CN1923241A - Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use - Google Patents
Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition, its preparing process and use, wherein the composition comprises epimedium extract, hooked uncaria extract and puerarin by the weight ratio of 20-500 : 3-80 : 40-1000. The composition can be prepared into clinically and pharmaceutically acceptable dosage forms including injections, tablets, capsules, soft capsules, dripping pills, oral liquids, and granules. The composition can be used for treating hypertension, cephalalgia, nervous prostration and cardiovascular and cerebrovascular diseases.
Description
1, technical field
The present invention relates to a kind of pharmaceutical composition of forming by Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine and its production and application, belong to medical technical field.
2, background technology
Herba Epimedii is the dry aerial parts of Berberidaceae plant Herba Epimedii (Epimedium brevicornum Maxin.), arrow leaf Herba Epimedii (Epimedium sagittatumMaxin.), pubescence Herba Epimedii (Epimedium pubescens Maxin.), Epimedium wushanense (Epimedium wushanense T.S.Ying) or Herba Epimedii (Epimedium koreanum Nakai.).Herba Epimedii is used as medicine and starts from Shennong's Herbal, and Compendium of Material Medica claims it that effect of " beneficial vital essence, hard muscles and bones, by the waist knee joint, heart tonifying power " is arranged.Modern pharmacology studies show that Herba Epimedii can increase the cardiovascular and cerebrovascular vessel blood flow, promotes hemopoietic function, immunologic function and bone metabolism, has effects such as defying age, antitumor.
Herba Epimedii extract is the extract that Herba Epimedii is processed into through extraction, and its main effective ingredient is a Herba Epimedii total flavones, mainly contains icariin and icariside etc.Pharmacological research finds that Herba Epimedii total flavones is that Herba Epimedii promotes immunologic function, participates in bone metabolism, antitumor, the effective ingredient of functions such as enhancing cardiovascular activity.Icariin has coronary blood flow increasing, cerebral blood flow increasing amount, regulates immunity, promotes the synthetic and androgen sample effect of DNA; Can be used for coronary heart disease, climacteric hypertension, sensation of oppression over the chest with shortness of breath and rheumatism etc.
Ramulus Uncariae Cum Uncis is the dry stem and branch with belt hook of Maguireothamnus speciosus Ramulus Uncariae Cum Uncis Uncaria rhynchOphylla (Miq.) Jacks., Ramulus Uncariae macrophyllae Uncaria macrophylla Wall., Ramulus Uncariae Cum Uncis Uncaria hirsute Havil., Uncaria sinensis (Oliv.) Havil. Uncaria sinensis (Oliv.) Havil. or stockless fruit Ramulus Uncariae Cum Uncis Uncaria sessilifructus Roxb..Ramulus Uncariae Cum Uncis is sweet, be slightly cold, and returns liver, pericardium channel; Have the heat clearing away suppressing the hyperactive liver, the effect of relieve dizziness, high fever, infantile convulsions, epilepsy, etc. arresting convulsion, promoting blood circulation to restore menstrual flow; Be used to have a dizzy spell, cardiovascular and cerebrovascular vessel and nervous system disease such as infantile convulsion tic, numb limbs and tense tendons.China's application Ramulus Uncariae Cum Uncis is used as medicine and from Song Mingchao long history is arranged so far.Modern medicine has confirmed the effect that Ramulus Uncariae Cum Uncis has relieving convulsion, calmness, diuresis and blood vessel dilating, brings high blood pressure down.
Ramulus Uncariae Cum Uncis extract is the extract that Ramulus Uncariae Cum Uncis is processed into through extraction, and its main effective ingredient is a Rhomotoxine, contains Ramulus Uncariae cum Uncis alkali, isorhynchophylline, corynoxeine, isocorynoxeine etc.Rhomotoxine has blood pressure lowering, decreased heart rate, arrhythmia, cerebral ischemia protection, and effects such as calmness, spasmolytic.
Gastrodine (Gastrodin) is 4-methylol benzene-β-D-pyranglucoside semihydrate, and structural formula is as shown below:
Pharmacological testing shows, gastrodine has multiple pharmacological effect, but with the most outstanding to central nervous system's effect, can recover the dysequilibrium between cerebral cortex excitement and process of inhibition, produce calm, sleep peacefully and central inhibitory action such as analgesia, can blood vessel dilating, improve myocardium microcirculation, increase the myocardial nutrition blood flow and improve oxygen delivery capacity; Also has hypotensive effect.Clinical neurasthenia, neurasthenic syndrome, brain traumatic syndrome, trigeminal neuralgia, sciatica, angioneurotic headache, migraine, vertigo, vertebro-basilar artery insufficiency and the hyperlipidemia etc. of being mainly used in.
Utilize the interaction of Herba Epimedii or its extract, Ramulus Uncariae Cum Uncis or its extract, gastrodine three medicines, composition of prescription, preparation improves vascular compliance and hemodynamics, treatment hypertension, headache, neurasthenia, and the medicine of regulating immunity, resisting cardiovascular disease etc., do not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, better treat cardiovascular and cerebrovascular disease etc., the invention provides a kind of new pharmaceutical composition and its production and application, it is characterized in that it comprises Herba Epimedii or its extract, Ramulus Uncariae Cum Uncis or its extract, gastrodine.
In the aforementioned pharmaceutical compositions, Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine are calculated as 20～500 parts of Herba Epimedii extracts, 3～80 parts of Ramulus Uncariae Cum Uncis extracts, 40～1000 parts of gastrodine according to components by weight percent, be preferably 50～200 parts of Herba Epimedii extracts, 8～32 parts of Ramulus Uncariae Cum Uncis extracts, 100～400 parts of gastrodine, the best is preferably 100 parts of Herba Epimedii extracts, 16 parts of Ramulus Uncariae Cum Uncis extracts, 200 parts of gastrodine.
The composition of above pharmaceutical composition as if being unit with the gram, can be made the preparation of 500～1000 consumptions, as injection, can be made into 1000,1～5 of each consumption.As tablet, can be made into 1000, take 1～5 at every turn.
The composition of above pharmaceutical composition is by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can kilogram be unit, or be unit with the ton, small-scale production also can restrain and be unit, weight can increase or reduce, but the constant rate of weight proportion between each composition.
The ratio of above weight proportion obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
Aforementioned pharmaceutical compositions can be used for preparation and improves vascular compliance and hemodynamics, treatment hypertension, headache, neurasthenia, and the medicine of aspects such as resisting cardiovascular disease, adjusting immunity.Pharmacological effect studies show that, aforementioned pharmaceutical compositions can significantly reduce rat blood pressure, significantly improve the dog hemodynamics, obviously enhance immunity suppresses cellular immunization and the humoral immune function of mice, at aspects such as resisting hypertension, resisting cardiovascular disease, adjusting immunity good curative effect will be arranged.
Aforementioned pharmaceutical compositions can be made clinically arbitrary or pharmaceutically acceptable dosage form, can add one or more pharmaceutically acceptable carriers, with oral, snuffing is gone into or the mode of parenteral is applied to the patient who needs this treatment.During oral administration, can be made into oral normal release dosage form (as sheet, enteric coatel tablets, dispersible tablet, chewable tablet, oral cavity disintegration tablet, capsule, soft capsule, enteric coated capsule etc.), sustained-release and controlled release dosage form (as slow releasing tablet, controlled release tablet, slow releasing capsule, controlled release capsule etc.), oral fluid agent (as oral administration solution, syrup etc.), drop pill, granule etc.; During parenteral, can be made into solution, water for injection or oil-suspending agent, the inhalant etc. of injection, as liquid drugs injection, powder pin, transfusion, spray etc.Preferred dosage form is injection and oral formulations commonly used, as powder pin, liquid drugs injection, transfusion, sheet, capsule, soft capsule, drop pill, oral liquid, granule.
The preparation of aforementioned pharmaceutical compositions, can adopt the conventional method production in the existing pharmaceutical field, various pharmaceutically acceptable carriers be can add when needing, the diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc. comprised.
In the aforementioned pharmaceutical compositions, Herba Epimedii extract contains that Herba Epimedii total flavones is not less than 20%, icariin is not less than 4%, and Ramulus Uncariae Cum Uncis extract contains Rhomotoxine and is not less than 30%.When making injection, Herba Epimedii extract contains that Herba Epimedii total flavones is not less than 50%, icariin is not less than 10%, and Ramulus Uncariae Cum Uncis extract contains Rhomotoxine and is not less than 50%.
Because injection has relatively high expectations to raw materials quality, the invention provides preferred Herba Epimedii extract and Rhomotoxine preparation technology, make with extra care, remove impurity etc., make its related substance etc. meet the injection requirement.
Aforementioned pharmaceutical compositions, effective ingredient is clear and definite in Herba Epimedii extract, the Ramulus Uncariae Cum Uncis extract, content is definite, and the gastrodine structure is clear and definite, determined curative effect; Directly feed intake with Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine, preparation technology is easy, and the quality of the pharmaceutical preparations is stable, and impurity content is few.Also can directly feed intake, but technology relatively bothers with Herba Epimedii, Ramulus Uncariae Cum Uncis, gastrodine.The pharmacological effect test shows that Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and three kinds of medicines of gastrodine have synergistic function, at aspects such as bringing high blood pressure down, improve hemodynamics, immunomodulating good effect are arranged; At aspects such as treatment hypertension, headache, neurasthenia and anti-hematuria effect disease, adjusting immunity good curative effect will be arranged.Long-term test results showed in 12 months, and every index of the injection that aforementioned pharmaceutical compositions is made is all more stable, can be used for amplifying producing.
Further specify the present invention below by the test example.Replace Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine compositions with YGT in the test example.
The test of test example 1 Herba Epimedii extract craft screening
Amount of water, extraction time, extraction time are bigger to the influence of extracting the result, are index with icariin and general flavone content therefore, investigate four kinds of factors to extracting result's influence with orthogonal experiment.Factor and level design see Table 1.
Table 1 Herba Epimedii extraction process by water is investigated the factor level table
| Level/factor | A amount of water (doubly) | B extraction time (inferior) | C extraction time (hour) |
| 1 2 3 | 16 18 20 | 1 2 3 | 2 3 4 |
Test method takes by weighing Herba Epimedii 100g, and totally 9 parts, extract by the requirement of each row of table 2 number, merge extractive liquid, filters, and filtrate concentrates and is settled to 1000ml, and is standby.
Content of total flavone is measured
The algoscopy precision is measured above-mentioned solution 1ml, puts in the 10ml measuring bottle, adds 70% and is diluted to scale, shakes up, as need testing solution.Other gets the icariin reference substance, adds 70% ethanol and makes the solution that every 1ml contains 10 μ g, in contrast product solution.Getting need testing solution and reference substance solution respectively, is blank with the corresponding reagent, detects according to spectrophotography, measures absorbance at 270nm wavelength place, calculates, promptly.The results are shown in Table 2.
Content Determination of Icariin is measured
Detect according to high performance liquid chromatography.
Chromatographic condition and system suitability test are filler with the octadecyl silane; With second eyeball-water (30: 70) is mobile phase; The detection wavelength is 270nm.Number of theoretical plate calculates by the icariin peak and is not less than 1500.
Reference substance solution must prepare precision, and to take by weighing the icariin reference substance an amount of, adds methanol and make the solution that every 1ml contains 0.1mg, promptly.
The preparation precision of need testing solution is measured each sample liquid 2ml, puts in the 25ml measuring bottle, adds 70% and is diluted to scale, shakes up, promptly.
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.The results are shown in Table 2.
Table 2 Herba Epimedii extraction process is investigated orthogonal test table
| Sequence number | Factor | General flavone content (%) | Icariin (%) | |||
| A | B | C | D | |||
| 1 2 3 4 5 6 7 8 9 | 1 1 1 2 2 2 3 3 3 | 1 2 3 1 2 3 1 2 3 | 1 2 3 2 3 1 3 1 2 | 1 2 3 3 1 2 2 3 1 | 3.23 3.91 3.14 3.09 3.67 3.31 3.07 3.48 3.81 | 0.396 0.452 0.381 0.372 0.425 0.401 0.352 0.431 0.447 |
| Total K 1Yellow K 2Ketone K 3 R | 10.28 10.07 10.36 0.29 | 9.37 11.06 10.26 1.69 | 10.02 10.81 9.88 0.93 | 10.71 10.29 9.71 1.00 | ||
| Excessive K 1Sheep K 2Leaves of pulse plants K 3Glycosides R | 1.229 1.198 1.23 0.031 | 1.12 1.308 1.229 0.188 | 1.228 1.271 1.158 0.113 | 1.268 2.753 1.184 0.084 | ||
Table 3 Herba Epimedii total flavones analysis of variance table
| Soruces of variation | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value |
| A B C D (error term) | 0.015 0.340 0.168 0.168 | 2 2 2 2 | 0.00748 0.170 0.0838 0.0840 | 0.089 2.023 0.997 |
Table 4 icariin analysis of variance table
| Soruces of variation | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value |
| A B C D (error term) | 0.000221 0.005941 0.002169 0.001274 | 2 2 2 2 | 0.00011 0.00297 0.00108 0.00064 | 0.173 4.663 1.702 |
By the result of table 2, table 3, table 4 as can be seen, Herba Epimedii total flavones and the descending factor of icariin extraction effect influence are followed successively by B＞C＞A,, determine that the Herba Epimedii extraction process is A in conjunction with industrial practical situation
3B
2C
2, that is: get Herba Epimedii, decoct with water twice, each 1.5 hours, add 10 times of amounts of water at every turn.
Test example 2 Herba Epimedii extract discrimination tests
Get Herba Epimedii extract 0.1g, add ethanol 10ml, warm macerating 30 minutes filters, and filtrate evaporate to dryness, residue add ethanol 1ml makes dissolving, as need testing solution.It is an amount of that other gets the icariin reference substance, adds methanol and make the solution that every 1ml contains 0.1mg, in contrast product solution.Test according to thin layer chromatography, draw each 10 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel H lamellae of adhesive with the sodium carboxymethyl cellulose, with ethyl acetate-butanone-formic acid-water (10: 1: 1: 1) as developing solvent, launch, take out, airing is put under the ultra-violet lamp (365nm) and is inspected.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the kermesinus speckle of same color; Spray is put under the ultra-violet lamp (365nm) again and is inspected with the aluminum chloride test solution, shows identical fluorescent red-orange speckle.
The test of test example 3 Herba Epimedii extract assays
(1) assay of Herba Epimedii total flavones
The algoscopy precision takes by weighing Herba Epimedii extract 0.01g, puts in the 50ml measuring bottle, adds methanol 25ml supersound process 30 minutes, adds methanol and is diluted to scale, shakes up, and filters, as need testing solution.Other gets the icariin reference substance, adds methanol and makes the solution that every 1ml contains 10 μ g, in contrast product solution.Getting need testing solution and reference substance solution respectively, is blank with the corresponding reagent, according to spectrophotography, measures absorbance at 270nm wavelength place, calculates, promptly.
(2) content Determination of Icariin is measured
Detect according to high performance liquid chromatography.
Chromatographic condition and system suitability test are filler with the octadecyl silane; With second eyeball-water (30: 70) is mobile phase; The detection wavelength is 270nm.Number of theoretical plate calculates by the icariin peak and is not less than 1500.
Reference substance solution must prepare precision, and to take by weighing the icariin reference substance an amount of, adds methanol and make the solution that every 1ml contains 0.1mg, promptly.
The preparation precision of need testing solution is measured each sample liquid 2ml, puts in the 25ml measuring bottle, adds 70% and is diluted to scale, shakes up, promptly.
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
Test example 4 Herba Epimedii extract preferred for preparation technologies
(1) basis
Test example 1The extraction conditions that screening obtains extracts, and is further refining, is the preferred for preparation technology of Herba Epimedii extract among the present invention.
Get Herba Epimedii, cut into pieces, decoct with water 2 times, each 1.5 hours, add water was 10 times of amounts at every turn, collecting decoction, cold preservation is placed and is spent the night, and filters, and filtrate is concentrated into the concentrated solution of relative density 1.08～1.10, be added on the polyamide resin column of having handled well, the water with 3～4 times of column volumes washes 20% alcohol flushing of 2～3 times of column volumes of reuse earlier, discard cleaning mixture, 95% ethanol of 4～5 times of column volumes of reuse carries out eluting, collects eluent, reclaim ethanol, spray drying, promptly.
By the Herba Epimedii extract of above-mentioned prepared, Herba Epimedii total flavones content is not less than 80%, and icariin content is not less than 15%.
(2) Herba Epimedii extract can also be by following prepared, but this should be interpreted as Herba Epimedii extract only limits to following preparation technology in the pharmaceutical composition of the present invention.
Technology one: get Herba Epimedii, decoct with water 2 times, each 1.5 hours, add 10 times of amounts of water, merge extractive liquid, filters at every turn, it is 1.08～1.10 concentrated solution that filtrate decompression is concentrated into relative density, adding the petroleum ether jolting, to be extracted into petroleum ether layer colourless, D101 macroporous resin column on the water layer, water, 20% ethanol, 60% ethanol elution successively, collect 60% ethanol elution, concentrating under reduced pressure, spray drying, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 60%, and icariin content is not less than 15%.
Technology two: get Herba Epimedii, cut into pieces, decoct with water 3 times, each 1.5 hours, amount of water was respectively 10,8,8 times, and collecting decoction filters, and filtrate is concentrated into the concentrated solution of relative density 1.08～1.10, and spray drying is pulverized, sieve, and packing, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 40%, and icariin content is not less than 8%.
Technology three: get Herba Epimedii, cut into pieces, decoct with water 3 times, each 1 hour, add 10 times of amounts of water, merge extractive liquid, at every turn, be concentrated into relative density 1.00～1.05, add ethanol to pure content and reach 70%, fully stir, left standstill 48 hours, the leaching supernatant reclaims ethanol to there not being the alcohol flavor, spray drying is pulverized, and sieves, packing, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 30%, and icariin content is not less than 6%.
Technology four: get Herba Epimedii, cut into pieces, add 70% ethanol and decoct 2 times, each 1 hour, add 10 times of amounts of alcohol, merge extractive liquid, at every turn, filter, filtrate recycling ethanol is not to there being the alcohol flavor, and adding the petroleum ether jolting, to be extracted into petroleum ether layer colourless, and water layer adds the ethyl acetate jolting, and to be extracted into ethyl acetate layer colourless, the ethyl acetate layer adds anhydrous sodium sulfate dehydration, concentrating under reduced pressure, spray drying, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 50%, and icariin content is not less than 10%.
Technology five: get Herba Epimedii, cut into pieces, add 70% ethanol and decoct 3 times, each 30 minutes, add 10 times of amounts of alcohol, merge extractive liquid, at every turn, filter, filtrate recycling ethanol is not to there being the alcohol flavor, and adding the ethyl acetate jolting, to be extracted into ethyl acetate layer colourless, anhydrous sodium sulfate dehydration, concentrating under reduced pressure, spray drying, pulverize, sieve, packing, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 45%, and icariin content is not less than 8%.
Technology six: get Herba Epimedii, cut into pieces, add 80% ethanol and decoct 3 times, each 1 hour, add 8 times of amounts of alcohol at every turn, merge extractive liquid, filters, filtrate recycling ethanol, spray drying is pulverized, sieves, packing, promptly.By the Herba Epimedii extract of this prepared, Herba Epimedii total flavones content is not less than 20%, and icariin content is not less than 5%.
The test of test example 5 Ramulus Uncariae Cum Uncis extract craft screenings
Alcohol adding amount, extraction time and extraction time are bigger to the influence of extracting the result, are index with the total alkaloid content therefore, investigate three kinds of factors to extracting result's influence with orthogonal experiment.Factor and level design see Table 5.
Test method takes by weighing Ramulus Uncariae Cum Uncis 100g, and totally 9 parts, extract by the requirement of each row of table 2 number, merge extractive liquid, filters, and filtrate concentrates and is settled to 500ml, and is standby.
Table 5 Ramulus Uncariae Cum Uncis alcohol extraction process is investigated the factor level table
| Level/factor | A concentration of alcohol (%) | B alcohol adding amount (doubly) | C extraction time (number of times) | D extraction time (hour) |
| 1 2 3 | 60 70 80 | 16 20 24 | 1 2 3 | 3 4 5 |
The assay of Rhomotoxine
Column chromatography-ultraviolet spectrophotometry
The drafting precision of standard curve takes by weighing the about 10mg of Rhomotoxine reference substance that is dried to constant weight in 105 ℃, puts in the 25ml measuring bottle, adds 3% sulfuric acid dissolution standardize solution, promptly.Accurate this solution 2ml that draws in the 10ml measuring bottle, with 3% Dilution of sulphuric acid to scale.This solution is measured trap at the 245nm wavelength.Retinue is blank.With volume x and absorption value y map a straight line.Calculate regression equation by straight line.
Algoscopy is accurate draws sample liquid 0.6ml in silicagel column (on 10 * 0.8cm), add the 3% sulfuric acid solution 0.2ml that is made into 95% ethanol simultaneously, with benzene-ethyl acetate (1: 1) 20ml eluting, continue with ethanol-ammonia (15: 2) 17ml eluting, collect this part eluent, water-bath boils off solvent, residue dissolves with 3% sulfuric acid solution, be transferred to standardize solution in the 10ml measuring bottle, measure absorbance in 245nm wavelength place, retinue is blank.By the total alkaloid content of regression equation calculation in the total alkali reference substance.The results are shown in Table 6.
Table 6 Ramulus Uncariae Cum Uncis extraction process is investigated orthogonal test table
| Sequence number | Factor | Total alkaloids (%) | Yield of extract (%) | |||
| A | B | C | D | |||
| 1 2 3 4 5 6 7 8 9 K 1 K 2 K 3 R | 1 1 1 2 2 2 3 3 3 1.015 1.184 0.989 0.195 | 1 2 3 1 2 3 1 2 3 0.977 1.154 1.057 0.177 | 1 2 3 2 3 1 3 1 2 1.027 1.057 1.104 0.164 | 1 2 3 3 1 2 2 3 1 1.054 1.105 1.029 0.076 | 0.295 0.381 0.319 0.353 0.436 0.395 0.329 0.337 0.323 | 16.55 17.47 18.77 19.74 20.15 20.22 21.37 21.54 21.45 |
By table 6 result as can be seen, concentration of alcohol, alcohol adding amount, extraction time are to influence the principal element that Ramulus Uncariae Cum Uncis extracts, and with reference to yield of extract, determine that the Ramulus Uncariae Cum Uncis extraction process is A in conjunction with commercial production
2B
2C
2D
2, that is: the hook taking rattan adds 70% ethanol extraction 2 times, each 2 hours, adds 10 times of amounts of alcohol at every turn.
Test example 6 Ramulus Uncariae Cum Uncis extract discrimination tests
Hook taking rattan extract 0.5g, porphyrize adds strong ammonia solution and makes moisteningly, adds chloroform 30ml, jolting was extracted 30 minutes, filter, filtrate evaporate to dryness, residue add hydrochloric acid solution (1 → 100) 5ml makes dissolving, filter, filtrate splits in three test tubes, adds 1～2 of bismuth potassium iodide test solution in the pipe, promptly generates yellow mercury oxide; Add 1～2 of test solution of mercuric potassium iodide in one pipe, promptly generate white precipitate; Add 1～2 of silico-tungstic acid test solution in another pipe, promptly generate white precipitate.
The test of test example 7 Ramulus Uncariae Cum Uncis extract assays
The assay of Rhomotoxine
The drafting precision of standard curve takes by weighing the about 10mg of Rhomotoxine reference substance that is dried to constant weight in 105 ℃, puts in the 25ml measuring bottle, adds 3% sulfuric acid dissolution standardize solution, promptly.Accurate this solution 2ml that draws in the 10ml measuring bottle, with 3% Dilution of sulphuric acid to scale.This solution is measured trap at the 245nm wavelength.Retinue is blank.With volume x and absorption value y map a straight line.Calculate regression equation by straight line.
The algoscopy precision takes by weighing Ramulus Uncariae Cum Uncis extract 200mg, and porphyrize adds 1ml ammonia, put into paper web, place in the Sha Shi extractor, with 50ml benzene reflux, extract, 4h, extracting solution reclaims solvent to doing, and residue is put standardize solution in the 10ml measuring bottle with benzene-ethyl acetate (2: 1) dissolving.Precision is measured sample liquid 0.6ml in silicagel column (on 10 * 0.8cm), add the 3% sulfuric acid solution 0.2ml that is made into 95% ethanol simultaneously, with benzene-ethyl acetate (1: 1) 20ml eluting, continue with ethanol-ammonia (15: 2) 17ml eluting, collect this part eluent, water-bath boils off solvent, residue dissolves with 3% sulfuric acid solution, be transferred to standardize solution in the 10ml measuring bottle, measure absorbance in 245nm wavelength place, retinue is blank.By the total alkaloid content of regression equation calculation in the total alkali reference substance.
Test example 8 Ramulus Uncariae Cum Uncis extract preferred for preparation technologies
(1) basis
Test example 5The extraction conditions that screening obtains extracts, and is further refining, is the preferred for preparation technology of Ramulus Uncariae Cum Uncis extract among the present invention.
The hook taking rattan is ground into coarse powder, adds 70% alcohol reflux 2 times, each 2 hours, add 10 times of amounts of alcohol, merge extractive liquid, at every turn, filter, reclaim ethanol, add water to an amount of (every 1ml is equivalent to crude drug 2g) to there not being the alcohol flavor, stir evenly, add concentrated hydrochloric acid adjust pH to 1～2, cold preservation was placed 4 hours, filter, filtrate adds the petroleum ether jolting extracts 1 time, discards petroleum ether liquid, acid liquid adds 10% sodium hydroxide adjust pH to 9～10, and cold preservation is placed and spent the night, the leaching precipitation, the dilute hydrochloric acid that adds 1mol/l again makes dissolving, cold preservation was placed 4 hours, filtered, and filtrate adds 10% sodium hydroxide adjust pH to 9～10 again, cold preservation is placed and is spent the night, the leaching precipitation, vacuum drying, promptly.
By the Ramulus Uncariae Cum Uncis extract of this prepared, Rhomotoxine content is not less than 80%.
(2) Ramulus Uncariae Cum Uncis extract can also be by following prepared, but this should be interpreted as Ramulus Uncariae Cum Uncis extract only limits to following preparation technology in the pharmaceutical composition of the present invention.
Technology one: the hook taking rattan, 70% alcohol reflux 2 times each 1.5 hours, adds 10 times of amounts of alcohol at every turn, merge extractive liquid, reclaims ethanol to there not being the alcohol flavor, is diluted with water to every 1ml and is equivalent to crude drug 2g, and cold preservation was placed 24 hours, filter, filtrate decompression concentrates, vacuum drying, promptly.By the Ramulus Uncariae Cum Uncis extract of this prepared, Rhomotoxine content is not less than 50%.
Technology two: the hook taking rattan, be ground into coarse powder, soaked 24 hours, with 20 times of amount 70% ethanol percolations, percolate reclaims ethanol to there not being the alcohol flavor, and being evaporated to relative density is 1.20～1.24 (50 ℃), and spray drying is promptly.By the Ramulus Uncariae Cum Uncis extract of this prepared, Rhomotoxine content is not less than 40%.
Technology three: hook taking rattan, 70% alcohol reflux 2 times, each 1.5 hours, add 10 times of amounts of alcohol, merge extractive liquid, reclaims ethanol to there not being the alcohol flavor at every turn, be diluted with water to every 1ml and be equivalent to crude drug 2g, being evaporated to relative density is 1.20～1.24 (50 ℃), and spray drying promptly.By the Ramulus Uncariae Cum Uncis extract of this prepared, Rhomotoxine content is not less than 35%.
Technology four: the hook taking rattan decocts with water each 2 hours 2 times, amount of water is respectively 10,8 times of amounts, and collecting decoction filters, it is 1.19～1.24 (50 ℃) that filtrate is concentrated into relative density, handles 2 times with ethanol precipitation, and containing amount of alcohol in the solution for the first time is 65%, be 85% for the second time, each all cold preservation is placed, and reclaims ethanol to there not being the alcohol flavor, be diluted with water to every 1ml and be equivalent to crude drug 2g, cold preservation was placed 24 hours, filtered, filtrate decompression concentrates, vacuum drying, promptly.By the Ramulus Uncariae Cum Uncis extract of this prepared, Rhomotoxine content is not less than 30%.
Test example 9 Herba Epimedii extracts, Ramulus Uncariae Cum Uncis extract, the test of gastrodine drug combination drug efficacy study---to the influence of rat blood pressure
The healthy male rat of animal subject, 310, body weight 200～230g is divided into 31 groups at random, 10 every group.
The test sample Herba Epimedii extract: self-control contains Herba Epimedii total flavones 81.24%, icariin 17.23%
Ramulus Uncariae Cum Uncis extract: self-control contains Rhomotoxine 82.21%
Gastrodine: commercial, Beijing Taiyang Pharmaceutical Co., Ltd.
The injection of Herba Epimedii extract+Ramulus Uncariae Cum Uncis extract+each proportioning of gastrodine: self-control sees Table 7
Herba Epimedii extract injection: self-control, 1ml: 10mg
Ramulus Uncariae Cum Uncis extract injection: self-control, 1ml: 10mg
Gastrodine injection: commercial, 1ml: 100mg, Beijing Double-Crane Pharmaceutical Co., Ltd
Sodium chloride injection: commercial, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.
Table 7 Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine drug combination to the influence of rat blood pressure (meansigma methods ± standard deviation, n=10)
| Animal groups | Proportioning | Blood pressure/kPa | Administration time | ||
| Before the administration | Administration 1h | 1h after the administration | |||
| Sodium chloride injection control group Shorthorned Epimedium P.E parenteral solution uncaria extract parenteral solution Injectio of gastrodine Shorthorned Epimedium P.E+uncaria extract+Gastrodin | - - - - 50mg+8mg+100mg 50mg+8mg+200mg 50mg+8mg+400mg 50mg+16mg+100mg 50mg+16mg+200mg | SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP | 20.42±1.04 13.78±0.77 20.51±1.03 13.81±0.71 20.06±0.72 14.23±0.88 20.32±1.02 14.21±1.01 20.44±1.10 14.17±0.56 20.25±1.07 13.67±0.57 20.41±1.08 13.71±0.62 20.15±0.47 14.22±0.75 20.17±0.98 13.97±1.21 | 20.33±1.12 13.77±0.87 17.25±1.13 12.13±1.15 17.02±1.08 12.11±1.23 17.03±1.06 12.07±0.97 * 15.42±1.05 ** 9.65±1.03 ** 15.44±0.98 * 9.25±1.11 ** 16.00±1.01 * 9.53±1.03 ** 15.84±1.01 * 10.33±0.97 ** 15.32±1.12 * 9.59±1.20 ** | 20.37±0.97 13.75±0.91 16.45±1.09 * 11.41±0.62 * 15.82±1.26 * 11.29±0.67 * 16.02±0.85 * 11.32±0.75 * 13.42±1.03 ** 7.20±1.13 ** 13.71±1.13 ** 7.36±0.99 ** 14.82±0.79 ** 8.23±0.97 ** 14.86±1.12 ** 9.21±0.87 ** 13.39±0.79 ** 7.89±0.76 ** |
| Herba Epimedii extract+Ramulus Uncariae Cum Uncis extract+gastrodine | 50mg+16mg+400mg 50mg+32mg+100mg 50mg+32mg+200mg 50mg+32mg+400mg 100mg+8mg+100mg 100mg+8mg+200mg 100mg+8mg+400mg 100mg+16mg+100mg 100mg+16mg+200mg 100mg+16mg+400mg 100mg+32mg+100mg 100mg+32mg+200mg 100mg+32mg+400mg 200mg+8mg+100mg 200mg+8mg+200mg 200mg+8mg+400mg 200mg+16mg+100mg 200mg+16mg+200mg 200mg+16mg+400mg 200mg+32mg+100mg 200mg+32mg+200mg 200mg+32mg+400mg | SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP SAP DAP | 19.96±1.08 13.49±0.89 20.27±0.79 13.97±0.74 20.43±1.04 13.89±0.68 20.05±0.82 14.43±0.81 20.46±1.07 14.01±1.21 20.39±1.11 14.02±0.74 20.45±1.13 13.97±0.72 20.32±1.05 13.78±0.69 20.15±0.77 13.75±0.68 20.23±1.02 14.19±1.01 20.35±1.09 13.91±1.21 20.37±1.02 13.88±0.86 20.36±1.05 13.81±0.67 20.09±0.54 13.97±0.82 20.34±0.95 14.23±1.04 20.19±1.07 13.83±0.73 20.16±0.97 13.89±0.74 20.33±1.12 13.94±0.82 20.15±0.43 14.13±0.67 20.35±0.92 14.12±1.04 20.41±1.13 13.82±0.55 20.46±1.08 13.93±0.77 | 15.74±1.09 * 9.78±1.05 ** 16.09±1.10 * 9.97±0.93 ** 15.89±0.84 * 9.69±0.73 ** 15.42±1.06 * 10.11±1.12 ** 16.27±1.05 * 10.25±1.15 ** 15.73±1.12 * 9.71±0.86 ** 15.97±1.03 * 9.88±1.00 ** 15.48±0.84 * 9.29±1.10 ** 15.03±1.17 ** 9.27±1.04 ** 15.31±1.11 * 9.40±1.05 ** 16.13±1.14 * 10.37±0.91 ** 15.56±1.04 * 9.34±0.85 ** 15.92±1.03 * 9.80±0.82 ** 15.92±1.13 * 10.46±1.05 ** 16.12±1.14 * 10.72±1.05 ** 15.70±1.13 * 9.64±0.76 ** 15.87±1.04 * 10.52±0.97 ** 15.69±1.04 * 9.64±1.03 ** 15.37±0.82 * 9.51±0.92 ** 16.02±0.94 * 10.74±0.89 ** 16.10±1.11 * 9.73±1.04 ** 15.35±1.06 ** 9.43±1.01 ** | 14.29±0.83 ** 8.51±0.82 ** 14.46±0.75 ** 8.58±0.91 ** 14.41±0.72 ** 8.01±0.92 ** 13.72±0.76 ** 8.34±0.84 ** 15.14±0.92 ** 9.12±0.59 ** 14.54±0.84 ** 8.41±1.03 ** 14.63±0.95 ** 8.46±0.86 ** 13.67±0.98 ** 7.29±0.82 ** 13.01±1.04 ** 6.64±1.14 ** 13.34±1.10 ** 7.42±0.86 ** 15.00±1.12 ** 9.07±0.74 ** 13.69±0.95 ** 7.47±0.81 ** 14.44±0.84 ** 8.39±0.79 ** 14.87±1.05 ** 9.25±1.02 ** 14.55±1.12 ** 9.40±1.06 ** 14.27±0.85 ** 8.31±0.77 ** 14.85±1.06 ** 9.10±0.89 ** 14.13±1.00 ** 7.85±1.06 ** 13.42±0.94 ** 7.62±0.84 ** 15.14±0.87 ** 9.53±0.77 ** 14.87±0.96 ** 8.22±0.85 ** 14.41±1.05 ** 6.91±0.97 ** |
*：p＜0.05，
**p＜0.01
The solution that all is mixed with 1mg/ml with sodium chloride injection with preceding is faced in the preparation of test liquid
Dosage 10mg/kg (10ml/kg instillation 1h)
Test method is respectively organized rat all with 2% pentobarbital sodium 45mg/kg intraperitoneal injection of anesthesia.Separate trachea, insert tracheal casing pipe; Separate right common carotid artery, intubate is after pressure transducer connects GY-40 four road physiology monitor record systolic pressure (SAP), diastolic pressure (DAP) and mean arterial pressures (MAP); Write down limbs II lead electrocardiogram simultaneously.Different medicines injects femoral vein by the WZ-50G micro-injection pump with 10ml/kg per hour, observes the periphery blood pressure of administration 0.5h, 1.0h and drug withdrawal 1h.
Result of the test and conclusion result of the test see Table 7.The result shows that Herba Epimedii extract+Ramulus Uncariae Cum Uncis extract+gastrodine administration group is compared with matched group, and systolic pressure, diastolic pressure, mean arterial pressure all significantly reduce (p＜0.01); Herba Epimedii extract injection administration group, Ramulus Uncariae Cum Uncis extract injection administration group, gastrodine injection administration group are compared with matched group, and systolic pressure, diastolic pressure, mean arterial pressure all obviously reduce (p＜0.05).And the effect of each proportioning administration group of Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine all is better than the effect of individually dosed group of Herba Epimedii extract injection, Ramulus Uncariae Cum Uncis extract injection or puerarin injection, points out three medicines that synergistic function is arranged; Proportioning effect with 100: 16: 200 is best, points out may be best proportioning at 100: 16: 200.
Test example 10 Herba Epimedii extracts, Ramulus Uncariae Cum Uncis extract, gastrodine drug combination are to the hemodynamic influence of dog
Animal subject hybrid dog, 54, the male and female dual-purpose, body weight 10.0～12.0kg is divided into 9 groups at random, 6 every group.
Test sample YGT injection 1: self-control, 5ml: 316mg contains Herba Epimedii extract 100mg, Ramulus Uncariae Cum Uncis extract 16mg, gastrodine 200mg
YGT injection 2: self-control, 5ml: 282mg contains Herba Epimedii extract 50mg, Ramulus Uncariae Cum Uncis extract 32mg, gastrodine 200mg
YGT injection 3: self-control, 5ml: 408mg contains Herba Epimedii extract 200mg, Ramulus Uncariae Cum Uncis extract 8mg, gastrodine 200mg
YGT injection 4: self-control, 5ml: 458mg contains Herba Epimedii extract 50mg, Ramulus Uncariae Cum Uncis extract 8mg, gastrodine 400mg
YGT injection 5: self-control, 5ml: 332mg contains Herba Epimedii extract 200mg, Ramulus Uncariae Cum Uncis extract 32mg, gastrodine 100mg
Herba Epimedii extract injection: 1ml: 10mg, self-control
Ramulus Uncariae Cum Uncis extract injection: 1ml: 10mg, self-control
Gastrodine injection: commercial, 2ml: 100mg, Yantai Lu Yin pharmaceutcal corporation, Ltd
Sodium chloride injection: Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.
Dosage 10mg/kg
The test method dog is anaesthetized with 3% pentobarbital sodium 1ml/kg forelimb intravenous injection, and dorsal position is fixed on the operating-table, cuts off the hair of cervical region, chest and right hind inboard.75% ethanol disinfection cropping district.Separate trachea, and insert tracheal intubation, be equipped with the artificial respiration and use; Separate external jugular vein, and enter right atrium and reach auricular sious through superior vena cava, be used to extract the blood of Coronary vein from the external jugular vein intubate; Separate femoral vein, insert venous cannulation, slow constant speed is injected 10% glucose in the whole experiment.Separate femoral artery, insert arterial cannulation (being full of the heparin sodium normal saline of 25U/ml in the pipe), connect TP-400T type pressure transducer, by AP-641G type blood pressure amplifier recording blood pressure (systolic pressure SAP, diastolic pressure DAP, mean arterial pressure MAP).Under the artificial respiration, open breast, cut off pericardium, separate root of ascending aorta and ramus descendens anterior arteriae coronariae sinistrae in the 4th intercostal, place respectively suitable internal diameter the electromagnetic blood flowmeter probe (13,2mm) measure cardiac output (CO) and coronary artery blood flow (CBF).With left ventricular cannulation (being full of the heparin-saline of 25U/ml in the pipe) in left ventricle heart mistake portion inserts left ventricle, by TP-400T type pressure transducer, by AP-641G type blood pressure amplifier record left indoor pressure (LVP), write down left chamber EDP (LVEDP) by AD-601G type amplifier: it is subcutaneous that needle electrode is inserted the dog extremity, traces standard I I lead electrocardiogram (ECG).Above-mentioned measuring-signal is all imported RM-6000 type eight road physiology monitor records, traces.The biomedical biosignal processing system of the signal of telecommunication of cardiac output, electrocardio, blood pressure and intraventricular pressure being imported microcomputer is handled simultaneously, and reads intraventricular pressure peak value (LVSP), EDP (LVEDP), ventricular systole parameter (+dp/dt by microcomputer
Max), ventricular diastole parameter (dp/dt
Max).At last, calculate parameters (TPVR) such as cardiac index (CI), stroke volume (SV), SI (SI), every stroke work index (SWI), blood vessel total peripheral resistance.Stablize 20min after operation is finished, medicine is dissolved in the 100ml normal saline, drip the people through the femoral vein constant speed in the 15min.
1h, 2h extract left ventricle and crown venous blood respectively before administration, after the administration, and anticoagulant heparin is injected among the i-STAT G3+Cartridges (G3+ of i-STAT company type test pieces), measure the artery and vein blood oxygen pressure by blood gas analyzer.Myocardial oxygen consumption is calculated by the Kanter formula, and its formula is: MVO
2=3.25 * 10 * CF (PaO
2-PvO
2)/Wt.MVO
2Be meant the oxygen consumption of chamber, every 100g left side cardiac muscle, CF is a coronary flow, PaO
2, PvO
2Represent the artery and vein blood oxygen pressure respectively, Wt is that left compartment muscle is heavy.
All data are all represented with meansigma methods ± standard deviation, according to the variation of each index in each group of medication front and back, adopt pairing t-to check and judge the statistical significance that the various indexs in medication front and back change.
Result of the test (1) is to the influence of the total peripheral vascular resistance of anesthetized dog: with matched group relatively, each proportioning YGT injection group all can obviously reduce the total peripheral vascular resistance of anesthetized dog (p＜0.01), and Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group, gastrodine group can obviously reduce the total peripheral vascular resistance of anesthetized dog (p＜0.05).
(2) to the influence of chamber, anesthetized dog left side EDP: with matched group relatively, each proportioning YGT injection group all can obviously reduce anesthetized dog left side chamber EDP (p＜0.01), and Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group, gastrodine injection group can obviously reduce anesthetized dog left side chamber EDP (p＜0.05).
(3) to the influence of anesthetized dog coronary artery blood flow: with matched group relatively, each proportioning YGT injection group all can obviously increase anesthetized dog coronary artery blood flow (p＜0.01), and Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group, gastrodine injection group can obviously increase anesthetized dog coronary artery blood flow (p＜0.05).
(4) to the influence of anesthetized dog ventricular systole parameter: with matched group relatively, each proportioning YGT injection group all can obviously increase anesthetized dog ventricular systole parameter (p＜0.01), and Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group, gastrodine injection group can obviously increase anesthetized dog ventricular systole parameter (p＜0.05).
(5) to the influence of anesthetized dog ventricular diastole parameter: with matched group relatively, each proportioning YGT injection group all can obviously increase anesthetized dog ventricular diastole parameter (p＜0.01), and Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group, gastrodine injection group can obviously increase anesthetized dog ventricular diastole parameter (p＜0.05).
(6) to the influence of anesthetized dog cardiac output, stroke volume, cardiac index and SI: with matched group relatively, each proportioning YGT injection group all can obviously increase cardiac output, stroke volume, cardiac index, the SI (p＜0.01) of anesthetized dog, Herba Epimedii extract group, Ramulus Uncariae Cum Uncis extract group can obviously increase cardiac output, stroke volume, cardiac index, the SI (p＜0.05) of anesthetized dog, and the gastrodine injection group can not obvious to the cardiac output of anesthetized dog (p＞0.05).
But conclusion Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract group, gastrodine drug combination coronary blood flow increasing, reduce left chamber EDP, significantly improve the blood-pumping function of heart, significantly improve the contraction and the diastolic function of heart, hemodynamics is had.The effect of Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract group, gastrodine drug combination is better than the effect of Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract group or the independent medication of gastrodine, points out three kinds of medicines that synergistic function is arranged.
Test example 11 Herba Epimedii extracts, Ramulus Uncariae Cum Uncis extract, gastrodine drug combination are to the immunosuppressed mice Immune Effects
The animal subject mice, 50, the male and female dual-purpose, body weight 25～28g is divided into 5 groups at random, 10 every group.
Test sample YGT injection 1: self-control, 5ml: 316mg contains Herba Epimedii extract 100mg, Ramulus Uncariae Cum Uncis extract 16mg, gastrodine 200mg
YGT injection 6: self-control, 5ml: 232mg contains Herba Epimedii extract 100mg, Ramulus Uncariae Cum Uncis extract 32mg, gastrodine 100mg
YGT injection 7: self-control, 5ml: 416mg contains Herba Epimedii extract 200mg, Ramulus Uncariae Cum Uncis extract 16mg, gastrodine 200mg
Sodium chloride injection: Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.
Dosage 30mg/kg
The test method mice is divided into 5 groups at random, is respectively YGT injection 1,6,7 administration groups after normal control group, irradiation control group, the irradiation.Handle 4 groups of irradiation group mices with the radiation gamma of 5Gy.Shine and began with the administration of lumbar injection mode the same day, administration concentration is 30mg/kg, with the sterile saline is contrast, successive administration 10 days, wherein pressed 0.5ml/ with 2%sRBC on the 6th day all mices row lumbar injection immunity are got blood behind the 10th day eyeball, dislocation is put to death, get spleen and obtain splenocyte, be made into 1 * 10
6Individual/ml is standby.Measure serum agglutinin, hemolysis plaque formation cell (PFC) and E rosette formation rate.
Table 8 Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine drug combination are to the immunosuppressed mice Immune Effects
(meansigma methods ± standard deviation, n=10)
| Organized by examination | Anti-sheep red blood cell (SRBC) antibody horizontal | Plaque forming cells's number | E rosette formation rate |
| 7 groups of 6 groups of YGT injection of 1 group of YGT injection of sodium chloride injection matched group irradiation control group YGT injection | 2.03+1.05 1.12+1.54 ** 1.92+1.24¤ 1.87+1.42¤ 1.89+1.32¤ | 0.159+0.0087 0.033+0.0017 ** 0.138+0.0097¤ 0.135+0.0059¤ 0.136+0.0076¤ | 5.34+0.72 2.65+0.86 * 13.4+1.02 **¤¤ 12.7+1.21 **¤¤ 13.0+0.95 **¤¤ |
Compare with the sodium chloride injection matched group:
*P＜0.05,
*P＜0.01; Compare with irradiation control group: ¤ p＜0.05, ¤ ¤ p＜0.01
Result of the test and conclusion The results see Table 8.Compare with sodium chloride injection matched group serum agglutinin level, irradiation group antibody horizontal significantly reduces (p＜0.01), and irradiation back YGT injection administration group antibody horizontal reduces a little, but does not have significant difference.Irradiation back YGT injection administration group is compared with irradiation control group, and administration group antibody horizontal obviously raises (p＜0.05), does not have significant difference between the different dosing group.Form cell number with the hemolysis plaque of sodium chloride injection matched group and compare, irradiation group level significantly reduces (p＜0.01), and irradiation back YGT injection administration group level reduces a little, but does not have significant difference.Irradiation back YGT injection administration group is compared with irradiation control group PFC, and administration group level all obviously raises (p＜0.05), does not have significant difference between the different dosing group.Compare with the E rosette formation rate of sodium chloride injection matched group, irradiation control group obviously reduces (p＜0.05), and irradiation back YGT injection administration group all significantly raises (p＜0.01), does not have significant difference between the different dosing group.The above results shows that Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine drug combination can significantly improve the cellular immunization and the humoral immune function of immunosuppressed mice.
Test example 11 YGT injection long-term stable experiments
Test sample YGT injection 1, self-control, 5ml: 316mg contains Herba Epimedii extract 100mg, Ramulus Uncariae Cum Uncis extract 16mg, gastrodine 200mg
Investigation project character, pH value, clarity, related substance, sign content, and at the aseptic and pyrogen test of long term test end of term increase
Test method is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and was placed 12 months.Respectively at 3rd month, 6 months, 9 months, 12 months, relatively after the outward appearance, test every index, with result and comparison in 0 month; And at 12 aseptic and pyrogen tests of increase at the end of month.
Placed under the condition of 25 ℃ ± 2 ℃ of result of the test temperature, relative humidity 60% ± 10% 12 months, every index has no significant change, and at 12 the end of month of long term test, pyrogen, sterility test are all up to specification.
Conclusion (of pressure testing) is reached a conclusion by above-mentioned investigation result, and in the long term test, YGT injection 1 is stable.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.Adjuvant in following examples among each dosage form preparation technology can be replaced with acceptable accessories, perhaps reduces, increases.Replace Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract and gastrodine compositions with YGT among the embodiment.
The preparation of embodiment 1 Herba Epimedii extract and discriminating and assay
Get epimedium herb, cut into pieces, decoct with water 2 times, each 1.5 hours, add water was 10 times of amounts at every turn.Collecting decoction, cold preservation are placed and are spent the night, and filter, filtrate is concentrated into the concentrated solution of relative density 1.08～1.10, be added on the polyamide resin column of having handled well, the water with 3～4 times of column volumes washes 20% alcohol flushing of 2～3 times of column volumes of reuse earlier, discard cleaning mixture, 95% ethanol of 4～5 times of column volumes of reuse carries out eluting, collects eluent, reclaims ethanol, spray drying, promptly.
Produce three batches respectively, and according to
Test example 2With
Test example 3Method under is differentiated and assay, the results are shown in Table 9.
The assay result and the yield of table 9 Herba Epimedii extract
| Batch | Herba Epimedii total flavones content (%) | Icariin content (%) | Yield (%) |
| 1 2 3 | 81.24 83.35 84.21 | 17.23 18.11 18.42 | 2.73 2.47 2.33 |
The preparation of embodiment 2 Ramulus Uncariae Cum Uncis extracts and discriminating and assay
Hook taking rattan 1000g is ground into coarse powder, adds 70% alcohol reflux 2 times, and each 2 hours, add alcohol at every turn and be 10L, merge extractive liquid, filters, and reclaims ethanol to there not being the alcohol flavor, adds water to an amount of (every 1ml is equivalent to crude drug 2g).Stir evenly, add concentrated hydrochloric acid adjust pH to 1～2, cold preservation was placed 4 hours, filter, filtrate adds the petroleum ether jolting extracts 1 time, discards petroleum ether liquid, acid liquid adds 10% sodium hydroxide adjust pH to 9～10, and cold preservation is placed and spent the night, the leaching precipitation, the dilute hydrochloric acid that adds 1mol/l again makes dissolving, and cold preservation was placed 4 hours, filters, filtrate adds 10% sodium hydroxide adjust pH to 9～10 again, and cold preservation is placed and spent the night, the leaching precipitation, vacuum drying, promptly.
Produce three batches respectively, and according to
Test example 6With
Test example 7Method under is differentiated and assay, the results are shown in Table 10.
The assay result and the yield of table 10 Ramulus Uncariae Cum Uncis extract
| Batch | Total alkaloid content (%) | Yield (%) |
| 1 2 3 | 82.21 83.57 85.33 | 1.29 1.27 1.13 |
The preparation technology of test example 3 YGT injection
1, prescription:
Prescription 1
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 2
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 4
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 40g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 5
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 6
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 200g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 7
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 400g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 8
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 400g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 9
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 400g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 10
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
2, concrete steps:
(1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse;
(2) fully with heated and stirred dissolving in the water for injection of Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine adding dosing amount 80%;
(3) benefit adds to the full amount of water for injection;
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes;
(5) through sand filtration rod filtering decarbonization, measure the also pH value of regulator solution;
(6) through the microporous filter membrane fine straining of 0.45 μ m;
(7) clarity of inspection solution, the semi-finished product chemical examination;
(8) with the solution sealing by fusing in glass ampule;
(9) 100 ℃ of flowing steam sterilizations 30 minutes;
(10) while hot sample being put into 0.01% methylene blue solution hunts leak;
(11) lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation technology of embodiment 2 injection YGT
1, prescription:
Prescription 1
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Mannitol 700g
Sterile water for injection adds to 2500ml
Prepare 1000 altogether
Prescription 2
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 400g
Mannitol 700g
Sterile water for injection adds to 2500ml
Prepare 1000 altogether
Prescription 3
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 100g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 4
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 100g
Mannitol 700g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 5
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 32g
Gastrodine 200g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 6
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 400g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 7
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 200g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 8
Herba Epimedii extract 50g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 100g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 9
Herba Epimedii extract 200g
Ramulus Uncariae Cum Uncis extract 8g
Gastrodine 200g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
Prescription 10
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 400g
Mannitol 400g
Sterile water for injection adds to 4000ml
Prepare 1000 altogether
2, concrete steps:
(1) vessel of at first dosing being used and antibiotic glass bottle, plugs etc. carry out aseptic process;
(2) take by weighing supplementary material according to recipe quantity;
(3) heating for dissolving in Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine adding dosing amount 50% sterile water for injection is complete; It is complete that mannitol adds the sterile water for injection heated and stirred dissolving of dosing amount 30%, merges above-mentioned solution, adds sterile water for injection to full dose;
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes;
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution;
(6) through the microporous filter membrane fine straining of 0.22 μ m;
(7) clarity of inspection solution, the semi-finished product chemical examination;
(8) be sub-packed in the antibiotic glass bottle half tamponade; Sample is put into the freeze dryer lyophilization;-45 ℃ of pre-freezes 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then;
(9) lyophilizing finishes, and lid is rolled in tamponade;
(10) finished product is examined entirely, the packing warehouse-in.
The preparation technology of embodiment 3 YGT sodium chloride injections
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
2, concrete steps:
(1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse;
(2) Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine are added the dissolving of dosing amount 40% water for injection heated and stirred fully, sodium chloride is complete with the water for injection dissolving of dosing amount 20%;
(3) merge two solution, benefit adds to the full amount of water for injection;
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes;
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution;
(6) through the microporous filter membrane fine straining of 0.45 μ m;
(7) clarity of inspection solution, the semi-finished product chemical examination;
(8) fill is in the infusion bottle of 100ml;
(9) 115 ℃ of pressure sterilizings 30 minutes;
(10) lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation technology of embodiment 4 YGT glucose injections
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
2, concrete steps:
(1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse;
(2) with heated and stirred dissolving in Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine adding dosing amount 20% water for injection fully, that glucose is complete with the water for injection dissolving of dosing amount 20%, heated and boiled 15 minutes;
(3) merge two solution, benefit adds to the full amount of water for injection;
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes;
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution;
(6) through the microporous filter membrane fine straining of 0.45 μ m;
(7) clarity of inspection solution, the semi-finished product chemical examination;
(8) fill is in the infusion bottle of 100ml;
(9) 115 ℃ of pressure sterilizings 30 minutes;
(10) lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation technology of embodiment 5 YGT drop pill
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Polyethylene glycol 6000 600g
Prepare 1000 balls altogether
2, concrete steps:
(1) polyethylene glycol 6000 heating and melting in water-bath;
(2) add Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine, stirring and dissolving after the whole fusions of polyethylene glycol 6000;
(3) crossing 60 mesh sieves filters;
(4) maintenance splashes in the liquid paraffin that is chilled to below 10 ℃ for 60 ℃ and makes ball;
(5) finished product is examined entirely, the packing warehouse-in.
The preparation technology of embodiment 6 YGT sheets
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Carboxymethylstach sodium 12.0g
Prepare 1000 altogether
2, concrete steps:
(1) it is standby Herba Epimedii extract and gastrodine to be pulverized 100 mesh sieves;
(2) take by weighing supplementary material according to recipe quantity;
(3) hypromellose 2% the aqueous solution made soluble in water is standby;
(4) with Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material;
(5) cross 20 mesh sieve system granules;
(6) granule is dried under 60 ℃ condition;
(7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously;
(8) sampling, the semi-finished product chemical examination;
(9) the sheet weight sheet of determining according to chemical examination;
(10) finished product is examined entirely, the packing warehouse-in.
The capsular preparation technology of embodiment 7 YGT
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Starch 60.0g
Microcrystalline Cellulose 20.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 1.0g
Prepare 1000 altogether
2, concrete steps:
(1) it is standby Herba Epimedii extract and gastrodine to be pulverized 100 mesh sieves;
(2) take by weighing supplementary material according to recipe quantity;
(3) hypromellose 2% the aqueous solution made soluble in water is standby;
(4) with Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material;
(5) cross 20 mesh sieve system granules;
(6) granule is dried under 60 ℃ condition;
(7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously;
(8) sampling, the semi-finished product chemical examination;
(9) loading amount of determining according to chemical examination incapsulates;
(10) finished product is examined entirely, the packing warehouse-in.
Embodiment 8 YGT preparation of soft capsule technologies
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Soybean oil 400g
Soybean phospholipid 20g
Cera Flava 12g
Prepare 1000 altogether
2, concrete steps:
(1) soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put cold;
(2) add Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine, mixing is crossed colloid mill;
(3) sampling, the semi-finished product chemical examination;
(4) be pressed into soft capsule;
(5) finished product is examined entirely, the packing warehouse-in.
Embodiment 9 YGT oral liquid preparation technologies
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Sodium benzoate 15g
Stevioside 10g
Water adds to 10000ml
Prepare 1000 altogether
2, concrete steps:
(1) fully with heated and stirred dissolving in the purified water of Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine adding dosing amount 50%;
(2) sodium benzoate and stevioside is complete with the water dissolution of dosing amount 20%;
(3) merge above-mentioned two solution, mend and add water to full dose;
(4) filtering with microporous membrane of mistake 0.8 μ m;
(5) semi-finished product chemical examination;
(6) fill; Finished product is examined entirely, the packing warehouse-in.
The particulate preparation technology of embodiment 10 YGT
1, prescription:
Herba Epimedii extract 100g
Ramulus Uncariae Cum Uncis extract 16g
Gastrodine 200g
Icing Sugar 1800.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
2, concrete steps:
(1) it is standby sucrose to be pulverized 100 mesh sieves; It is standby that Herba Epimedii extract and gastrodine were pulverized 100 mesh sieves;
(2) take by weighing supplementary material according to recipe quantity;
(3) the method mix homogeneously that Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine and Icing Sugar are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material;
(4) cross 20 mesh sieve system granules;
(5) granule is dried under 60 ℃ condition;
(6) dried granule is crossed 18 mesh sieve granulate;
(7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule;
(8) packing; Finished product is examined entirely, the packing warehouse-in.
Claims (10)
1, a kind of pharmaceutical composition is characterized in that it comprises Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine.
2, pharmaceutical composition as claimed in claim 1 is characterized in that described Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine are calculated as according to composition by weight: 20～500 parts of Herba Epimedii extracts, 3～80 parts of Ramulus Uncariae Cum Uncis extracts, 40～1000 parts of gastrodine.
3, pharmaceutical composition as claimed in claim 2 is characterized in that described Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine are calculated as according to composition by weight: 50～200 parts of Herba Epimedii extracts, 8～32 parts of Ramulus Uncariae Cum Uncis extracts, 100～400 parts of gastrodine.
4, pharmaceutical composition as claimed in claim 3 is characterized in that described Herba Epimedii extract, Ramulus Uncariae Cum Uncis extract, gastrodine are calculated as according to composition by weight: 100 parts of Herba Epimedii extracts, 16 parts of Ramulus Uncariae Cum Uncis extracts, 200 parts of gastrodine.
5, as the described arbitrary pharmaceutical composition of claim 1～4, in the application that brings high blood pressure down, improves aspect hemodynamics, immunomodulating, neurasthenia, the resisting cardiovascular disease.
6,, it is characterized in that described Herba Epimedii extract contains that Herba Epimedii total flavones is not less than 20%, icariin is not less than 4% as the described arbitrary pharmaceutical composition of claim 1～4.
7,, it is characterized in that described Ramulus Uncariae Cum Uncis extract contains Rhomotoxine and is not less than 30% as the described arbitrary pharmaceutical composition of claim 1～4.
8,, it is characterized in that said composition can be made into any clinically or pharmaceutically acceptable dosage form as the described arbitrary pharmaceutical composition of claim 1～4.
9, pharmaceutical composition as claimed in claim 8 is characterized in that said composition can be made into injection or oral formulations.
10, pharmaceutical composition as claimed in claim 9 is characterized in that said composition can be made into injection, and Herba Epimedii extract wherein contains that Herba Epimedii total flavones is not less than 50%, icariin is not less than 10%, and Ramulus Uncariae Cum Uncis extract contains Rhomotoxine and is not less than 50%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100445307A CN1923241B (en) | 2005-08-31 | 2005-08-31 | Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100445307A CN1923241B (en) | 2005-08-31 | 2005-08-31 | Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1923241A true CN1923241A (en) | 2007-03-07 |
| CN1923241B CN1923241B (en) | 2010-04-28 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005100445307A Active CN1923241B (en) | 2005-08-31 | 2005-08-31 | Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use |
Country Status (1)
| Country | Link |
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| CN (1) | CN1923241B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791342B (en) * | 2009-02-04 | 2012-05-23 | 复旦大学 | Uncaria extract and application thereof in preparing medicines for reducing blood fat and resisting cardiac hypertrophy |
| CN102626453A (en) * | 2011-09-09 | 2012-08-08 | 吉林省博时药物新技术开发有限公司 | Method for preparing total alkaloids of uncaria |
| CN102698091A (en) * | 2012-06-04 | 2012-10-03 | 黄芸 | Traditional Chinese medicine oral liquid for relieving neurasthenia and preparation method |
| WO2013143323A1 (en) * | 2012-03-31 | 2013-10-03 | 昆明制药集团股份有限公司 | Application of gastrodin as solubilizer and method for preparing injection or powder for injection |
| CN106421447A (en) * | 2016-12-21 | 2017-02-22 | 福建中医药大学 | Medicine composition for controlling blood pressure and protecting blood vessels and preparation method and purpose thereof |
| CN109342585A (en) * | 2018-10-10 | 2019-02-15 | 泓博元生命科技（深圳）有限公司 | The determination method of Herba Epimedii |
-
2005
- 2005-08-31 CN CN2005100445307A patent/CN1923241B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791342B (en) * | 2009-02-04 | 2012-05-23 | 复旦大学 | Uncaria extract and application thereof in preparing medicines for reducing blood fat and resisting cardiac hypertrophy |
| CN102626453A (en) * | 2011-09-09 | 2012-08-08 | 吉林省博时药物新技术开发有限公司 | Method for preparing total alkaloids of uncaria |
| WO2013143323A1 (en) * | 2012-03-31 | 2013-10-03 | 昆明制药集团股份有限公司 | Application of gastrodin as solubilizer and method for preparing injection or powder for injection |
| CN102698091A (en) * | 2012-06-04 | 2012-10-03 | 黄芸 | Traditional Chinese medicine oral liquid for relieving neurasthenia and preparation method |
| CN106421447A (en) * | 2016-12-21 | 2017-02-22 | 福建中医药大学 | Medicine composition for controlling blood pressure and protecting blood vessels and preparation method and purpose thereof |
| CN109342585A (en) * | 2018-10-10 | 2019-02-15 | 泓博元生命科技（深圳）有限公司 | The determination method of Herba Epimedii |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1923241B (en) | 2010-04-28 |
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Effective date of registration: 20081212 Address after: Room 6304, office building, Jinhua sea logistics center, 14A, Hainan, Hainan Yangpu Economic Development Zone, zip code: 570125 Applicant after: Hainan four ring Pharmaceutical Co., Ltd. Co-applicant after: Beijing Sihuan Pharmaceutical Co., Ltd. Co-applicant after: Hainan Sihuan Research Institute of Cardio-cerebral Vascular Medicine Co., Ltd. Address before: The new business building, No. 48 Hainan city of Haikou province China World Trade Center Avenue, 31 floor post encoding: 570125 Applicant before: Hainan Sihuan Pharmaceutical Co.,Ltd |
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Effective date of registration: 20220216 Address after: 101114 Beijing city Tongzhou District Zhangjiawan Village East Shanzhuang Qi Patentee after: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee after: HAINAN SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee after: Shenzhen Sihuan Pharmaceutical Co.,Ltd. Address before: 570125, Hainan Yangpu Economic Development Zone 14A Hainan Jinhua sea logistics center office building, room 6304 Patentee before: HAINAN SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee before: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee before: Hainan Sihuan Cardiovascular Drug Research Institute Co.,Ltd. Patentee before: Shenzhen Sihuan Pharmaceutical Co.,Ltd. |