CN1718191A - Total secondary ginseng glucoside oral disintegration tablets prepn. method and application thereof - Google Patents

Total secondary ginseng glucoside oral disintegration tablets prepn. method and application thereof Download PDF

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CN1718191A
CN1718191A CN 200510083852 CN200510083852A CN1718191A CN 1718191 A CN1718191 A CN 1718191A CN 200510083852 CN200510083852 CN 200510083852 CN 200510083852 A CN200510083852 A CN 200510083852A CN 1718191 A CN1718191 A CN 1718191A
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total secondary
ginsenoside
glucoside
secondary ginseng
ginseng glucoside
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孙从新
王巍
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China Medicament Research & Development Center Co Ltd
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China Medicament Research & Development Center Co Ltd
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Priority to CN 200510083852 priority Critical patent/CN1718191A/en
Publication of CN1718191A publication Critical patent/CN1718191A/en
Priority to JP2008520691A priority patent/JP2009500432A/en
Priority to KR1020087003434A priority patent/KR101182917B1/en
Priority to PCT/CN2006/001574 priority patent/WO2007006208A1/en
Priority to CA2614700A priority patent/CA2614700C/en
Priority to ES06761360.4T priority patent/ES2515891T3/en
Priority to US11/995,320 priority patent/US7973014B2/en
Priority to PL06761360T priority patent/PL1905444T3/en
Priority to EP06761360.4A priority patent/EP1905444B1/en
Priority to HK08104922.7A priority patent/HK1110520A1/en
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Abstract

An oral disintegrating tablet of hypopanaxin for treating the stuffiness and blocking sensation of chest, cardialgia, myocardial ischemia, hemorrhagic shock, etc contains 20-(S)-Rg3, 20-(R)-Rg3, 20-(S)-Rg2, 20-(R)-Rg2, 20-(S)-Rh1, 20-(R)-Rh1 and filler. Its preparing process is also disclosed.

Description

Total secondary ginseng glucoside oral disintegration tablets and its production and application
Technical field
The present invention relates to a kind of pharmaceutical composition that contains Radix Ginseng effective site and its production and application, particularly relate to a kind of total secondary ginseng glucoside oral disintegration tablets and its production and application.
Background technology
Radix Ginseng is the key medicine of traditional Chinese medical science QI invigorating.Nature and flavor with return through sweet, little hardship, flat.Function with cure mainly: strongly invigorating primordial QI, multiple arteries and veins takes off admittedly, invigorating the spleen to benefit the lung promotes the production of body fluid, and calms the nerves.Be used for weak body and prostration, the cold extremities faint pulse, insufficiency of the spleen lack of appetite, the deficiency of the lung is breathed with cough, and Tianjin wound is thirsty, and interior-heat is quenched one's thirst, and prolonged illness is empty wins, palpitation with fear insomnia, sexual impotence cold womb; Heart failure, cardiogenic shock.
The traditional Chinese medical science and the combination of Chinese and Western medicine are clinical to be confirmed; Radix Ginseng and preparation thereof have pharmacologically actives such as the myocardial contraction of enhancing, coronary artery dilator, coronary blood flow increasing, minimizing myocardial oxygen consumption, protection reperfusion injury of cardiac muscle, anticoagulant, antithrombase, and clinical practice is in treatment of diseases such as obstruction of qi in the chest and cardialgia (coronary heart disease), arteriosclerosis.
The cause of disease of obstruction of qi in the chest and cardialgia mainly be " weakened YANG QI is not transported in the heart, for a long time then the yin subjugating yang position and be numbness knot " (" Lei Zheng Zhi Cai a ● thoracic obstruction piece of writing "), " or because of experiencing the cold-evil; mouthful cold thing of food; in have hot and suffocatingly, have the dead blood of pertinacious phlegm, or form chest pain because of the angry stagnation of QI " (" doctor's mirror at all times ● pained ").
After people in middle age, body constitution descends, the five internal organs degradation, and visceral dysfunction, plain body YANG QI deficiency is attacked by pathogen such as cold and summer-heat again, or eating and drinking without temperance, and have a liking for the food delicious food, or ponder over overstrain, or disorder of emotion and cause obstruction of qi in the chest and cardialgia.Its sick position is at the heart, and it is all dirty to relate to lung, spleen, liver, kidney.Pathological change is the imbalance of internal organs negative and positive of qi and blood, deficiency of heart-blood, and flaccidity of the heart-yang causes stagnating heart meridians such as the stagnation of QI, cold coagulation, expectorant are turbid, blood stasis, causes blockage of the cardiac vessels, qi depression to blood stasis and falling ill.Pathogenesis is a deficiency in origin and excess in superficiality, and deficiency in origin is that the motive, painstaking effort, the heart-yin are lost void or deficiency of heart-YANG and kidney-YANG; Mark is real to be that the stagnation of QI, cold coagulation, expectorant are turbid, blood stasis resistance numbness heart arteries and veins etc., and deficiency in origin aggravates disease with the real often reciprocal causation of mark in the pathogenic process, presents simulataneous insufficiency and excessive, specimen with existing complicated syndrome.The rule of treatment is a rule of treatment with YIN and YANG balance regulating, temperature compensation yang-energy, promoting flow of QI and blood.Qi being the governor of blood, gas promoting the circulation of blood are then gone.The QI invigorating sun that shakes, blood circulation promoting and blood stasis dispelling are the important rules of treatment obstruction of qi in the chest and cardialgia.
Modern scientific research is the result show: the main bioactive ingredients of Radix Ginseng is the ginsenoside.Though Radix Ginseng Rubra and Radix Ginseng are contained saponin, its saponin monomer is different, contains the saponin that does not have in the Radix Ginseng in the Radix Ginseng Rubra---ginsenoside Rg2, Rg3, Rh1, Rh2 etc.These new saponin are in the Radix Ginseng course of processing, through steaming, when dry, the secondary saponin that ginsenoside's hydrolysis produces.
These secondary saponin have many new activity, for example: ginsenoside Rh1, Rh2, Rg3 have tangible active anticancer, and cancerous cell is induced differentiation again, but inducing cancer cell is divided into healthy cell again, other saponin monomer does not but have this effect, perhaps action intensity a little less than.The ginsenoside Rg3 has stronger inhibitory action to collagen or the inductive platelet aggregation of ADP.Ginsenoside Rh1 is converted into fibrin to the Fibrinogen of thrombin induction the obvious suppression effect.
In addition, in recent years use the result of serum pharmacological theory research ginsenoside's internal metabolism to show, former Radix Ginseng saponin is human body internal absorption factor very low (ginsenoside Rb1 is oral only to absorb 1%), and the active ingredient that really is absorbed by the body is the secondary saponin that produces through the Enterobacter cloaca metabolism.The Wang Benxiang professor finds that behind the oral ginsenoside Rg1, the biological activity that is absorbed into blood mainly is the secondary saponin Rh1 that produces through the Enterobacter cloaca metabolism when research ginsenoside internal metabolism process.
The Yan Yongqing professor is in the active ingredient process of research SHENGMAI YIN, find the common good effect of frying in shallow oil than single medicinal material branch that decocts of SHENGMAI YIN compound recipe, after the common decoction of compound recipe, the ginsenoside in the soup mainly is the secondary saponin Rg2 of Radix Ginseng, Rg3, Rh1, and former Radix Ginseng saponin disappears.This result of study shows that the main biological activity of compound recipe SHENGMAI YIN is ginsenoside Rg2, Rg3, Rh1.
But these saponin natural content are extremely low, and for example: the content of Rg3 in Radix Ginseng is 0.0003% only, and the content in Radix Ginseng Rubra is about 0.03%, and Rh2 and C-K do not exist in natural ginseng, only contain Rh2 about 0.001% in Radix Ginseng Rubra.And C-K is ginsenoside's an intestinal metabolite.The secondary saponin compound of these Radix Ginsengs is owing to obtain difficulty, and essential feather weight amount almost is impossible to carry out drug development.Therefore, it is significant to adopt new method to prepare above-claimed cpd.
Summary of the invention
One of purpose of the present invention is the extremely low shortcoming of secondary saponin content that overcomes active component in the very low and natural ginseng of former Radix Ginseng saponin absorption rate in human body, and a kind of total secondary ginseng glucoside oral disintegration tablets is provided.
One of the present invention's total secondary ginseng glucoside oral disintegration tablets is to realize like this.
Total secondary ginseng glucoside oral disintegration tablets of the present invention is characterized in that, described oral cavity disintegration tablet comprises following component:
The A active component is total secondary ginseng glucoside's pharmaceutical composition, wherein
3. be the ginsenoside of aglycon with the former glycol of Radix Ginseng, comprise the ginsenoside Rg3;
4. be the ginsenoside of aglycon with the former triol of Radix Ginseng, comprise ginsenoside Rg2 and ginsenoside Rh1;
By weight percentage, with the former glycol of Radix Ginseng, the former triol of Radix Ginseng be aglycon the ginsenoside's and account for more than 20% of A component; The B helper component is comprising filler;
The ratio of weight and number of the whole oral cavity disintegration tablet of A ingredients constitute is (3~80): 100.
In the A component: the ginsenoside Rg3 is ginsenoside 20-(S)-Rg3 and/or ginsenoside 20-(R)-Rg3; Ginsenoside Rg2 is ginsenoside 20-(S)-Rg2 and/or ginsenoside 20-(R)-Rg2; Ginsenoside Rh1 is ginsenoside Rh1 20-(S)-Rh1 and/or ginsenoside 20-(R)-Rh1;
By the weight percent meter that accounts for the A component:
Rg3 is 10-30%, preferred 12-20%;
Rg2 is 1-20%, preferred 4-16%;
Rh1 is 1-10%, preferred 3-5%.
With the former glycol of Radix Ginseng, the former triol of Radix Ginseng be aglycon the ginsenoside's and more than 50%.
The described plant that is used to extract total secondary ginseng glucoside's pharmaceutical composition is the araliaceae ginseng plant, comprises various Radix Ginsengs, Radix Panacis Quinquefolii, Rhizoma Panacis Japonici, Radix Notoginseng, wherein preferably ginseng, particularly Leptoradix Ginseng.
The extraction preparation method of described total secondary ginseng glucoside's pharmaceutical composition A comprises hydrolysing step; As hydrolyst, preferred especially acetic acid is as hydrolyst with mineral acid or organic acid for described hydrolysing step.
A component in the total secondary ginseng glucoside oral disintegration tablets of the present invention be Radix Ginseng extract through the weak acid hydrolysis, extract the total secondary saponin of preparation.Its main component source of students is closed: ginsenoside Rg3's (secondary glycosides) that ginsenoside Rb class (primary glycosides) hydrolysis produces, the ginsenoside Rg2 (secondary glycosides) that ginsenoside Re's class (primary glycosides) hydrolysis produces, and the ginsenoside Rh1 (secondary glycosides) of ginsenoside Rg1's class (primary glycosides) hydrolysis generation.Through the exploration of system, we have filtered out good high-pressure liquid phase condition of gradient elution, 20-of the present invention (S)-Rg3, and 20-(R)-Rg3,20-(S)-Rg2,20-(R)-Rg2,20-(S)-Rh1,20-(R)-Rh1 can reach good separating effect.
Among the described oral cavity disintegration tablet helper component B:
Described filler is selected from one or more in starch, dextrin, lactose, microcrystalline Cellulose, pregelatinized Starch, xylitol, mannitol, sorbitol, erithritol, sucrose, glucose, fructose, trehalose, the maltose;
Described helper component B can also comprise following component:
Disintegrating agent is selected from low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, the crosslinked carboxymethyl fecula sodium one or more;
Screening agent is selected from cyclodextrin and derivant thereof, Polyethylene Glycol, polyvinylpyrrolidone, methacrylate polymer;
Binding agent is selected from alcoholic solution, water, polyvinylpyrrolidonesolution solution, starch slurry;
Effervescent is selected from citric acid, tartaric acid, boric acid, fumaric acid, sodium bicarbonate, sodium carbonate;
Correctives is selected from Herba Menthae essence, Fructus Citri Limoniae essence, cyclamate, aspartame, stevioside
Fluidizer is selected from micropowder silica gel, Pulvis Talci;
Lubricant is selected from magnesium stearate, Polyethylene Glycol;
Various helper components account for whole oral cavity disintegration tablet weight ratio: filler 10-95, disintegrating agent 0-50, screening agent 0-50, bonding agent 0-10, effervescent 0-60, correctives 0-20, fluidizer 0-15, lubricant 0-30.
Two of purpose of the present invention provides a kind of preparation method of total secondary ginseng glucoside oral disintegration tablets.
The preparation method of the present invention's two total secondary ginseng glucoside oral disintegration tablets is to realize like this.
The preparation method of total secondary ginseng glucoside oral disintegration tablets of the present invention, its preparation method is:
(1) Radix Ginseng total saponins extracting solution preparation: with panax species, water or organic solvent extraction concentrate extracting solution again;
(2) hydrolyzed solution preparation: with mineral acid or organic acid is the above-mentioned concentrated extracting solution of catalyst hydrolysis;
(3) resin absorption: hydrolyzed solution adsorbs by the macroporous resin adsorption post,
(4) remove impurity: the adsorption column that has absorbed hydrolyzed solution is removed impurity through water elution, aqueous alkali eluting, concentration at the ethanol elution below 35% again;
(5) eluting, concentrated, dry: use concentration at the ethanol elution adsorption column more than 35% after removing impurity, collect this ethanol elution, be condensed into fluid extract, vacuum drying gets A component total secondary ginseng glucoside pharmaceutical composition;
(6) with other component mix homogeneously among total secondary ginseng glucoside A and the helper component B, dry, pulverize, tabletting according to a conventional method, promptly.
Three of purpose of the present invention provides the application of a kind of total secondary ginseng glucoside oral disintegration tablets in the following medicine of preparation:
At preparation treatment flaccidity of the heart-yang, a little less than the insufficiency of heart-QI, the application in the medicine of the obstruction of qi in the chest and cardialgia that qi depression to blood stasis causes;
Application in the medicine of preparation treatment myocardial ischemia;
Application in the medicine of preparation treatment hemorrhagic shock;
Application in the medicine of preparation treatment heart failure.
The indication of total secondary ginseng glucoside's pharmaceutical composition of three of the present invention is to realize like this.
This medicine is that the function according to Radix Ginseng cures mainly, actual efficacy in conjunction with modern Chinese medicine clinical practice Radix Ginseng treatment coronary heart disease, with reference to the latest developments of relevant Radix Ginseng pharmaceutical research both at home and abroad, extract the effective site-total secondary ginseng of preparation Radix Ginseng and give birth to saponin, development cure mainly flaccidity of the heart-yang, a little less than the insufficiency of heart-QI, the new drug of the obstruction of qi in the chest and cardialgia that qi depression to blood stasis causes.
We adopt modern pharmaceutical engineering means, are the total secondary ginseng glycosides effective part of Main Ingredients and Appearance by extracting preparation in the Radix Ginseng with ginsenoside Rg2, Rg3, Rh1.Pharmacodynamic experiment studies show that,
1. the total secondary ginseng glucoside has the remarkable effect that improves the dog acute myocardial ischemia, obviously alleviates by the degree of myocardial ischemia of epicardial electrogram mapping (∑-ST);
2. reduce through the shown infarct area of N-BT dyeing; Coronary flow in the time of can obviously increasing myocardial ischemia promotes that side Zhi Xunhuan is open and sets up the oxygen supply of increase cardiac muscle;
3. blood plasma 6-ketone-prostaglandin F in the time of can obviously raising myocardial ischemia 1a(6-Keto-PGF 1a) level and 6-Keto-PGF 1a/ TXB 2Ratio;
4. can significantly suppress the rat heart muscle ischemia that pituitrin causes;
5. can prevent and treat the myocardial ischemia that the rat coronary ligation causes by significance, its effect significantly is better than Radix Ginseng total saponins (P<0.01);
6. the anti-cardiogenic shock effect of highly significant is arranged, to anesthetized dog shock model due to the ischemia, under the identical situation of dosage, Radix Ginseng total output time glycosides about 20min after administration begins to play a role, and Radix Ginseng total saponins about 40min after administration begins to play a role, action effect a little less than; Generally speaking, the total secondary ginseng glucoside 20,30, the 40min time point, compare with Radix Ginseng total saponins, action effect has significant difference (P<0.05 or P<0.01), is being better than Radix Ginseng total saponins aspect speed of action and the action effect;
7. to BaCl 2Cause the animal model of rat ventricular, total secondary ginseng glucoside 200mg/kg can significantly delay the time (P<0.05, P<0.05) that VP, VT occur, significantly shorten the arrhythmia persistent period (P<0.05), 100,50mg/kg can significantly shorten the arrhythmia persistent period (P<0.05, P<0.05);
8. total secondary ginseng glucoside 200mg/kg administration 7d in advance is to the inhibitory action that is formed with of test rat neck arteriovenous shut thrombosis;
9. the total secondary ginseng glucoside has inhibitory action to the platelet aggregation that ADP brings out, and especially high dose group has significant inhibitory effect to external platelet aggregation;
10. to the isolated rat heart ischemia-reperfusion, can improve coronary flow, improve heart beating strength within a certain period of time, and ischemic myocardium is had the certain protection ability.
Based on above traditional theory of Chinese medical science and tcm clinical practice experience and pharmacodynamic experiment scientific achievement, having developed is the flaccidity of the heart-yang that cures mainly of Main Ingredients and Appearance with total secondary ginseng glucoside, a little less than the insufficiency of heart-QI, and the new drug of the obstruction of qi in the chest and cardialgia that qi depression to blood stasis causes.The patient takes and is developed into oral cavity disintegration tablet for convenience.
The main result of test of pesticide effectiveness research
1, the total secondary ginseng glucoside is to the influence of dog to the dog myocardial ischemia
(1), the total secondary ginseng glucoside adopts ligation dog anterior descending coronary (LAD) to cause acute myocardial infarction model to the effect experiment of experimental dog acute myocardial infarction.With epicardial electrogram (EECG) mapping degree of myocardial ischemia (∑-ST) and myocardial ischemia scope (N-ST); Learn method (N-BT staining) with quantitative tissue and measure myocardial infarct size (MIS); Femoral vein is got blood thought-read flesh three enzymes: glutamic oxaloacetic transaminase, GOT (AST), creatine phosphokinase (CPK) and lactic acid dehydrogenase (LDH).Experimental result shows that the total secondary ginseng glucoside has the remarkable effect that improves the dog acute myocardial ischemia, obviously alleviates by the degree of myocardial ischemia of epicardial electrogram mapping (∑-ST); Reduce through the shown infarct of N-BT dyeing.Positive control drug DIAOXINXUE KANG, Radix Ginseng saponin and stem and leaf of Radix Ginseng saponin also show the identical effect that reduces myocardial infarction area.
(2), total secondary ginseng glucoside's rat heart muscle ischemia of adopting pituitrin to cause to the effect of rat heart muscle ischemia, observe the influence that medicine raises to the variation and the T ripple of ST section among the standard cardioelectric figure II.The result shows: compare with the blank group, Ginseng secondary glycoside 100-200mg/kg can significantly resist the variation of ST, the rising of T ripple (P<0.05 or P<0.01), its effect is relevant with dosage, shows that Ginseng secondary glycoside can significantly suppress the rat heart muscle ischemia that pituitrin causes; Under equal experiment condition, Radix Ginseng total saponins 100mg/kg only shows and makes the T ripple raise degree to alleviate, but diltiazem 50mg/kg significance suppresses the variation (P<0.05 or P<0.01) of ST ripple, T ripple.
(3), the total secondary ginseng glucoside causes that to coronary ligation the influence of rat heart muscle ischemia is to rat coronary ligation model, successive administration 7d in advance, physical signs such as record electrocardio ECG II, heart rate, systolic pressure, diastolic pressure are put in the operation of execution coronary ligation in each observing time.The result shows, total secondary ginseng glucoside 100-200mg/kg all can suppress the variation (P<0.01) that J is ordered by highly significant, and tangible dose-effect relationship is arranged, Ischemic Heart heart rate and blood pressure are not seen that significance influence (P>0.05) is arranged, show and can prevent and treat the myocardial ischemia that coronary ligation causes by significance, its effect significantly is better than Radix Ginseng total saponins (P<0.01).Under equal experiment condition, diltiazem 50mg/kg also can prevent and treat the myocardial ischemia effect that coronary ligation causes by significance, and selected Radix Ginseng total saponins 100mg/kg dosage, DIAOXINXUE KANG 100mg/kg dosage act on very not remarkable on this model.
2, the total secondary ginseng glucoside is to the influence of animal hemodynamics and myocardial oxygen consumption
The variation of every index of hemodynamics and myocardial oxygen consumption after the employing anesthetized open-chest dog observation administration.The result shows that after ligation anesthetized dog coronary artery formed myocardial ischemia, coronary flow had the short time compensatory to increase increasing degree about 10%.The visible coronary flow that obviously increases behind total secondary ginseng glucoside's medicine, the coronary flow in the time of can obviously increasing myocardial ischemia, promotion side Zhi Xunhuan opens and sets up, and increases the oxygen supply of cardiac muscle.15 ~ 180min coronary flow all has obvious rising behind three dosage group medicines, and the effect of 60min ~ 120min coronary blood flow increasing is the most remarkable, with before the medicine and the normal saline group relatively, notable difference (P<0.01 and P<0.0.001) are all arranged.The effect of remarkable increase Ischemic Heart coronary flow is arranged behind the positive control drug diltiazem medicine; DIAOXINXUE KANG also has the increase effect to the Ischemic Heart coronary flow, and increasing degree is about 10%; Radix Ginseng saponin and stem and leaf of Radix Ginseng saponin also increase coronary flow simultaneously.Blood plasma 6-ketone-prostaglandin F when the total secondary ginseng glucoside can obviously raise myocardial ischemia 1a(6-Keto-PGF 1a) level and 6-Keto-PGF 1a/ TXB 2Ratio.
3, Ginseng secondary glycoside is to the influence of dog cardiogenic shock
Adopt anesthetized dog hemorrhagic shock model, each time point after administration is observed systolic arterial pressure (SBP) diastolic pressure (DBP), left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), maximum the rate of change (± dP/dt of left ventricular pressure Max), physical signs such as heart rate.Select for use SHENMAI ZHUSHEYE to compare medicine, and compare with Radix Ginseng total saponins.The result shows, total secondary ginseng glucoside 100-200mg/kg systolic arterial pressure that hemorrhagic shock causes and diastolic pressure are descended significantly raise (P<0.05), left ventricular systolic pressure and diastolic pressure remarkable rising (P<0.05, P<0.01), ± dP/dt MaxAll significance raises (P<0.05, P<0.01), and comparatively obvious for the effect of left ventricle, low dosage 50mg/kg also shows remarkable effect, and obviously is better than Radix Ginseng total saponins 200mg/kg.Show that the total secondary ginseng glucoside has the anti-cardiogenic shock effect of highly significant.To anesthetized dog shock model due to the ischemia, under the identical situation of dosage, total secondary ginseng glucoside about 20min after administration begins to play a role, and Radix Ginseng total saponins about 40min after administration begins to play a role, action effect a little less than; Generally speaking, the total secondary ginseng glucoside 20,30, the 40min time point, compare with Radix Ginseng total saponins, action effect has significant difference (P<0.05 or P<0.01), thereafter time point, the action effect there was no significant difference, this illustrates that also the total secondary ginseng glucoside is better than Radix Ginseng total saponins at speed of action and action effect.
4, the total secondary ginseng glucoside is to BaCl 2Cause the influence of rat ventricular
Adopt rat sublingual vein injection BaCl 2Cause arrhythmia.Successive administration 7d in advance, implement modeling, putting physical signs such as record electrocardio ECG II, heart rate in each observing time, quivers (VF) incidence rate, arrhythmia persistent period in time and chamber that the time that observation and counting chamber premature beat (VP) occur, ventricular tachycardia (VT) occur.The result shows, total secondary ginseng glucoside 200mg/kg can significantly delay the time (P<0.05, P<0.05) that VP, VT occur, significantly shorten the arrhythmia persistent period (P<0.05), 100,50mg/kg can significantly shorten the rule not normal persistent period (P<0.05, P<0.05); The positive control drug diltiazem not only significantly delays VP, VT time of occurrence (P<0.01, P<0.01), shortens the arrhythmia persistent period (P<0.01), has also effectively suppressed VF incidence rate (P<0.05); Selected Radix Ginseng total saponins 100mg/kg dosage, DIAOXINXUE KANG 100mg/kg dosage act on not remarkable on this model.
5, the total secondary ginseng glucoside is to the influence of thrombus in vivo formation
Total secondary ginseng glucoside 200mg/kg in advance administration 7d to the inhibitory action that is formed with of test rat neck arteriovenous shut thrombosis, as seen positive drug and tried thing and respectively organize thrombus weight and all be lower than matched group, relatively there were significant differences (P<0.05) for positive drug diltiazem and matched group, relatively there were significant differences (P<0.05) according to group to be tried object height dosage, along with the increase of drug dose, its thrombosis suppression ratio also increases.
6, the total secondary ginseng glucoside is to the influence of platelet aggregation
Total secondary ginseng is given birth to saponin has inhibitory action to the platelet aggregation that ADP brings out, and especially total secondary ginseng saponin high dose group has significant inhibitory effect to external platelet aggregation, suppression ratio even be higher than the aspirin positive controls.Adenyl cyclase on the excited platelet membrane of total secondary ginseng saponin energy is described, and suppresses the activity of phosphodiesterase, the cAMP level in the platelet is significantly improved, thereby can be good at suppressing hematoblastic gathering.
Compare comparison with Radix Ginseng total saponins, at the dosage of total secondary ginseng glucoside's dosage and Radix Ginseng total saponins identical or be lower than it in, the total secondary ginseng glucoside will obviously be better than the action effect of Radix Ginseng total saponins to the inhibitory action of platelet aggregation, even illustrate that the total secondary ginseng glucoside under the situation of smaller dose, also has inhibitory action to hematoblastic gathering.
7, the total secondary ginseng glucoside is to the influence of isolated heart ischemia-reperfusion
With total secondary ginseng glucoside 500mg/kg; Radix Ginseng total saponins 1000mg/kg; diltiazem 100mg/kg and DIAOXINXUE KANG 500mg/k dosage are given rat continuous oral administration 7d; the blood sampling separation of serum; the dilution of total secondary ginseng glucoside's serum is a series of concentration groups; isolated rat heart is carried out perfusion; the result shows: total secondary ginseng glucoside's high concentration group increases multiple filling 20min heart skip frame degree; irritate coronary flow increase in the 20-30min again; myocardium MDA content is significantly reduced; show that the active component of total secondary ginseng glucoside in serum can improve coronary flow; improve heart beating strength within a certain period of time, and ischemic myocardium is had the certain protection ability.Same effect is all arranged when Radix Ginseng total saponins, diltiazem, DIAOXINXUE KANG high concentration.There is not significant difference between the effect of total secondary ginseng glucoside 500mg/kg serum and Radix Ginseng total saponins 1000mg/kg serum.
General pharmacology research
For investigating the total secondary ginseng glucoside, carried out following research work to animal spirit nervous system, organism balance motion, with the synergism of spiritual nervous system medicine and to the influence of cardiovascular system, respiratory system etc.:
1, the total secondary ginseng glucoside is to the neural effect of spirit: to the active influence of mice general behavior; Influence to the mice autonomic activities; Influence to the motion of mice organism balance.
2, the synergism of total secondary ginseng glucoside and spiritual nervous system medicine: observe with the synergism of sleep threshold dose pentobarbital sodium; Observe with the synergism of pentobarbital sodium under the sleep threshold.
3, the total secondary ginseng glucoside is to the influence of cardiovascular system: to the influence of the blood pressure of Beagle dog, the rhythm of the heart, each ripple of electrocardio (ECGII).
4, the total secondary ginseng glucoside is to the influence of respiratory system: to the influence of the respiratory frequency of Beagle dog, degree of depth etc.
Experimental result shows: mice is oral 70,140, during the 280mg/kg total secondary ginseng glucoside, mice general behavior, autonomic activities, balance exercise are not seen that the significance influence is arranged, oral 70,140,280mg/kg total secondary ginseng glucoside, do not see with sleep threshold dose (40mg/kg) and threshold under pentobarbital sodium (30mg/kg) generation synergism.Give the Beagle dog respectively oral total secondary ginseng glucoside 50,100,200mg/kg to respiratory frequency and the degree of depth, to systolic arterial pressure and diastolic pressure, to there are no significant the influence of electrocardio and heart rate.
Therefore can judge that the total secondary ginseng glucoside of oral pharmacodynamics dosage does not have obvious influence to respiratory system, the cardiovascular system of the animal spiritual nervous system of unifying, and does not have synergism with pentobarbital sodium class medicine.
Safety (toxicity) evaluation study
Carry out the chmice acute toxicity research, recovered 4 all toxicity tests in 13 weeks of SD rat repeat administration, 13 weeks of Beagle dog repeat administration recovered 4 all toxicity tests.
1, The acute toxicity tests
Total secondary ginseng glucoside's mouse stomach administration maximum dosage-feeding is 8g/kg.
The total secondary ginseng glucoside injects to mouse peritoneal, calculates LD through the Bliss method 50And 95% average fiducial limit scope is 0.246 ± 0.023mg/kg.
2,13 weeks of SD rat repeat administration are recovered 4 all toxicity test results
With the total secondary ginseng glucoside respectively with 1500,750,250mg/kg gavages 13w for the SD rat continuously, detect behind the administration 13w and the generally variation of indexs such as situation, blood biochemical, hemogram, electrocardio, routine urinalysis, each organs and tissues pathology such as the weight of animals, appetite behind the drug withdrawal 4w, the result is as follows:
The total secondary ginseng glucoside is to the long-term continuous several times administration of Rodents rat, when being equivalent to 300 times of clinical plan consumptions, certain inhibitory action may be arranged the body weight gain of buck, may certain stimulation be arranged to immune system, male sexual organ and blood RBC, and make that blood BUN significantly raises, the GLU significance descends, the kidney metabolic function is produced certain toxic reaction, but do not see that obvious damage sexually transmitted disease (STD) reason changes, do not produce the organic lesion of internal organs, can recover no cumulative action after the drug withdrawal.Therefore can think, being equivalent to the administration below 150 times of clinical plan consumption, be safe dose to the Rodents rat.
3,13 weeks of Beagle dog repeat administration are recovered 4 all toxicity test results
With the total secondary ginseng glucoside respectively in 900,450,210mg/kg is (with 60kg people 300mg every day, be equivalent to the clinical plan of people 180,90,42 times respectively) with dosage, gavage 13w continuously for the Beagle dog, detect behind the administration 13w and the generally variation of indexs such as situation, blood biochemical, hemogram, electrocardio, routine urinalysis, each organs and tissues pathology such as the weight of animals, appetite behind the drug withdrawal 4w, the result is as follows:
The total secondary ginseng glucoside is to the long-term continuous several times administration of non-Rodents Beagle dog, when being equivalent to 180 times of clinical plan consumptions, certain facilitation may be arranged the body weight gain of animal, make blood WBC that certain rising be arranged, since 6w, BUN in the serum, the rising of significance appears in ALP, to 13w, and Crea in the serum, BUN, ALT, ALP, T-P significance all occurs and raises, and liver, kidney device coefficient has significance to raise, spleen heavily has trend of rising, and thymus heavily has a declining tendency, but there is no the difference of significance between group, pathological examination, two routine liver Mild edema are arranged, the visible atrophy of thymus gland of an example wherein, a routine kidney renal tubules kitchen range shape calcification.Result of the test shows, during 180 times of clinical plan consumptions, to liver, kidney, may produce certain toxicity damage.Can recover no cumulative toxicity behind the drug withdrawal 4w.
According to evaluation of test result, the total secondary ginseng glucoside is safe dose being equivalent to the administration below 90 times of clinical plan consumption to non-Rodents Beagle dog.
Oral cavity disintegration tablet of the present invention is a kind ofly not need water or only need the low amounts of water can disintegrate or dissolved tablet in the oral cavity.Compare with conventional tablet, oral cavity disintegration tablet provides a kind of new drug administration mode for the patient of indication of the present invention, thus make things convenient for special population such as old man, infant, dysphagia person or in particular cases the patient take.Simultaneously, this new dosage form also provides brand-new selection mode for common medication person.Do not go out, just before going to bed, can not influence normally taking of medicine under anhydrous, the case of emergency, even also light receiving port cavity disintegrating tablet of the people who does not want to take the trouble.Therefore, it can greatly improve patient's compliance, helps effective treatment.
Total secondary ginseng glucoside oral disintegration tablets of the present invention is owing to having the above-mentioned convenience of taking medicine, absorbing characteristics rapid, drug effect generation piece, particularly be used for the treatment of indication of the present invention, as treating flaccidity of the heart-yang, a little less than the insufficiency of heart-QI, in the application of the obstruction of qi in the chest and cardialgia that qi depression to blood stasis causes, at the treatment myocardial ischemia, in the application of preparation treatment hemorrhagic shock and in the clinical practice at treatment heart failure etc., its irreplaceable effect is arranged more.
The preparation stabilization Journal of Sex Research
Total secondary ginseng glucoside oral disintegration tablets simulation commercially available back of the present invention was placed 6 months in the constant temperature and humidity accelerated test, placed 9 months naturally under the room temperature condition, observed to detect to have or not qualitative variation.Result of the test:
1, room temperature is deposited: three batch samples of aluminium foil blister airtight package are investigated 9 months at the room temperature storage condition, and test result shows, this product is surveyed every index all in the scope of quality standard defined, so its stability is qualified.
2, constant temperature and humidity accelerated test: three batch samples of aluminium foil blister airtight package, at temperature 37-40 ℃, the condition of relative humidity 80% is investigated 6 months, and measurement result shows, and this product is surveyed every index all in the scope that quality standard is measured, and is stable.Its storage life is equivalent to room temperature and deposited 2 years.
The instructions of taking of total secondary ginseng glucoside oral disintegration tablets of the present invention:
The oral cavity buccal, one time 1~2,3 times on the one.
Points for attention:
1. under physician guidance, take by usage and dosage.
2. should not obey together with Rhizoma et radix veratri (Radix Rhizoma Veratri).
3. should not take during cat fever.
The specific embodiment
Introduce specific embodiments more of the present invention below, but protection scope of the present invention is as the criterion with claims, is not subjected to the restriction of following specific embodiment.
Embodiment 1:
Total secondary ginseng glucoside's pharmaceutical composition 50g gets microcrystalline Cellulose, mannitol pulverize separately, sieves, and is standby; Get methacrylate polymer Eudragit E100 type 15g, be dissolved in an amount of alcoholic solution, under stirring condition, slowly add the total secondary ginseng glucoside, continue to be stirred to the total secondary ginseng glucoside and be uniformly dispersed, drying under reduced pressure is pulverized, sieve, add crospolyvinylpyrrolidone 10g, microcrystalline Cellulose 70g, mannitol 190g, aspartame 2g, micropowder silica gel 17.5g, magnesium stearate 1.5g, mixing is measured content, the calculating sheet is heavy, tabletting, promptly.
Embodiment 2:
Total secondary ginseng glucoside's pharmaceutical composition 100g gets methacrylate polymer Eudragit E type 0.6g, is dissolved in an amount of alcoholic solution, slowly adds the total secondary ginseng glucoside under stirring condition, continues to be stirred to the total secondary ginseng glucoside and is uniformly dispersed, and drying under reduced pressure is pulverized, and sieves; Add microcrystalline Cellulose 12g, crosslinked carboxymethyl fecula sodium 7g mix homogeneously, water system soft material is granulated, drying, granulate is measured content, and it is heavy to calculate sheet, tabletting, promptly.
Embodiment 3:
Take by weighing total secondary ginseng glucoside's pharmaceutical composition 50g, starch 30g, citric acid 55g, tartaric acid 55g, sodium bicarbonate 40g, Herba Menthae essence 5g, cyclamate 15g, micropowder silica gel 45g, Pulvis Talci 5g, mixing is measured content, and it is heavy to calculate sheet, tabletting, promptly.
Embodiment 4:
Total secondary ginseng glucoside's pharmaceutical composition 10g gets polyvinylpyrrolidone 10g, is dissolved in an amount of alcoholic solution, slowly adds the total secondary ginseng glucoside under stirring condition, continue to be stirred to the total secondary ginseng glucoside and be uniformly dispersed, drying under reduced pressure is pulverized, and sieves, with mannitol 80g, maltose 70g, erithritol 57g, sucrose 70g, cross-linking sodium carboxymethyl cellulose 8g, magnesium stearate 2g, micropowder silica gel 3g, mixing is measured content, the calculating sheet is heavy, tabletting, promptly.
Embodiment 5:
Get cyclodextrin 130g, add suitable quantity of water, grind well, add total secondary ginseng glucoside's pharmaceutical composition 10g, fully be ground to into pasty state, drying is pulverized, and adds carboxymethyl starch sodium 80g, crospolyvinylpyrrolidone 50g, mannitol 30g, mixing is measured content, and it is heavy to calculate sheet, tabletting, promptly.
Embodiment 6:
Take by weighing lactose 100g, fructose 57g, sorbitol 40g mix homogeneously, granulate drying, granulate with 40% starch slurry 75g, add total secondary ginseng glucoside's pharmaceutical composition 20g, low-substituted hydroxypropyl cellulose 20g, crospolyvinylpyrrolidone 10g, micropowder silica gel 10g, Polyethylene Glycol 10g, stevioside 3g, mixing is measured content, and it is heavy to calculate sheet, tabletting, promptly.
Embodiment 7:
Take by weighing total secondary ginseng glucoside's pharmaceutical composition 50g, microcrystalline Cellulose 70g, mannitol 132g, crospolyvinylpyrrolidone 8g, cross-linking sodium carboxymethyl cellulose 15g, aspartame 5g, micropowder silica gel 15g, magnesium stearate 5g, mixing, measure content, it is heavy to calculate sheet, tabletting, promptly.

Claims (10)

1. a total secondary ginseng glucoside oral disintegration tablets is characterized in that, described oral cavity disintegration tablet comprises following component:
The A active component is total secondary ginseng glucoside's pharmaceutical composition, wherein
1. be the ginsenoside of aglycon with the former glycol of Radix Ginseng, comprise the ginsenoside Rg3;
2. be the ginsenoside of aglycon with the former triol of Radix Ginseng, comprise ginsenoside Rg2 and ginsenoside Rh1;
By weight percentage, with the former glycol of Radix Ginseng, the former triol of Radix Ginseng be aglycon the ginsenoside's and account for more than 20% of A component;
The B helper component is comprising filler;
The ratio of weight and number of the whole oral cavity disintegration tablet of A ingredients constitute is (3~85): 100.
2. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 1 is characterized in that:
In the A component, the ginsenoside Rg3 is ginsenoside 20-(S)-Rg3 and/or ginsenoside 20-(R)-Rg3; Ginsenoside Rg2 is ginsenoside 20-(S)-Rg2 and/or ginsenoside 20-(R)-Rg2; Ginsenoside Rh1 is ginsenoside Rh1 20-(S)-Rh1 and/or ginsenoside 20-(R)-Rh1;
To account for the weight percent meter of A component, Rg3 is 10-30%, and Rg2 is 1-20%, and Rh1 is 1-10%.
3. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 2 is characterized in that:
To account for the weight percent meter of A component, Rg3 is 12-20%, and Rg2 is 4-16%, and Rh1 is 3-5%; With the former glycol of Radix Ginseng, the former triol of Radix Ginseng be aglycon the ginsenoside's and more than 50%.
4. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 1 is characterized in that:
The extraction preparation method of described total secondary ginseng glucoside's pharmaceutical composition comprises hydrolysing step; Described hydrolysing step uses acetic acid as hydrolyst.
5. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 1 is characterized in that:
Comprise clathrate or solid dispersion in the B component of described total secondary ginseng glucoside oral disintegration tablets with the screening agent preparation.
6. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 1 is characterized in that,
Among the described oral cavity disintegration tablet helper component B: described filler is selected from one or more in starch, dextrin, lactose, microcrystalline Cellulose, pregelatinized Starch, xylitol, mannitol, sorbitol, erithritol, sucrose, glucose, fructose, trehalose, the maltose.
7. total secondary ginseng glucoside oral disintegration tablets as claimed in claim 6 is characterized in that:
Described helper component B also comprises following component:
Disintegrating agent is selected from low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, the crosslinked carboxymethyl fecula sodium one or more;
Screening agent is selected from cyclodextrin and derivant thereof, Polyethylene Glycol, polyvinylpyrrolidone, methacrylate polymer;
Binding agent is selected from alcoholic solution, water, polyvinylpyrrolidonesolution solution, starch slurry;
Effervescent is selected from citric acid, tartaric acid, boric acid, fumaric acid, sodium bicarbonate, sodium carbonate;
Correctives is selected from Herba Menthae essence, Fructus Citri Limoniae essence, cyclamate, aspartame, stevioside;
Fluidizer is selected from micropowder silica gel;
Lubricant is selected from Pulvis Talci, magnesium stearate, Polyethylene Glycol;
Various helper components account for whole oral cavity disintegration tablet weight ratio: filler 10-95, disintegrating agent 0-50, screening agent 0-50, bonding agent 0-10, effervescent 0-60, correctives 0-20, fluidizer 0-15, lubricant 0-30.
8. as the described total secondary ginseng glucoside oral disintegration tablets of one of claim 1~7, described screening agent is a methacrylate polymer.
9. as the preparation method of the described total secondary ginseng glucoside oral disintegration tablets of one of claim 1~8, it is characterized in that:
(1) Radix Ginseng total saponins extracting solution preparation: with panax species, water or organic solvent extraction concentrate extracting solution again;
(2) hydrolyzed solution preparation: with mineral acid or organic acid is the above-mentioned concentrated extracting solution of catalyst hydrolysis;
(3) resin absorption: hydrolyzed solution adsorbs by the macroporous resin adsorption post;
(4) remove impurity: the adsorption column that has absorbed hydrolyzed solution is removed impurity through water elution, aqueous alkali eluting, concentration at the ethanol elution below 35% again;
(5) eluting, concentrated, dry: use concentration at the ethanol elution adsorption column more than 35% after removing impurity, collect this ethanol elution, be condensed into fluid extract, vacuum drying gets A component total secondary ginseng glucoside pharmaceutical composition;
(6) with other component mix homogeneously among total secondary ginseng glucoside A and the helper component B, dry, pulverize, tabletting according to a conventional method, promptly.
10. the application of total secondary ginseng glucoside's pharmaceutical composition in the following medicine of preparation as one of claim 1~7:
At preparation treatment flaccidity of the heart-yang, a little less than the insufficiency of heart-QI, the application in the medicine of the obstruction of qi in the chest and cardialgia that qi depression to blood stasis causes;
Application in the medicine of preparation treatment myocardial ischemia;
Application in the medicine of preparation treatment hemorrhagic shock;
Application in the medicine of preparation treatment heart failure.
CN 200510083852 2005-07-14 2005-07-14 Total secondary ginseng glucoside oral disintegration tablets prepn. method and application thereof Pending CN1718191A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CN 200510083852 CN1718191A (en) 2005-07-14 2005-07-14 Total secondary ginseng glucoside oral disintegration tablets prepn. method and application thereof
EP06761360.4A EP1905444B1 (en) 2005-07-14 2006-07-05 Preparation method of a medicinal composition containing ginseng secondary glycosides
CA2614700A CA2614700C (en) 2005-07-14 2006-07-05 Medicinal composition containing ginseng secondary glycosides, its preparation method and application
KR1020087003434A KR101182917B1 (en) 2005-07-14 2006-07-05 Medicinal composition containing ginseng secondary glycosides, its preparation method and application
PCT/CN2006/001574 WO2007006208A1 (en) 2005-07-14 2006-07-05 Medicinal composition containing ginseng secondary glycosides, its preparation method and application
JP2008520691A JP2009500432A (en) 2005-07-14 2006-07-05 Ginseng secondary glycoside pharmaceutical composition and its production method and application
ES06761360.4T ES2515891T3 (en) 2005-07-14 2006-07-05 Method of Preparation of a Pharmaceutical Composition Containing Ginseng Secondary Glycosides
US11/995,320 US7973014B2 (en) 2005-07-14 2006-07-05 Medicinal composition containing ginseng secondary glycosides, its preparation method and application
PL06761360T PL1905444T3 (en) 2005-07-14 2006-07-05 Preparation method of a medicinal composition containing ginseng secondary glycosides
HK08104922.7A HK1110520A1 (en) 2005-07-14 2008-05-02 Preparation method of a medicinal composition containing ginseng secondary glycosides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200510083852 CN1718191A (en) 2005-07-14 2005-07-14 Total secondary ginseng glucoside oral disintegration tablets prepn. method and application thereof

Publications (1)

Publication Number Publication Date
CN1718191A true CN1718191A (en) 2006-01-11

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Country Link
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102058645A (en) * 2009-11-17 2011-05-18 天津天士力制药股份有限公司 Ginseng glycoside H extractive and preparation method thereof
CN102641315A (en) * 2012-04-20 2012-08-22 吉林敖东延边药业股份有限公司 Ginseng effervescent granule and preparation method thereof
TWI627972B (en) * 2013-05-10 2018-07-01 花王股份有限公司 Bath preparation composition

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102058645A (en) * 2009-11-17 2011-05-18 天津天士力制药股份有限公司 Ginseng glycoside H extractive and preparation method thereof
CN102058645B (en) * 2009-11-17 2013-09-11 天士力制药集团股份有限公司 Ginseng glycoside H extractive and preparation method thereof
CN102641315A (en) * 2012-04-20 2012-08-22 吉林敖东延边药业股份有限公司 Ginseng effervescent granule and preparation method thereof
CN102641315B (en) * 2012-04-20 2014-03-19 吉林敖东延边药业股份有限公司 Ginseng effervescent granule and preparation method thereof
TWI627972B (en) * 2013-05-10 2018-07-01 花王股份有限公司 Bath preparation composition

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