CN105193869A - Applications of drynaria fortune and drynaria fortune extract in prevention or treatment of heart failure - Google Patents
Applications of drynaria fortune and drynaria fortune extract in prevention or treatment of heart failure Download PDFInfo
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- CN105193869A CN105193869A CN201510724464.1A CN201510724464A CN105193869A CN 105193869 A CN105193869 A CN 105193869A CN 201510724464 A CN201510724464 A CN 201510724464A CN 105193869 A CN105193869 A CN 105193869A
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Abstract
The invention provides applications of drynaria fortune and drynaria fortune extract in prevention or treatment of heart failure. The drynaria fortune and the drynaria fortune extract can effectively reduce the heart weight index of a rat with heart failure, reduce levels of BNP (B-type natriuretic peptide), Ang II (Angiotensin II) and ALD (aldosterone) and remarkably improve the left ventricular systolic function of the rat with heart failure, thereby having the function of preventing or treating heart failure and having positive significance for development and utilization of Chinese herbal medicines, and a new scheme is provided for the treatment of the disease.
Description
Technical field
The present invention relates to the field of Chinese medicines, be specifically related to Rhizoma Drynariae and extract thereof for preventing or treat the purposes of heart failure.
Background technology
Rhizoma Drynariae, another name precipice Rhizoma Zingiberis Recens, rock connect Rhizoma Zingiberis Recens, delevay drynaria, the broken benefit of meat, the broken benefit of stone, flying apsaras Mus, Niu Feilong, sudden wind, moth grass, English name Drynariafortunei, belonging to Polypodiales, Davalliaceae pteridophyta, is the rhizome of Plants of Polypodiaceae Mongolian oak Herba pteridii latiusculi or drynaria baronii Diels (Qinling Mountains Mongolian oak Herba pteridii latiusculi).
Rhizoma Drynariae extract has the kidney invigorating bone strengthening, continuous hinders pain relieving, the effect such as to invigorate blood circulation, and be used for the treatment of lumbago due to renal deficiency, Hiccough and deaf, odontoseisis, falling winks frustrates, injured bone; External treatment alopecia areata, vitiligo etc.
And the application of Rhizoma Drynariae other side rarely has report.
Summary of the invention
One object of the present invention is that the compositions providing Rhizoma Drynariae, Rhizoma Drynariae extract or comprise Rhizoma Drynariae extract is preparing the purposes prevented and/or treated in the medicine of heart failure.
Another object of the present invention is the compositions providing Rhizoma Drynariae, Rhizoma Drynariae extract or comprise Rhizoma Drynariae extract, and it is used for the treatment of heart failure.
Another object of the present invention is to provide a kind of method for the treatment of heart failure, and described method comprises to be used prevention or the treatment Rhizoma Drynariae of effective dose, Rhizoma Drynariae extract to experimenter in need or comprise the compositions of Rhizoma Drynariae extract.
Detailed Description Of The Invention
The compositions that a first aspect of the present invention relates to Rhizoma Drynariae, Rhizoma Drynariae extract or comprises Rhizoma Drynariae extract is preparing the purposes prevented and/or treated in the medicine of heart failure.
In one embodiment of the invention, described heart failure comprises acute heart failure and chronic heart failure.
In a specific embodiments of the present invention, described heart failure is caused by following reason: coronary heart disease, senile degenerative heart valve disease, rheumatic valvular heart disease, dilated cardiomyopathy, acute severe myocarditis, myocardial infarction, hypertension, ischemic heart desease, be exposed to cardiac toxic, myocarditis, thyroid disease, viral infection, gingivitis, drug dependence, alcohol abuse, pericarditis, atherosclerosis, angiopathy, hypertrophic cardiomyopathy, acute myocardial infarction, left ventricular systolic dysfunction, coronary artery bypass surgery, hungry, drinking and eating irregularly, or genetic defect.
In one embodiment of the invention, in described Rhizoma Drynariae extract, general flavone content is 30-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-65%.
In a specific embodiments of the present invention, the content of described total flavones is 50-65%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-100%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 40-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 50-80%.
In a preferred embodiment of the invention, in described total flavones, the content of naringin is 60-70%.
In one embodiment of the invention, in described Rhizoma Drynariae extract, the content of naringin is 20-100%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-45%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-40%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-38%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 30-40%.
In one embodiment of the invention, wherein said Rhizoma Drynariae extract prepares by the following method:
1) by Rhizoma Drynariae pulverizing medicinal materials, with water or alcohol or its mixture extracting;
2) extracting solution resin absorption;
3) having adsorbed the resin water of extract or alcohol or its mixture eluting.
In a specific embodiments of the present invention, wherein step 1) in carry out extracting with water.
In a specific embodiments of the present invention, wherein step 1) middle alcohol/aqueous mixtures carries out extracting.
In a specific embodiments of the present invention, in described alcohol/aqueous mixtures, alcohol content is 40-90% weight.
In a specific embodiments of the present invention, described alcohol is selected from methanol and ethanol.
In a specific embodiments of the present invention, wherein step 2) in resin be macroporous adsorbent resin.
In a specific embodiments of the present invention, wherein step 3) in first wash with water, then use alcohol/aqueous mixtures eluting.
In a preferred embodiment of the invention, described Rhizoma Drynariae extract prepares through following method: take Rhizoma Drynariae, is ground into coarse powder, with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug adds 1.5 ~ 2L water) boil (such as, 0.5 ~ 3 hour, preferably 1 hour), release medicinal liquid, residue adds water boil (such as again, first time and second time add water ratio for (1 ~ 3): 1, such as 1.5:1), release medicinal liquid.Twice medicinal liquid merges, filter, medicinal liquid flows through and treated WLD adsorbent resin is housed (such as, the addition of resin is 1.2 ~ 1.5 times of Rhizoma Drynariae crude drug) adsorption column, effluent tetrahydro boron potassium reaction and judgement collects terminal, till namely occurring that suddenly flavanone compounds reaction-resin reaches saturated adsorption with effluent.Adsorb complete, wash resin column with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L washes), washing liquid discards, use ethanol again (such as, 70% ethanol) eluting (such as, the consumption of ethanol is every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L ethanol elution), judge with tetrahydro boron potassium chromogenic reaction to receive the starting point and the terminal that connect eluent.Reclaim eluent, eluent reclaims ethanol, and debris is steamed to thick paste in water-bath, vacuum drying, obtains described Rhizoma Drynariae extract.
In a preferred embodiment of the invention, the described compositions comprising Rhizoma Drynariae extract is through that following method prepares: get the Rhizoma Drynariae extract that any one of first aspect present invention is obtained, add starch, mixing, be filled with capsule, described in obtaining, comprise the compositions (every containing effective ingredient 180mg) of Rhizoma Drynariae extract.
A second aspect of the present invention relates to Rhizoma Drynariae, Rhizoma Drynariae extract or comprises the compositions of Rhizoma Drynariae extract, and it is used for the treatment of heart failure.
In one embodiment of the invention, described heart failure comprises acute heart failure and chronic heart failure.
In a specific embodiments of the present invention, described heart failure is caused by following reason: coronary heart disease, senile degenerative heart valve disease, rheumatic valvular heart disease, dilated cardiomyopathy, acute severe myocarditis, myocardial infarction, hypertension, ischemic heart desease, be exposed to cardiac toxic, myocarditis, thyroid disease, viral infection, gingivitis, drug dependence, alcohol abuse, pericarditis, atherosclerosis, angiopathy, hypertrophic cardiomyopathy, acute myocardial infarction, left ventricular systolic dysfunction, coronary artery bypass surgery, hungry, drinking and eating irregularly, or genetic defect.
In one embodiment of the invention, in described Rhizoma Drynariae extract, general flavone content is 30-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-65%.
In a specific embodiments of the present invention, the content of described total flavones is 50-65%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-100%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 40-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 50-80%.
In a preferred embodiment of the invention, in described total flavones, the content of naringin is 60-70%.
In one embodiment of the invention, in described Rhizoma Drynariae extract, the content of naringin is 20-100%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-45%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-40%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-38%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 30-40%.
In one embodiment of the invention, wherein said Rhizoma Drynariae extract prepares by the following method:
1) by Rhizoma Drynariae pulverizing medicinal materials, with water or alcohol or its mixture extracting;
2) extracting solution resin absorption;
3) having adsorbed the resin water of extract or alcohol or its mixture eluting.
In a specific embodiments of the present invention, wherein step 1) in carry out extracting with water.
In a specific embodiments of the present invention, wherein step 1) middle alcohol/aqueous mixtures carries out extracting.
In a specific embodiments of the present invention, in described alcohol/aqueous mixtures, alcohol content is 40-90% weight.
In a specific embodiments of the present invention, described alcohol is selected from methanol and ethanol.
In a specific embodiments of the present invention, wherein step 2) in resin be macroporous adsorbent resin.
In a specific embodiments of the present invention, wherein step 3) in first wash with water, then use alcohol/aqueous mixtures eluting.
In a preferred embodiment of the invention, described Rhizoma Drynariae extract prepares through following method: take Rhizoma Drynariae, is ground into coarse powder, with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug adds 1.5 ~ 2L water) boil (such as, 0.5 ~ 3 hour, preferably 1 hour), release medicinal liquid, residue adds water boil (such as again, first time and second time add water ratio for (1 ~ 3): 1, such as 1.5:1), release medicinal liquid.Twice medicinal liquid merges, filter, medicinal liquid flows through and treated WLD adsorbent resin is housed (such as, the addition of resin is 1.2 ~ 1.5 times of Rhizoma Drynariae crude drug) adsorption column, effluent tetrahydro boron potassium reaction and judgement collects terminal, till namely occurring that suddenly flavanone compounds reaction-resin reaches saturated adsorption with effluent.Adsorb complete, wash resin column with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L washes), washing liquid discards, use ethanol again (such as, 70% ethanol) eluting (such as, the consumption of ethanol is every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L ethanol elution), judge with tetrahydro boron potassium chromogenic reaction to receive the starting point and the terminal that connect eluent.Reclaim eluent, eluent reclaims ethanol, and debris is steamed to thick paste in water-bath, vacuum drying, obtains described Rhizoma Drynariae extract.
In a preferred embodiment of the invention, the described compositions comprising Rhizoma Drynariae extract is through that following method prepares: get the Rhizoma Drynariae extract that any one of first aspect present invention is obtained, add starch, mixing, be filled with capsule, described in obtaining, comprise the compositions (every containing effective ingredient 180mg) of Rhizoma Drynariae extract.
A third aspect of the present invention relates to a kind of method for the treatment of heart failure, and it comprises the compositions used prevention or the treatment Rhizoma Drynariae of effective dose, Rhizoma Drynariae extract to experimenter in need or comprise Rhizoma Drynariae extract.
In one embodiment of the invention, described heart failure comprises acute heart failure and chronic heart failure.
In a specific embodiments of the present invention, described heart failure is caused by following reason: coronary heart disease, senile degenerative heart valve disease, rheumatic valvular heart disease, dilated cardiomyopathy, acute severe myocarditis, myocardial infarction, hypertension, ischemic heart desease, be exposed to cardiac toxic, myocarditis, thyroid disease, viral infection, gingivitis, drug dependence, alcohol abuse, pericarditis, atherosclerosis, angiopathy, hypertrophic cardiomyopathy, acute myocardial infarction, left ventricular systolic dysfunction, coronary artery bypass surgery, hungry, drinking and eating irregularly, or genetic defect.
In one embodiment of the invention, described method is carried out in vitro.
In one embodiment of the invention, described method is carried out in vivo.
In one embodiment of the invention, described experimenter is mammal, such as bovid, equine species, caprid, porcine animals, Canis animals, felid, rodent, primate; Wherein, particularly preferably experimenter behaves.
In one embodiment of the invention, in described Rhizoma Drynariae extract, general flavone content is 30-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-100%.
In a specific embodiments of the present invention, the content of described total flavones is 40-65%.
In a specific embodiments of the present invention, the content of described total flavones is 50-65%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-100%.
In one embodiment of the invention, in described total flavones, the content of naringin is 30-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 40-90%.
In a specific embodiments of the present invention, in described total flavones, the content of naringin is 50-80%.
In a preferred embodiment of the invention, in described total flavones, the content of naringin is 60-70%.
In one embodiment of the invention, in described Rhizoma Drynariae extract, the content of naringin is 20-100%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-45%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-40%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 20-38%.
In a specific embodiments of the present invention, in described Rhizoma Drynariae extract, the content of naringin is 30-40%.
In one embodiment of the invention, wherein said Rhizoma Drynariae extract prepares by the following method:
1) by Rhizoma Drynariae pulverizing medicinal materials, with water or alcohol or its mixture extracting;
2) extracting solution resin absorption;
3) having adsorbed the resin water of extract or alcohol or its mixture eluting.
In a specific embodiments of the present invention, wherein step 1) in carry out extracting with water.
In a specific embodiments of the present invention, wherein step 1) middle alcohol/aqueous mixtures carries out extracting.
In a specific embodiments of the present invention, in described alcohol/aqueous mixtures, alcohol content is 40-90% weight.
In a specific embodiments of the present invention, described alcohol is selected from methanol and ethanol.
In a specific embodiments of the present invention, wherein step 2) in resin be macroporous adsorbent resin.
In a specific embodiments of the present invention, wherein step 3) in first wash with water, then use alcohol/aqueous mixtures eluting.
In a preferred embodiment of the invention, described Rhizoma Drynariae extract prepares through following method: take Rhizoma Drynariae, is ground into coarse powder, with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug adds 1.5 ~ 2L water) boil (such as, 0.5 ~ 3 hour, preferably 1 hour), release medicinal liquid, residue adds water boil (such as again, first time and second time add water ratio for (1 ~ 3): 1, such as 1.5:1), release medicinal liquid.Twice medicinal liquid merges, filter, medicinal liquid flows through and treated WLD adsorbent resin is housed (such as, the addition of resin is 1.2 ~ 1.5 times of Rhizoma Drynariae crude drug) adsorption column, effluent tetrahydro boron potassium reaction and judgement collects terminal, till namely occurring that suddenly flavanone compounds reaction-resin reaches saturated adsorption with effluent.Adsorb complete, wash resin column with water (such as, the consumption of water is that every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L washes), washing liquid discards, use ethanol again (such as, 70% ethanol) eluting (such as, the consumption of ethanol is every hectogram Rhizoma Drynariae crude drug 0.2 ~ 1L ethanol elution), judge with tetrahydro boron potassium chromogenic reaction to receive the starting point and the terminal that connect eluent.Reclaim eluent, eluent reclaims ethanol, and debris is steamed to thick paste in water-bath, vacuum drying, obtains described Rhizoma Drynariae extract.
In a preferred embodiment of the invention, the described compositions comprising Rhizoma Drynariae extract is through that following method prepares: get the Rhizoma Drynariae extract that any one of first aspect present invention is obtained, add starch, mixing, be filled with capsule, described in obtaining, comprise the compositions (every containing effective ingredient 180mg) of Rhizoma Drynariae extract.
The various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes again to these terms and the more detailed description and interpretation of phrase, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Term used herein " heart failure " refers to and is characterized as abnormal low kinemic any morbid state, and its cardiac can not carry out pump blood with enough speed or enough amounts.When heart can not fully pump blood to health other parts or when one or more cardiac valve become narrow or afunction time, blood can be back in lung, causes liquid in lung to fill.If, can heart failure be there is in this backflow long-term existence.The classical symptom of heart failure comprises short of breath (dyspnea), fatigue, weakness, be difficult to breathe and lower limb, ankle or abdominal part swelling (edema) when lying low.The reason of heart failure is relevant with various disease conditions, comprises coronary heart disease, systemic hypertension, cardiomyopathy or myocarditis, congenital heart disease, heart lobe exception or valvular heart disease, severe pulmonary disorder, diabetes, severe anemia, hyperthyroidism, arrhythmia or dysrhythmia and myocardial infarction.The outstanding feature of congestive heart failure is cardiac hypertrophy (heart becomes large), rapid breathing (is breathed fast; Occur when left side exhaustion) and hepatomegaly (liver becomes large; Occur when right side exhaustion).
Term used herein " effective dose " refers to the amount being enough to prevent and/or treat effect needed for realization, such as, realizes prevention or alleviates the amount with the symptom of disease association to be treated.
Term used herein " treatment " refers to therapeutic treatment and preventive measure, its objective is prevention or delay (alleviating) for morbid state or disease.If after experimenter receives the described Rhizoma Drynariae of therapeutic dose, Rhizoma Drynariae extract according to methods described herein or comprises the compositions of Rhizoma Drynariae extract, one or more heart failure indications of this experimenter and Symptoms go out observable and/or detectable reduction or improvement, then the heart failure of experimenter is by successfully " treatment ", and described heart failure indication and symptom such as cardiac hypertrophy, Assessment of Left Ventricular Systolic Function weaken, rapid breathing and hepatomegaly etc.What it is also understood that the prevention of described morbid state or disease or treatment not only comprises fully prevention or treatment, also comprises and does not reach fully prevention or treatment, but achieves some biologys or the relevant result of medical science.Treatment heart failure used herein also refers to treatment any one or the multiple morbid state that may cause heart failure, include but not limited to the cardiac contractility ability reduced, abnormal diastole compliance, reduction stroke volume, pulmonary congestion and reduction cardiac output, reduce serum brain natriuretic peptide in patients (BNP), Angiotensin II (AngII) and aldosterone (ALD) level etc.
Term used herein " prevention " refers in statistics sample, relative to untreated control sample, compositions of the present invention can reduce the generation of disease or morbid state in the sample of process, or delay disease or morbid state one or more symptoms outbreak or reduce its order of severity.Prevention heart failure described herein comprise stop heart failure to start, postpone heart failure start, stop the development of heart failure or progress, the development slowing down heart failure or progress, delay heart failure development or progress and make the progress of heart failure be improved to the more early stage stage from late stage.
Rhizoma Drynariae of the present invention (RhizomaDrynariae) refers to Polypodiaceae (PolypodiaceaeS.F.Gary) Mongolian oak Cyclosorus (Drynaria (Bory) J.Sm.) plant such as Mongolian oak Herba pteridii latiusculi Drynariafortunei (Kunze) J.Sm., Qinling Mountains Mongolian oak Herba pteridii latiusculi D.baronii (Chist) Diels, drynaria baronii Diels D.sinicaDiels, Drynaria delavayi christ D.delavayiChirst, and the rhizome of one or more plants such as Davalliaceae Davallia (DavalliaSm.) plant Rhizoma Drynariae DavalliamariesiiMooreexBak or herb.The above-mentioned plant used as Rhizoma Drynariae can be used alone or as a mixture in the present invention, and the present invention is without restriction to this.
The preparation method of Rhizoma Drynariae extract of the present invention can with reference to CN1484529A embodiment 1 method, and Rhizoma Drynariae extract exemplary manufacturing process comprises following steps:
(pulverizing medicinal materials →) water/alcohol decoction → resin absorption → (washing →) alcohol/water elution → post processing.
In said method, the pulverizing of medical material is conventional steps well-known to those skilled in the art.For the method pulverized, the present invention is without restriction.Powder after pulverizing, if granularity is excessively thick, then effective ingredient is difficult to abundant proposition; If powder is meticulous, then bring to the step of the extraction fluid after decocting unfavorable, to this, those skilled in the art can be selected according to practical experience, also do not limit this.
In order to extract effective ingredient, water and/or alcohol can be adopted to infiltrate the mode extracted, but be not easy completely, so adopt the mode heating extracting due to the leaching of effective ingredient.Heating-up temperature is the boiling point of room temperature-extraction solvent.
During heating extraction, preferably carry out (backflow) at the boiling point of solvent.
During as used merely water, at 100 DEG C, extraction time is 0.5-3 hour, extraction time 2-4 time, extract at every turn the amount of solution added make a living dose 5-20 doubly.If by alcohol or alcohol-water solution reflux, extract, then consumption make a living dose 5-20 doubly, extraction time is 0.5-3 hour, extracts 2-4 time.Alcohol can use methanol and ethanol, from the angle etc. of safety, and preferred alcohol.When adopting ethanol, the preferred 20%-90% of concentration of ethanol.For reference only, in reality as required, those skilled in the art can rule of thumb suitably change above-mentioned quantity, are understood that, this change is no more than scope of the present invention.
After obtaining extracting solution, can be filtered extracting solution as required, then extracting solution resin absorption.The resin that can be used for adsorbing is macroporous adsorbent resin, such as D101 resin (resin processing plant of Tianjin Nankai university product), AB-8 resin (Tianjin osseocolla factory product), WLD resin (Traditional Chinese Medicine Research Institute, Sichuan Province product), CAD-40 (North China Pharmaceutical Factory's product) etc., but the inventive method is not by the restriction of above-mentioned resin column model, as long as macroporous adsorbent resin, namely the inventive method can be completed.For the method for resin absorption see CN1072089A, the document is described in detail resin sorption processes, and the application refer to method disclosed in document, and as the part of the inventive method, is documented in present specification.
According to the result of study of the present inventor, maximum with WLD adsorption capacity in three kinds of tree resins, eluting is also easier.Therefore this extracting method preferred WLD type adsorbent resin is adsorbent.The ratio of adsorbent resin and crude drug, suitably can select between 0.5 ~ 2: 1 (weight), and preferably 0.5 ~ 1.5: 1, most preferably about 1: 1, those skilled in the art can rule of thumb suitably select.If ratio is less than 0.5: 1, then may adsorb not exclusively, if be greater than 1.5: 1, then because the flavone amount of absorption no longer increases, can resin be wasted, be unfavorable for cost.
When use adsorbent resin, according to the general knowledge that those skilled in the art are familiar with, resin should first carry out pretreatment and then could use, and pretreatment can adopt known method to carry out, such as, can operate as follows:
Resin is filled post, ethanol, concentrated hydrochloric acid (1: 1) is first used to rinse, when being washed till the water gaging dilutions such as effluent, after not aobvious muddiness, use 10 times of hot water to resin column volume (80 DEG C) instead to rinse, then rinse with 2% sodium hydroxide solution of same volume, when final rinse water to resin column effluent is neutral, with water recoil, resin is loosened, then by medicinal liquid upper prop again.
Must control the flow velocity of extracting solution during absorption, guarantee absorption completely.In general, during commercial production, use
adsorption column, in-built 100kg resin, adsorbs with 10 ~ 20L/ minute flow velocity, can ensure absorption completely.With this understanding, if higher than 20L/ minute, be then difficult to ensure that absorption completely, may reduce productive rate.If lower than 10L/ minute, then absorption expends time in, and is unfavorable for enhancing productivity.
The alcohol that after upper prop, eluting is used can be ethanol or methanol, preferred alcohol viewed from health perspectives, when adopting ethanol elution, the preferred 50-95% of concentration, from the angle that ethanol can be recycled, best 70% (become because of physical condition, also can ± 5%) left and right.
During eluting, when the consumption of alcohol and the usage ratio of medical material are 2 times amount ~ 10 times amount, when consumption is less than 2 times, eluting is incomplete.Consumption is more than 10 times, and elution amount no longer increases, nonsensical.From production angle, preferably 2 ~ 5 times amount.
After alcohol eluting, collect eluent, reconcentration after ethanol in recovery eluent, finally, pulverize after spray-dried or lyophilization or convection drying, obtain powder that is brown or rufous, gained powder can be refined further, or directly make suitable dosage form, and such as, capsule, pill, tablet, granule, solution or injection etc.
First debris should be concentrated into relative density before spraying dry is 1.10-1.18, then spraying dry.First debris should be concentrated into relative density during vacuum drying is 1.3-1.4, then vacuum drying, for processing conveniently further after dry, can be ground into fine powder.Spraying dry and vacuum drying are conventional dry technologies, and implement this step not difficult, the present invention is without restriction to this.
Extract of the present invention described above, can preparation process conveniently, is prepared into any pharmaceutical dosage form being applicable to Clinical practice, such as, and capsule, pill, tablet, granule, solution or injection etc.Wherein extract contained by each dosage form amount according to dosage form composition, treat the situation, Clinical practice condition etc. of patient and different.Generally, when general flavone content in extract is with 50% timing, patient's administration every day 0.1 ~ 5 gram, divides and takes for 1 ~ 4 time.
The compositions comprising Rhizoma Drynariae extract of the present invention refers to the Rhizoma Drynariae extract and one or more pharmaceutically acceptable carrier or excipient that comprise and prepared by said method.
The preparation of compositions of the present invention meets the route of administration of its expection.Compositions of the present invention can by following administration: parenteral, locally, intravenous, oral, subcutaneous, intra-arterial, intradermal, percutaneous, rectum, intracranial, intraperitoneal, intranasal, intramuscular route or as inhalant.Described compositions can optionally with treating in various disease other agents administration having certain effect at least.
Oral formulations comprises the acceptable inert diluent of pharmacy or edible carrier usually.Can oral formulations be encapsulated in gelatine capsule or be compressed into tablet.In order to oral therapeutic administration, the present composition can merge with excipient, and for the form of tablet, lozenge or capsule.Fluid carrier for collutory can also be used to prepare Orally administered composition, and wherein in fluid carrier, compound is oral administration, gargles and spue or swallow.Tablet, pill, capsule, lozenge etc. can contain any following compositions or have the compound of similar quality: binding agent, such as microcrystalline Cellulose, Tragacanth or gelatin; Excipient, such as starch or lactose; Disintegrate compound, such as alginic acid, Primogel or corn starch; Lubricant, such as magnesium stearate or Sterotes; Fluidizer, such as colloidal silica; Edulcorant compound, such as sucrose or glucide; Or flavor compound, such as Oleum menthae, methyl salicylate or flavoring orange essence.
In embodiments of the invention, carry out suitable external or in vivoassay whether to be applicable to treat individual institute to the effect and administration of determining the present composition and to suffer from the disease or medical condition.These examples measured are described in conjunction with disease specific or therapeutic treatment in hereafter non-limiting example.Usually, the effective dose of the present composition realizing prevention or therapeutic effect is enough to for about 0.001mg/ kg body weight/sky to about 10,000mg/ kg body weight/sky.When suitable, dosage is about 0.01mg/ kg body weight/sky to about 1000mg/ kg body weight/sky.Dosage range can be every day, every two days or every three days about 0.01 to 1000mg/kg host body weight, be more typically 0.1 to 500mg/kg host body weight.Exemplary therapeutic scheme be every two days once or once in a week or monthly administration.Usually repeatedly give described reagent, the interval between single dose can be every day, weekly, monthly or every year.Or, described reagent can be given with the form of slow releasing preparation, in this case, need less administration frequency.Dosage and frequency are different from the half-life of reagent in experimenter.Also can according to being preventative process or therapeutic treatment and different.In prophylactic use, give relatively low dosage for a long time with the interval of rather low-frequency rate.In therapeutic application, sometimes need to give relatively high dosage with relatively short interval, until the progress of disease is delayed or stops, and preferably until individuality shows the partially or completely improvement of disease symptoms, after this, patient's prevention scheme can be given.
The beneficial effect of the invention
The invention provides the Rhizoma Drynariae for preventing or treat heart failure, Rhizoma Drynariae extract or comprise the compositions of Rhizoma Drynariae extract, in the Chronic heart failure model of rat, medicine of the present invention obviously can reduce serum brain natriuretic peptide in patients (BNP), Angiotensin II (AngII) and aldosterone (ALD) content in the heavy index of the rat heart, blood; In rat acute Heart Failure Model, medicine of the present invention obviously can improve left ventricular systolic function in rats.Above experimental result shows that medicine of the present invention has the effect of prevention or treatment acute and chronic heart failure, for the prevention of above-mentioned disease or treatment provide a kind of new scheme, and also has positive effect for the exploitation of Chinese herbal medicine resource.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1
Take 100 grams of Rhizoma Drynariae, be ground into coarse powder, boil 1 hour with water 1500ml, release medicinal liquid, residue adds 1000ml water boil again, releases medicinal liquid.Twice medicinal liquid merges, and filter, medicinal liquid flows through the adsorption column that 120 grams of treated WLD adsorbent resiies are housed
flow velocity 4ml/ divides, and effluent tetrahydro boron potassium reaction and judgement collects terminal, till namely occurring that suddenly flavanone compounds reaction-resin reaches saturated adsorption with effluent.Adsorb complete, with 500ml water washing resin post, washing liquid discards, then uses 400ml70% ethanol elution, judges to receive the starting point and the terminal that connect eluent with tetrahydro boron potassium chromogenic reaction.Reclaim eluent, eluent reclaims ethanol, and debris is steamed to thick paste in water-bath, vacuum drying, obtains Rhizoma Drynariae extract 1.88 grams.Its general flavone content surveyed by gained sample ultraviolet spectrophotometry, and general flavone content 55.08%, HPLC method measures naringin content 36.6% (accounting for 66.4% of total flavones).
Embodiment 2
Except reflux solvent and eluting solvent all adopt 70% alcoholic solution, according to the operation of embodiment 1 method, obtain extract 1.69 grams, general flavone content 53.12%, HPLC method measures naringin content 32.5% (accounting for 61.2% of total flavones).
Embodiment 3
Except adsorbent resin adopts AB-8 resin, adopt the operation of embodiment 1 same procedure, obtain 0.95 gram of extract, general flavone content 61.80%.
Embodiment 4
Except adsorbent resin adopts D101 resin, adopt the operation of embodiment 1 same procedure, obtain 1.07 grams of extracts, general flavone content 57.35%.
Embodiment 5
Except Rhizoma Drynariae amount of powder is 10 grams, adsorbent resin amount is respectively beyond 5 grams, 10 grams, 20 grams, 25 grams, according to embodiment 1 method obtain respectively extract 0.16 gram, 0.20 gram, 0.27 gram, 0.27 gram, general flavone content is respectively 53.88%, 52.29%, 42.65%, 41.88%, total flavones receipts amount is respectively 86.2mg, 104.6mg, 115.2mg, 113.1mg, and total flavones yield is respectively 0.86%, 1.05%, 1.15%, 1.13%.Visible when medical material amount: adsorbent resin amount, more than after 1: 2, almost no longer increases for its absorption total flavones amount of equivalent medical material, when illustrating that adsorbent resin amount is 2 times of medical material amount, adsorbs complete.But when medical material amount: when adsorbent resin amount is 1: 1, its adsorbate general flavone content is higher, and total flavones must be measured and reached 90.8% of complete adsorbance, and in product, general flavone content reaches 52.29%, therefore consider aborning, medical material amount: more suitable when adsorbent resin amount is 1: 1.
Embodiment 6
With the glass column (Φ=20) of 4 processed good WLD macroporous adsorbent resin 10g of filling, by Rhizoma Drynariae medicinal material coarse powder 40g, add 1000mL soak by water one hour (micro-boil), filter.Filtrate is divided into 4 parts, and every part is respectively passed through an above-mentioned glass column, and coutroi velocity is respectively 2mL/min, 4mL/min, 8mL/min and 16mL/min, and checks that result is as table 1 with or without flavonoid glycoside in waste liquid with tetrahydro boron potassium reaction.
Table 1
Find out from upper table, adsorption flow rate must control, and guarantee absorption completely.
Embodiment 7
Get Rhizoma Drynariae medicinal material coarse powder 300g, filtrate is obtained by embodiment 1 method, filtrate is divided into three parts, upper prop (Φ=40 respectively, in-built WLD resin 100g), use different concentration ethanol eluting respectively, the eluent of collection is through concentrated, dry, by its total flavones amount of determined by ultraviolet spectrophotometry, the results are shown in Table 2.
Table 2
From upper table data, concentration of alcohol has impact to elute effect, and wherein 70% ethanol elution effect is better.
Formulation example 1 capsule
Get the extract powder of the present invention that 180g obtains according to embodiment 1 method, add starch 70g, mixing, is filled with capsule, obtains the capsule (every containing effective ingredient 180mg) of 1000 extracts of the present invention.
Formulation example 2 tablet
Get 180g according to the obtained extract powder of the present invention of embodiment 1 method, mix with 70g starch, the aqueous solution then adding a small amount of sodium carboxymethyl cellulose is kneaded soft material processed, conventionally granulates, dry, and add a small amount of magnesium stearate, mixing, beats sheet.Obtain the tablet (every sheet is containing effective ingredient 180mg) of 1000 extracts of the present invention.
Formulation example 3 injection
Get of the present invention extract of 180g according to embodiment 1 method gained, add 800ml distilled water for injection, heating makes entirely molten, with filtering with microporous membrane, filtrate is put in refrigerator (4 DEG C ~ 8 DEG C) and is placed 24 hours, again use filtering with microporous membrane, regulate pH (being 6.5) and osmotic pressure to isotonic with medical hydrochloric acid (12N) and NaOH aqueous solution (12N), inject with distilled water to 1000ml, heat sterilization, filter, be sub-packed in ampoule, often prop up 5ml (containing effective ingredient 180mg).
the protective effect of experimental example 1 pair of amycin induced rat chronic heart failure
1. material
1.1 animal
Cleaning grade male Wistar rat 60, body weight (200 ± 20) g, is provided by Jilin University's Experimental Animal Center, quality certification SCXK (Ji) 2012-0001, and ad lib is drunk water.
1.2 reagent
Except as otherwise noted, this is tested medicine used and has following dosage and content:
Extract of the present invention: formulation example 1 capsule, every containing effective ingredient 0.18g.
Hydrochloride for injection doxorubicin (amycin, Haizheng Medicine Stock Co., Ltd., Zhejiang Prov);
Captopril tablets (Sino-U.S. executes in Shanghai limited point of expensive precious pharmacy department);
Rat brain natriuretic peptide (BNP) test kit, rat angiotensin II (Ang II) test kit, rat aldosterone (ALD) test kit, all purchased from Xi Tang bio tech ltd, Shanghai;
Other chemical reagent is domestic analytical pure.
1.3 instrument
DENLEYDRAGONWellscanMK3 type microplate reader (Thermo company of the U.S.);
Trigger (Thermo company of the U.S.) washed by Wellwash4MK2 type;
AvantiJ-E type multipurpose high-efficiency centrifuge (Beckman company of the U.S.);
5415R type miniature high-speed refrigerated centrifuger (German Eppendorf company);
XS-105 type electronic balance (MettlerToledo company of Switzerland);
Ultra cold storage freezer (Thermo company of the U.S.).
2. method
Rat is divided into normal group and modeling group after raising 7d by 2.1 rat experiment prospective adaptations at random.
Make Heart Failure Wistar Rats model: doxorubicin hydrochloride powder pin normal saline is made into the solution that concentration is 2.5g/L, except normal group, modeling group rat respectively at lumbar injection (ip) Doxorubicin solution 2.0mg/kg weekly, 1 time weekly, totally 6 weeks, total amount was 12mg/kg.Normal group is lumbar injection (ip) normal saline (i.e. 0.8ml/kg) simultaneously.Observe ordinary circumstance (mental status, activity, food-intake, body weight and fur etc.) and the death condition of rat every day.
Beginning administration in modeling the 5th week, by group and dosage gavage (ig) administration respectively: high dose group (135mg/kg, compound concentration is 2.7%); Low dose group (67.5mg/kg, compound concentration is 1.35%); Captopril positive drug group (6.25mg/kg, compound concentration is 0.125%), normal group and model group give same volume distilled water ig.Administration volume is 5ml/kg, every day 1 time, continuous 4 weeks.
After 2.2 serum brain natriuretic peptide in patients (BNP), rat angiotensin II (Ang II), the administration of rat aldosterone (ALD) assay rat last, water 12h is can't help in fasting, after weighing next day, with 25% urethane 4mL/kg lumbar injection (ip) anesthetized rat, abdominal aortic blood, after leaving standstill 4h, 4 DEG C, the centrifugal 20min of 3000r/min, separation of serum, is stored in 80 DEG C of refrigerators.Detect according to ELISA kit description.
The heavy assessment of indices of 2.3 hearts
Animal is weighed, and (BW) puts to death afterwards, open breast, clip heart, rinse well in pre-cold saline, filter paper suck dry moisture, accurately weigh, record weight (HW) whole-heartedly, then atrium, blood vessel and connective tissue (operating) is removed on ice, along interventricular septum, left and right ventricles is separated, record left ventricular mass (LVW), calculates heavy index HWI (HWI=HW/BW) and heavy index LVW (LVWI=LVW/BW) of left ventricle whole-heartedly, evaluates left ventricular remodeling degree.
T inspection between statistical analysis employing group, with P < 0.05 for difference has statistical significance.
3 results
3.1 animal ordinary circumstances
Whole experimental session, normal group 10 rats are in good condition, and hair color is normal, and body weight increases by 5 ~ 7g/d, and gradually there is following symptom in modeling group rat after the 1st, 2 ip doxorubicin hydrochloride: as poor in appetite, body weight increasess slowly, like agglomerate curling oneself up etc., and after this symptom increases the weight of gradually.During modeling dead 10, remain 40 modeling rats: model group 10, high dose group 10, low dose group 10, Captopril group 10.Medication stage administration group symptom is obviously improved (as food-intake increases, action is active), and model group symptom is not improved.
3.2 weigh the impact of index to the heart
Compare with normal group, the HWI of model group obviously raises (P < 0.05), administration and to captopril intervene after, this index and the obvious reduction of model group (P < 0.05).Model group rats LVWI compared with normal group obviously raises (P < 0.05), compare with model group, Captopril group can make this index obviously reduce (P < 0.05), high dose group has the effect trend of reduction, the results detailed in Table 3 to LVWI.
Table 3 is on the impact (x ± s) of the heavy index of the Heart Failure Wistar Rats heart
Note: compare * P < 0.05 with normal group; △ P < 0.05 is compared with model group.
3.3 on the impact of serum brain natriuretic peptide in patients (BNP), rat angiotensin II (Ang II), rat aldosterone (ALD) Content
Compare with normal group, Heart Failure Model group rat BNP, Ang II and ALD content significantly increase (P < 0.01), compare with model group, each treatment group all can reduce BNP, Ang II and ALD level (P < 0.01, P < 0.05).
Table 4 is on the impact (x ± s) of Heart Failure Wistar Rats serum BNP, Ang II and ALD level
Note: compare * * P < 0.01 with normal group; △ P < 0.05, △ △ P < 0.01 is compared with model group
experimental example 2 pairs of propranolols cause the protective effect of rat acute heart failure
1. material
1.1 animal
Cleaning grade male Wistar rat 40, body weight (220 ± 20) g, is provided by Jilin University's Experimental Animal Center, quality certification SCXK (Ji) 2012-0001, and ad lib is drunk water.
1.2 reagent
Except as otherwise noted, this is tested medicine used and has following dosage and content:
Extract of the present invention: formulation example 1 capsule, every containing effective ingredient 0.18g.
Propranolol (sigma company).
1.3 instrument
RM6240B type multi-path physiology signal acquiring processing system (Chengdu Instruement Factory);
ALC-V8 type animal respirator, ALC-IP800 type micro-injection pump (Alcott bio tech ltd, Shanghai).
2. method
2.1 grouping of acute heart failure rat and administrations
After rat experiment prospective adaptation raises 7d, 40 rats are divided into 4 groups at random, Normal group, propranolol model group, high dose group (135mg/kg, compound concentration is 2.7%) and low dose group (67.5mg/kg, compound concentration is 1.35%), often organize 10.The according to dosage administration of high and low dose group, continuous 10 days.After last administration, rat operation stablizes 30 minutes, basic value before record modeling, and except Normal group, all the other respectively organize the modeling of intravenous injection 0.4% propranolol, after modeling success, and the change of record modeling 30min cardiac function.
2.2 operation technique
Each group of rat, with after 10% urethane solution (1.2g/kg) intraperitoneal injection of anesthesia, records II lead electrocardiogram, and tracheal intubation ligation are fixed, and connects artificial respirator (parameter setting: inspiratory to expiratory ratio is 1: 2; Respiratory frequency is 70 times/min; Tidal volume is 8ml).Be separated right carotid, insert the polyethylene tube being full of heparin in advance slowly to advance, make it arrive left ventricle (occurring that negative value is the index entering left ventricle with diastolic pressure) by aortic valve, ligation is fixed, Bonding pressure transducer record left ventricular pressure.Left femoral vein intubate, connects micro-injection pump, in order to constant speed injection propranolol.Namely post surgery stabilization 30min starts to record parameters of left ventricular function: heart rate (HR), left ventricular systolic pressure (LVSP), the maximum climbing speed (+dp/dtmax) of left indoor pressure.
2.3 set up acute propranolol brings out Heart Failure Model
Through micro-injection pump quiet note 0.4% propranolol solution 4mg/kg, adjust flow velocity subsequently to 0.25mg/kgmin, animal occurs that myocardial contraction reduces, left room ± dp/dtmax reduces, decreased heart rate, heart failure modeling success.
3. statistical procedures
Data represent with x ± s, and adopt t inspection, P<0.05 has statistical significance.
4. result
The impact of 4.1 acute heart failure rat left chamber contractile functions
Intravenous Propranolol rat LVSP ,+dp/dtmax and HR obviously reduce, and the range of decrease, all more than 40%, more all has significant differences (P<0.01) with Normal group.Administration high and low dose group LVSP ,+dp/dtmax comparatively model control group all significantly raise (P<0.05 or P<0.01).Effect (P<0.05) is also increased significantly to the rat model rhythm of the heart.
Table 5 is on the impact (x ± s) of acute heart failure rat left chamber contractile function
Note: compare * * P < 0.01 with normal group; △ P < 0.05, △ △ P < 0.01 is compared with model group
Conclusion: the effect with treatment and prevention heart failure, can be used for preparing treatment and preventing acute, chronic heart failure.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (15)
1. Rhizoma Drynariae, Rhizoma Drynariae extract or the compositions that comprises Rhizoma Drynariae extract are preparing the purposes prevented and/or treated in the medicine of heart failure.
2. the purposes of claim 1, described heart failure comprises acute heart failure and chronic heart failure.
3. the purposes of claim 1, described heart failure is caused by following reason: coronary heart disease, senile degenerative heart valve disease, rheumatic valvular heart disease, dilated cardiomyopathy, acute severe myocarditis, myocardial infarction, hypertension, ischemic heart desease, be exposed to cardiac toxic, myocarditis, thyroid disease, viral infection, gingivitis, drug dependence, alcohol abuse, pericarditis, atherosclerosis, angiopathy, hypertrophic cardiomyopathy, acute myocardial infarction, left ventricular systolic dysfunction, coronary artery bypass surgery, hungry, drinking and eating irregularly, or genetic defect.
4. the purposes of claim 1, in described Rhizoma Drynariae extract, general flavone content is 30-100%, such as, be 40-100%, then is such as 40-65%, then is such as 50-65%.
5. the purposes of claim 1, in described Rhizoma Drynariae extract, the content of naringin is 20-100%, such as, be 20-45%, then is such as 20-40%, then is such as 20-38%, then is such as 30-40%.
6. the purposes of claim 1, wherein said Rhizoma Drynariae extract prepares by the following method:
1) by Rhizoma Drynariae pulverizing medicinal materials, with water or alcohol or its mixture extracting;
2) extracting solution resin absorption;
3) having adsorbed the resin water of extract or alcohol or its mixture eluting.
7. the purposes of claim 6, wherein step 1) in carry out extracting with water.
8. the purposes of claim 6, wherein step 1) middle alcohol/aqueous mixtures carries out extracting.
9. the purposes of claim 6 or 8, in described alcohol/aqueous mixtures, alcohol content is 40-90% weight.
10. the purposes of claim 6,8 or 9, described alcohol is selected from methanol and ethanol.
The purposes of 11. claim 6, wherein step 2) in resin be macroporous adsorbent resin.
12. the purposes of claim 6 or 11, wherein step 3) in first wash with water, then use alcohol/aqueous mixtures eluting.
The purposes of 13. claim 12, wherein step 1) middle alcohol/aqueous mixtures carries out extracting.
The purposes of 14. claim 12 or 13, in described alcohol/aqueous mixtures, alcohol content is 40-90% weight.
The purposes of 15. any one of claim 12-14, described alcohol is selected from methanol and ethanol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100418521C (en) * | 2000-12-29 | 2008-09-17 | 北京岐黄制药有限公司 | Gusuibu extracts for trvating osteoporosis and method for extracting same |
| CN102526676A (en) * | 2012-02-09 | 2012-07-04 | 刘思娟 | Traditional Chinese medicine for treating chronic heart failure, preparation method and administration mode |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100418521C (en) * | 2000-12-29 | 2008-09-17 | 北京岐黄制药有限公司 | Gusuibu extracts for trvating osteoporosis and method for extracting same |
| CN102526676A (en) * | 2012-02-09 | 2012-07-04 | 刘思娟 | Traditional Chinese medicine for treating chronic heart failure, preparation method and administration mode |
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Address after: 101200 No. 17 South Street, Pinggu Town, Pinggu District, Beijing, Pinggu Applicant after: Beijing Qihuang pharmaceutical Limited by Share Ltd Address before: 101200 No. 17 South Street, Pinggu Town, Pinggu District, Beijing, Pinggu Applicant before: BEIJING QIHUANG PHARMACEUTICAL MANUFACTURING CO., LTD. |
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Application publication date: 20151230 |