CN100484543C - Medicament composition for treating hepatitis, prepartion method and use - Google Patents

Medicament composition for treating hepatitis, prepartion method and use Download PDF

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CN100484543C
CN100484543C CNB2004100815511A CN200410081551A CN100484543C CN 100484543 C CN100484543 C CN 100484543C CN B2004100815511 A CNB2004100815511 A CN B2004100815511A CN 200410081551 A CN200410081551 A CN 200410081551A CN 100484543 C CN100484543 C CN 100484543C
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medicine
injection
acute
extract
chronic hepatitis
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CN1795893A (en
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蒲旭峰
杨幼琪
银海
林庆华
文永盛
张德波
孙继林
曾雁鸣
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Chengdu Dikang pharmaceutical Limited by Share Ltd
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DIKANG SCIENCE AND TECHNOLOGY PHARMACEUTICAL Co Ltd SICHUAN PROV
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Abstract

A Chinese medicine for treating hepatitides by oral taking or injecting is prepared from red sage root and notoginseng. Its preparing process is also disclosed.

Description

A kind of pharmaceutical composition for the treatment of hepatitis and its production and use
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of hepatitis, specifically, relating to Chinese medicine is the pharmaceutical composition of treatment hepatitis of feedstock production, belongs to the field of Chinese medicines.
Background technology
Liver is one of internal organs of wanting of body weight for humans, and theory of Chinese medical science is thought, main catharsis and main store blood are the major physiological functions of liver.Liver controlling conveyance and dispersion means that liver has diastole, carries out, transfers to reach, declare and loose, circulate to keep the smooth effect of whole body mechanism of qi a surname.The normal performance of this function can be regulated spiritual feelings will, makes the people in high spirits, and is happy; But facilitating digestion absorbs again, coordinates the taste ascending or descending movement of vital Qi; Can also keep the operation of QI and blood, regulate the metabolism of water liquid.Liver storing blood is meant that liver has storage blood again and regulates the effect of blood volume.The blood that liver is hidden is the material base of its catharsis function, and catharsis is again the function performance of store blood.Catharsis normal relies moistening of cloudy blood foster entirely; The operation of blood is unobstructed, be unable to do without the adjusting of irritability again.In case the liver failing to maintain the normal flow of QI, the resistance of the liver blood stasis of blood then appears in depression and stagnation of QI, and dysfunction of the spleen in transportation stops in the expectorant water, and then causes the enlargement of liver body, and the side of body is the convulsion pain down, and liver function waits pathological change unusually.
At present, " antihepatitis drug " of western medical treatment clinical practice mainly contains three major types: antiviral agents, immunomodulator and hepatoprotective medicine (vitamin medicaments, have function of detoxification class medicine, promote energy metabolism class medicine, promote protein synthesis class medicine).Antiviral agents mainly contains interferons antiviral agents and ucleotides antiviral agents, and clinical practice mainly contains interferon and lamivudine; The main clinical practice of immunomodulator thymosin, lentinan etc. are arranged; The clinical practice of hepatoprotective medicine mainly contain diammonium glycyrrhizinate (diammonium glycyrrhizinate), kurarinone etc.But, often all be to carry out symptomatic treatment clinically at the abnormal liver function symptom because the treatment of the nosetiology of viral hepatitis does not still have breakthrough so far.
In the Chinese medicine of the abnormal liver function that hepatitis etc. is caused, be the main rule of treatment with clearing away heat and eliminating dampness, blood circulation promoting and blood stasis dispelling, strengthening the body resistance.Wherein,, can contain medical material Radix Salviae Miltiorrhizae, Radix Notoginseng etc., hepatitis is presented following treatment characteristics based on the Chinese medicine of blood circulation promoting and blood stasis dispelling: 1. recover liver function better, very fast, have and significantly fall enzyme, the turbid descending, fall the red matter effect of gallbladder; 2. the liver spleen that bounces back improves stasis of blood disease; 3. anti-hepatic fibrosis; 4. stimulated hepatic cell regeneration.Present existing Chinese patent medicine product all is oral crude preparation by using basically, does not see effective site injection dosage form.Because liver is the detoxifcation organ of human body, many medicines need through liver metabolism, in treating hepatitis, take a large amount of medicines and usually increase the weight of the burden of liver, need refining the purification, reduce the consumption of taking medicine, and crude preparation by using is non-active ingredients more than 90%, and being absorbed in the body to increase very big burden to liver; Simultaneously, most of patients is because of the hepatitis acute attack clinically, obvious liver injury occurs and is admitted to hospital and seeks medical advice, and is dangerously ill this moment, changes rapidly, case fatality rate is high.Therefore,, suddenly wait to develop the oral formulations of making and the injection formulation of effective site or effective ingredient, with efficacy enhancing and toxicity reducing and rapid performance therapeutical effect at acute abnormal liver function patient.
Now contain Radix Salviae Miltiorrhizae, Radix Notoginseng material medicine preparation, comprise oral formulations and injection, as Radix Salviae Miltiorrhizae Injection, FUFANG DANSHEN DIWAN etc. interior, all without the extraction purification process of strictness, effective site content is lower, and the function of report cures mainly with indication and is used for the treatment of cardiovascular and cerebrovascular vessel.At present, report (Wu Shanming etc., Radix Notoginseng injection for treating blood stasis type chronic hepatitis and hemorheological preliminary observation thereof, the journal of shanghai Chinese medicine 1983 of the oral or injection for curing hepatitis B of two flavor crude drug injected or contained to existing Radix Salviae Miltiorrhizae and Radix Notoginseng respectively; 8,14; Tong Shaohong, the treatment of Radix Salviae Miltiorrhizae acupoint injection therapy is moved, chronic hepatitis 39 routine short term effects are observed Fujian medical journal 1980; 1,50; Hu Zhiming. Hu gold bead, the development of YIGANBAO electuary and observation of curative effect, modern Chinese medicine research and practice, 1996 03 phases; Xu Liming., " Radix Astragali detoxifcation blood activating decoction " treatment chronic viral hepatitis B 107 examples, the Jiangsu traditional Chinese medical science, 2000 10 phases; The flat liver heat removing soup treatment of bavin hepatitis A 146 examples, the practical Chinese and western medicine magazine of China, 2002 01 phases), but because Chinese medicine ingredients complexity, the effect difference that medical material is brought into play in preparation, and in the Chinese medicine single medicine and extract are mixed use, may produce unpredictable drug effect and toxicity, since the particularity of Chinese medicine medication, the medicament selection difference, the consumption difference, route of administration difference, drug effect are also different, therefore, so far do not see the report that has Radix Salviae Miltiorrhizae, Radix Notoginseng to share the injection for curing hepatitis B, do not have raw material Radix Salviae Miltiorrhizae, Radix Notoginseng compatibility to use the report of treatment hepatitis yet.
Summary of the invention
Technical scheme of the present invention has provided a kind of treatment hepatitis pharmaceutical composition, particularly, be a kind of be the pharmaceutical composition of the treatment hepatitis of feedstock production with Chinese crude drug Radix Salviae Miltiorrhizae, Radix Notoginseng, the present invention also provides this preparation of drug combination method and purposes.
The invention provides a kind of pharmaceutical composition for the treatment of hepatitis, it is the medicament that is prepared from by the following weight proportion raw material:
Radix Salviae Miltiorrhizae 3-10 part, Radix Notoginseng 1-3 part.
Wherein, Radix Salviae Miltiorrhizae is the dry root and rhizome of labiate Radix Salviae Miltiorrhizae Salvia miltiorrhiza Bge.; Radix Notoginseng is the dry root of panax araliaceae plant Panax notoginseng (Burk.) F.H.Chen.
Further, it be by following weight proportion raw material preparation and medicament:
6 parts of Radix Salviae Miltiorrhizaes, 1 part of Radix Notoginseng.
This pharmaceutical composition is to be active component by water extract of medical material Radix Salviae Miltiorrhizae, Radix Notoginseng or alcohol extract, adds the medicament that acceptable accessories or complementary composition are prepared from.
Described medicament is oral formulations or injection.
Further, described oral formulations is capsule, tablet, pill, granule, powder; Described injection is injection water injection, quiet drop type, injectable powder.
Wherein, described injection contains salvia-soluble total phenols 3.24~3.36mg, total saponins 1.69~1.76mg, danshensu 0.83~0.91mg, protocatechualdehyde 0.23~0.25mg, ginsenoside Rg1 0.63~0.69mg for every milliliter.
Wherein, the HPLC finger printing of this pharmaceutical composition is made up of 4 characteristic peaks as shown in Figure 1,
Wherein chromatographic condition is: octadecylsilane chemically bonded silica is a filler; Methanol-acetonitrile-1.67% formic acid solution (volume ratio 23:7:70) is a mobile phase; The detection wavelength is 286nm.
Further, the relative standard deviation RSD of described 4 total peak relative retention time is all less than 10.0%, wherein, and No. 1 average relative retention time RT0.134% in peak, No. 2 peak RT0.184, No. 3 peak RT0.724, No. 4 peaks 1.000.
The present invention also provides this preparation of drug combination method, comprises the following steps:
A, take by weighing raw material: Radix Salviae Miltiorrhizae 3-10 part, Radix Notoginseng 1-3 part by each weight proportion;
The preparation of b, Radix Salviae Miltiorrhizae extract: the material Radix Salviae Miltiorrhizae of getting it filled, decoct with water extraction, to filter, filtrate concentrates, drying, the powdered extract powder is made solvent with 50-95% ethanol, and percolation extracts, and gets percolate, adds active carbon, heating and refluxing extraction, filter, reclaim ethanol, be dissolved in water, aqueous solution passes through D 101Macroporous adsorbent resin is used the 30-85% ethanol elution, and ethanol elution reclaims ethanol and promptly gets Radix Salviae Miltiorrhizae extract;
The preparation of c, Radix Notoginseng extract: the material Radix Notoginseng of getting it filled is a solvent with 35-95% ethanol, and percolation extracts, and gets percolate, to add active carbon in the percolate, reflux, extract, filters decompression filtrate recycling ethanol, get pure extractum, pure extractum is dissolved in water, filter, aqueous solution passes through D 101Macroporous adsorptive resins, reuse 30-90% ethanol elution effective site gets ethanol elution, and decompression recycling ethanol promptly gets Radix Notoginseng extract;
D, the Radix Salviae Miltiorrhizae extract of step b preparation, the Radix Notoginseng extract of step c preparation are mixed, be dissolved in water, add acceptable accessories or complementary composition, be prepared into preparation pharmaceutically commonly used.
Wherein, the d step is that the Radix Salviae Miltiorrhizae extract of step b, step c preparation, Radix Notoginseng extract are mixed, and is dissolved in water, and adds oral formulations pharmaceutically commonly used adjuvant commonly used and gets drug composition oral preparation of the present invention; Or
Steps d is that the Radix Salviae Miltiorrhizae extract of step b, step c preparation, Radix Notoginseng extract are mixed, and is dissolved in water, and adds injection pharmaceutically commonly used additives commonly used, and adjust pH is 5.5~6.5, promptly gets drug combination injection of the present invention.
The present invention also provides the purposes of each materials of weight proportions in the medicine of the acute and chronic hepatitis of preparation treatment.
Further, the purposes of each materials of weight proportions in the medicine of the acute and chronic hepatitis of preparation oral medication.
Further, the purposes of each materials of weight proportions in the medicine of the acute and chronic hepatitis of preparation injection for curing.
Further, each materials of weight proportions is treated purposes in the medicine of acute and chronic hepatitis in the preparation intravenous injection.
Pharmaceutical composition composition of raw materials of the present invention instructs based on Chinese medical theory, select medicine reasonable, precise and appropriate, Radix Salviae Miltiorrhizae in the side, bitter in the mouth is slightly cold, nontoxic, have cold and heat and gather , Po Disorder, end stuffy sensation with restlessness except that abdominal mass, the QI invigorating effect, blood stasis dispelling is difficult for consumption and hinders healthy energy by heresy, and can promote nutrient blood new life, is suitable for clothes of a specified duration, and be difficult for causing untoward reaction, modern study shows: Radix Salviae Miltiorrhizae not only has many-sided pharmacological action to cardiovascular and cerebrovascular vessel, microcirculation etc., and effect for reducing blood fat is preferably arranged, for liver, the hepatic injury that can protect multiple reason to cause also has anti-liver toxicity; Experimental cirrhosis there is preventive and therapeutic effect, also can promotes cell regeneration, suppress hepatic fibroplasia etc., so be used as monarch drug in the side.Radix Notoginseng, sweet, the little hardship of nature and flavor and wet partially.The master returns Liver Channel, has the merit (Higher Education Publishing House, course teaching materials geared to the 21st century " Chinese materia medica ") of benefiting qi and nourishing blood concurrently, and modern study shows, but the Radix Notoginseng blood fat reducing promotes hemopoietic, analgesia; Anti-liver injury improves the liver blood circulation, improves the chronic index of liver function, and raise immunity and strong effect etc. are arranged.Radix Notoginseng is in order to the power of the blood circulation promoting and blood stasis dispelling , Xiao Disorder pain relieving of assisting Radix Salviae Miltiorrhizae, and sets upright gas, and the effect of replenishing QI and blood disappears full side and do not hinder, and pretends to be accessory drugs.Two crude drug proportionings are used, the effect of performance Synergistic.
Principal component is not too many owing to single medicinal material, and simultaneously the character of part effective ingredient is also unstable, and the oxidation polymerization of chemical constituent takes place the injection that Chinese medicine is mixed with easily, reduce curative effect of medication, even produce precipitation, the many untoward reaction of clinical appearance, even cause death.By extraction, the process for purification of drug regimen raw material of the present invention, the medicine composite for curing hepatitis of the present invention for preparing is extracted purification effective site, and the raw material consumption is few, taking convenience.Injection solution does not produce precipitation, steady quality; Intravenous injection has no side effect, safety, and can overcome the defective of aqueous injection.And pharmaceutical composition of the present invention adopts the quality of finger printing control injection, makes pharmaceutical composition of the present invention controlled, stable.
In sum, medicine of the present invention is the preparation of feedstock production with Radix Salviae Miltiorrhizae, Radix Notoginseng, extract salvia-soluble total phenols in the medical material, Radix Notoginseng total arasaponins mixing had both reduced dosage, remove impurity simultaneously, dosage is more accurate, treatment hepatitis good effect, safe, controlled, stable is the clinical selection that a kind of new treatment hepatitis medicament is provided.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again 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 example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
Fig. 1 pharmaceutical composition HPLC of the present invention finger printing, wherein, No. 1 peak retention time RT is: 3.950min, No. 2 peak retention time RT5.425min, No. 3 peak retention time RT21.892min, No. 4 peak retention time 30.533min.
The specific embodiment
The preparation of the quiet drop type of embodiment 1 pharmaceutical composition of the present invention
A, get Radix Salviae Miltiorrhizae 1000g, cut sheet, add 8 times of water gagings and decoct and extract 4 times, decocted 1.5 hours at every turn, collecting decoction filters, and filtrate is concentrated into the clear paste of relative density about 1.05 (60 ℃ of heat are surveyed), spray drying, extract powder.Get extract powder and 3 times of amount kieselguhr mixings, the percolation under photograph fluid extract and the extractum item (" appendix I0 of Chinese pharmacopoeia version in 2000), make solvent with 92% ethanol, flood after 4 hours,, collect percolate 15000m1 with the speed of per minute 3ml percolation slowly, add active carbon 50g, reflux 60 minutes is put cold, filter, decompression filtrate recycling ethanol adds water 2500m1 and makes dissolving to doing, and leaves standstill 24 hours, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins adds water 5000m1 eluting, discards water lotion, continues with 50%% ethanol 20000m1 eluting, collects 50% ethanol elution, and decompression recycling ethanol promptly gets Radix Salviae Miltiorrhizae extract, and this Radix Salviae Miltiorrhizae extract is the salvia-soluble total phenols.
Wherein water boiling and extraction technology salvia-soluble total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 95%, and dried cream yield is about 63%, and Radix Salviae Miltiorrhizae total phenolic acids content about 5.5% in the dried cream; The pre-impurity removal process salvia-soluble of ethanol percolation total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 85%, and it is about 10% that dried cream yield is reduced to, and the salvia-soluble total phenol content about 35% in the dried cream; Extract obtained yield is about 3.0% behind the purification with macroreticular resin, and the water solublity total phenol content is about 85% in the extract, and content of Danshensu is about 25%, and protocatechualdehyde content is about 8%, has reached the requirement of vein with the injection new drug.
B, Radix Notoginseng are extracted purification: get Radix Notoginseng coarse powder 1000g, the percolation under photograph fluid extract and the extractum item (" appendix IQ of Chinese pharmacopoeia version in 2000), make solvent with 9 times of amount 65% ethanol, dipping spends the night, and with the speed percolation of per minute 5m1, collects percolate, add active carbon 30g, reflux 60 minutes is put coldly, filters, decompression filtrate recycling ethanol, add water 2500m1 and make dissolving, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins is washed with water to cleaning mixture closely colourless (about 1200m1), discards washing liquid, continues with 50% ethanol elution of 11 times of amounts of medical material, collects eluent, and decompression recycling ethanol promptly gets Radix Notoginseng extract, and this Radix Notoginseng extract is a Radix Notoginseng total arasaponins.
Wherein ethanol percolate extraction technology Radix Notoginseng total arasaponins, ginsenoside Rg1's rate of transform be all more than 90%, and the extractum yield is about 20%, and content of the total saponins in radix notoginseng is about 45% in the extractum; The Radix Notoginseng extract yield of gained is about 8.5% behind the purification with macroreticular resin, and content of the total saponins in radix notoginseng has reached the requirement of vein with injection more than 90%.
C, get Radix Salviae Miltiorrhizae extract 3.3g, Radix Notoginseng extract 1.7g, add injection water 400m1 and make dissolving, standby; Other gets sodium chloride for injection 9g, and sodium sulfite 0.2g adds injection water 100ml and makes dissolving, heated and boiled adds active carbon 0.2g, stirs evenly, continued to boil 15 minutes, and filtered filtrate and above-mentioned medicinal liquid mixing, add the injection water to 1000m1, the sodium hydroxide solution adjust pH to 6.0 with 10%, ultrafiltration is to clear and bright, be sub-packed in the 100ml infusion bottle, roll lid, sterilization, check clarity, packing, promptly.
The preparation method of embodiment 2 medicine injectable powder of the present invention
A, get Radix Salviae Miltiorrhizae 1000g, cut sheet, add 8 times of water gagings and decoct and extract 4 times, decocted 1.5 hours at every turn, collecting decoction filters, and filtrate is concentrated into the clear paste of relative density about 1.05 (60 ℃ of heat are surveyed), spray drying, extract powder.Get extract powder and 3 times of amount kieselguhr mixings, the percolation under photograph fluid extract and the extractum item (" appendix I0 of Chinese pharmacopoeia version in 2000), make solvent with 92% ethanol, flood after 4 hours,, collect percolate 15000ml with the speed of per minute 3ml percolation slowly, add active carbon 50g, reflux 60 minutes is put cold, filter, decompression filtrate recycling ethanol adds water 2500ml and makes dissolving to doing, and leaves standstill 24 hours, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins adds water 5000ml eluting, discards water lotion, continues with 50% ethanol 20000ml eluting, collects 50% ethanol elution, and decompression recycling ethanol promptly gets Radix Salviae Miltiorrhizae extract, and this Radix Salviae Miltiorrhizae extract is the salvia-soluble total phenols.
Wherein water boiling and extraction technology salvia-soluble total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 95%, and dried cream yield is about 63%, and Radix Salviae Miltiorrhizae total phenolic acids content about 5.5% in the dried cream; The pre-impurity removal process salvia-soluble of ethanol percolation total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 85%, and it is about 10% that dried cream yield is reduced to, and the salvia-soluble total phenol content about 35% in the dried cream; Extract obtained yield is about 3.0% behind the purification with macroreticular resin, and the water solublity total phenol content is about 85% in the extract, and content of Danshensu is about 25%, and protocatechualdehyde content is about 8%, has reached the requirement of injectable powder new drug.
B, Radix Notoginseng are extracted purification: get Radix Notoginseng coarse powder 1000g, according to the percolation (appendix IQ of Chinese Pharmacopoeia version in 2000) under fluid extract and the extractum item, make solvent with 9 times of amount 65% ethanol, dipping spends the night, and with the speed percolation of per minute 5ml, collects percolate, add active carbon 30g, reflux 60 minutes is put coldly, filters, decompression filtrate recycling ethanol, add water 2500ml and make dissolving, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins is washed with water to cleaning mixture closely colourless (about 1200ml), discards washing liquid, continues with 50% ethanol elution of 11 times of amounts of medical material, collects eluent, and decompression recycling ethanol promptly gets Radix Notoginseng extract, and this Radix Notoginseng extract is a Radix Notoginseng total arasaponins.
Wherein ethanol percolate extraction technology Radix Notoginseng total arasaponins, ginsenoside Rg1's rate of transform be all more than 90%, and the extractum yield is about 20%, and content of the total saponins in radix notoginseng is about 45% in the extractum; The Radix Notoginseng extract yield of gained is about 8.5% behind the purification with macroreticular resin, and content of the total saponins in radix notoginseng has reached the requirement of injectable powder new drug more than 90%.
C, get Radix Salviae Miltiorrhizae extract 3.3g, Radix Notoginseng extract 1.7g, add injection water 400ml and make dissolving, standby; Injection supplementary material 100-200g puts in the sterile chamber in addition, adds injection water 450ml, stirs and makes dissolving, with above-mentioned medicinal liquid mixing, add the injection water and complement to 1000ml, be stirred to whole dissolvings gently, under positive pressure, with the micropore filter filtering liquid medicine of two polyphones, process spray drying under aseptic condition, make red seven sterilized powders, be sub-packed in the bottle, jump a queue, the jewelling lid, envelope bottle, sterilization, packing, promptly.
The preparation of embodiment 3 drug oral preparations of the present invention
A, get Radix Salviae Miltiorrhizae 1000g, cut sheet, add 8 times of water gagings and decoct and extract 4 times, decocted 1.5 hours at every turn, collecting decoction filters, and filtrate is concentrated into the clear paste of relative density about 1.05 (60 ℃ of heat are surveyed), spray drying, extract powder.Get extract powder and 3 times of amount kieselguhr mixings,, make solvent with 92% ethanol according to the percolation (appendix I0 of Chinese Pharmacopoeia version in 2000) under fluid extract and the extractum item, flood after 4 hours,, collect percolate 15000ml with the speed of per minute 3ml percolation slowly, add active carbon 50g, reflux 60 minutes is put cold, filter, decompression filtrate recycling ethanol adds water 2500ml and makes dissolving to doing, and leaves standstill 24 hours, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins adds water 5000ml eluting, discards water lotion, continues with 50% ethanol 20000ml eluting, collects 50% ethanol elution, and decompression recycling ethanol promptly gets Radix Salviae Miltiorrhizae extract.
Wherein water boiling and extraction technology salvia-soluble total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 95%, and dried cream yield is about 63%, and Radix Salviae Miltiorrhizae total phenolic acids content about 5.5% in the dried cream; The pre-impurity removal process salvia-soluble of ethanol percolation total phenols, danshensu, the protocatechualdehyde rate of transform be all more than 85%, and it is about 10% that dried cream yield is reduced to, and the salvia-soluble total phenol content about 35% in the dried cream; Extract obtained yield is about 3.0% behind the purification with macroreticular resin, and the water solublity total phenol content is about 85% in the extract, and content of Danshensu is about 25%, and protocatechualdehyde content is about 8%, has reached the requirement of injectable powder new drug.
B, Radix Notoginseng are extracted purification: get Radix Notoginseng coarse powder 1000g, according to the percolation (appendix IQ of Chinese Pharmacopoeia version in 2000) under fluid extract and the extractum item, make solvent with 9 times of amount 65% ethanol, dipping spends the night, and with the speed percolation of per minute 5ml, collects percolate, add active carbon 30g, reflux 60 minutes is put coldly, filters, decompression filtrate recycling ethanol, add water 2500ml and make dissolving, filter, filtrate is passed through the good D of pretreatment 101Macroporous adsorptive resins is washed with water to cleaning mixture closely colourless (about 1200ml), discards washing liquid, continues with 50% ethanol elution of 11 times of amounts of medical material, collects eluent, and decompression recycling ethanol promptly gets Radix Notoginseng extract.
Wherein ethanol percolate extraction technology Radix Notoginseng total arasaponins, ginsenoside Rg1's rate of transform be all more than 90%, and the extractum yield is about 20%, and content of the total saponins in radix notoginseng is about 45% in the extractum; The Radix Notoginseng extract yield of gained is about 8.5% behind the purification with macroreticular resin, and content of the total saponins in radix notoginseng has reached the requirement of injectable powder new drug more than 90%;
C, get Radix Salviae Miltiorrhizae extract 3.3g, Radix Notoginseng extract 1.7g, add water 300ml and make dissolving, standby; Oral formulations is put in the sterile chamber with adjuvant 100-200g in addition, adds water 400ml, stirs and makes dissolving, with above-mentioned medicinal liquid mixing, adds water and complements to 1000ml, is stirred to whole dissolvings gently, concentrates, and granulates drying.Make DANQI PIAN agent, granule or capsule, packing, sterilization.Packing, promptly.
The preparation of embodiment 4 injections of the present invention
Press the method for embodiment 1, the material Radix Salviae Miltiorrhizae 4000g that gets it filled, Radix Notoginseng 400g, the Radix Salviae Miltiorrhizae extract 13g of preparation gained, Radix Notoginseng extract 1g is prepared into aqueous injection.
The preparation of embodiment 5 injections of the present invention
Press the method for embodiment 1, the material Radix Salviae Miltiorrhizae 3000g that gets it filled, Radix Notoginseng 1000g, the Radix Salviae Miltiorrhizae extract 9.8g of preparation gained, Radix Notoginseng extract 1.8g is prepared into aqueous injection.
The preparation of embodiment 6 injections of the present invention
Press the method for embodiment 1, the material Radix Salviae Miltiorrhizae 5000g that gets it filled, Radix Notoginseng 2000g, the Radix Salviae Miltiorrhizae extract 16.6g of preparation gained, Radix Notoginseng extract 3.5g is prepared into aqueous injection.
The HPLC quantitative control methodin of embodiment 7 medicines of the present invention
Getting the pharmaceutical composition of the present invention of embodiment 1~3 preparation, according to high effective liquid chromatography for measuring, is filler with octadecylsilane chemically bonded silica; Methanol-acetonitrile-1.67% formic acid solution (volume ratio 23: 7: 70) is a mobile phase; The detection wavelength is 286nm.Its standard finger-print as shown in Figure 1.
The relative retention time of its standard finger-print is followed successively by 0.134 (1), and 0.184 (2), 0.724 (3), 1.000 (S), its relative deviation must not surpass 10%.
Embodiment 8 medicine quantitative control methodins of the present invention
1. water solublity total phenols
◆ instrument and reagent: Tianjin, island UV-2501 uv-spectrophotometric instrument; The reagent reagent is analytical pure; The danshensu sodium reference substance is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute (lot number 0855-200102).
◆ analytical method: red seven injection liquid samples are diluted with water, and trap is measured in ferric chloride and the colour developing of potassium ferricyanide mixed solution at 770nm wavelength place, be contrast with the danshensu, adopts standard curve method to calculate content.
◆ methodological study: it is feasible to prove conclusively this method through precision, repeatability, stability and application of sample recovery test.
◆ measurement result: see Table 1.
The red seven injection water solublity determining total phenol results of table 1
Figure C200410081551D00111
2. total saponins
◆ instrument and reagent: Tianjin, island UV-2501 uv-spectrophotometric instrument; The reagent reagent is analytical pure; Ginsenoside Rg1's reference substance provides (lot number 0703-200015) by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
◆ analytical method: red seven injection are with n-butanol extraction, and dissolve with ethanol dilutes, and vanillin-perchloric acid colour developing is measured trap at 551nm wavelength place, be contrast with ginsenoside Rg1, adopts standard curve method to calculate content.
◆ methodological study: it is feasible to prove conclusively this method through precision, repeatability, stability and application of sample recovery test.
◆ measurement result: see Table 2.
The red seven injection total saponins measurement results of table 2
Figure C200410081551D00121
3. danshensu and protocatechualdehyde
◆ instrument and reagent: Tianjin, island LC-10A high performance liquid chromatograph, SPD-10AV UV-detector.Methanol in the mobile phase is chromatographically pure, and other reagent reagents are analytical pure.Danshensu sodium, protocatechualdehyde reference substance provide available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute that (lot number is respectively 0855-200102,0810-200004).
◆ analytical method: red seven injection thin ups are as need testing solution, and the HPLC method is measured.Chromatographic column is selected Shimpack CLC-ODS post for use; Mobile phase is methanol-0.5% glacial acetic acid solution (11: 89); Detect wavelength 280nm; External standard method is calculated content.
◆ methodological study: it is feasible to prove conclusively this method through precision, repeatability, stability and application of sample recovery test.
◆ measurement result: see Table 3.
Red seven injection danshensus of table 3 and protocatechualdehyde measurement result
Figure C200410081551D00122
4. ginsenoside Rg1
◆ instrument and reagent: Tianjin, island LC-10A high performance liquid chromatograph, SPD-10AV UV-detector.Ginsenoside Rg1's reference substance provides (lot number 0703-200015) by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.Its high performance liquid chromatography main peak is single, and it is 99.8% that normalization method is measured purity.
◆ analytical method: red seven injection are directly as need testing solution, and the HPLC method is measured.The chromatographic column chromatographic column is selected octyl silane group silicagel column for use; Mobile phase is selected acetonitrile-0.05% phosphoric acid solution (19:81) for use; Detect wavelength 203nm; External standard method is calculated content.
◆ methodological study: it is feasible to prove conclusively this method through precision, repeatability, stability and application of sample recovery test.
Measurement result: see Table 4.
The red seven injection ginsenoside Rg1 measurement results of table 4
Figure C200410081551D00131
Radix Salviae Miltiorrhizae and Radix Notoginseng all are the effective ingredient in the material medicine, therefore, simultaneously the composition in the two flavor crude drug are carried out quality control, and controllability is strong, more stable quality, controlled.
Below prove beneficial effect of the present invention by pharmacodynamics test.
Experimental example 1 anti-acute liver damage model test:
To rat acute liver injury model due to the CCL4, medicaments injection 17.0mg/kg of the present invention can raise significantly and the rising of AST (aspartate amino transferase) value has the reduction effect (P<0.001, P<0.01) of highly significant to ALT (alanine aminotransferase) value; 8.5mg/kg the reduction ALT value (P<0.01) of energy highly significant.Medicaments injection 4.2,8.5 of the present invention, 17.0mg/kg have certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).Drug oral preparation of the present invention (embodiment 3 preparation) 21.0mg/kg can raise to ALT value to be had extremely significantly and the rising of AST value has the reduction effect (P<0.001, P<0.01) of highly significant; 10.5mg/kg the reduction ALT value (P<0.01) of energy highly significant.Drug oral preparation 5.2,10.5 of the present invention, 21.0mg/kg have certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
Table 5 medicaments injection of the present invention is to the influence of rat acute liver injury model due to the CCL4
Figure C200410081551D00132
Annotate: each administration group and model group are relatively *P<0.05 *P<0.01 * *P<0.001
Model group and the comparison of normal control group ▲ ▲ ▲ P<0.001 (sided t check)
As can be known from the above table: to rat acute liver injury model due to the CCL4, medicaments injection 17.0mg/kg of the present invention can raise to the ALT value to be had extremely significantly and the rising of AST value has the reduction effect (P<0.001, P<0.01) of highly significant; 8.5mg/kg the reduction ALT value (P<0.01) of energy highly significant.Medicaments injection 4.2,8.5 of the present invention, 17.0mg/kg have certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
To CCL4 induced mice acute liver damage model, medicaments injection 17.0mg/kg of the present invention can reduce ALT, AST value (P<0.001, P<0.001) extremely significantly; 8.5mg/kg reduction ALT, the AST value (P<0.01) of energy highly significant; 4.2mg/kg can reduce ALP (alkali phosphatase) value (P<0.05) significantly.4.2,8.5,17.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).Drug oral preparation 21.0mg/kg of the present invention can reduce ALT, AST value (P<0.001, P<0.001) extremely significantly; 10.5mg/kg reduction ALT, the AST value (P<0.01) of energy highly significant; 5.2mg/kg can reduce ALP value (P<0.05) significantly.5.2,10.5,21.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
Table 6 medicaments injection of the present invention is to the influence of CCL4 induced mice acute liver damage model
Figure C200410081551D00141
Annotate: each administration group and model group are relatively *P<0.05 *P<0.01 * *P<0.001
Model group and the comparison of normal control group ▲ ▲ ▲ P<0.001 (sided t check)
To CCL4 induced mice acute liver damage model, medicaments injection 17.0mg/kg of the present invention can reduce ALT, AST value (P<0.001, P<0.001) extremely significantly; 8.5mg/kg reduction ALT, the AST value (P<0.01) of energy highly significant; 4.2mg/kg can reduce ALP value (P<0.05) significantly.4.2,8.5,17.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
High as can be seen from the test of above dose-effect relationship, the dosage group more obvious than low dose group effect.
To ethanol induced mice acute liver damage model, medicaments injection 17.0mg/kg of the present invention has highly significant and reduces ALT extremely significantly and TB value effect (P<0.01, P<0.001); 8.5mg/kg significant reduction ALT value effect (P<0.05) is arranged.Drug oral preparation 21.0mg/kg of the present invention has highly significant and reduces ALT extremely significantly and TB value effect (P<0.01, P<0.001); 10.5mg/kg significant reduction ALT value effect (P<0.05) is arranged.
The anti-ethanol induced mice of table 7 medicaments injection of the present invention acute liver damage model test
Figure C200410081551D00151
Annotate: each administration group and model group are relatively *P<0.05 *P<0.01 * *P<0.001
Model group and the comparison of normal control group ▲ ▲ ▲ P<0.001 (sided t check)
To ethanol induced mice acute liver damage model, medicaments injection 17.0mg/kg of the present invention has highly significant and reduces ALT extremely significantly and TB value effect (P<0.01, P<0.001); 8.5mg/kg significant reduction ALT value effect (P<0.05) is arranged.
To rat acute liver injury model due to the TAA (thioacetamide), medicaments injection 17.0mg/kg of the present invention can significantly reduce TBil value (p<0.05); 8.5mg/kg can significantly reduce ALT value (P<0.05); 4.2mg/kg ALT, AST and TBil are all had significant reduction effect (P<0.05).4.2,8.5,17.0mg/kg all has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).Drug oral preparation 21.0mg/kg of the present invention can significantly reduce Tbi1 (total bilirubin) value (P<0.05); 10.5mg/kg can significantly reduce ALT value (P<0.05); 5.2mg/kg ALT, AST and TBil are all had significant reduction effect (P<0.05).5.2,10.5,21.0mg/kg all has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
To rat acute liver injury model due to the D-GLAN (D-Gal amine), the reduction ALT value (P<0.01) that medicaments injection 17.0mg/kg of the present invention can highly significant, significantly reduce AST value (P<0.025); 8.5mg/kg remarkable reduction ALT value effect (P<0.05, P<0.025) is arranged.8.5mg/kg the damage hepatocyte is had significant restitution (P<0.05); 4.2,17.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).Drug oral preparation 21.0mg/kg of the present invention can highly significant reduction ALT value (P<0.01), significantly reduce AST value (P<0.025); 10.5mg/kg remarkable reduction ALT value effect (P<0.05, P<0.025) is arranged.10.5mg/kg the damage hepatocyte is had significant restitution (P<0.05); 5.2,21.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
To D-GLAN induced mice acute liver damage model, medicaments injection 17.0mg/kg of the present invention has remarkable and extremely significantly reduces ALT, ALP value effect (P<0.025, P<0.001); 8.5mg/kg reduction AST, ALT, the ALP value effect (P<0.01, P<0.05, P<0.01) of remarkable and highly significant are arranged; Significantly and extremely significantly reduce ALT, ALP effect (P<0.025, P<0.001) 4.2mg/kg have.4.2,8.5,17.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).Drug oral preparation 21.0mg/kg of the present invention has remarkable and extremely significantly reduces ALT, ALP value effect (P<0.025, P<0.001); 10.5mg/kg reduction AST, ALT, the ALP value effect (P<0.01, P<0.05, P<0.01) of remarkable and highly significant are arranged; Significantly and extremely significantly reduce ALT, ALP effect (P<0.025, P<0.001) 5.2mg/kg have.5.2,10.5,21.0mg/kg has certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
The test of experimental example 2 anti-immune liver injury models
To the mouse immune liver damage model that bacterial endotoxin causes, medicaments injection 17.0mg/kg of the present invention has highly significant to reduce ALT effect (P<0.01); 8.5mg/kg remarkable reduction ALT, AST effect (P<0.05) are arranged.17.0mg/kg hepatic necrosis is had obvious reduction effect (P<0.05); Can significantly increase liver cell proliferation (P<0.05); 8.5mg/kg hepatocellular degeneration is had extremely significantly improvement effect (P<0.001); 4.2mg/kg can extremely significantly improve hepatocellular degeneration, necrosis (P<0.001); Can significantly improve hepatocellular inflammatory lesion (P<0.05); Can extremely significantly increase liver cell proliferation (P<0.001).Drug oral preparation 21.0mg/kg of the present invention has highly significant to reduce ALT effect (P<0.01); 10.5mg/kg remarkable reduction ALT, AST effect (P<0.05) are arranged.21.0mg/kg hepatic necrosis is had obvious reduction effect (P<0.05); Can significantly increase liver cell proliferation (P<0.05); 10.5mg/kg hepatocellular degeneration is had extremely significantly improvement effect (P<0.001); 5.2mg/kg can extremely significantly improve hepatocellular degeneration, necrosis (P<0.001); Can significantly improve hepatocellular inflammatory lesion (P<0.05); Can extremely significantly increase liver cell proliferation (P<0.001).
The test of experimental example 3 jaundice eliminatings
The rat obstructive jaundice model that right-ANIT causes, medicaments injection 17.0mg/kg of the present invention have remarkable reduction DBil, ALT and ALP value effect (P<0.05); 8.5mg/kg can significantly reduce ALT and ALP value (P<0.05); 4.2mg/kg can extremely significantly reduce the reduction ALP (P<0.01) of ALT (P<0.001), highly significant.Drug oral preparation 21.0mg/kg of the present invention has remarkable reduction DBil, ALT and ALP value effect (P<0.05); 10.5mg/kg can significantly reduce ALT and ALP value (P<0.05); 5.2mg/kg can extremely significantly reduce the reduction ALP (P<0.01) of ALT (P<0.001), highly significant.
The test of experimental example 4 immunologic functions
Medicaments injection 17.0mg/kg energy highly significant of the present invention and 4.2mg/kg can strengthen the effect (P<0.01, P<0.05) of mouse monokaryon cytophagy foreign body significantly, 17.0,8.5,4.2mg/kg to the acute liver damage model mice that D-GALN caused have respectively extremely significantly, highly significant and significantly strengthen its mononuclear cell and engulf the effect of foreign body (P<0.001, P<0.01, P<0.05), have the enhance immunity effect.17.0mg/kg remarkable reduction ALT value effect (P<0.025) is arranged.
Drug oral preparation 21.0mg/kg energy highly significant of the present invention and 5.2mg/kg can strengthen the effect (P<0.01, P<0.05) of mouse monokaryon cytophagy foreign body significantly, 21.0,10.5,5.2mg/kg to the acute liver damage model mice that D-GALN caused have respectively extremely significantly, highly significant and significantly strengthen its mononuclear cell and engulf the effect of foreign body (P<0.001, P<0.01, P<0.05), have the enhance immunity effect.21.0mg/kg remarkable reduction ALT value effect (P<0.025) is arranged.
The test of experimental example 5 anti-stress abilities
The effect that medicaments injection 8.5,17.0 of the present invention, 34.0mg/kg improved to the time-to-live of normal mouse under the normobaric hypoxia state, but do not have significance meaning (P〉0.05).34.0,17.0mg/kg can improve mice time-to-live (P<0.01) in frozen water very significantly.
The effect that drug oral preparation 10.5,21.0 of the present invention, 42.0mg/kg improved to the time-to-live of normal mouse under the normobaric hypoxia state, but do not have significance meaning (P〉0.05).42.0,21.0mg/kg can improve mice time-to-live (P<0.01) in frozen water very significantly.
Experimental example 6 improves rheology test
To rat depression of liver-QI and the QI stagnated by cold model that epinephrine causes, medicaments injection 50.0mg/kg of the present invention has and reduces whole blood viscosity effect (P<0.001) extremely significantly; To whole blood reduced viscosity and whole blood relative indices have extremely significantly, highly significant increase effect (P<0.001, P<0.01) 25.0,12.5mg/kg all has reduction whole blood viscosity effect (P<0.01, P<0.001) extremely remarkable, highly significant; Whole blood reduced viscosity and whole blood relative indices there are highly significant, increase effect (P<0.01, P<0.05) significantly.25.0mg/kg can be extremely significant and 12.5mg/kg can significantly reduce whole blood fibrin (P<0.001, P<0.05).Drug oral preparation 60.0mg/kg of the present invention has and reduces whole blood viscosity effect (P<0.001) extremely significantly; To whole blood reduced viscosity and whole blood relative indices have extremely significantly, highly significant increase effect (P<0.001, P<0.01) 30.0,15.0mg/kg all has reduction whole blood viscosity effect (P<0.01, P<0.001) extremely remarkable, highly significant; Whole blood reduced viscosity and whole blood relative indices there are highly significant, increase effect (P<0.01, P<0.05) significantly.30.0mg/kg can be extremely significant and 15.0mg/kg can significantly reduce whole blood fibrin (P<0.001, P<0.05).
The test of experimental example 7 microcirculation improvement
Medicaments injection 50.0 of the present invention, 25.0mg/kg all can expand blood capillary caliber (P<0.05) significantly; All the blood capillary caliber that can cause antiadrenergic drug significantly dwindles (P<0.05).12.5,25.0,50.0mg/kg all can be significantly, highly significant and the utmost point be significantly to the influence of antiadrenergic drug to the blood fluidised form, has the effect (P<0.05, P<0.01, P<0.001) of microcirculation improvement.
Drug oral preparation 60.0 of the present invention, 30.0mg/kg all can expand blood capillary caliber (P<0.05) significantly; All the blood capillary caliber that can cause antiadrenergic drug significantly dwindles (P<0.05).15.0,30.0,60.0mg/kg all can be significantly, highly significant and the utmost point be significantly to the influence of antiadrenergic drug to the blood fluidised form, has the effect (P<0.05, P<0.01, P<0.001) of microcirculation improvement.
Experimental example 8 is repaired the damage hepatocyte and is promoted liver cell regeneration
To rat acute liver injury model due to the D-GLAN, medicaments injection 8.5mg/kg of the present invention has significant restitution (P<0.05) to the damage hepatocyte; The mouse immune liver damage model that bacterial endotoxin is caused, medicaments injection 17.0mg/kg of the present invention has obvious reduction hepatic necrosis effect (P<0.05), 8.5mg/kg have and extremely significantly improve hepatocellular degeneration effect (P<0.001), 4.2mg/kg can extremely significantly improve hepatocellular degeneration, downright bad effect (P<0.001), can also significantly improve hepatocellular inflammatory lesion effect (P<0.05).Simultaneously, medicaments injection 17.0mg/kg of the present invention and 4.2mg/kg can significantly, extremely significantly promote liver cell proliferation effect (P<0.05, P<0.001).Drug oral preparation 10.5mg/kg of the present invention has significant restitution (P<0.05) to the damage hepatocyte; The mouse immune liver damage model that bacterial endotoxin is caused, medicaments injection 21.0mg/kg of the present invention has obvious reduction hepatic necrosis effect (P<0.05), 10.5mg/kg have and extremely significantly improve hepatocellular degeneration effect (P<0.001), 5.2mg/kg can extremely significantly improve hepatocellular degeneration, downright bad effect (P<0.001), can also significantly improve hepatocellular inflammatory lesion effect (P<0.05).Simultaneously, drug oral preparation 21.0mg/kg of the present invention and 5.2mg/kg can significantly, extremely significantly promote liver cell proliferation effect (P<0.05, P<0.001).
In addition, rat acute liver injury model due to CCL4, the TAA, and the result of the test of CCL4, D-GLAN (D-Gal amine) induced mice acute liver damage model all shows, medicaments injection 4.2-17.0mg/kg of the present invention and drug oral preparation 5.2-21.0mg/kg of the present invention all have certain restitution to the damage hepatocyte, but nonsignificance (P〉0.05).
Above-mentioned pharmacodynamic study proves, medicaments injection of the present invention and oral formulations all cause that to multiple reason ALT, AST due to acute liver damage and the immunologic liver injury, the active rising of ALP, TB all have tangible reduction effect; Tectology hepatocellular degeneration, necrosis, inflammatory degree to hepatic injury have some improvement and the effect of hypertrophy hepatocyte; Jaundice rising due to the biliary obstruction there is certain regressive effect; Can improve intact animal and hepatic injury animal body cellular immunization regulating and controlling effect; Have and improve hemorheology and microcirculatory effect preferably, certain anti-stress effect is arranged.
The toxicity of Chinese medicine and anaphylaxis are the problems that is difficult to solve always, mainly due to containing a large amount of indefinite compositions in the Chinese crude drug.For estimating the reaction of its drug action and toxicity, said preparation has been carried out curing mainly relevant main pharmacodynamics with function, general pharmacology is learned, acute toxicity, long term toxicity (Beagle dog long term toxicity, rat long term toxicity) and specific safety experimental study, and division is as follows:
Experimental example 9 animal acute toxicity tests
Try to achieve medicaments injection of the present invention to the LD50 of ICR kind mouse mainline administration and credible 2684.81 (2554.52~2821.75) mg/Kg that is limited to of 95% thereof with the calculating of Biliss method; The LD50 of intraperitoneal injection and credible 2750.85 (2538.73~2980.70) mg/Kg that is limited to of 95% thereof.Try to achieve drug oral preparation of the present invention to the LD50 of ICR kind mouse stomach administration and credible 2879.81 (2684.57~3078.63) mg/Kg that is limited to of 95% thereof with the calculating of Biliss method.
Try to achieve medicaments injection of the present invention to the LD50 of SD rat intravenous injection administration and credible 2189.35 (2073.62~2311.53) mg/Kg that is limited to of 95% thereof with the calculating of Biliss method; The LD50 of intraperitoneal injection and credible 2682.58 (2493.14~2886.42) mg/Kg that is limited to of 95% thereof.Try to achieve drug oral preparation of the present invention to the LD50 of SD rat oral gavage administration and credible 2714.35 (2531.84~2916.45) mg/Kg that is limited to of 95% thereof with the calculating of Biliss method.
Dyspnea appears in animal behind the intravenous administration, symptoms such as movable minimizings, and the many death in back 30 minutes of injection of dead animal, the minimizing with dosage of dead quantity and time reduces and prolongs, anatomic observation, the visible pathological changes of no naked eyes.Surviving animals is recovered after 24 hours normally, and food ration and body weight do not have obvious minimizing, behind the execution animal, and all no abnormal discovery of perusal vitals (heart, liver, spleen, lung, kidney etc.).
Dyspnea appears in animal behind the intraperitoneal injection, symptoms such as movable minimizings, the many death in back 8 hours of injection of dead mouse; Rats death is how dead in back 12 hours of injection, and the minimizing with dosage of dead quantity and time reduces and prolongs, anatomic observation, the visible pathological changes of no naked eyes.Surviving animals is recovered after 48 hours normally, and food ration and body weight do not have obvious minimizing, behind the execution animal, and all no abnormal discovery of perusal vitals (heart, liver, spleen, lung, kidney etc.).
Dyspnea appears in animal behind the gastric infusion, and symptoms such as movable minimizing recover normal after 48 hours, and food ration and body weight do not have obvious minimizing, behind the execution animal, and all no abnormal discovery of perusal vitals (heart, liver, spleen, lung, kidney etc.).
Conclusion: above test shows that medicaments injection of the present invention and oral formulations safe dose scope are bigger.
Experimental example 10 long-term toxicity test for animals
1, Beagle dog long term toxicity test
Medicaments injection of the present invention is equivalent to 30,15 and 7.5 times of its clinical vein instillation dosage respectively by 250,125 and three dosage of 62.5mg/kg, and to Beagle dog intravenously administrable 45 days and drug withdrawal 15 days, the result was as follows continuously:
(1) growth promoter and ordinary circumstance are observed: observe with drug withdrawal during the administration, animal mental act, activity, fur, breathing, circulation, appetite, defecation etc. show no obvious abnormalities, between administration and withdrawal time, dog body weight gain and growth are not had obviously influence, do not have the retardance toxic reaction yet.
(2) routine urianlysis: no abnormality seen.
(3) to the influence of hemogram: no abnormality seen.
(4) to the influence of liver function: no abnormality seen.
(5) to the influence of renal function: no abnormality seen.
(6) to the influence of blood glucose and serum cholesterol: no abnormality seen.
(7) to Electrocardiographic influence: no abnormality seen.
(8) living animal bone marrow examination: no abnormality seen.
(9) system becomes celestial and organ index: no abnormality seen.
(10) histopathologic examination: administration checked that lymphatic nodule formed under the low dose group buck 1 routine mucous membrane of colon in 45 days; Low dose group jenny 1 routine lymph follicle increases, and comes across medullary substance.Administration group and matched group comparison no difference of science of statistics (P〉0.05).Drug withdrawal checked that each was organized the internal organs inspection and there is no unusually in 15 days.
Conclusion: medicaments injection of the present invention is given 250mg/Kg45 days non-toxic reactions of Beagle dog intravenous drip continuously.250mg/Kg and following dosage show no obvious abnormalities influence to the every index of dog, also do not have obvious retardance toxic reaction, belong to the safe dose scope.
2, rat long term toxicity test data summary
Medicaments injection of the present invention is by 250,125 and three dosage of 62.5mg/kg, drug oral preparation of the present invention is by 630,157.5 and three dosage of 78mg/kg, be equivalent to 30,15 and 7.5 times of clinical daily dosage respectively, respectively continuously to rats by intraperitoneal injection administration 45 days and drug withdrawal 14 days, observed medicaments injection of the present invention and oral formulations and be the main adverse reaction of animal:
(1) ordinary circumstance and body weight: 14 days each groups of administration 45 days and drug withdrawal are tried the rat behavior activity normally, and the animal wool pool is smooth, no abnormal secretions.The weight of animals and food ration be normal growth in time, and each group does not all have animal dead.
(2) routine blood test: medicaments injection of the present invention is continuously to rats by intraperitoneal injection administration blood routine examination in 45 days, compare with matched group, female group of RBC of medicaments injection high and low dose of the present invention significantly raises (P<0.05) respectively, female group of RBC highly significant rising of middle dosage (P<0.01); Male group of PLT of high, medium and low dosage P<0.001 that extremely significantly raises respectively); Female, male group of RC of high, medium and low dosage respectively significantly, highly significant and extremely significantly raise (P<0.05, P<0.01 and P<0.001); Female group of MCHC of high, middle dosage highly significant respectively reduces (P<0.01), all the other every index no abnormality seens (P〉0.05), and each organizes index all in normal range, and practical significance is not obvious.Drug withdrawal 14 days check with matched group relatively, female group of RBC of medicaments injection high dose of the present invention significantly reduces (P<0.05), female group of PDW highly significant of middle dosage reduces (P<0.01), each organizes index all in normal range, practical significance is not obvious.
Drug oral preparation group of the present invention is continuously to rats by intraperitoneal injection administration blood routine examination in 45 days, compare with matched group, female group of RBC of drug oral preparation group high and low dose of the present invention significantly raises (P<0.05) respectively, female group of RBC highly significant rising of middle dosage (P<0.01); Male group of PLT of high, medium and low dosage P<0.001 that extremely significantly raises respectively); Female, male group of RC of high, medium and low dosage respectively significantly, highly significant and extremely significantly raise (P<0.05, P<0.01 and P<0.001); Female group of MCHC of high, middle dosage highly significant respectively reduces (P<0.01), all the other every index no abnormality seens (P〉0.05), and each organizes index all in normal range, and practical significance is not obvious.Drug withdrawal 14 days check with matched group relatively, female group of RBC of drug oral preparation group high dose of the present invention significantly reduces (P<0.05), female group of PDW highly significant of middle dosage reduces (P<0.01), each organizes index all in normal range, practical significance is not obvious.
(3) liver function: medicaments injection successive administration of the present invention was checked in 45 days, compared with matched group, and female group of TP of dosage has highly significant to raise (P<0.01) in the medicaments injection of the present invention, and the liver function index of all the other each treated animals is all in normal range.Drug withdrawal 14 days checks and the matched group inspection, do not see notable difference (P〉0.05).The liver function index of each treated animal is all in normal range.
Drug oral preparation group successive administration of the present invention was checked in 45 days, compared with matched group, and female group of TP of dosage has highly significant to raise (P<0.01) in the drug oral preparation group of the present invention, and the liver function index of all the other each treated animals is all in normal range.Drug withdrawal 14 days checks and the matched group inspection, do not see notable difference (P〉0.05).The liver function index of each treated animal is all in normal range.
(4) renal function: medicaments injection of the present invention, oral formulations group successive administration 45 days and 14 days kidney function test of drug withdrawal, with matched group relatively, do not see notable difference (P〉0.05), each treated animal renal function index is all in normal range.
(5) other biochemical indicator: medicaments injection of the present invention, oral formulations group successive administration 45 days, compare with matched group, medicaments injection of the present invention, female group of CHOL of oral formulations group high and low dose significantly reduce (P<0.05) respectively.Drug withdrawal checks after 14 days, with matched group relatively, do not see notable difference (P〉0.05).
(6) system becomes celestial and organ index: the result shows, administration 45 days and drug withdrawal 14 days, and medicaments injection of the present invention, each dosage group of oral formulations group and matched group compare, no significant difference (P〉0.05).
(7) histopathologic examination: administration 45 days and drug withdrawal 14 days, each dosage group of medicaments injection of the present invention and control rats brain (cerebellum), hypophysis, optic nerve, the heart, liver, spleen, lung, kidney, the adrenal gland, thyroid, pancreas, thymus, bladder, stomach, duodenum, ileum, colon, ovary, the uterus, testis, epididymis, prostate, lymph node, spinal cord, breastbone, nasal septum, amphiblestroid tectology inspection found that: 45 days medicaments injection high dose group buck 1 examples of the present invention of administration, middle dosage group jenny 1 routine stomach lower part vasodilation companion neutrophilic infiltration.High dose group buck 2 examples, jenny 1 example, middle dosage is female, lymphatic nodule forms under each 1 example of buck and the matched group buck 1 routine mucous membrane of colon.The obvious hemorrhage companion's monokaryon of high dose group buck 1 routine bladder with partial flesh layer, neutrophil cell soak into.High dose group 1 example is film and a little neutrophilic infiltration of flesh layer in utero.All the other respectively organize every index, all do not find tangible pathomorphology infringement.Administration group and matched group compare, no difference of science of statistics (P〉0.05).Drug withdrawal checked that each group was not all found tangible pathomorphology infringement in 14 days.
Histopathologic examination: administration 45 days and drug withdrawal 14 days, each dosage group of drug oral preparation group of the present invention and control rats brain (cerebellum), hypophysis, optic nerve, the heart, liver, spleen, lung, kidney, the adrenal gland, thyroid, pancreas, thymus, bladder, stomach, duodenum, ileum, colon, ovary, the uterus, testis, epididymis, prostate, lymph node, spinal cord, breastbone, nasal septum, amphiblestroid tectology inspection found that: 45 days drug oral preparation group high dose group buck 2 examples of the present invention of administration, middle dosage group jenny 1 routine stomach lower part vasodilation companion neutrophilic infiltration.High dose group buck 1 example, jenny 1 example, middle dosage is female, lymphatic nodule forms under each 1 example of buck and the matched group buck 1 routine mucous membrane of colon.The obvious hemorrhage companion's monokaryon of high dose group buck 1 routine bladder with partial flesh layer, neutrophil cell soak into.High dose group 1 example is film and a little neutrophilic infiltration of flesh layer in utero.All the other respectively organize every index, all do not find tangible pathomorphology infringement.Administration group and matched group compare, no difference of science of statistics (P〉0.05).Drug withdrawal checked that each group was not all found tangible pathomorphology infringement in 14 days.
Conclusion: medicaments injection of the present invention, heavy dose of lumbar injection of drug oral preparation group leader's phase of the present invention give animal subject and overt toxicity reaction and pathological lesion do not occur.
3, specific safety experimental data and study summary
3.1 hemolytic test
Medicaments injection of the present invention mixes with 2% rabbit erythrocyte suspension, incubation 4 hours, and haemolysis and coacervation do not appear in the result.
3.2 vascular stimulation test
Medicaments injection of the present invention is to rabbit auricular vein instillation 50mg/kg, and for three days on end, perusal does not have irritant reaction such as hyperemia, edema, degeneration, necrosis, and each structure of pathological tissue morphological examination is normal, shows that this medicine has no stimulation to the injection site blood vessel.
3.3 muscular irritation test
Medicaments injection of the present invention after 48 hours, is observed the irritant reaction situation to rabbit quadriceps femoris injection 1ml (5mg), and the result does not have irritant reaction such as hyperemia, edema, degeneration, shows that this medicine has no stimulation to injection site muscle.
3.4 whole body is hypersensitive test initiatively
Medicaments injection of the present invention is every 0.5ml sensitization of lumbar injection to Cavia porcellus the next day, totally 3 times, animal is respectively at injecting first behind the medicaments injection of the present invention the 14th day and the 21st day, intravenous injection medicaments injection 2mi of the present invention attacks, whole body active anaphylaxis symptom does not all appear in the result, positive reaction all appears in egg protein positive control treated animal, shows that this medicine does not cause allergic reaction.
3.5 depressor substance inspection
Medicaments injection of the present invention is that the blood pressure lowering experiment is carried out in contrast to anesthetized cat vena femoralis injection 8.3mg/kg with the histamine, and medicaments injection of the present invention does not as a result cause the blood pressure lowering reaction, shows that this medicine does not have hypotensive effect.
Brief summary: medicaments injection of the present invention does not produce haemolysis and aggregation, to muscle, blood vessel nonirritant, does not cause the whole body active anaphylaxis, and no hypotensive effect meets the requirement of injection Generally Recognized as safe.
Learn through the pharmacological toxicology of system and studies have shown that, medicaments injection of the present invention has multiple reason is caused that ALT, AST due to acute liver damage and the immunologic liver injury, the active rising of ALP, TB all have tangible reduction effect; Tectology hepatocellular degeneration, necrosis, the inflammatory degree of hepatic injury had some improvement and repair the hepatocyte effect; Jaundice rising due to the biliary obstruction there is the choleretic effect that necessarily disappears; Can improve intact animal and hepatic injury animal body cellular immunization regulating and controlling effect; Have and improve hemorheology and microcirculatory effect preferably, intact animal and hepatic injury animal are all had anti-stress effect effect preferably, for clinical practice provides the pharmacology foundation; In addition, acute toxicity test in mice, Beagle dog, rat long term toxicity test and general pharmacology are learned the experimental study result and are shown, the said preparation toxic reaction is low, and degree of safety is bigger, for its data for clinical drug use provides the toxicology foundation, each system of intact animal is not had influence, have no adverse reaction.The specific safety experimental study shows and meets the requirement of injection Generally Recognized as safe.
Medicine material compatibility of the present invention is determined with the side's of tearing open research through the pharmacodynamics screening, the medicaments injection preparation made from this material combination of the present invention proves that through drug effect and toxicological study the liver injury that a variety of causes is caused has stronger pharmacologically active, and toxic and side effects is lower.Though there is not the nosetiology therapeutical effect, applied widely to fall enzyme and to promote that liver cell regeneration is characteristic, can improve clinical symptoms rapidly, adopt oral formulations and injection dosage form can strengthen the means of tcm emergency treatment.

Claims (10)

1, the purposes of pharmaceutical composition in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described pharmaceutical composition is the medicament that is prepared by following method:
A, take by weighing raw material by the weight proportion of Radix Salviae Miltiorrhizae 3-10 part, Radix Notoginseng 1-3 part;
The preparation of b, Radix Salviae Miltiorrhizae extract: the material Radix Salviae Miltiorrhizae of getting it filled, decoct with water extraction, filter, filtrate concentrates, drying, and the powdered extract powder is made solvent with 50-95% ethanol, percolation extracts, and gets percolate, adds active carbon, heating and refluxing extraction filters, and reclaims ethanol, be dissolved in water, aqueous solution is used the 30-85% ethanol elution by macroporous adsorbent resin, ethanol elution reclaims ethanol and promptly gets Radix Salviae Miltiorrhizae extract;
The preparation of c, Radix Notoginseng extract: the material Radix Notoginseng of getting it filled is a solvent with 35-95% ethanol, and percolation extracts, get percolate, will add active carbon, reflux, extract, in the percolate, filter, decompression filtrate recycling ethanol gets pure extractum, pure extractum is dissolved in water, filters, aqueous solution passes through macroporous adsorptive resins, reuse 30-90% ethanol elution, get ethanol elution, reclaim ethanol, promptly get Radix Notoginseng extract;
D, the Radix Salviae Miltiorrhizae extract of step b preparation, the Radix Notoginseng extract of step c preparation are mixed, be dissolved in water, add acceptable accessories or complementary composition and be prepared from.
2, the purposes of pharmaceutical composition according to claim 1 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: the weight proportion of Radix Salviae Miltiorrhizae, Radix Notoginseng is:
6 parts of Radix Salviae Miltiorrhizaes, 1 part of Radix Notoginseng.
3, the purposes of pharmaceutical composition according to claim 1 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described medicament is oral formulations or injection.
4, the purposes of pharmaceutical composition according to claim 3 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described oral formulations is capsule, tablet, pill, granule or powder.
5, the purposes of pharmaceutical composition according to claim 3 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described injection is injection water injection, quiet drop type or injectable powder.
6, the purposes of pharmaceutical composition according to claim 5 in the medicine of the acute and chronic hepatitis of preparation treatment is characterized in that: contain salvia-soluble total phenols 3.24~3.36mg, Radix Notoginseng total arasaponins 1.69~1.76mg, danshensu 0.83~0.91mg, protocatechualdehyde 0.23~0.25mg and ginsenoside Rg1 0.63~0.69mg in every milliliter of injection water injection.
7, the purposes in the medicine of the acute and chronic hepatitis of preparation treatment according to claim 5 or 6 described pharmaceutical compositions, it is characterized in that: the HPLC finger printing of this pharmaceutical composition is made up of 4 characteristic peaks, the relative standard deviation RSD of 4 characteristic peak relative retention time is all less than 10.0%, wherein, No. 1 average relative retention time RT 0.134 in peak, 0.724, No. 4 peak RT 1.000 of 0.184, No. 3 peak RT of No. 2 peak RT;
Wherein chromatographic condition is: octadecylsilane chemically bonded silica is a filler; Methanol-acetonitrile-1.67% formic acid solution, its volume ratio are 23: 7: 70 mobile phase; The detection wavelength is 286nm.
8, the purposes of pharmaceutical composition according to claim 1 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described medicine is the medicine of the acute and chronic hepatitis of oral medication.
9, the purposes of pharmaceutical composition according to claim 1 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described medicine is the medicine of the acute and chronic hepatitis of injection for curing.
10, the purposes of pharmaceutical composition according to claim 9 in the medicine of the acute and chronic hepatitis of preparation treatment, it is characterized in that: described medicine is the medicine that acute and chronic hepatitis is treated in intravenous injection.
CNB2004100815511A 2004-12-21 2004-12-21 Medicament composition for treating hepatitis, prepartion method and use Active CN100484543C (en)

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CN107441161A (en) * 2017-06-19 2017-12-08 上海华源安徽锦辉制药有限公司 A kind of preparation method of red sage roo drip liquid
CN107260803A (en) * 2017-06-19 2017-10-20 上海华源安徽锦辉制药有限公司 The preparation method of Sodium Danshensu content in a kind of raising red sage roo drip liquid
EP4193996A1 (en) * 2021-12-11 2023-06-14 Mendel University in Brno Ginsenosides for treatment of chronic hepatitis b virus infections

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1089496A (en) * 1993-01-06 1994-07-20 山东烟台西苑制药厂 Compound sodium alginati diesteras
CN1415303A (en) * 2002-10-24 2003-05-07 成都浦泓生物科技开发有限公司 Red sage root and Tienchi sustained release medication, its preparation method and medicinal application in vascular dementia
CN1425379A (en) * 2002-12-19 2003-06-25 上海博泰医药科技有限公司 Traditional Chinese medicine active part compound preparation for curing cardiac and cerebral vascular diseases and its preparing method
CN1456187A (en) * 2002-05-10 2003-11-19 徐希平 Use of red sage root and notoginseng in preparation of medicine for prevention of acute coronary syndrome
CN1456188A (en) * 2002-05-10 2003-11-19 徐希平 Use of red rage root and notoginseng in preparation of medicine for prevention of cerebral apoplexy
CN1470255A (en) * 2002-07-22 2004-01-28 王智民 Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use
CN1168496C (en) * 2002-01-09 2004-09-29 中国药科大学 Powder snuff of insulin for administration of lung and its preparing process

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1089496A (en) * 1993-01-06 1994-07-20 山东烟台西苑制药厂 Compound sodium alginati diesteras
CN1168496C (en) * 2002-01-09 2004-09-29 中国药科大学 Powder snuff of insulin for administration of lung and its preparing process
CN1456187A (en) * 2002-05-10 2003-11-19 徐希平 Use of red sage root and notoginseng in preparation of medicine for prevention of acute coronary syndrome
CN1456188A (en) * 2002-05-10 2003-11-19 徐希平 Use of red rage root and notoginseng in preparation of medicine for prevention of cerebral apoplexy
CN1470255A (en) * 2002-07-22 2004-01-28 王智民 Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use
CN1415303A (en) * 2002-10-24 2003-05-07 成都浦泓生物科技开发有限公司 Red sage root and Tienchi sustained release medication, its preparation method and medicinal application in vascular dementia
CN1425379A (en) * 2002-12-19 2003-06-25 上海博泰医药科技有限公司 Traditional Chinese medicine active part compound preparation for curing cardiac and cerebral vascular diseases and its preparing method

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