CN1803182A - Traditional Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and preparation method thereof - Google Patents
Traditional Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and preparation method thereof Download PDFInfo
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- CN1803182A CN1803182A CN 200510001952 CN200510001952A CN1803182A CN 1803182 A CN1803182 A CN 1803182A CN 200510001952 CN200510001952 CN 200510001952 CN 200510001952 A CN200510001952 A CN 200510001952A CN 1803182 A CN1803182 A CN 1803182A
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to a traditional Chinese pharmaceutical composition for treating cerebrovascular diseases and process for preparation, wherein the composition is prepared from ginkgo leaves and rhizoma Gastrodiae as the raw materials through various physical-chemical treatment processes.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition for the treatment of cardiovascular and cerebrovascular disease, specifically mainly is to be raw material with Chinese crude drug Rhizoma Gastrodiae, Folium Ginkgo, and the medicine that is prepared from relates to the preparation method of this medicine simultaneously.
Background technology
Cardiovascular and cerebrovascular disease is the first cause of the death of present industrialized country, its sickness rate even more taller than cancer, only at the annual number of patients of the U.S. just up to more than 1,000,000 person-times.Along with the raising day by day of Chinese society progress and living standards of the people, cardiovascular and cerebrovascular disease has become and has threatened one of able-bodied principal disease of China people, therefore, the prevention and the treatment of cardiovascular and cerebrovascular disease is just had extremely important realistic meaning.
Cardiovascular drugs also is the most active in a new drug research field.According to statistics, kind surplus the new drug that enters clinical research every year on average has 20 approximately makes the Drug therapy of cardiovascular and cerebrovascular disease reach higher level.Treatment to primary disease at present mainly relies on Drug therapy, comprises beta receptor blocker, calcium antagonists, angiotensin-convertion enzyme inhibitor, angiotensin-convertion enzyme inhibitor, anti-heart failure medicine, antiplatelet drug etc. substantially.These medicines cost an arm and a leg mostly, and have than significant side effects, and the drawback that rebounds after the ubiquity drug withdrawal.
In recent years, particularly in China, people have strengthened the research of treatment by Chinese herbs cardiovascular and cerebrovascular disease, mainly be from traditional prescription, to screen, obtained certain achievement, existing a plurality of kinds are used for clinical, and oral drugs have FUFANG DANSHEN PIAN, FUFANG DANSHEN DIWAN etc., wherein FUFANG DANSHEN DIWAN is because its good effect, acts on rapid extensive use with clinical but owing to it exists the shortcoming that solid preparation can't overcome for solid preparation.XUESAITONG, FUFANG DANSHEN ZHUSHEYE, Radix Salviae Miltiorrhizae Injection, ligustrazine injection, YINXINGYE ZHUSHEYE etc. are only arranged injectable drug but curative effect is all not ideal.Chinese patent CN00113023 discloses a kind of ginkgo and gastrodia taber capsule, and it is combined by Folium Ginkgo extract, the smart powder of Rhizoma Gastrodiae and Radix Panacis Quinquefolii Saponin, and we find only can reach the curative effect that is equal to substantially with Folium Ginkgo and Rhizoma Gastrodiae after deliberation.Chinese patent CN03113341,03113818,03115286 discloses a kind of Folium Ginkgo extract injection and preparation method, but curative effect is not ideal.
Therefore, can think like this that the sickness rate of present clinical cardiovascular and cerebrovascular disease is very high, but lack safe and effective medicine, the novel drugs of actively developing the treatment cardiovascular and cerebrovascular disease is very necessary.
Summary of the invention
The Chinese medicine composition that the purpose of this invention is to provide a kind of effective treatment cardiovascular and cerebrovascular disease, another object of the present invention provide the preparation method of this Chinese medicine composition.
For achieving the above object, we have adopted following technical scheme:
Chinese medicine composition of the present invention is to be made by the raw material of following weight ratio:
Rhizoma Gastrodiae 5-50 weight portion Folium Ginkgo 6-60 weight portion
The weight ratio of the raw material of preparation Chinese medicine composition of the present invention is preferably:
Rhizoma Gastrodiae 8-30 weight portion Folium Ginkgo 10-40 weight portion
The weight ratio for preparing its raw material is preferably:
Rhizoma Gastrodiae 15-20 weight portion Folium Ginkgo 16-25 weight portion
Aforementioned pharmaceutical compositions also can add Borneolum Syntheticum 0.005-0.08 weight portion.
Chinese medicine composition of the present invention can the preparation process preparation by routine become clinical acceptable various dosage forms as granule, tablet, pill, capsule, injection or oral liquid, tincture, suppository, mixture, powder, lotion, membrane, drop pill etc.
The preparation of Chinese medicine composition of the present invention is preferably injection (comprising liquid drugs injection, powder pin, transfusion).Be preferably the injection liquid drugs injection.
Effective ingredient contains Gastrodine 0.05-40 mg/ml in the Chinese medicine composition aqueous injection of the present invention, and Ginkgo total flavones 0.05-20 mg/ml is preferably Gastrodine 0.5-20 mg/ml, Ginkgo total flavones 0.1-10 mg/ml; Wherein also can contain bilobalide 0.01-5 mg/ml, wherein comprise bilobalide, ginkalide A, ginkalide B, ginkalide C etc.
The suitable pH value of injection can reduce the absorption of medicinal liquid to the untoward reaction of human body, the stability that increases injection, acceleration medicine, so injection must have the suitable substance P H-number.Effective ingredient is a Gastrodine in the Rhizoma Gastrodiae, and it belongs to glycoside, can issue unboiled water in the bronsted lowry acids and bases bronsted lowry condition and separate reaction, and Folium Ginkgo thinks that at present its effective ingredient is flavonoid and ginkgolide compound, but the quality of the content direct reaction product of Ginkgo total flavones.Ginkgetin mainly is single, double, three glucosides of the galloyl of Quercetin, kaempferol, isorhamnetin, hydrolysis takes place under acid-base condition easily, and the effective ingredient in the medicinal liquid is changed, thereby influence drug effect and medicine stability.We by a large amount of evidences pH value scope of the present invention between 4～9 time hinge stable.
Because contained bilobalide etc. is soluble in methanol, ethanol, acetone, ethyl acetate in the preparation of the present invention, and is water insoluble; Borneolum Syntheticum mainly contains compositions such as Borneolum Syntheticum, isoborneol, Camphora simultaneously.Borneolum Syntheticum application clinically at present is very extensive, but since Borneolum Syntheticum, Camphora etc. to belong to monoterpenes composition dissolubility in water little, thereby Borneolum Syntheticum belongs to the fat-soluble monoterpenes material of micromolecule, can't be applied to liquid preparations such as injection always; Therefore when the preparation injection, need add cosolvent: alcohol, fatty acid esters of sorbitan, polyoxyethylene fatty acid ester, polyethenoxy sorbitan fatty acid or polyoxyethylene aliphatic alcohol ether etc.; Be preferably lower alcohol, the most frequently used with propylene glycol and/or ethanol again.
The preparation technology of medicaments injection of the present invention is:
Get the Folium Ginkgo medical material, pulverize, add 4-15 and doubly measure the 40-80% alcohol reflux 1-3 time, each 0.5-3 hour, filter, merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, filter, macroporous resin column on the filtrate, after the washing clarification, the ethanol elution of reuse 2-8 times bed volume 20%, use the ethanol elution of 30-90% then, collect ethanol elution and be condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying, carry out silica gel column chromatography then, with ethyl acetate and acetone difference eluting, eluent ethyl acetate liquid reclaims solvent, gets A.The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the reuse ethanol elution is collected, and concentrates, and merges with A, and is standby;
Get the Rhizoma Gastrodiae coarse powder, add 5-12 times of water gaging, extract 1-4 time, each 0.5-3 hour, filter merging filtrate, be evaporated to the about 1.0-1.4 of relative density, add ethanol and reach 65%-85%, Cryoprecipitation to containing the alcohol amount, filter, be evaporated to every 1ml and contain raw medicinal herbs 1-5g, it is heavy to add water-cooled, filters, concentrating under reduced pressure, standby;
Get Borneolum Syntheticum and add that solubilizing agent is ultrasonic to make dissolving, slowly add water for injection, merge, add the injection water and be assigned to full dose, filter with above-mentioned two kinds of medicinal liquids, fine straining, inflated with nitrogen embedding sterilization or lyophilization are aseptic subpackaged, check, promptly.
Pharmaceutical composition of the present invention, good effect, toxic and side effects are few.Be the therapeutical effect and the toxic and side effects that show medicine of the present invention, we have done a large amount of experimentatioies, below experimental example be used to further specify the present invention.
One, collagen protein-epinephrine is brought out the influence that the mice thrombus in vivo forms
[test objective] observed preparation of the present invention collagen protein-epinephrine brought out the inhibitory action that the mice thrombus in vivo forms.
[being subjected to the reagent thing]
1, be subjected to the reagent thing: preparation of the present invention is provided by Lunan Pharmacy Co. Ltd.
3, contrast medicine: YINXINGYE ZHUSHEYE (SHUXUENING), what 999 medical groups produced provides.
[animal]
1, source, kind, strain, the quality certification: Medical University Of Anhui's Experimental Animal Center provides, Kunming mouse, outbreeding sealing system, moving accurate No. 01 of Anhui doctor.
2, body weight: 18～22g
3, sex: ♂ ♀ half and half.
4, number of animals: 50,10 every group.
5, experimental situation: laboratory temperature is 18-28 ℃, and relative humidity is 50-70%.
6, pellet: provide by Nanjing An Limo Science and Technology Ltd..
[reagent and instrument]
1, collagen protein: source, Shanghai consor thing Science and Technology Ltd..
2,80-2 centrifugation device, Shanghai Surgical Operation Equipment Factory's product.
3, adrenalin hydrochloride injection: Shanghai Hefeng Pharmaceutical Co., Ltd. produces.
4, manual homogenizer, operating theater instruments is some.
[test method]
1, the preparation of collagen protein-epinephrine mixing derivant: take by weighing collagen protein 30mg, be soaked in 3～4ml normal saline more than the 2h, manually homogenate (requires to grind fully; can't see granule or float), add normal saline 40ml, centrifugal (3000rpm; 10min), get supernatant.Other gets 1 of 1mg/2ml epinephrine inj and adds in the above-mentioned supernatant, adds normal saline to 50ml.
The standard that the mice thrombus in vivo forms modelling is that physiology saline control group thrombosis rate is greater than 90%.The standard that should at first set up according to thrombus model during the experiment beginning is found out the appropriate injection amount of mixing derivant, only is generally 0.3～0.5ml/.
2, the reference literature method, get 70 of healthy mices, body weight 18～22g, male and female half and half, be divided into 5 groups at random, every group 14, be respectively the normal saline group, the YINXINGYE ZHUSHEYE group, preparation of the present invention is little, in, heavy dose of group (is equivalent to 5 of clinical consumption respectively, 10,20 times), be diluted to normal saline and respectively organize desired concn, the injection of the quiet hydroxylamine of tail gave 0.1ml/10g corresponding test liquid respectively, and successive administration 7 days gave medicine tail vein injection collagen protein-epinephrine mixing derivant after 1 hour in the 7th day, observe dead mouse number in the 5min after the injection immediately, the mice hemiplegia is recovered number and is not recovered number in the 15min, carries out X
2Check.
[result of the test]
By test as can be known; Mice is after intravenous injection collagen protein-epinephrine combined induction agent, and the thrombus in vivo formation rate illustrates and adopts the method can cause the acute thrombus in vivo of animal to form model greater than 90%.Give YINXINGYE ZHUSHEYE group and preparation of the present invention little, in, after the heavy dose, dead mouse number reduction in the 5min after the modeling, the mice hemiplegia is recovered number in the 15min increases, the interior dead mouse number of 5min is compared with model group in the preparation wherein of the present invention, after the modeling of heavy dose of group, significance (P＜0.01 and P＜0.01 respectively); Wherein the present invention new in, after the modeling of heavy dose of group in the 15min mice hemiplegia recover number and compare significance (being P＜0.05) with model group.The thrombus in vivo that this explanation preparation of the present invention can suppress model mice forms, and has certain anti-thrombosis function.The results are shown in Table 1
Table 1 preparation of the present invention forms the influence (x ± SD) of suppression ratio to the mice thrombus in vivo
| Group | Number of animals (only) | 5min death toll (only) | 15min recovers number (only) | 15min does not recover number (only) |
| Dosage heavy dose of the present invention among the low dose of the present invention of normal saline YINXINGYE ZHUSHEYE the present invention | 14 14 14 14 14 | 12 4 ** 4 ** 3 ** 2 ** | 1 6 * 6 * 8 * 9 * | 1 4 4 3 3 |
Annotate: compare with the normal saline group
*P＜0.05
*P＜0.01
Two, the ligation coronary artery is caused the influence of rat myocardial ischemia
[test objective] observes preparation of the present invention causes LDH, CPK in rat myocardial ischemia ECG ST section, infarct size and the serum to the ligation coronary artery influence.
[being subjected to the reagent thing]
1, be subjected to the reagent thing: preparation of the present invention is provided by Lunan Pharmacy Co. Ltd.
2, contrast medicine: YINXINGYE ZHUSHEYE (SHUXUENING), what 999 medical groups produced provides.
[animal]
1, source, kind, strain, the quality certification: Medical University Of Anhui's Experimental Animal Center provides, Wister rat, outbreeding sealing system, moving accurate No. 03 of Anhui doctor.
2, body weight: 250～300g
3, sex: ♂ ♀ half and half.
4, number of animals: more than 50 (operation has failure), 10 every group.
5, experimental situation: laboratory temperature is 18-28 ℃, and relative humidity is 50-70%.
6, pellet: provide by Nanjing An Limo Science and Technology Ltd..
[reagent and instrument]
1, N-BT stain.
2, LDH test kit.
3, CPK test kit.
4, manual homogenizer, operating theater instruments is some.
5, electrocardiograph.
6, AT-738 semi-automatic biochemical analyzer, Shanghai ANTAI Diagnostics Co., Ltd. produces.
[test method]
Healthy male wistar rat is selected in experiment for use, body weight 250-300g is divided into model control group (sublingual vein injecting normal saline 0.5ml/100g body weight) and high, medium and low three the dosage groups of preparation of the present invention (sublingual vein injection preparation 0.83ml/kg of the present invention, 1.65ml/kg and 3.30ml/kg respectively) at random.Each organizes rat under the anesthesia of urethane 0.65g/kg abdominal cavity superficial vein, and back of the body position is fixing.Elder generation's mark accurate limb lead electrocardiogram (1mv=10mm, chart speed 50mm/ second).Chest unhairing, sterilization separate the flesh layer along the about 2cm of left mid-clavicular line longitudinal incision skin in the 4th or the 5th intercostal passivity, open the thoracic cavity, cut off pericardium, please press the right side thorax, and heart is put back to the thoracic cavity, sew up thoracic wall rapidly.After 10 minutes, use with the accurate limb lead electrocardiogram of quadrat method mark.Then by above-mentioned grouping and dosage be administered once (after ligation, being administered once again in 4 hours), and different time thought-read electrograph changes after administration, observe the ST section and change situation, and carry out comparing before and after self and between group, after experiment finishes, get hematometry creatine phosphokinase (CPK) and lactic acid dehydrogenase (LDH), take out heart, wash on the rearmounted torsion balance of most blood with normal saline and weigh, ventricle is cut off do not cut off then, put in the N-BT liquid and dye, dyeing is 15 minutes in 37 ℃ of waters bath with thermostatic control, and normal myocardium dyes skipper, and the infarct cardiac muscle is not painted, account for dirty whole-heartedly weight percent with gravimetric method calculating myocardium infarct, the result carries out statistical procedures.
[test method]
The result as can be seen, after the rat coronary artery ligation, myocardial ischemia can continue more than 8 hours.0.5 hour electrocardiogram just changes after the preparation administration of the present invention; Its high dose group, middle dosage group and YINXINGYE ZHUSHEYE are in administration ECG ST section change and model control group comparison p＜0.05～p＜0.01 after 2 hours; The ECG ST section of other each groups all has clear improvement, but the statistics there was no significant difference.
Simultaneously preparation of the present invention can dwindle infarct size, and can reduce because of myocardial ischemia causes growing tall of LDH in the serum, CPK, handles the middle and high dosage of preparation of the present invention p＜0.05～p＜0.01 of comparing with the normal saline group by statistics.See Table 2,3.
Table 2 preparation of the present invention causes cardiac muscle to the ligation rat coronary artery
The influence that ECG ST section changes due to the ischemia (x ± SD)
| Group | Number of animals (only) | After the ligation | The different time ECG ST section changes (mv) after the administration | |||||
| 0.5h | 1.0h | 2.0h | 4.0h | 8.0h | 12.0h | |||
| Dosage heavy dose in the physiological saline positive drug low dose | 10 10 10 10 10 | 0.238 ±0.093 0.209 ±0.141 0.202 ±0.109 0.222 ±0.122 0.201 ±0.087 | 0.373 ±0.132 0.191 ±0.093 ** 0.249 ±0.105 * 0.193 ±0.081 ** 0.165 ±0.093 *** | 0.331 ±0.124 0.191 ±0.121 * 0.252 ±0.099 0.226 ±0.092 * 0.162 ±0.085 ** | 0.322 ±0.161 0.171 ±0.107 * 0.257 ±0.104 0.234 ±0.104 0.116 ±0.079 ** | 0.297 ±0.158 0.159 ±0.092 * 0.258 ±0.128 0.215 ±0.080 0.117 ±0.086 ** | 0.258 ±0.130 0.150 ±0.087 * 0.240 ±0.102 0.200 ±0.123 0.158 ±0.086 * | 0.233 ±0.153 0.161 ±0.087 0.189 ±0.122 0.191 ±0.139 0.135 ±0.104 |
Annotate: compare with model group
*P＜0.05
*P＜0.01
* *P＜0.001
Table 3 preparation of the present invention causes due to the myocardial ischemia the ligation rat coronary artery
The influence of infarct size and Serum LDH, CPK (x ± SD)
| Group | Number of animals (only) | Infarction size | LDH | CPK |
| ％ | U/L | U/L | ||
| Normal saline positive drug low dose | 10 10 10 | 9.99±1.63 7.64±1.27 ** 8.19±2.30 | 257.99±67.42 185.54±51.25 * 243.18±54.90 | 303.50±82.14 212.52±86.30 ** 252.19±55.42 |
| Middle dosage heavy dose | 10 10 | 7.46±2.03 ** 6.89±1.94 ** | 205.51±23.71 * 169.71±63.99 ** | 179.17±115.04 * 206.37±78.91 * |
Annotate: compare with model group
*P＜0.05
*P＜0.01
Three, function of promoting blood circulation to disperse blood clots---rheology test
Influence to blood stasis model rat packed cell volume, whole blood viscosity, plasma viscosity
[test objective] observes the influence of preparation of the present invention to blood stasis model rat packed cell volume, whole blood viscosity, plasma viscosity.
[being subjected to the reagent thing]
1, be subjected to the reagent thing: preparation of the present invention is provided by Lunan Pharmacy Co. Ltd.
2, contrast medicine: Folium Ginkgo is provided by Lunan Pharmacy Co. Ltd.
[animal]
1, source, kind, strain, the quality certification: Medical University Of Anhui's Experimental Animal Center provides, Wister rat, outbreeding sealing system, moving accurate No. 03 of Anhui doctor.
2, body weight: 250～300g
3, sex: ♂.
4, number of animals: 60,10 every group.
5, experimental situation: laboratory temperature is 18-28 ℃, and relative humidity is 50-70%.
6, pellet: provide by Nanjing An Limo Science and Technology Ltd..
[reagent and instrument]
1, Liang-100 type blood viscometer (a complete set of equipment), experimental apparatus factory of Chinese Shanghai medical university produces.
2,80-2 centrifugation device, Shanghai Surgical Operation Equipment Factory's product.
3, adrenalin hydrochloride injection: Shanghai Hefeng Pharmaceutical Co., Ltd. produces, lot number 20021219.
4, heparin sodium: the Shanghai first Sheng Dai pharmaceutcal corporation, Ltd, lot number 021123.
5, operating theater instruments is some.
[test method]
1, the preparation of blood stasis model: reference literature method, every day, (Sublingual or tail) vein gave corresponding test liquid, continuous 7 days, in the 7th day adrenaline subcutaneous injection (adrenalin hydrochloride) 0.08ml/100g body weight totally 2 times, two minor ticks 4 hours, (front and back each at interval 2 hours) were immersed rat in the frozen water 5 minutes between double injection Adr.Stop eating after the disposal, inferior administration in morning detected after 1 hour.
2, (concrete instrumentation is seen the Li Yikui chief editor to the reference literature method, the herbal pharmacology experimental methodology, Science and Technology of Shanghai publishing house, P50) select 60 of the rats of body weight 250～300g for use, be divided into 6 groups at random, be respectively the normal saline group, model group, Folium Ginkgo, preparation of the present invention is little, in, heavy dose of group (is equivalent to 2.5 of clinical consumption respectively, 5,10 times), successive administration 7 days, got blood and survey packed cell volume time morning after stopping eating by last method modeling in the 7th day, whole blood viscosity, plasma viscosity calculates the respectively average and the standard deviation of group, and make t and check comparable group differences significance.
[result of the test]
By test as can be known, rat causes whole blood viscosity and plasma viscosity to raise after giving epinephrine and frozen water and handling, model group whole blood viscosity and the plasma viscosity value highly significant meaning (being respectively P＜0.001 and P＜0.001) of having compared with the normal saline group; Model group packed cell volume value increases, and the highly significant meaning of having compared with the normal saline group (for P＜0.001) illustrates and adopts the method to cause the stasis syndrome model.After giving preparation of the present invention and Folium Ginkgo, animal erythrocyte hematocrit value reduces, in the preparation wherein of the present invention, heavy dose of group packed cell volume value compares significance (being respectively P＜0.01 and P＜0.01) with model group; Animal's whole blood viscosity and plasma viscosity value reduce, in the preparation wherein of the present invention, the high shear rate value of heavy dose of group whole blood viscosity compares significance (being respectively P＜0.05 and P＜0.05) with model group; In the preparation of the present invention, heavy dose of group whole blood viscosity low shear rate value compares significance (being respectively P＜0.01 and P＜0.05) with model group; In the preparation of the present invention, heavy dose of group plasma viscosity value compares significance (being respectively P＜0.01 and P＜0.05) with model group.Illustrate that preparation of the present invention can reduce the blood viscosity of rat model, has certain function of promoting blood circulation to disperse blood clots.The results are shown in Table 4.
Table 4 preparation of the present invention is to the influence of blood stasis model hemorheology of rat (x ± SD)
| Group | Number of animals (only) | Packed cell volume (HCT%) | Plasma viscosity | Whole blood viscosity | |
| Low shear rate | High shear rate | ||||
| Dosage in the normal saline model group Folium Ginkgo low dose | 10 10 10 10 10 | 49.2±2.2 53.9±2.0### 50.1±2.2 ** 51.9±2.8 49.7±2.5 ** | 1.55±0.12 2.33±0.22### 1.85±0.21 * 2.02±0.29 1.75±0.11 ** | 10.42±1.55 16.68±2.85### 13.34±2.69 * 14.33±1.80 12.75±2.01 ** | 6.03±1.12 10.35±1.97## 7.69±1.63 ** 9.39±1.35 8.44±1.79 * |
| Heavy dose of | 10 | 49.9±2.3 ** | 1.83±0.32 * | 13.35±2.21 * | 8.57±1.61 * |
Annotate: ##P＜0.01 ###P＜0.001 of comparing with the normal saline group; Compare with model group
*P＜0.05
*P＜0.01
Following embodiment is further openly the present invention, need to prove that these embodiment only for optimal way of the present invention, do not limit the scope of protection of present invention.
Embodiment 1
Rhizoma Gastrodiae 5Kg Folium Ginkgo 60Kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 12 times of water gagings and decoct 2 times, decocted 2 hours at every turn, merge decoction liquor; concentrate, add ethanol and make precipitation, make to contain the alcohol amount and reach 50%; cold preservation 48 hours filters decompression filtrate recycling ethanol; concentrate; drying is pulverized, and above-mentioned fine powder adds an amount of lactose, magnesium stearate, sweet, the mixing of A Siba; with dry granulation mechanism grain, promptly get granule.
Embodiment 2
Rhizoma Gastrodiae 50Kg Folium Ginkgo 6Kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 8 times of water gagings and decoct 1 time, decocted the merging decoction liquor 3 hours; concentrate, add ethanol and make precipitation, make to contain the alcohol amount and reach 60%; cold preservation 24 hours filters decompression filtrate recycling ethanol; concentrate; above-mentioned fine powder adds an amount of dextrin, Icing Sugar system soft material, and granulator is granulated, drying; packing promptly gets granule.
Embodiment 3
Rhizoma Gastrodiae 5Kg Folium Ginkgo 6Kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 6 times of water gagings and decoct 3 times, decocted 1 hour at every turn, merge decoction liquor, concentrate, add ethanol and make precipitation, make to contain alcohol amount and reach 70%, cold preservation 12 hours filters, and decompression filtrate recycling ethanol concentrates, be dried to fine powder, add right amount of auxiliary materials system granule, the fill capsule promptly gets capsule.
Embodiment 4
Rhizoma Gastrodiae 8Kg Folium Ginkgo 40Kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 5 times of water gagings and decoct 2 times, decocted 1.5 hours at every turn, merge decoction liquor, concentrate, add ethanol and make precipitation, make to contain alcohol amount and reach 85%, cold preservation 12-48 hour, filter decompression filtrate recycling ethanol, concentrate drying becomes fine powder, adds right amount of auxiliary materials system granule, and tabletting promptly gets tablet.
Embodiment 5
Rhizoma Gastrodiae 30Kg Folium Ginkgo 10Kg
Get the Folium Ginkgo medical material, pulverize, add 15 times of amount 40% alcohol refluxs 3 times, each 3 hours, filter, merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, filter, D101 macroporous resin column on the filtrate, after the washing clarification, the ethanol elution of 2 times of bed volumes 20% of reuse, use 70% ethanol elution then, collect ethanol elution and be condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying, carry out silica gel column chromatography then, with ethyl acetate and 4 times of volume eluting of acetone difference, eluent ethyl acetate liquid reclaims solvent, gets A.The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the ethanol elution of reuse 90% is collected, and concentrates, and merges with A, and is standby;
Get the Rhizoma Gastrodiae coarse powder, add 10 times of water gagings, extract 2 times, each 1 hour, filter, merging filtrate, it is about 1.2 to be evaporated to relative density, adds ethanol and reaches 65% to containing the alcohol amount, and Cryoprecipitation filters, be evaporated to every 1ml and contain raw medicinal herbs 2g, it is heavy to add water-cooled, filter, and concentrating under reduced pressure, standby;
Above-mentioned two kinds of medicinal liquids merge, and add the injection water and are assigned to full dose, filter, and fine straining, inflated with nitrogen embedding sterilization, check, promptly.
Embodiment 6
Rhizoma Gastrodiae 8Kg Folium Ginkgo 40Kg
Get the Folium Ginkgo medical material, pulverize, add 10 times of amount 80% alcohol refluxs 2 times, each 2 hours, filter, merging filtrate reclaims ethanol and is concentrated into an amount of, add water-soluble loosing, filter the last 1400 type macroporous resin column of filtrate, after the washing clarification, the ethanol elution with 70% is collected ethanol elution and is condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying carries out silica gel column chromatography then, with ethyl acetate and 3 times of volumes difference of acetone eluting, eluent ethyl acetate liquid reclaims solvent, gets A; The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the ethanol elution of reuse 70% is collected, and concentrates, and merges with A, and is standby;
Get the Rhizoma Gastrodiae coarse powder, add 6 times of water gagings, extract 3 times, each 2.5 hours, filter, merging filtrate, it is about 1.3 to be evaporated to relative density, adds ethanol and reaches 85% to containing the alcohol amount, and Cryoprecipitation filters, be evaporated to every 1ml and contain raw medicinal herbs 2g, it is heavy to add water-cooled, filter, and concentrating under reduced pressure, standby;
Above-mentioned two kinds of medicinal liquids merge, and add the injection water and are assigned to full dose, filter, and fine straining, lyophilization is aseptic subpackaged, check, promptly.
Embodiment 7
Rhizoma Gastrodiae 15Kg Folium Ginkgo 25Kg
Get the Folium Ginkgo medical material, pulverize, add 6 times of amount 80% alcohol refluxs 1 time, each 3 hours, filter, merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, filter, AB-8 macroporous resin column on the filtrate, after the washing clarification, the ethanol elution of 6 times of bed volumes 10% of reuse, use 50% ethanol elution then, collect ethanol elution and be condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying, carry out silica gel column chromatography then, with ethyl acetate and each 5 times amount difference of acetone eluting, eluent ethyl acetate liquid reclaims solvent, gets A.The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the reuse ethanol elution is collected, and concentrates, and merges with A, and is standby;
Get the Rhizoma Gastrodiae coarse powder, add 5 times of water gagings, extract 2 times, each 1.5 hours, filter, merging filtrate, it is about 1.4 to be evaporated to relative density, adds ethanol and reaches 65% to containing the alcohol amount, and Cryoprecipitation filters, be evaporated to every 1ml and contain raw medicinal herbs 4g, it is heavy to add water-cooled, filter, and concentrating under reduced pressure, standby;
Above-mentioned two kinds of medicinal liquids merge, and add the injection water and are assigned to full dose, filter, and fine straining, embedding, sterilization, check, promptly.
Embodiment 8
Rhizoma Gastrodiae 20Kg Folium Ginkgo 16Kg
Get the ethanol extraction 2 times that Folium Ginkgo, Rhizoma Gastrodiae add 8 times of amounts 60%, each 2 hours, merge extractive liquid, concentrated, and adds ethanol and makes precipitation, make to contain alcohol amount and reach 70%, cold preservation 12 hours filters, and decompression filtrate recycling ethanol concentrates, the ethanol that adds normal concentration stirs, and filters, and promptly gets tincture.
Embodiment 9
Rhizoma Gastrodiae 5Kg Folium Ginkgo 60Kg Borneolum Syntheticum 0.08kg
Get the Folium Ginkgo medical material, pulverize, add 8 times of amount 50% alcohol refluxs 2 times, each 1.5 hours, filter merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, and filters, HPD-450 macroporous resin column on the filtrate, after the washing clarification, the ethanol elution with 40% is collected ethanol elution and is condensed into thick extractum, drying, standby;
Get the Rhizoma Gastrodiae coarse powder, add 6 times of water gagings, extract 2 times, each 1 hour, filter, merging filtrate, it is about 1.1 to be evaporated to relative density, adds ethanol and reaches 65% to containing the alcohol amount, and Cryoprecipitation filters, concentrating under reduced pressure, drying, standby;
Get Borneolum Syntheticum and pulverize and above-mentioned dry extract merging,, add dry medicated powder the substrate heating and melting, mixing, impouring scribbles in the bolt mould of releasing agent, and cooling is taken out, and promptly gets suppository.
Embodiment 10
Rhizoma Gastrodiae 50Kg Folium Ginkgo 6Kg Borneolum Syntheticum 0.08kg
Get Rhizoma Gastrodiae, Folium Ginkgo, add 10 times of amount ethanol extractions of 40% 2 times, each 3 hours; Merge extractive liquid,, decompression recycling ethanol, and be condensed into the clear paste shape, and drying gets dried powder, and Borneolum Syntheticum is pulverized, and merges with above-mentioned medicated powder, adds appropriate amount of starch, and the general ball of making promptly gets pill.
Embodiment 11
Rhizoma Gastrodiae 50Kg Folium Ginkgo 60Kg Borneolum Syntheticum 0.005kg
Folium Ginkgo, Rhizoma Gastrodiae add 8 times of water gagings and decoct 2 times, decoct 1 hour at every turn, merge decoction liquor, concentrate, add ethanol and make precipitation, make to contain alcohol amount and reach 40%, cold preservation 24 hours filters, decompression filtrate recycling ethanol is concentrated in right amount, and other gets sucrose and adds an amount of heated and boiled of water, dissolving is filtered, and concentrates and makes syrup, with above-mentioned concentrated solution mixing, boil, put cold, add antiseptic and essence, thin up promptly gets syrup.
Embodiment 12
Rhizoma Gastrodiae 8Kg Folium Ginkgo 40Kg Borneolum Syntheticum 0.08kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 8 times of water gagings and decoct 2 times, decocted 1.5 hours at every turn, merge decoction liquor, concentrate, add ethanol and make precipitation, make to contain the alcohol amount and reach 65%, cold preservation 12-48 hour, filter decompression filtrate recycling ethanol, concentrate, get that Borneolum Syntheticum adds ethanol and propylene glycol makes dissolving, other gets sucrose and makes syrup, merge with above-mentioned medicinal liquid, add water system full dose, filter, fill, sterilization promptly gets mixture.
Embodiment 13
Rhizoma Gastrodiae 30Kg Folium Ginkgo 10Kg Borneolum Syntheticum 0.08kg
Get the ethanol extraction 2 times that Folium Ginkgo, Rhizoma Gastrodiae add 5 times of amounts 75%, decocted 0.5 hour at every turn, merge extractive liquid, filters, and decompression filtrate recycling ethanol concentrates, and is dried to fine powder, and Borneolum Syntheticum is pulverized and above-mentioned western powder mixing, sieves, and promptly gets powder.
Embodiment 14
Rhizoma Gastrodiae 30Kg Folium Ginkgo 40Kg Borneolum Syntheticum 0.005kg
Get the Folium Ginkgo medical material, pulverize, add 8 times of amount 50% alcohol refluxs 3 times, each 2.5 hours, filter merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, and filters, HPD-500 macroporous resin column on the filtrate, after the washing clarification, the ethanol elution of 2 times of bed volumes 10% of reuse, use 40% ethanol elution then, collect ethanol elution and be condensed into thick extractum, drying, standby;
Get the Rhizoma Gastrodiae coarse powder, add 8 times of water gagings, extract 3 times, each 1.5 hours, filter, merging filtrate, it is about 1.1 to be evaporated to relative density, adds ethanol and reaches 85% to containing the alcohol amount, and Cryoprecipitation filters, concentrating under reduced pressure, drying, standby;
Get Borneolum Syntheticum and pulverize, merge with above-mentioned medicated powder, other gets the PVA adding distil water and soaks, and heating for dissolving adds dry extract again, stirring and dissolving adds glycerol, tween 80 again, stirs evenly, and leaves standstill and removes bubble, is coated on the glass plate and makes film, 80 ℃ of demouldings are cut into suitable size, and sealing promptly gets membrane.
Embodiment 15
Rhizoma Gastrodiae 15Kg Folium Ginkgo 25Kg Borneolum Syntheticum 0.08kg
Get the Folium Ginkgo medical material, pulverize, add 5 times of amount 55% alcohol refluxs 2 times, each 1.5 hours, filter, merging filtrate reclaims ethanol and is concentrated into an amount of, add water-soluble loosing, filter HPD-800 macroporous resin column on the filtrate, after the washing clarification, use 30%% ethanol elution then, collect ethanol elution and be condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying carries out silica gel column chromatography then, with ethyl acetate and acetone difference eluting, eluent ethyl acetate liquid reclaims solvent, gets A; The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the reuse ethanol elution is collected, and concentrates, merge with A, drying, standby;
Get the Rhizoma Gastrodiae coarse powder, add 6 times of water gagings, extract 2 times, each 2 hours, filter, merging filtrate, it is about 1.2 to be evaporated to relative density, adds ethanol and reaches 65%% to containing the alcohol amount, and Cryoprecipitation filters, concentrating under reduced pressure, drying, standby;
Get Borneolum Syntheticum and pulverize, merge with above-mentioned medicated powder, the taking polyethylene glycol heating and melting adds dry extract, drips and makes ball, and packing promptly gets drop pill.
Embodiment 16
Rhizoma Gastrodiae 20Kg Folium Ginkgo 16Kg Borneolum Syntheticum 0.08kg
Get the Folium Ginkgo medical material, pulverize, add 12 times of amount 40% alcohol refluxs 2 times, each 2 hours, filter merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, and filters, macroporous resin column is used 90% ethanol elution then with the ethanol elution of 2 times of bed volumes 20% on the filtrate, collects ethanol elution and is condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying carries out silica gel column chromatography then, with ethyl acetate and 3 times of volumes difference of acetone eluting, eluent ethyl acetate liquid reclaims solvent, gets A, the acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, last polyamide column is after the washing clarification, the ethanol elution of reuse 60% is collected, and concentrates, merge with A, standby;
Get the Rhizoma Gastrodiae coarse powder, add 8 times of water gagings, extract 2 times, each 1 hour, filter, merging filtrate, it is about 1.3 to be evaporated to relative density, adds ethanol and reaches 70% to containing the alcohol amount, and Cryoprecipitation filters, be evaporated to every 1ml and contain raw medicinal herbs 3g, it is heavy to add water-cooled, filter, and concentrating under reduced pressure, standby;
Get Borneolum Syntheticum and add that dehydrated alcohol is ultrasonic to make dissolving, slowly add water for injection, merge, add the injection water and be assigned to full dose, filter with above-mentioned two kinds of medicinal liquids, fine straining, lyophilization is aseptic subpackaged, check, promptly.
Embodiment 17
Rhizoma Gastrodiae 20Kg Folium Ginkgo 25Kg Borneolum Syntheticum 0.005kg
Get Rhizoma Gastrodiae, Folium Ginkgo, add 8 times of water gagings and decoct 2 times, decocted 2.5 hours at every turn; Merge decoction liquor, concentrate; Add ethanol and make precipitation, make to contain alcohol amount and reach 60%, cold preservation 24 hours; filter, decompression filtrate recycling ethanol, and be condensed into the clear paste shape; add 3 times of amounts of injection water; left standstill 24 hours, and filtered, concentrate; be dried to western powder; above-mentioned fine powder adds an amount of dextrin, magnesium stearate, stevioside, mixing, with dry granulation mechanism grain, promptly.
Embodiment 18
Rhizoma Gastrodiae 5Kg Folium Ginkgo 40Kg
Get Folium Ginkgo, Rhizoma Gastrodiae and add 6 times of water gagings and decoct 3 times, decocted 1 hour at every turn, merge decoction liquor, concentrate, add ethanol and make precipitation, make to contain the alcohol amount and reach 45%, cold preservation 32 hours, filter, decompression filtrate recycling ethanol concentrates, add starch, dextrin, Icing Sugar system soft material, the system granule, oven dry, packing promptly gets granule.
Embodiment 19
Rhizoma Gastrodiae 5Kg Folium Ginkgo 30Kg
Get Rhizoma Gastrodiae, Folium Ginkgo, add 8 times of water gagings and decoct 2 times, decocted 1.5 hours at every turn; Merge decoction liquor, concentrate; Add ethanol and make precipitation, make to contain alcohol amount and reach 60%, cold preservation 48 hours filters decompression filtrate recycling ethanol, and be condensed into the clear paste shape, and add 6 times of amounts of injection water, left standstill 48 hours, filter, concentrate, add n-butanol extraction 5 times, add 2 times of n-butyl alcohol at every turn, n-butyl alcohol liquid evaporate to dryness is dissolved in water, Cryoprecipitation 48 hours, filter, filtrate concentrates, and to regulating PH to 8, adds 0.1% active carbon, heated and boiled 30 minutes, filter, add to the full amount of water for injection, regulate pH value, filter, fine straining, the embedding sterilization, check, promptly.
Embodiment 20
Rhizoma Gastrodiae 5Kg Folium Ginkgo 35Kg
Get Rhizoma Gastrodiae, Folium Ginkgo, add 8 times of amount alcohol refluxs of 60% 2 times, each 1.5 hours; Merge backflow, concentrate; Add ethanol and make precipitation, make to contain alcohol amount and reach 75%, cold preservation 48 hours filters, decompression filtrate recycling ethanol, and be condensed into the clear paste shape, add 6 times of amounts of injection water, left standstill 48 hours, filter, filtrate concentrates, and to regulating PH to 8, adds 0.1% active carbon, heated and boiled 30 minutes is filtered, and adds to the full amount of water for injection, and regulates pH value, filter fine straining, lyophilization, aseptic subpackaged, check, promptly.
Claims (16)
1, a kind of Chinese medicine composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that it is to be formed by following feedstock production:
Rhizoma Gastrodiae 5-50 weight portion Folium Ginkgo 6-60 weight portion.
2, compositions as claimed in claim 1 is characterised in that its raw material of preparation is:
Rhizoma Gastrodiae 8-30 weight portion Folium Ginkgo 10-40 weight portion.
3,, be characterised in that its raw material of preparation is according to the described compositions of claim 1:
Rhizoma Gastrodiae 15-20 weight portion Folium Ginkgo 16-25 weight portion.
4, as stating compositions as described in the claim 1-3, it is characterized in that it also adds Borneolum Syntheticum 0.005-0.08 weight portion.
5, as stating compositions as described in the claim 1-4, this pharmaceutical composition adds excipient and makes clinical acceptable various dosage forms.
6, as stating compositions as described in the claim 5, be characterised in that the dosage form of this medicine is: granule, tablet, pill, capsule, injection or oral liquid, tincture, suppository, mixture, powder, lotion, membrane, drop pill.
7, compositions as claimed in claim 6, the dosage form that is characterised in that this medicine is an injection.
8, injection as claimed in claim 7 is characterized in that described injection is liquid drugs injection, powder pin, transfusion.
9, liquid drugs injection as claimed in claim 8 is characterized in that its effective ingredient contains: Gastrodine 0.05-40 mg/ml, Ginkgo total flavones 0.05-20 mg/ml.
10, liquid drugs injection as claimed in claim 9 is characterized in that its composition contains: Gastrodine 0.5-20 mg/ml, Ginkgo total flavones 0.1-10 mg/ml.
11,, it is characterized in that its composition also contains: bilobalide 0.01-5 mg/ml as the described injection of claim 7-10.
12,, it is characterized in that pH value is 4.0～9.0 as the described injection of claim 7-11.
13, as the described injection of claim 6-12, it is characterized in that adding in the solvent cosolvent: alcohol, fatty acid esters of sorbitan, polyoxyethylene fatty acid ester, polyethenoxy sorbitan fatty acid or polyoxyethylene aliphatic alcohol ether.
14,, it is characterized in that adding cosolvent in the solvent is lower alcohol as the described injection of claim 6-12.
15, injection as claimed in claim 14 is characterized in that adding cosolvent in the solvent is propylene glycol and/or ethanol.
16, as injection as described in the claim 6-15, be characterised in that its preparation technology is:
Get the Folium Ginkgo medical material, pulverize, add 4-15 and doubly measure the 40%-80% alcohol reflux 1-3 time, each 0.5-3 hour, filter, merging filtrate, recovery ethanol also is concentrated in right amount, adds water-soluble loosing, filter, macroporous resin column on the filtrate, after the washing clarification, the ethanol elution of reuse 2-8 times bed volume 20%, use the ethanol elution of 30%-90% then, collect ethanol elution and be condensed into thick extractum, add silica gel and mix thoroughly, vacuum drying, carry out silica gel column chromatography then, with ethyl acetate and acetone difference eluting, eluent ethyl acetate liquid reclaims solvent, gets A; The acetone eluent reclaims solvent, and the extractum thin up leaves standstill, filter, and last polyamide column, after the washing clarification, the reuse ethanol elution is collected, and concentrates, and merges with A, and is standby;
Get the Rhizoma Gastrodiae coarse powder, add 5-12 times of water gaging, extract 1-4 time, each 0.5-3 hour, filter merging filtrate, be evaporated to the about 1.0-1.4 of relative density, add ethanol and reach 65%-85%, Cryoprecipitation to containing the alcohol amount, filter, be evaporated to every 1ml and contain raw medicinal herbs 1-5g, it is heavy to add water-cooled, filters, concentrating under reduced pressure, standby;
Get Borneolum Syntheticum and add that solubilizing agent is ultrasonic to make dissolving, slowly add water for injection, merge, add the injection water and be assigned to full dose, filter with above-mentioned two kinds of medicinal liquids, fine straining, inflated with nitrogen embedding sterilization or lyophilization are aseptic subpackaged, check, promptly.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100019526A CN100484563C (en) | 2005-01-13 | 2005-01-13 | Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100019526A CN100484563C (en) | 2005-01-13 | 2005-01-13 | Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and preparation method thereof |
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| CN1803182A true CN1803182A (en) | 2006-07-19 |
| CN100484563C CN100484563C (en) | 2009-05-06 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013143323A1 (en) * | 2012-03-31 | 2013-10-03 | 昆明制药集团股份有限公司 | Application of gastrodin as solubilizer and method for preparing injection or powder for injection |
| CN104758654A (en) * | 2015-04-07 | 2015-07-08 | 周茂荣 | Medicine for treating frequently-occurring diseases caused by viruses and preparation method of medicine |
| CN104940651A (en) * | 2015-06-05 | 2015-09-30 | 昆药集团股份有限公司 | Pharmaceutical composition and preparation method, preparation and application thereof |
| CN115944689A (en) * | 2023-01-31 | 2023-04-11 | 福建古田药业有限公司 | Ginkgo leaf dropping pill and preparation method thereof |
-
2005
- 2005-01-13 CN CNB2005100019526A patent/CN100484563C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013143323A1 (en) * | 2012-03-31 | 2013-10-03 | 昆明制药集团股份有限公司 | Application of gastrodin as solubilizer and method for preparing injection or powder for injection |
| CN104758654A (en) * | 2015-04-07 | 2015-07-08 | 周茂荣 | Medicine for treating frequently-occurring diseases caused by viruses and preparation method of medicine |
| CN104940651A (en) * | 2015-06-05 | 2015-09-30 | 昆药集团股份有限公司 | Pharmaceutical composition and preparation method, preparation and application thereof |
| CN115944689A (en) * | 2023-01-31 | 2023-04-11 | 福建古田药业有限公司 | Ginkgo leaf dropping pill and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN100484563C (en) | 2009-05-06 |
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Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000511 Denomination of invention: Chinese medicine composition for treating cardio-cerabral vascular diseases and its preparing method Granted publication date: 20090506 License type: Exclusive License Open date: 20060719 Record date: 20100909 |
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Effective date of registration: 20211213 Address after: 276006 No. 209 Hongqi Road, Shandong, Linyi Patentee after: LUNAN HOPE PHARMACEUTICAL Co.,Ltd. Address before: 276005 No. 209 Hongqi Road, Shandong, Linyi Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
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Denomination of invention: The invention relates to a traditional Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and a preparation method thereof Effective date of registration: 20211228 Granted publication date: 20090506 Pledgee: China Construction Bank Corporation Linyi Shizhong sub branch Pledgor: LUNAN HOPE PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016801 |
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Date of cancellation: 20230331 Granted publication date: 20090506 Pledgee: China Construction Bank Corporation Linyi Shizhong sub branch Pledgor: LUNAN HOPE PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016801 |
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