Puerariae total flavones and 0.2 part of Radix Notoginseng total arasaponins.
Embodiment 10The granule of pharmaceutical composition of the present invention or Tabules
Prescription:
Radix Puerariae total flavones 10g, Radix Notoginseng total arasaponins 10g and sucrose 80g.
Preparation:
Adopt the technology of conventional preparation granule,, get Radix Puerariae total flavones 10g with the raw material that embodiment 1 is provided, Radix Notoginseng total arasaponins 10g and sucrose 80g mixing are granulated, sieve, drying promptly makes the granule forms of pharmaceutical compositions of closing 1 part of Radix Puerariae total flavones and 1 part of Radix Notoginseng total arasaponins.
Through further tabletting, drying promptly makes the pharmaceutical composition of the Tabules that closes 1 part of Radix Puerariae total flavones and 1 part of Radix Notoginseng total arasaponins with the granule that makes.
Embodiment 11The slow releasing tablet dosage form of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 2g, Radix Notoginseng total arasaponins 20g, and polyvinylpyrrolidone (K30) 70g
Preparation:
Adopt the technology of conventional preparation tablet, with the raw material that embodiment 1 is provided, get Radix Puerariae total flavones 2g, Radix Notoginseng total arasaponins 20g, with polyethylene 70g mixing, granulate, sieve, tabletting, drying promptly makes the pharmaceutical composition of the slow releasing tablet dosage form that contains 1 part of Radix Notoginseng total arasaponins and 10 parts of Radix Puerariae total flavoness.
Embodiment 12The dispersible tablet dosage form of pharmaceutical composition of the present invention
Prescription:
Radix Puerariae total flavones 7g, Radix Notoginseng total arasaponins 3g, microcrystalline Cellulose 22g, hyprolose 8g and micropowder silica gel 0.1g.
Preparation:
Adopt the technology of conventional preparation tablet, the raw material that is provided with embodiment 1, get Radix Puerariae total flavones 7g, Radix Notoginseng total arasaponins 3g, microcrystalline Cellulose 22g, hyprolose 8g and micropowder silica gel 0.1g mix homogeneously, tabletting promptly makes the pharmaceutical composition of the tablet formulation that contains 31 parts of Radix Notoginseng total arasaponinss and 7 parts of Radix Puerariae total flavoness.
Embodiment 13The test of pesticide effectiveness of pharmaceutical composition of the present invention
The curative effect of medicine of the present invention is proved by following pharmacodynamics test: designed Radix Notoginseng total arasaponins, Radix Puerariae total flavones and both different proportioning samples, employing blocking-up intraluminal middle cerebral artery occlusion in rats causes the rat cerebral ischemia model, the intravenous injection high molecular dextran causes rat blood high viscosity syndrome model and rats in vitro thrombotic model, observe the action effect of Radix Notoginseng total arasaponins and the different proportionings of Radix Puerariae total flavones, determine best proportioning.
(1) experiment material
1, medicine and reagent
(1) Radix Puerariae total flavones: chocolate brown powder, lot number 050301 is according to the method preparation of embodiment 1;
(2) Radix Notoginseng total arasaponins: buff powder, lot number 050812, available from Yunnan Plant Pharmaceutical Industry Co., Ltd., total saponin content 82.7%;
(3) puerarin injection: Anhui friendship ties Pharmaceutical limited company product, lot number 050149;
(4) XUESAITONG ZHUSHEYE (Radix Notoginseng total arasaponins, content is greater than 80%): Kunming Medicine Stock Co., Ltd's product, lot number 20040943.02;
(5) 10% high molecular dextrans: molecular weight 300,000, Blood Research Institute scientific ﹠ technical corporation of Chinese Academy of Sciences product, lot number 050512.
2, instrument LG-R-80C type cone and plate viscometer: diligent generation Supreme Being's scientific instrument company limited product in Beijing; The experimental thrombus in vivo of BT87-3 type forms analyzer: packet header medical college product.
3, animal rat: the Wistar kind is provided by animal housing of Tianjin medicine institute.
(2) experimental technique and result
1, the Radix Notoginseng total arasaponins of different proportionings and Radix Puerariae total flavones are to the therapeutical effect of cerebral ischemia due to the blocking-up intraluminal middle cerebral artery occlusion in rats
Select healthy male Wistar kind rat for use, body weight 290～350g, lumbar injection chloral hydrate 350mg/kg anesthesia.By the operation that experimentizes of blocking-up intraluminal middle cerebral artery occlusion in rats method, expose the right side middle cerebral artery, under operating microscope, middle cerebral artery is burnt disconnected with high frequency electric knife, postoperative steams again raises, room temperature remains on 20～23 ℃, laggard every trade was scoring in 4 hours, the rat that typical brain ischemia feature will be arranged, by the even model control group that is divided into of mild symptoms weight average, (ratio of Radix Notoginseng total arasaponins and Radix Puerariae total flavones is respectively sample 1 (10: 0) to sample 1～9 dosage group of 75mg/kg, sample 2 (8: 2), sample 3 (7: 3), sample 4 (6: 4), sample 5 (5: 5), sample 6 (4: 6), sample 7 (3: 7), sample 8 (2: 8), sample 9 (0: 10), the XUESAITONG ZHUSHEYE of 75mg/kg, the GEGEN ZHUSHEYE of 40mg/kg, carry out intravenous administration, every day 1 time, continuous 7 days, mark to the behavior of animal every day, the results are shown in Table 1.
After the last administration animal broken end is got brain, after confirming that under operating microscope middle cerebral artery has been blocked, put into cold saline again, after 10 minutes, remove olfactory bulb, cerebellum and low brain stem, be cut into 5 along coronalplane, brain section is placed the 5ml dyeing liquor that contains 1.5ml 4% red tetrazolium and 0.1ml 1MK2HPO4, and lucifuge is after 37 ℃ of temperature are incubated 30 minutes, formalin solution is put in taking-up, keep in Dark Place, normal structure is rose, and infarct is white in color, white organized carefully to dig down weigh, and calculate the percentage ratio that blocking tissue's weight accounts for cerebral hemisphere weight, observe the effect of medicine, the result, result of the test adopts two groups of mean statistical analysiss-t value method to carry out significance test, see Table 2.
The behavior scoring standard is as follows:
(1) carry the Mus tail: about 1 chi of built on stilts, observe two forelimb active situation.Intact animal's two forelimbs protract symmetry.After the operation, ischemia brain hemisphere offside forelimb inward turning and interior receipts, visual range degree difference was commented 0～4 fen.
(2) with on the sliding ground of animal horizontalization, push away both shoulders respectively, check resistance to side shifting.Normal rat bilateral resistance symmetry, the resistance descender according to decline degree difference, commented 0～3 fen when the operation offside promotes.
(3) tractive two forelimbs, normal symmetry, myasthenia of limbs before the offside of operation back according to the degree difference, was commented 0～3 fen.
(4) animal has ceaselessly to a side person of turn-taking, and pluses fifteen.
According to above standards of grading, full marks are 11 minutes, and mark is high more, and the behavior disorder of animal is serious more.Behavior scoring is evaluated by trained personnel special messenger.
The Radix Notoginseng total arasaponins of the different proportionings of table 1. and Radix Puerariae total flavones intravenously administrable are to the influence (X ± SD) of behavior disorder due to the blocking-up intraluminal middle cerebral artery occlusion in rats
| Group | Dosage (1mg/kg) | Proportioning | Before the administration | After the administration | ||||||
| 1 day | 2 days | 3 days | 4 days | 5 days | 6 days | 7 days | ||||
| No. 9 sample XUESAITONG of model contrast No. 8 samples of No. 7 samples of No. 6 samples of No. 5 samples of No. 4 samples of No. 3 samples of No. 2 samples of No. 1 sample puerarin | ?75?75?75?75?75?75?75?75?75?75?40 | 10∶0 8∶2 7∶3 6∶4 5∶5 4∶6 3∶7 2∶8 0∶10 | 8.5±1.3 8.6±1.3 8.7±1.5 8.5±1.2 8.6±1.0 8.5±1.0 8.7±1.3 8.6±1.3 8.6±1.3 8.5±1.5 8.6±1.2 9.1±1.6 | 8.1±1.5 7.4±1.3 7.3±1.2 7.4±1.2 7.6±1.4 7.7±1.1 7.8±1.3 7.3±1.4 7.6±1.1 7.4±1.7 7.7±1.3 8.1±1.7 | ?7.6±1.7?6.8±1.3?6.8±1.3?7.1±1.0?6.9±0.7?7.6±1.2?6.8±1.2?6.5±1.0?6.7±1.1?6.5±1.8?7.0±0.9?7.1±1.6 | ?7.0±2.0?6.3±1.1?6.2±1.3?6.1±1.1?6.3±0.8?6.4±1.2?5.7±0.9?5.6±0.7 *?6.1±1.4?5.9±1.4?6.2±0.8?6.2±1.2 | ?6.9±2.3?5.5±1.0?5.6±1.0?5.5±1.1?5.7±1.0?5.3±0.8 *?5.2±0.8 *?5.2±0.8 *?5.2±1.0 *?5.1±1.1?5.6±0.8?5.2±0.9 | 6.7±2.15.0±0.7 *5.1±1.2 *5.2±0.9 *5.1±1.0 *4.8±0.9 *5.0±0.9 *4.9±1.1 *5.0±1.1 *4.9±1.2 *5.0±0.9 *5.1±1.1 * | 6.6±2.24.7±0.6 *4.7±1.0 *4.7±1.0 *4.8±0.9 *4.6±0.9 *4.5±0.4 *4.3±0.7 **4.6±0.6 *4.5±1.2 *4.7±0.7 *4.7±1.3 * | 6.3±1.84.5±0.7 **4.6±1.0 *4.6±0.8 *4.4±0.8 **4.3±1.0 **4.4±0.4 **4.2±0.7 **4.5±0.5 **4.4±0.9 **4.4±0.6 **4.2±1.1 ** |
*: P＜0.05
*: P＜0.01 (comparing) with model control group
The Radix Notoginseng total arasaponins of the different proportionings of table 2. and Radix Puerariae total flavones are to the influence (X ± SD) of cerebral ischemia area due to the blocking-up intraluminal middle cerebral artery occlusion in rats
| Group | Dosage (g/kg) | Number of animals (only) | Blocking tissue's weight (mg) | Cerebral hemisphere weight (mg) | Blocking tissue's weight/cerebral hemisphere weight (%) | Blocking tissue reduces (%) |
| No. 9 sample XUESAITONG of No. 8 samples of No. 7 samples of No. 6 samples of No. 5 samples of No. 4 samples of No. 3 samples of No. 2 samples of No. 1 sample of matched group puerarin | 10∶0 8∶ 7∶3 6∶4 5∶5 4∶6 3∶7 2∶8 0∶10 6 3 | 11 11 9 11 10 11 11 11 11 11 11 10 | ?118.9±17.5?91.2±22.2?96.4±26.0?90.6±30.0?87.1±26.9?84.4±27.7?81.5±16.4?79.5±18.9?92.4±25.3?94.3±26.9?89.1±17.6?85.1±20.9 | 613.2±91.6 625.4±87.4 642.5±143.6 618.9±104.6 617.3±90.9 601.1±119.8 601.3±72.7 621.7±101.2 640.4±140.5 631.9±82.9 612.6±100.5 598.1±94.3 | 19.7±4.1 14.7±3.8 * 15.3±4.6 * 14.7±5.0 * 14.1±3.7 ** 14.2±4.7 ** 13.7±3.1 ** 12.9±3.6 *** 14.8±4.6 * 14.9±4.0 * 14.7±3.2 ** 14.4±3.6 ** | 26.0 22.3 26.0 28.4 27.9 30.4 34.5 24.9 24.4 26.0 26.9 |
*: P＜0.05
*: P＜0.01
* *: P＜0.01 (comparing) with the ischemic control group
Blocking tissue reduces %=matched group and administration group blocking tissue percentage difference/matched group blocking tissue * 100%
Table 1 result shows, compare with model control group, the Radix Notoginseng total arasaponins of different proportionings and Radix Puerariae total flavones all can improve the behavior disorder of rats with cerebral ischemia after administration, wherein, proportioning is that (Radix Notoginseng total arasaponins: onset the fastest (after the administration 4 days) Radix Puerariae total flavones) acted on the strongest in 3: 7.
Table 2 result shows: compare with model control group, the Radix Notoginseng total arasaponins of different proportionings and Radix Puerariae total flavones all can obviously reduce rats with cerebral ischemia after administration infarct size, wherein, proportioning is 3: 7 (Radix Notoginseng total arasaponinss: Radix Puerariae total flavones) act on the strongest (having reduced 34.5%), be better than isodose Radix Notoginseng total arasaponins (25.5%) or Radix Puerariae total flavones (28.9%).With the basically identical as a result that improves behavior disorder.
2, different proportioning Radix Notoginseng total arasaponinss and Radix Puerariae total flavones are sticking to blood high viscosity syndrome rat whole blood
Select above-mentioned healthy rat for use, the male and female dual-purpose, body weight 190～230g, (ratio of Radix Notoginseng total arasaponins and Radix Puerariae total flavones is respectively the XUESAITONG ZHUSHEYE group of sample 1 (10: 0), sample 2 (8: 2), sample 3 (7: 3), sample 4 (6: 4), sample 5 (5: 5), sample 6 (4: 6), sample 7 (3: 7), sample 8 (2: 8), sample 9 (0: 10), 75mg/kg, the puerarin injection group of 40mg/kg to be divided into sample 1～9 dosage group of normal control group, model control group, 50mg/kg at random in sex, body weight.Carry out intravenous administration one time, the administration capacity is the 0.5ml/100g body weight, the contrast liquid of capacity such as normal control group and the equal intravenous injection of model control group, each organized rat (except the normal control group) all after administration 20 minutes, tail vein injection 10% high molecular dextran injection 1ml/kg causes the blood high viscosity syndrome model.After 10 minutes,,, on LG-R-80C type cone and plate viscometer, measure 4 whole blood viscosity of cutting under the speed, relatively the difference of each dosage group after the moulding with 3.8% sodium citrate anticoagulant (anticoagulant is 1: 9 with the ratio of whole blood) from abdominal aortic blood.Result of the test adopts two groups of mean statistical analysiss-t value method to carry out significance test, see Table 3.
Table 3 result shows, compares with the normal control group, and the whole blood viscosity that model control group is respectively cut under the speed all obviously raises, and shows and causes rat blood high viscosity syndrome model, the moulding success.With model control group relatively, the formation of the inhibition rat blood high viscosity syndrome that the sample 1～9 of 75mg/kg, the XUESAITONG ZHUSHEYE of 75mg/kg and 40mg/kg puerarin injection all can be in various degree.Wherein, isodose XUESAITONG ZHUSHEYE and Radix Notoginseng total arasaponins, puerarin injection are suitable with the Radix Puerariae total flavones action intensity; The Radix Notoginseng total arasaponins and the Radix Puerariae total flavones of different proportionings all have obvious effect, and with sample 7 (Radix Notoginseng total arasaponins: Radix Puerariae total flavones is 3: 7) best results, effect is better than isodose Radix Notoginseng total arasaponins or Radix Puerariae total flavones.
The different proportioning Radix Notoginseng total arasaponinss of table 3, Radix Puerariae total flavones to the influence of blood high viscosity syndrome hemorheology of rat (
)
| Group | Dosage (mg/kg) | Number of animals (only) | Proportioning Radix Notoginseng: Radix Puerariae | Whole blood viscosity (mpa.s) | |||
| 1S -1 | 5S -1 | 30S -1 | 200?S -1 | ||||
| No. 9 sample XUESAITONG of normal control model contrast No. 8 samples of No. 7 samples of No. 6 samples of No. 5 samples of No. 4 samples of No. 3 samples of No. 2 samples of No. 1 sample puerarin | 75 75 75 75 75 75 75 75 75 75 40 | 8 8 8 8 8 8 8 8 8 8 8 8 8 | 10∶0 8∶2 7∶3 6∶4 5∶5 4∶6 3∶7 2∶8 0∶10 | 10.92±1.23 20.63±2.47 △△△ 16.45±1.72 ** 16.52±3.32 * 17.08±2.92 * 16.78±2.84 * 17.39±2.45 * 16.58±3.24 * 15.43±1.51 *** 17.52±2.73 * 17.39±2.85 * 16.40±1.91 ** 17.59±2.04 * | 4.69±0.60 8.50±0.92 △△△ 6.91±0.68 ** 7.008±1.30 * 7.08±1.18 * 6.97±1.18 * 7.30±1.10 * 6.82±1.26 * 6.55±0.66 *** 7.21±1.19 * 7.25±0.97 * 6.89±0.65 ** 7.3?1±0.77 * | 2.62±0.41 4.57±0.55 △△△ 3.79±0.44 ** 3.88±0.72 * 3.83±0.66 * 3.78±0.69 * 3.99±0.68 3.65±0.68 * 3.63±0.46 ** 3.87±0.72 * 3.95±0.52 * 3.78±0.39 ** 3.97±0.46 | 1.93±0.33 3.27±0.45 △△△ 2.74±0.38 * 2.83±0.55 2.75±0.50 * 2.72±0.54 * 2.904±0.54 2.61±0.51 * 2.664±0.41 * 2.71±0.57 2.86±0.42 2.75±0.35 * 2.86±0.38 |
△ △ △: p＜0.001 (comparing) with the normal control group
* p＜0.05, * * p＜0.01, * * * p＜0.001 (with model control group relatively)
3, different proportioning Radix Notoginseng total arasaponinss and Radix Puerariae total flavones are to the influence of thrombus in vivo formation
Select above-mentioned healthy Wistar kind rat for use, be divided into 4 groups of sample 6, sample 7, sample 8 and normal controls at random by sex, body weight.Each dosage group is all by the dosage intravenous administration of 150mg/kg, the administration volume is the 0.5ml/100g body weight, the normal control group is irritated stomach and is waited the capacity normal saline, after the administration 30 minutes, pentobarbital sodium intraperitoneal anesthesia (40mg/kg), separate the about 15mm of a bilateral common carotid artery, with BT87-3 type thrombosis instrument stimulating electrode and temperature sensor hook on carotid artery, electric current with 1.5mA continues to stimulate blood vessel wall 7 minutes, stops then stimulating, simultaneously by temperature sensor monitors blood vessel surface variation of temperature, work as thrombosis, during plug flow, blood vessel distal end temperature bust, instrument is reported to the police, record is from stimulating beginning to the time of reporting to the police, as thrombus formation time (OT value), result of the test adopts two groups of mean statistical analysis t-value methods to carry out test of significance, sees Table 4.
The influence of 6～8 pairs of normal rat carotid artery thrombus formation time of table 4 sample (
)
| Group | Proportioning (Radix Notoginseng/Radix Puerariae) | Dosage (mg/kg) | Number of animals (only) | OT value (second) |
| No. 8 samples of No. 7 samples of No. 6 samples of normal control | 4∶6 3∶7 2∶8 | 150 150 150 | 6 6 6 6 | 553.2±86.1892.2±212.6 **1061.7±195.2 ***961.0±194.9 ** |
*:: P＜0.01
* *:: P＜0.001 (comparing) with the normal control group
Table 4 result shows, compares with the normal control group, and all obvious prolong rats carotid artery thrombus formation time of sample 6, sample 7, sample 8, No. 7 sample effect is best.
(3) experiment conclusion
Above experimental result shows that the Radix Notoginseng total arasaponins of different proportionings, Radix Puerariae total flavones all can obviously improve the behavior disorder of rats with cerebral ischemia, obviously reduce cerebral infarct size, obviously suppress the formation of rat blood high viscosity syndrome, obviously suppress the formation of carotid artery thrombosis.Wherein, sample 7 (Radix Notoginseng total arasaponins: Radix Puerariae total flavones is 3: 7) best results, effect is better than isodose Radix Notoginseng total arasaponins or Radix Puerariae total flavones, and showing has certain synergism.
Described embodiment of the present invention now in detail, clearly can do a lot of improvement and variation for a person skilled in the art and can not deviate from essence spirit of the present invention.All these changes and improvements think all within the scope of the present invention that its feature is determined by above-mentioned description.
Claims (10)
1. pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, said composition is made up of Radix Notoginseng total arasaponins, Radix Puerariae total flavones and pharmaceutical carrier; The purity of wherein said Radix Puerariae total flavones is more than 50%, and the purity of described Radix Notoginseng total arasaponins is more than 80%; The weight ratio of described two kinds of active component is 1 part of a Radix Notoginseng total arasaponins, 1.5～2.5 parts of Radix Puerariae total flavoness.
2. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 1, the purity of wherein said Radix Puerariae total flavones is more than 80%.
3. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 2, wherein said Radix Notoginseng total arasaponins are extracted by Radix Notoginseng and Radix Puerariae total flavones is wherein extracted by Radix Puerariae.
4. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 3, wherein said is that Radix Puerariae total flavones is according to following method preparation: Radix Puerariae medical material water or Different concentrations of alcohol are extracted, and extracting solution reclaims ethanol, is concentrated into proper volume; The concentrated solution macroporous resin adsorption washes with water to effluent colourlessly earlier, and reuse low-concentration ethanol desorption is collected ethanol elution, reclaims ethanol, and drying promptly gets Radix Puerariae total flavones.
5. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 4, the weight ratio of wherein said two kinds of active component is preferably: Radix Notoginseng total arasaponins: Radix Puerariae total flavones is 3: 7 parts.
6. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 4, the weight ratio of wherein said two kinds of active component is preferably: Radix Notoginseng total arasaponins: Radix Puerariae total flavones is 4: 6 parts.
7. according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease of claim 1-6, said composition is made into to be suitable for dosage form oral and injection.
8. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 7 wherein saidly is suitable for oral dosage form and is selected from following arbitrary dosage form: tablet, capsule, soft capsule, granule, drop pill, dispersible tablet, slow releasing tablet, controlled release tablet or oral cavity quick disintegrating slice.
9. the pharmaceutical composition of treatment cardiovascular and cerebrovascular disease according to claim 7, the wherein said dosage form that is suitable for injecting can be injection, transfusion or powder injection formulation.
10. according to the application of any described pharmaceutical composition of claim 1-9 in the medicine of preparation treatment cardiovascular and cerebrovascular disease.
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| CN1857388A (en) * | 2006-03-17 | 2006-11-08 | 崔彬 | Preparation and application of notoginseng stem and leaf total saponin composition |
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| CN1857388A (en) * | 2006-03-17 | 2006-11-08 | 崔彬 | Preparation and application of notoginseng stem and leaf total saponin composition |
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| 周国海等.葛根中总黄酮及葛根素的含量测定.湖南林业科技31 5.2004,31(5),71-72. |
| 周国海等.葛根中总黄酮及葛根素的含量测定.湖南林业科技31 5.2004,31(5),71-72. * |
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