CN101292986B - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

Info

Publication number
CN101292986B
CN101292986B CN2007100972713A CN200710097271A CN101292986B CN 101292986 B CN101292986 B CN 101292986B CN 2007100972713 A CN2007100972713 A CN 2007100972713A CN 200710097271 A CN200710097271 A CN 200710097271A CN 101292986 B CN101292986 B CN 101292986B
Authority
CN
China
Prior art keywords
salvianolic acid
danshen root
root salvianolic
enoxolone
derivant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2007100972713A
Other languages
Chinese (zh)
Other versions
CN101292986A (en
Inventor
顾群
李志刚
渠守峰
郭小鹏
刘严
米长江
栗艳彬
林治荣
鄯慧珍
金治刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BENCAO TIANYUAN PHARMACEUTICAL RESEARCH INST BEIJING
Original Assignee
BENCAO TIANYUAN PHARMACEUTICAL RESEARCH INST BEIJING
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BENCAO TIANYUAN PHARMACEUTICAL RESEARCH INST BEIJING filed Critical BENCAO TIANYUAN PHARMACEUTICAL RESEARCH INST BEIJING
Priority to CN2007100972713A priority Critical patent/CN101292986B/en
Publication of CN101292986A publication Critical patent/CN101292986A/en
Application granted granted Critical
Publication of CN101292986B publication Critical patent/CN101292986B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a drug composite that is characterized in that after dose-effect relationship experiments, pharmacodynamics verification experiments, pharmacokinetics experiments and toxicology experiments, the drug composite is determined by weight proportion: A1-10 weight portions of salvianolic acid of salvia miltiorrhiza, containing 1-20 weight portions of one or more of general formula drugs; A1-5 weight portions of preferred salvianolic acid of the salvia miltiorrhiza, containing 10-20 weight portions of one or more of general formula drugs; A6-10 weight portions of preferred salvianolic acid of the salvia miltiorrhiza, containing 1-9 weight portions of one or more of general formula drugs. The Pharmacological experiments are proved that the drug composite has very good pharmacological effects.

Description

Pharmaceutical composition
Technical field
The present invention relates to medical technical field, be specifically related to a kind of pharmaceutical composition, promptly comprise danshen root salvianolic acid A and have following general formula medicine one or more:
Figure S07197271320070509D000011
Formula one
Figure S07197271320070509D000012
Formula two
Figure S07197271320070509D000013
Formula three
Wherein R1, R2, R3, R4 can be H, Na, Mg, K, ammonium;
The medicine of above-mentioned general formula is one or more in glycyrrhizic acid and enoxolone and the derivant thereof;
The application's the medicine with general formula also can be Radix Glycyrrhizae fluidextract or Radix Glycyrrhizae extractum or the Pharmacopoeia of the People's Republic of China (version in 2005, one one) 273,274 pages of Radix Glycyrrhizae fluidextract or Radix Glycyrrhizae extractum.
Background technology
People's rhythm of life is fast in the modern society, and operating pressure is big, environmental pollution seriously causes people's liver load excessive, immunity degradation, and the defective of the cooking culture of China has more been deepened the damage to liver, hepatopathy is a common clinical, frequently-occurring disease.It is reported and be about 1,20/,100,000 at China's hepatopathy annual sickness rate, because hepatopathy disease course is long, be easy to repeatedly and chronicity, closely related with cancer, now become one of principal disease of serious harm China people ' s health, therefore, the treatment hepatopathy is current important topic both domestic and external, it also is a difficult problem still failing to obtain fine solution so far, around this world's medicine difficult problem, various countries' medical science, pharmacy, the enterpriser has paid huge and hard effort for this reason, develops numerous new drugs in succession, and wherein representative drugs has: lamivudine, vidarabine, acyclovir (being chemical synthetic drug); Interferon (biological engineering medicine).These medicines have brought new hope for the treatment of hepatopathy.But the clinical practice through the several years is found, the clinical efficacy of these medicines is very not remarkable, and is unstable yet, no matter is import chemical synthetic drug or biological preparation so far, all can not fundamentally solve the problem of treatment hepatopathy, also just can not cure hepatopathys such as hepatic injury from " root "; The treatment liver disease drug of China's development and production is also a lot, wherein Chinese medicine and natural drug mainly contain: as YIGANNING CHONGJI, matrine injection (capsule), liver-protecting tablet, the silibinin sheet, glycyrrhizin tablet, the safe electuary of Coriolous Dersicolor (Fr.) Quel glycosides, ZHULINGDUOTANG ZHUSHEYE etc., the colchicine sheet, FUFANG BIEJIA RUANGAN PIAN etc., Yinzhihuang Injection, Fel Ursi capsule etc., but, how just these medicines play a role in a certain stage or a certain link of hepatopathy reason process, and at hepatopathy inflammation particularly, downright bad, hypertrophy (hepatocyte, collagen fiber) and the complicated pathological process of depositing, the effect of these medicines is limited to some extent, simple for the particularly early stage fibrosis effect of then seeming of chronic hepatopathy, and it is even more important than the treatment that reverses hepatic fibrosis effectively to block the pathology process in this stage.
The pathological changes of liver relates to numerous organs, its control has been become the key research projects of countries in the world.
Chinese medicine has been obtained certain effect with Radix Salviae Miltiorrhizae and Radix Glycyrrhizae compatibility treatment hepatopathy, Chinese patent " 200510115662.4 " " a kind of Chinese medicine composition and preparation method that is used for hepatic fibrosis and portal hypertension " carries out compatibility with Radix Salviae Miltiorrhizae Radix Salviae Miltiorrhizae total phenolic acids and Radix Glycyrrhizae extract, is prepared into the medicine of treatment hepatopathy; Though said medicine has certain drug effect, just Chinese medicine or its effective site are carried out the effect that compatibility reaches " effectively ", and do not study at active very strong composition in the Chinese medicine, can't reach the purpose of " excellent effect "; Salvianolic acid A [salvianolic acid A] is a strongest active composition in the Radix Salviae Miltiorrhizae, has great pharmacological effects (Du Guanhua [preclinical medicine and clinical, 2000,20 (5): 10～14], Hu Yiyang [herbal pharmacology journal, 1997,18 (5): 478-480]); Glycyrrhizic acid and enoxolone and derivant thereof have great pharmacological effects [" effective liquorice glycyrrhizic acid and enoxolone and derivant pharmacological action progress thereof " be the 2nd the 3rd phase of volume of " Chinese medical is studied and put into practice " March in 2004 (Li Cuiqin), 48-51] in the Radix Glycyrrhizae; Therefore, danshen root salvianolic acid A and glycyrrhizic acid and enoxolone and derivant thereof are made up, the treatment hepatopathy should be good selection; But danshen root salvianolic acid A content in Radix Salviae Miltiorrhizae is very low, have only about 5/10000ths, even it is extracted by a series of technology, can only obtain the salvianolic acid A of trace level, therefore Chinese medicine carries out compatibility with Radix Salviae Miltiorrhizae or Radix Salviae Miltiorrhizae total phenolic acids and other medical material, its essence is and the compatibility of the more weak composition (such as TANSHINONES, salvianolic acid B etc.) of other relativity of Radix Salviae Miltiorrhizae that the salvianolic acid A of level has or not internal relation with the compatibility of effective liquorice in batches, is one of need difficult problem to be solved.
Consult document and patent, the report that danshen root salvianolic acid A and glycyrrhizic acid and enoxolone and pharmaceutical salts compatibility thereof are not arranged, but the compatibility that Radix Salviae Miltiorrhizae total phenolic acids and glycyrrhizic acid and enoxolone and derivant thereof are arranged, though this drug regimen has certain curative effect, but because prior art exist certain defective: obtain salvia miltiorrhiza tanshinoate and be salvianolic acid class material based on salvianolic acid B of Radix Salviae Miltiorrhizae, and can't obtain the danshen root salvianolic acid A of level in batches, therefore, can the danshen root salvianolic acid A of level and glycyrrhizic acid and enoxolone and derivant thereof make up in batches, and needing the scientific research personnel to pass through a large amount of scientific experiments could determine.
Summary of the invention
For these reasons, we are by carrying out a series of transformation experiment to red rooted salvia, be about to Radix Salviae Miltiorrhizae total phenolic acids and obtained the danshen root salvianolic acid A of level in batches by certain chemical reaction, pass through medicine efficacy screening again, dose-effect relationship research, dosage is preferably studied with compatibility, system's drug effect, experiments such as safety evaluatio have determined that experiment determined that danshen root salvianolic acid A and glycyrrhizic acid and enoxolone and derivant thereof can make up, this drug regimen is except the effect with addition, also has well collaborative effect, having reached 1+1 promptly increases curative effect greater than 2, reduces the effect of untoward reaction; We find in pharmacodynamic study, behind danshen root salvianolic acid A and the effective liquorice compatibility, each link of hepatopathy are had good therapeutical effect, can reach prevention and the double effects for the treatment of, and have solved some defectives of modern clinical medicine; Find also in the research that this combination all has good therapeutical effect to cardiovascular and cerebrovascular disease, tumor disease etc.
The application realizes by following proposal.
The application's pharmaceutical composition comprises danshen root salvianolic acid A and the pharmaceutical composition with following general formula:
Formula one
Formula two
Figure S07197271320070509D000033
Formula three
R wherein 1, R 2, R 3, R 4Can be H, Na, Mg, K, ammonium;
Wherein: danshen root salvianolic acid A 1-10 weight portions have one or more 1-20 weight portions in the medicine of general formula;
Pharmaceutical composition wherein is preferably: danshen root salvianolic acid A 1-5 weight portions have one or more 10-20 weight portions in the medicine of general formula;
Pharmaceutical composition wherein is preferably: danshen root salvianolic acid A 6-10 weight portions have one or more 1-9 weight portions in the medicine of general formula;
Aforementioned pharmaceutical compositions can also add one or more in ginsenoside, Radix Astragali saponin, Fructus Crataegi total flavones, ligustrazine, ginkgetin, bilobalide, paeonol, the Carthamus yellow.
Wherein the content of danshen root salvianolic acid A is more than or equal to 50% and less than 100%;
Preparation of pharmaceutical compositions becomes tablet, capsule, granule, soft capsule, pellet, drop pill, oral liquid, aqueous injection, infusion solution, the injectable powder of unit dose;
Wherein tablet, capsule, granule, soft capsule, pellet, drop pill, oral liquid unit dose are 10mg-2000mg; Wherein preferred unit dosage is 20-1000mg.Unit dose is lower than 10mg does not have effect in clinical use, unit dose can produce certain toxicity greater than 2000mg in clinical use;
Wherein aqueous injection, infusion solution, injectable powder unit dose are 5mg-1000mg; Wherein preferred unit dosage is 10-500mg.Unit dose is lower than 5mg does not have effect in clinical use, unit dose can produce certain toxicity greater than 1000mg in clinical use;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
The application's hepatic injury comprises hepatic disease such as various types of hepatitis, liver cirrhosis, fatty liver, hepatocarcinoma, alcoholic liver.
For sake of convenience, in below discussing, the medicine that the application has general formula is written as glycyrrhizic acid and enoxolone and derivant thereof;
One, preparation method
Danshen root salvianolic acid A extracts purification:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, transfer pH value to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hours or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heated 1-6 hours; Solution filters, filtrate is separated through nonpolar or low pole macroporous resin column chromatography, macroporous resin column is HPD-100, HPD-100A, HPD-300, HPD-400, HPD-400A, HPD-450, D101,1300-I, 1400 or AB-8, elder generation's water, 10-30% Diluted Alcohol eluting are removed impurity, the ethanol elution of reuse 30-70% concentration, collect eluent, concentrate, drying obtains danshen root salvianolic acid A;
Or:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, transfer pH value to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hours or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heated 1-6 hours; Solution filters, filtrate is separated through nonpolar or low pole macroporous resin column chromatography, macroporous resin column is HPD-100, HPD-100A, HPD-300, HPD-400, HPD-400A, HPD-450, D101,1300-I, 1400 or AB-8, elder generation's water, 10-30% Diluted Alcohol eluting, remove impurity, the ethanol elution of reuse 30-70% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with sephadex lh-20 or polyamide column chromatography, and first water, 20-50% alcoholic solution eluting discard eluent, and reuse 50-95% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A;
Or:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, transfer pH value to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hours or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heated 1-6 hours; Solution filters, filtrate is separated through nonpolar or low pole macroporous resin column chromatography, macroporous resin column is HPD-100, HPD-100A, HPD-300, HPD-400, HPD-400A, HPD-450, D101,1300-I, 1400 or AB-8, elder generation's water, 10-30% Diluted Alcohol eluting, remove impurity, the ethanol elution of reuse 30-70% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with sephadex lh-20 or polyamide column chromatography, and first water, 20-50% alcoholic solution eluting discard eluent, and reuse 50-95% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 2-5, and through organic solvent extraction, organic solvent is selected from a kind of in ethyl acetate, propyl acetate, butyl acetate, n-butyl alcohol, the isopropyl alcohol, separate the organic solvent phase, must contain drug solns, concentrate, drying or lyophilization get danshen root salvianolic acid A;
Medicine with general formula is the glycyrrhizic acid of prior art for preparing and enoxolone and derivant thereof (commercially available or extract purification according to literature method obtain), glycyrrhizic acid and enoxolone and derivant thereof can be the Radix Glycyrrhizae fluidextract or the Radix Glycyrrhizae extractum of prior art for preparing simultaneously, can also be the Pharmacopoeia of the People's Republic of China (version in 2005, an one) 273,274 pages of Radix Glycyrrhizae fluidextract or Radix Glycyrrhizae extractum.
Prior art is meant disclosed method in existing document and the patent, also comprises market sale simultaneously.
Formulation preparation: get danshen root salvianolic acid A, glycyrrhizic acid and enoxolone and derivant thereof, be prepared into tablet, capsule, granule, soft capsule, pellet, drop pill, oral liquid, aqueous injection, infusion solution, injectable powder according to the conventional requirement of pharmaceutics.
Two, check and analysis method
1. detection and analytic method for red sage root dan phenolic acid A:
Chromatographic column: C 18Reversed phase chromatographic column, NUCLEODUR, 250*4.6mm, ODS;
Chromatographic condition and system suitability experiment: with the octadecylsilane chemically bonded silica is filler; Flow velocity 1.0ml/min; 35 ℃ of column temperatures; Detect wavelength 286nm; With acetonitrile-0.2% aqueous acetic acid is mobile phase, carries out gradient elution by following condition of gradient elution, moves 90 minutes;
In the time of 0-15 minute, the ratio of acetonitrile reduces to 80% by 10% ratio that rises to 20%, 0.2% aqueous acetic acid by 90%; In the time of 15-55 minute, the ratio of acetonitrile reduces to 70% by 20% ratio that rises to 30%, 0.2% aqueous acetic acid by 80%; In the time of 55-65 minute, the ratio of acetonitrile reduces to 50% by 30% ratio that rises to 50%, 0.2% aqueous acetic acid by 70%; In the time of 65-72 minute, the ratio of acetonitrile reduces to 20% by 50% ratio that rises to 80%, 0.2% aqueous acetic acid by 50%; In the time of 72-77 minute, the ratio 20% of ratio 80%, 0.2% aqueous acetic acid of acetonitrile; In the time of 77-80 minute, the ratio of acetonitrile rises to 90% by 80% ratio of reducing to 10%, 0.2% aqueous acetic acid by 20%; In the time of 80-90 minute, keep acetonitrile-0.2% aqueous acetic acid to carry out eluting with the ratio of 10:90;
The preparation of reference substance solution: precision takes by weighing the salvianolic acid A reference substance in volumetric flask, adds dissolve with methanol and shakes up, and be diluted to scale;
The preparation of sample solution: precision takes by weighing the salvianolic acid A sample, adds dissolve with methanol and shakes up, and be diluted to scale; Or precision measures or takes by weighing preparation, carries out pretreatment, adds dissolve with methanol and shakes up, and be diluted to scale;
Algoscopy: accurate respectively reference substance solution and the sample solution drawn, inject chromatograph of liquid, the record chromatogram adopts external standard method with calculated by peak area, promptly;
2. glycyrrhizic acid and enoxolone and derivant check and analysis thereof:
Experimental result sees Table 1, table 2:
The check and analysis of table 1 crude drug
Figure S07197271320070509D000051
The check and analysis of table 2 preparation
Experiment conclusion: show that by above-mentioned experiment the application's drug regimen has practical significance.
Three, dose-effect relationship research
Danshen root salvianolic acid A and glycyrrhizic acid and enoxolone and derivant thereof are treated the effective ingredient of diseases such as hepatic injury, hepatic fibrosis simultaneously, and whether the two exists certain dose-effect relationship, and by following experiment, we have had further understanding:
To CCl 4Cause the influence of rat liver fibrosis
Experimental program one:
Scheme 1: danshen root salvianolic acid A 0.2 weight portion;
Scheme 2: danshen root salvianolic acid A 0.4 weight portion;
Scheme 3: danshen root salvianolic acid A 0.6 weight portion;
Scheme 4: danshen root salvianolic acid A 0.8 weight portion;
Scheme 5: danshen root salvianolic acid A 1 weight portion;
Scheme 6: danshen root salvianolic acid A 2 weight portions;
Experimental technique: select male and healthy Wistar rat, body weight 180-200g all divides normal group, model group, different schemes group at random with rat, and except that the normal control group, all the other respectively organize rat first in subcutaneous injection CCl 45ml/kg, 2 back subcutaneous injection 40%CCl4 olive oil 3ml/kg, totally 6 weeks weekly later on.Except that normal group, the 1-2 week, each group all gave the Semen Maydis powder feedstuff that 20% Adeps Sus domestica adds 0.5% cholesterol at duration of test, and the 3-6 week raised with normal diet.Each administration group is irritated the medicinal liquid that stomach gives corresponding dosage simultaneously when modeling begins, administration time is totally 6 weeks.Each is organized after the medication cycle finishes, and cuts open the belly under the etherization, through the lower chamber dooor venous blood collection, detects Serum ALT, AST, Alb respectively, and experimental result sees Table 3:
Experimental program two:
Scheme 1: glycyrrhizic acid 1 weight portion;
Scheme 2: glycyrrhizic acid 5 weight portions;
Scheme 3: glycyrrhizic acid 9 weight portions;
Scheme 4: glycyrrhizic acid 10 weight portions;
Scheme 5: glycyrrhizic acid 15 weight portions;
Scheme 6: glycyrrhizic acid 20 weight portions;
Experimental technique: the experimental technique according to experiment one, experimentize, experimental result sees Table 4:
Table 3 salvianolic acid A is to the influence of Liver Fibrosis Model rat blood serum biochemical indicator
Figure S07197271320070509D000062
Figure S07197271320070509D000071
Annotate: with the model group rate of exchange *P＜0.01, *P＜0.05.
Table 4 glycyrrhizic acid is to the influence of Liver Fibrosis Model rat blood serum biochemical indicator
Annotate: with the model group rate of exchange *P＜0.01, *P＜0.05.
Annotate: above-mentioned experimental program is carried out the tail vein injection administration, and experimental result is close with above-mentioned experimental result, and glycyrrhizin derivative, enoxolone and derivant consumption thereof convert according to above-mentioned glycyrrhizic acid experiment.
The experiment brief summary: experimental program one experimental result shows, danshen root salvianolic acid A is during by 0.2 weight portion to 0.8 weight portion, with model group relatively, serum biochemistry index ALT, AST have a declining tendency, but no difference of science of statistics; When danshen root salvianolic acid A during greater than 1 weight portion, with model group relatively, serum biochemistry index ALT, AST obviously reduce, and have significant difference.Equally, experimental program two experimental results show, effective liquorice and pharmaceutical salts thereof 1-less than 10 weight portions and model group relatively, serum biochemistry index ALT, AST have a declining tendency, but no difference of science of statistics; When glycyrrhizic acid and enoxolone and derivant thereof greater than 10 weight portions, serum biochemistry index ALT, AST obviously descend, with model group relatively, have significant difference.The drug effect that shows the danshen root salvianolic acid A of 1 weight portion and the glycyrrhizic acid more than 10 weight portions and enoxolone and derivant thereof by above-mentioned experimental result is basic identical, the danshen root salvianolic acid A that equivalent is described is better than glycyrrhizic acid and enoxolone and derivant drug effect thereof, point out us when carrying out the compatibility screening, when the salvia miltiorrhiza tanshinoate weight portion after a little while, the glycyrrhizic acid of the more weight portions of needs and enoxolone and derivant thereof are replenished, to reach great pharmacological effects.
Above-mentioned experimental program is carried out experiment in vitro such as cardiovascular and cerebrovascular vessel experiment, tumor, obtain above-mentioned experimental result equally.
Four, medicine efficacy screening experiment
1, carbon tetrachloride is caused the influence of rat chronic hepatic injury
Experimental program:
Scheme 1: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 2: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 3: danshen root salvianolic acid A 8 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 4: danshen root salvianolic acid A 9 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 5: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 6: danshen root salvianolic acid A 8 weight portions, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 8: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get the Wistar rat, by the body weight random packet, normal control group, liver injury model group, the application's scheme group (gastric infusion, dosage are 40mg/kg).Except that the normal control group, each treated animal lumbar injection 10%CCl 4Vegetable oil 0.5ml/100g body weight, weekly twice, totally 12 weeks, normal control group ip normal saline.Every day, ig was administered once simultaneously in modeling.Before experiment finished, femoral artery blood was got in animal fasting 12 hours, with 3000 rev/mins centrifugal 10 minutes, separation of serum is measured ALT, AST, experimental result sees Table 5:
Table 5 different schemes group is to the result that influences of hepatic injury
Figure S07197271320070509D000081
Annotate: compare with model group *P＜0.01, *P＜0.05; Compare #P＜0.05 with scheme 9, scheme 10.
2, to the inhibitory action of liver tissues of rats lipid peroxidation
Experimental program:
Scheme 1: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 2: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 25 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 2 weight portions, glycyrrhizic acid and enoxolone and derivant 19 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 8: danshen root salvianolic acid A 11 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get the SD male rat, body weight 200-250g is divided into normal saline group, different schemes group, and each scheme group rat is in subcutaneous injection CCl 4In the time of 5ml/kg, different schemes group tail intravenously administrable, dosage is 10mg/kg, the normal saline group waits the normal saline of capacity, after the fasting 16 hours, hepatic tissue is taken out in the broken end blood-letting rapidly, adds normal saline and makes 5% homogenate, every test tube is got homogenate 1.5ml, homogenate adds trichloroacetic acid 1.5ml cessation reaction in 37 ± 0.5 ℃ of constant temperature oscillating reactionss 2 hours, and 3500 rev/mins centrifugal 10 minutes, get supernatant 2ml, measure the content of lipid peroxidation product malonaldehyde (MDA) with the TBA method of improvement, calculate MDA and generate suppression ratio, the results are shown in Table 6:
The influence that table 6 couple liver tissues of rats MDA generates
Figure S07197271320070509D000082
Figure S07197271320070509D000091
3, in the duck body to the influence of DHV
Experimental program:
Scheme 1: danshen root salvianolic acid A 11 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 2: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 3: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 25 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 19 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 8: danshen root salvianolic acid A 9 weight portions, glycyrrhizic acid and enoxolone and derivant 2 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get Beijing duck, clear through the positive Sanguis Anas domestica of lower limb shin intravenous injection Shanghai sheldrake DHBV-DNA, every 0.3ml infects and got blood in back 7 days, and separation of serum detects DHBV-DNA content in the serum.Duckling serum is divided into group with duck: virus control group, the application's scheme group (gastric infusion 40mg/kg), gastric infusion, every day 2 times after DHBV is positive after testing at random.Matched group gives with the volume normal saline, successive administration 10 days.Respectively with Drug therapy after after 5 days (T5), 10 days (T10) and the drug withdrawal 3 days (P3) get blood from duck shin vein, separation of serum, press nick translation test kit description method, with 32P labelling DHBV-DNA probe, and make the clear dot blot hybridization of Sanguis Anas domestica, autoradiography diaphragm speckle, microplate reader is measured OD value (optical filter is 490nm), calculate serum DHBV-DNA optical density, as specimen DHBV-DNA level value, experimental result sees Table 7 with hybridization spot OD value.
Table 7 in the duck body to the influence of DHV DHBV-DNA
Figure S07197271320070509D000092
Figure S07197271320070509D000101
Annotate: compare with model group *P＜0.01, *P＜0.05; Compare #P＜0.05 with scheme 9, scheme 10.
4, mouse immune is influenced
Experimental program:
Scheme 1: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 2: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 3 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 8: danshen root salvianolic acid A 9 weight portions, glycyrrhizic acid and enoxolone and derivant 2 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get healthy Kunming mouse, body weight 18-20g, male and female half and half mice is divided into group at random, normal control group, model group, the application's scheme group (15mg/kg), mice ig administration 2 times/day, totally 10 days.Before the administration except that the normal control group, every caudal vein injection 0.25%BCG2.5mg, every Mus tail vein injection LPS2.5 μ g again after 10 days, the eyeball rear vein beard is got blood and is surveyed Serum ALT, AST, experimental result table 8 after 12 hours.
The influence of table 8 pair mouse immune
Figure S07197271320070509D000102
Annotate: compare with model group *P＜0.01, *P＜0.05; Compare #P＜0.05 with scheme 9, scheme 10.
5, to the influence of rat cerebral infarction
Experimental program:
Scheme 1: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 2: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 3 weight portions, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 3 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 3 weight portions, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 8: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get the healthy SD rat, body weight 240-260g, random packet: model control group, experimental program group, each experimental group dosage 10mg/kg, tail intravenously administrable.After the administration 3 days,, get rat in last administration 1 hour, chloral hydrate 300mg/kgip anesthesia, cervical incision separates and the ligation right carotid, behind the suture muscles skin, right lateral position is fixed, and cuts skin at auris dextra and right eye outer canthus line mid point, separate temporalis, expose zygomatic process and temporal bone, open the bone window of about a 3 * 3mm at head end 1～2mm place of zygomatic process, expose middle cerebral artery (MCA), it is disconnected that MCA is burnt, and sews up the incision.With reference to the Bederson method, put to death animal, get right cerebral hemisphere, be cut into 5, place 37 ℃ of incubation 15min dyeing of 2g/LNPT, the white infarct cerebral tissue that carefully takes and weigh and do not dyed blue color.
The experiment brief summary: experimental result shows that scheme 1-8 relatively has utmost point significant difference (P＜0.01) with model control group; Relatively has thin significant difference (P＜0.05) with scheme 9,10; By antithrombotic experiment, microcirculation experiment, experiment conclusion is identical with above-mentioned conclusion, illustrates that the application's experimental program has the effect of good treatment cerebrovascular disease again.
6, to the protective effect of anesthetized rat myocardial ischemia reperfusion injury
Scheme 1: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 2: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 5: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 7: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 8: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: get the healthy SD rat, body weight 240-260g, random packet: blank group, experimental program group.Place the pre-raising of equivalent environment 2 days, free diet.After pre-raising finishes, experimentize, animal is weighed, and 20% urethane is pressed the 0.6ml/100g lumbar injection, after treating that anesthesia is satisfied, lie on the back and be fixed on the Mus plate, tracheal intubation connects respirator, by 10～12ml tidal volume, 70 times/minute frequency is exhaled, and continuous positive pressure breathing is inhaled: exhale than being 1: 1.Adjust respiration parameter according to the respiratory frequency and the degree of depth.Connect electrocardiograph subsequently, survey normal ECG.Cut off front field of operation hair, iodine disinfection, cut off skin, subcutaneous tissue, front muscle and fascia 3～4cm, it is long to separate Intercostal muscle 3cm with the 18# vascular forceps along the 3rd intercostal passivity, open thoracic cavity and pericardium, recording ecg, strut 3,4 ribs refer to hold thoracic cavity, rat right side with left hand four, and the assistant upwards pushes away thymus with the ophthalmology tweezer, between left auricle and pulmonary conus, find ligation sign blood vessel great cardiac vein, 2mm place noinvasive roundlet pin band 6-0 silk thread threading below left auricle, depth of needle is 1～1.5mm, wide 2～3mm, recording ecg behind the threading, gastric infusion (dosage is 40mg/kg), the blank group gives the normal saline of respective amount, recording ecg behind the administration 10min, and with one the band groove little plastics pipe pad at the ligation position, the ligation thereon of two rear line heads.At once recording ecg after the ligation is cyanosis or the II S-T section back of a bow that leads with left chamber antetheca and upwards raises greater than 0.1mv and be that ligation successfully indicates (it is superseded that the S-T section does not have the changer) more than the lasting 0.5h.10min recording ecg is once more cut off ligature behind the ligation 30min after the ligation, realizes perfusion again, irritates 3 hours again, dissects to core dirtyly, and the residual blood of ice normal saline flush away cuts off atrium and right ventricle, puts into refrigerator and cooled immediately and freezes.With heart after refrigerator and cooled is frozen 10min, from the apex of the heart entad the parallel coronary sulcus direction in the end 5 of equal thickness are cut in left chamber, put into the 1%TTC dye liquor, 37 ℃ of dyeing 10min, the necrotic area is not a kermesinus, the necrotic area is canescence.Digital camera is taken pictures.Weighed respectively in necrotic area and non-necrotic area, calculate the percentage ratio that the necrotic area accounts for left ventricular mass, i.e. infarction size.
The experiment brief summary: experimental result shows that scheme 1-8 relatively has utmost point significant difference (P＜0.01) with the blank group; Relatively has thin significant difference (P＜0.05) with scheme 9,10; By antithrombotic experiment, microcirculation experiment, experiment conclusion is identical with above-mentioned conclusion, illustrates that the application's experimental program has the effect of good treatment cardiovascular disease again.
7, active Immunotherapy of Cancer Induced
Experimental program:
Scheme 1: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 3 weight portions thereof;
Scheme 2: danshen root salvianolic acid A 6 weight portions, glycyrrhizic acid and enoxolone and derivant 4 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 6 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 7 weight portions, glycyrrhizic acid and enoxolone and derivant 7 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 8 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 6: danshen root salvianolic acid A 9 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: with the antimutagenic effect of mouse Bone marrow cells micronucleus experiment and testicular chromosome distortion laboratory observation scheme group, with the antitumous effect of S-180 and H-22 transplanted tumor observation plan group, scheme group gastric infusion, dosage is 40mg/kg.
Experimental result: scheme 1-6 groups all have the obvious suppression effect to the mouse testis cell chromosome that mouse Bone marrow cells micronucleus takes place and mitomycin the brings out distortion that cyclophosphamide brings out; S-180 and the growth of H-22 mice transplanted tumor also there is the obvious suppression effect.Show that scheme 1-6 groups all have protective effect to the DNA damage of somatic cell and sexual cell, also have certain tumor-inhibiting action to mice transplanted tumor.
The pharmacological evaluation brief summary: the result shows by experiment, and the application's experimental program has great pharmacological effects.
Five, pharmacokinetic
Experimental program:
Scheme 1: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 2: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 7: danshen root salvianolic acid A 11 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 8: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Laboratory animal: the SD rat, male, 8 ages in week, SPF level; Assay method: select for use the LC-MS/MS method to detect; The plasma treatment method: precision is measured plasma specimen 100 μ l, adds 100 μ l0.1% phosphoric acid, 400 μ l methanol, behind the vortex mixing, and the centrifugal 5min of 10000r/min.After 0.2 μ m filter filtered, supernatant was by the automatic sampler sample introduction; Male SD rat, through gastric infusion, get blank blood before the medicine, in taking medicine back 15min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 12h extracting vein blood 0.3ml in anticoagulant tube, separated plasma, with danshen root salvianolic acid A and effective liquorice is that the ejection preparation that feedstock production becomes is a benchmark, calculates the different schemes absolute bioavailability, and experimental result sees Table 9:
The investigation of table 9 different schemes bioavailability
Figure S07197271320070509D000121
Figure S07197271320070509D000131
Six, toxicologic study
Experimental program:
Scheme 1: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 5 weight portions thereof;
Scheme 2: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 10 weight portions thereof;
Scheme 3: danshen root salvianolic acid A 1 weight portion, glycyrrhizic acid and enoxolone and derivant 20 weight portions thereof;
Scheme 4: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 5: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 9 weight portions thereof;
Scheme 6: danshen root salvianolic acid A 10 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 7: danshen root salvianolic acid A 11 weight portions, glycyrrhizic acid and enoxolone and derivant 1 weight portion thereof;
Scheme 8: danshen root salvianolic acid A 5 weight portions, glycyrrhizic acid and enoxolone and derivant 15 weight portions thereof;
Scheme 9: danshen root salvianolic acid A;
Scheme 10: glycyrrhizic acid and enoxolone and derivant thereof;
Experimental technique: the pharmaceutical composition of above-mentioned different schemes, carry out toxicological experiment, measure the LD of mouse tail vein administration acute toxicity 50, experimental result sees Table 10:
The LD of table 10 different schemes 50Value
Figure S07197271320070509D000132
Experiment conclusion: by dose-effect experiment, pharmacodynamics screening experiment, pharmacodynamics experiments, pharmacokinetics experiment, toxicological experiment, we determine danshen root salvianolic acid A 1-10 weight portions, glycyrrhizic acid and enoxolone and derivant 1-20 weight portions thereof; Preferred danshen root salvianolic acid A 1-5 weight portions, glycyrrhizic acid and enoxolone and derivant 10-20 weight portions thereof; Preferred danshen root salvianolic acid A 6-10 weight portions, glycyrrhizic acid and enoxolone and derivant 1-9 weight portions thereof.
Six. preparation embodiment
Embodiment 1
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae extracts with 70% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 4 hours; Solution filters, and filtrate is separated through the HPD-450 macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 50% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 53.8%.
Or
Radix Salviae Miltiorrhizae extracts with 60% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 2 hours; Solution filters, and filtrate is separated through the D101 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 35% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25 alcoholic solution eluting discard eluent, and reuse 55% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 79.7%.
Or
Radix Salviae Miltiorrhizae extracts with 65% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 5.5,130 ℃ of temperature, gauge pressure 0.17MPa pressure, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 45% alcoholic solution eluting discard eluent, and reuse 90% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 4.5, through the organic solvent n-butyl acetate extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 91.2%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000141
Formula one
R wherein 1, R 2, R 3Can be H, Na, Mg, K, ammonium;
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 20 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 10mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 5 grams, glycyrrhizic acid and enoxolone and derivant 5 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 5mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 2
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae extracts with 70% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 4 hours; Solution filters, and filtrate is separated through the HPD-450 macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 50% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 55.1%.
Or
Radix Salviae Miltiorrhizae extracts with 60% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 2 hours; Solution filters, and filtrate is separated through the D101 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 35% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25 alcoholic solution eluting discard eluent, and reuse 55% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 80.1%.
Or
Radix Salviae Miltiorrhizae extracts with 65% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 5.5,130 ℃ of temperature, gauge pressure 0.17MPa pressure, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 45% alcoholic solution eluting discard eluent, and reuse 90% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 4.5, through the organic solvent n-butyl acetate extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 90.3%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000151
Formula two
R wherein 1, R 2Can be H, Na, Mg, K, ammonium;
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 200 grams, glycyrrhizic acid and enoxolone and derivant 400 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 2000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 50 grams, glycyrrhizic acid and enoxolone and derivant 100 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 1000mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 3
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae extracts with 85% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 9.0,80 ℃ of temperature, heating 6 hours, solution filters, filtrate is separated through the HPD-400 macroporous resin column chromatography, and first water, 30% Diluted Alcohol eluting are removed impurity, the ethanol elution of reuse 70% concentration, collect eluent, concentrate drying, obtain danshen root salvianolic acid A, danshen root salvianolic acid A content 59.3%.
Or
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 3.5,110 ℃ of temperature, gauge pressure 0.05MPa pressure, heats 6 hours; Solution filters, and filtrate is separated through the HPD-400A macroporous resin column chromatography, and first water, 30% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 70% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 50% alcoholic solution eluting discard eluent, and reuse 95% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, danshen root salvianolic acid A content 89.7%
Or
Radix Salviae Miltiorrhizae extracts with 80% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 6.0,130 ℃ of temperature, gauge pressure 0.17MPa pressure, heats 6 hours; Solution filters, and filtrate is separated through the HPD-450 macroporous resin column chromatography, and first water, 30% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 70% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 50% alcoholic solution eluting discard eluent, and reuse 95% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 5, through the extraction of organic solvent propyl acetate, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, danshen root salvianolic acid A content 99.4%.
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000161
Formula three
R wherein 1, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 200 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 220mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 5 grams, glycyrrhizic acid and enoxolone and derivant 50 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 55mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 4
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae 35% alcoholic solution extracts and to obtain alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,115 ℃ of temperature, gauge pressure 0.07MPa pressure, heats 5 hours; Solution filters, and filtrate is separated through the HPD-100 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 40% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 58.1%.
Or
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 4.5,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 3.5 hours; Solution filters, and filtrate is separated through the HPD-100A macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 45% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 30% alcoholic solution eluting discard eluent, and reuse 70% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 69.7%.
Or
Radix Salviae Miltiorrhizae 50% alcoholic solution extracts and to obtain alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 6 hours; Solution filters, and filtrate is separated through the HPD-300 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 35% alcoholic solution eluting discard eluent, and reuse 60% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 2.5, through the extraction of organic solvent isopropyl alcohol, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, content 91.2%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000171
Formula one
Figure S07197271320070509D000172
Formula two
R wherein 1, R 2, R 3Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 400 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 420mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 5 grams, glycyrrhizic acid and enoxolone and derivant 100 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 105mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 5
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae extracts with 70% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 4 hours; Solution filters, and filtrate is separated through the HPD-450 macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 50% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 55.1%.
Or
Radix Salviae Miltiorrhizae extracts with 60% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,130 ℃ of temperature, gauge pressure 0.17MPa pressure, heats 2 hours; Solution filters, and filtrate is separated through the D101 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 35% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25 alcoholic solution eluting discard eluent, and reuse 55% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 80.1%.
Or
Radix Salviae Miltiorrhizae extracts with 65% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 5.5,115 ℃ of temperature, gauge pressure 0.08MPa pressure, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 45% alcoholic solution eluting discard eluent, and reuse 90% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 4.5, through the organic solvent n-butyl acetate extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 90.3%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000191
Formula one
Figure S07197271320070509D000192
Formula three
R wherein 1, R 2, R 3, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 100 grams, glycyrrhizic acid and enoxolone and derivant 200 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1500mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 25 grams, glycyrrhizic acid and enoxolone and derivant 50 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 750mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 6
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transferred pH value to 7.5,30 ℃ of temperature, heating 1 hour, solution filters, and filtrate is separated through the HPD-100 macroporous resin column chromatography, first water, 10% Diluted Alcohol eluting, remove impurity, the ethanol elution of reuse 30% concentration is collected eluent, concentrates, drying obtains danshen root salvianolic acid A.Danshen root salvianolic acid A content 50.1%.
Or
Radix Salviae Miltiorrhizae extracts with 20% alcoholic solution and obtains alcohol extract, alcohol extract concentrates ethanol to most, transferred pH value to 9.0,80 ℃ of temperature, heating 6 hours, solution filters, and filtrate is separated through the HPD-100A macroporous resin column chromatography, first water, 30% Diluted Alcohol eluting, remove impurity, the ethanol elution of reuse 70% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 20% alcoholic solution eluting discard eluent, and reuse 50% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A.Danshen root salvianolic acid A content 61.3%;
Or
Radix Salviae Miltiorrhizae extracts with 50% alcoholic solution and obtains alcohol extract, alcohol extract concentrates ethanol to most, transferred pH value to 8.0,50 ℃ of temperature, heating 4 hours, solution filters, and filtrate is separated through the HPD-300 macroporous resin column chromatography, first water, 20% Diluted Alcohol eluting, remove impurity, the ethanol elution of reuse 50% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 35% alcoholic solution eluting discard eluent, and reuse 75% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 2, through the organic solvent ethyl acetate extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A; Danshen root salvianolic acid A content 90.03%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000201
Formula two
R wherein 1, R 2, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 100 grams, glycyrrhizic acid and enoxolone and derivant 400 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 25 grams, glycyrrhizic acid and enoxolone and derivant 100 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 500mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 7
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 8.5,50 ℃ of temperature, heating 4 hours, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 55% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 52.9%.
Or
Radix Salviae Miltiorrhizae extracts with 50% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 8.0,75 ℃ of temperature, heating 2 hours; Solution filters, and filtrate is separated through 1400 macroporous resin column chromatographies, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25% alcoholic solution eluting discard eluent, and reuse 60% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 84.1%.
Or
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 4.0,110 ℃ of temperature, gauge pressure 0.05MPa pressure, heats 5.5 hours; Solution filters, and filtrate is separated through the AB-8 macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 30% alcoholic solution eluting discard eluent, and reuse 80% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 3.5, through the organic solvent n-butanol extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 94.7%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000211
Formula one
Figure S07197271320070509D000221
Formula two
Figure S07197271320070509D000222
Formula three
R wherein 1, R 2, R 3, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 60 grams, glycyrrhizic acid and enoxolone and derivant 240 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 20mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 15 grams, glycyrrhizic acid and enoxolone and derivant 60 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 10mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 8
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae 35% alcoholic solution extracts and to obtain alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 5 hours; Solution filters, and filtrate is separated through the HPD-100 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 40% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 58.1%.
Or
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 4.5,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 3.5 hours; Solution filters, and filtrate is separated through the HPD-100A macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 45% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 30% alcoholic solution eluting discard eluent, and reuse 70% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 69.7%.
Or
Radix Salviae Miltiorrhizae 50% alcoholic solution extracts and to obtain alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,110 ℃ of temperature, gauge pressure 0.05MPa pressure, heats 6 hours; Solution filters, and filtrate is separated through the HPD-300 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 35% alcoholic solution eluting discard eluent, and reuse 60% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 2.5, through the extraction of organic solvent isopropyl alcohol, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, content 91.2%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000231
Formula one
R wherein 1, R 2, R 3Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 120 grams, glycyrrhizic acid and enoxolone and derivant 20 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 140mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 30 grams, glycyrrhizic acid and enoxolone and derivant 5 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 35mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 9
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 8.5,50 ℃ of temperature, heating 4 hours, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 55% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 52.9%.
Or
Radix Salviae Miltiorrhizae extracts with 50% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 8.0,75 ℃ of temperature, heating 2 hours; Solution filters, and filtrate is separated through 1400 macroporous resin column chromatographies, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25% alcoholic solution eluting discard eluent, and reuse 60% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 84.1%.
Or
Radix Salviae Miltiorrhizae obtains aqueous extract with water extraction, transfers pH value to 4.0,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 5.5 hours; Solution filters, and filtrate is separated through the AB-8 macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 30% alcoholic solution eluting discard eluent, and reuse 80% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 3.5, through the organic solvent n-butanol extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 94.7%;
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000241
Formula two
R wherein 1, R 2, R 3, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 120 grams, glycyrrhizic acid and enoxolone and derivant 180 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1200mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 30 grams, glycyrrhizic acid and enoxolone and derivant 45 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 750mg;
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 10
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae extracts with 70% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.5,120 ℃ of temperature, gauge pressure 0.10MPa pressure, heats 4 hours; Solution filters, and filtrate is separated through the HPD-450 macroporous resin column chromatography, and first water, 20% Diluted Alcohol eluting are removed impurity, reuse, and the ethanol elution of 50% concentration is collected eluent, concentrates, and drying obtains danshen root salvianolic acid A, and content is 57.2%.
Or
Radix Salviae Miltiorrhizae extracts with 60% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 4.0,125 ℃ of temperature, gauge pressure 0.14MPa pressure, heats 2 hours; Solution filters, and filtrate is separated through the D101 macroporous resin column chromatography, and first water, 15% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 35% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with polyamide chromatography post, and first water, 25 alcoholic solution eluting discard eluent, and reuse 55% alcoholic solution eluting concentrates, and drying obtains danshen root salvianolic acid A, and content is 82.3%.
Or
Radix Salviae Miltiorrhizae extracts with 65% alcoholic solution and obtains alcohol extract, and alcohol extract concentrates ethanol to the greatest extent, transfers pH value to 5.5,130 ℃ of temperature, gauge pressure 0.17MPa pressure, heats 3 hours; Solution filters, and filtrate is separated through the 1300-I macroporous resin column chromatography, and first water, 25% Diluted Alcohol eluting are removed impurity, and the ethanol elution of reuse 65% concentration is collected eluent, reclaims ethanol to most; Concentrated solution separates with the sephadex lh-20 chromatographic column, and first water, 45% alcoholic solution eluting discard eluent, and reuse 90% alcoholic solution eluting reclaims ethanol to most; Concentrated solution is transferred pH value to 4.5, through the organic solvent n-butyl acetate extraction, separates the organic solvent phase, must contain drug solns, concentrates, and drying or lyophilization get danshen root salvianolic acid A, and content is 91.0%; Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000251
Formula three
R wherein 1, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 200 grams, glycyrrhizic acid and enoxolone and derivant 180 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 380mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 50 grams, glycyrrhizic acid and enoxolone and derivant 45 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 95mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 11
Danshen root salvianolic acid A is according to embodiment 1 preparation
Medicine with general formula is a prior art for preparing:
Formula one
Figure S07197271320070509D000262
Formula two
R wherein 1, R 2, R 3Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 160 grams, glycyrrhizic acid and enoxolone and derivant 40 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 20mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 40 grams, glycyrrhizic acid and enoxolone and derivant 10 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 10mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 12
Danshen root salvianolic acid A is according to embodiment 2 preparations
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000271
Formula one
Figure S07197271320070509D000272
Formula three
R wherein 1, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 40 grams, glycyrrhizic acid and enoxolone and derivant 60 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 10 grams, glycyrrhizic acid and enoxolone and derivant 15 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 500mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 13
Danshen root salvianolic acid A is according to embodiment 3 preparations
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000281
Formula two
Figure S07197271320070509D000282
Formula three
R wherein 1, R 2, R 4Can be H, Na, Mg, K, ammonium
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 180 grams, glycyrrhizic acid and enoxolone and derivant 360 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1080mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 45 grams, glycyrrhizic acid and enoxolone and derivant 90 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 135mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 14
Danshen root salvianolic acid A is according to embodiment 4 preparations
Medicine with general formula is a prior art for preparing:
Figure S07197271320070509D000291
Formula one
Figure S07197271320070509D000292
Formula two
Figure S07197271320070509D000293
Formula three
R wherein 1, R 4Can be H, Na, Mg, K, ammonium;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 80 grams, glycyrrhizic acid and enoxolone and derivant 320 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 2000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 80 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 1000mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 15
Danshen root salvianolic acid A is according to embodiment 5 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 20 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 10mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 5 grams, glycyrrhizic acid and enoxolone and derivant 5 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 5mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 16
Danshen root salvianolic acid A is according to embodiment 6 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 200 grams, glycyrrhizic acid and enoxolone and derivant 400 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 2000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 50 grams, glycyrrhizic acid and enoxolone and derivant 100 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 1000mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 17
Danshen root salvianolic acid A is according to embodiment 7 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 20 grams, glycyrrhizic acid and enoxolone and derivant 200 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 20mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 25 grams, glycyrrhizic acid and enoxolone and derivant 50 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 10mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 18
Danshen root salvianolic acid A is according to embodiment 8 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 100 grams, glycyrrhizic acid and enoxolone and derivant 400 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1000mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 25 grams, glycyrrhizic acid and enoxolone and derivant 100 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 500mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 19
Danshen root salvianolic acid A is according to embodiment 9 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 60 grams, glycyrrhizic acid and enoxolone and derivant 240 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1500mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 15 grams, glycyrrhizic acid and enoxolone and derivant 60 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 750mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 20
Danshen root salvianolic acid A is according to embodiment 10 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing; (the version pharmacopeia was one one in 2005)
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 120 grams, glycyrrhizic acid and enoxolone and derivant 20 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 140mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 30 grams, glycyrrhizic acid and enoxolone and derivant 5 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 35mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 21
Danshen root salvianolic acid A is according to embodiment 1 preparation
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 120 grams, glycyrrhizic acid and enoxolone and derivant 180 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 300mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 30 grams, glycyrrhizic acid and enoxolone and derivant 45 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 75mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 22
Danshen root salvianolic acid A is according to embodiment 2 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 200 grams, glycyrrhizic acid and enoxolone and derivant 20 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 220mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 50 grams, glycyrrhizic acid and enoxolone and derivant 5 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 55mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 23
Danshen root salvianolic acid A is according to embodiment 3 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 200 grams, glycyrrhizic acid and enoxolone and derivant 180 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 720mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 50 grams, glycyrrhizic acid and enoxolone and derivant 45 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 190mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 24
Danshen root salvianolic acid A is according to embodiment 4 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 160 grams, glycyrrhizic acid and enoxolone and derivant 40 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1600mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 40 grams, glycyrrhizic acid and enoxolone and derivant 10 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 700mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 25
Danshen root salvianolic acid A is according to embodiment 5 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 180 grams, glycyrrhizic acid and enoxolone and derivant 360 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 1080mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 45 grams, glycyrrhizic acid and enoxolone and derivant 90 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 135mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Embodiment 26
Danshen root salvianolic acid A is according to embodiment 9 preparations
Medicine with general formula is the Radix Glycyrrhizae extractum or the Radix Glycyrrhizae fluidextract of prior art for preparing;
Formulation preparation:
The oral formulations preparation:
Drug regimen is: danshen root salvianolic acid A 40 grams, glycyrrhizic acid and enoxolone and derivant 60 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have pellet, drop pill that the glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into tablet, capsule, granule, soft capsule, the oral liquid of 1000 quantity respectively or are prepared into 10000 quantity respectively;
Unit dose is 20mg;
The ejection preparation preparation:
Pharmaceutical composition is: danshen root salvianolic acid A 10 grams, glycyrrhizic acid and enoxolone and derivant 15 grams thereof; Pharmaceutic adjuvant;
Get danshen root salvianolic acid A, have aqueous injection, infusion solution, injectable powder that the medicine glycyrrhizic acid of general formula and enoxolone and derivant thereof are prepared into 1000 quantity respectively;
Unit dose is 10mg.
Pharmaceutical composition treats and/or prevents application in hepatic injury, hepatic fibrosis, cardiovascular and cerebrovascular disease, the tumour medicine in preparation.
Annotate: the present invention's concrete technical scheme required for protection is not limited to the concrete combination of the expressed technical scheme of the foregoing description.

Claims (11)

1. pharmaceutical composition is characterized in that comprising danshen root salvianolic acid A and has one or more of following general formula medicine:
Figure FSB00000055272700011
Formula one
Formula two
Figure FSB00000055272700013
Formula three
Wherein R1, R2, R3, R4 can be H, Na, Mg, K, ammonium; Wherein danshen root salvianolic acid A is the 1-10 weight portion, has in the medicine of general formula one or more and is the 1-20 weight portion.
2. a kind of pharmaceutical composition according to claim 1, wherein danshen root salvianolic acid A is the 1-5 weight portion, has in the medicine of general formula one or more and is the 10-20 weight portion.
3. a kind of pharmaceutical composition according to claim 1, wherein danshen root salvianolic acid A is the 6-10 weight portion, has in the medicine of general formula one or more and is the 1-9 weight portion.
4. according to claim 1,2,3 each described a kind of pharmaceutical compositions, the medicine that wherein has general formula is a Radix Glycyrrhizae extractum.
5. according to claim 1,2,3 each described a kind of pharmaceutical compositions, the medicine that wherein has general formula is a Radix Glycyrrhizae fluidextract.
6. according to claim 1,2,3 each described a kind of pharmaceutical compositions, wherein the content of danshen root salvianolic acid A is more than or equal to 50% and less than 100%.
7. according to claim 1,2,3 each described a kind of pharmaceutical compositions, wherein tablet, capsule, granule, pellet, drop pill, oral liquid, aqueous injection, infusion solution, the injectable powder of the unit dose that becomes of preparation of pharmaceutical compositions.
8. a kind of pharmaceutical composition according to claim 7, wherein tablet, capsule, granule, pellet, drop pill, oral liquid unit dose are 10mg-2000mg.
9. a kind of pharmaceutical composition according to claim 7, wherein tablet, capsule, granule, pellet, drop pill, oral liquid unit dose are 20mg-1000mg.
10. a kind of pharmaceutical composition according to claim 7, wherein the unit dose of aqueous injection, infusion solution, injectable powder is 5mg-1000mg.
11. a kind of pharmaceutical composition according to claim 7, wherein the unit dose of aqueous injection, infusion solution, injectable powder is 10mg-500mg.
CN2007100972713A 2007-04-29 2007-04-29 Pharmaceutical composition Expired - Fee Related CN101292986B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2007100972713A CN101292986B (en) 2007-04-29 2007-04-29 Pharmaceutical composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2007100972713A CN101292986B (en) 2007-04-29 2007-04-29 Pharmaceutical composition

Publications (2)

Publication Number Publication Date
CN101292986A CN101292986A (en) 2008-10-29
CN101292986B true CN101292986B (en) 2010-09-08

Family

ID=40063694

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2007100972713A Expired - Fee Related CN101292986B (en) 2007-04-29 2007-04-29 Pharmaceutical composition

Country Status (1)

Country Link
CN (1) CN101292986B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116585335B (en) * 2023-06-07 2024-02-09 广东植肤生物科技有限公司 A skin external composition for inhibiting TYR activity and MC1R expression

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1563075A (en) * 2004-04-02 2005-01-12 江苏正大天晴药业股份有限公司 Method of preparing general phenolic acid of red sange root for treating hepatic fibrosis
CN1772042A (en) * 2005-11-09 2006-05-17 北京华信万邦医药技术有限公司 Chinese medicine composition for treating liver fibrosis and portal vein hypertension and its prepn

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1563075A (en) * 2004-04-02 2005-01-12 江苏正大天晴药业股份有限公司 Method of preparing general phenolic acid of red sange root for treating hepatic fibrosis
CN1772042A (en) * 2005-11-09 2006-05-17 北京华信万邦医药技术有限公司 Chinese medicine composition for treating liver fibrosis and portal vein hypertension and its prepn

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
刘树峰等.优化甘参复方抗肝纤维化组分配伍的研究.中华中医药杂志20 6.2005,20(6),373-375. *
张胜华等.丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用.药学学报39 7.2004,39(7),496-499. *
杜冠华等.丹参水溶性有效成分-丹酚酸研究进展.基础医学与临床20 5.2000,20(5),10-14. *

Also Published As

Publication number Publication date
CN101292986A (en) 2008-10-29

Similar Documents

Publication Publication Date Title
CN100569219C (en) A kind of pharmaceutical composition that is used for oral formulations and preparation method thereof
CN101311160B (en) Method for preparing red sage root salviandic acid A
CN100490795C (en) Red sage root salvianolic acid A injection formulation for treating cardiovascular diseases and preparation process thereof
CN101230003B (en) Preparation method of salvia miltiorrhiza tanshinoate A
CN1931236B (en) Medicine composition of red sage and rhodiola root
CN101283999B (en) Medicinal composition mainly for curing cardiovascular and cerebrovascular diseases and preparation method thereof
CN101301300A (en) Medicament composition
CN101006984B (en) An injection preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application
CN101759672B (en) Salvianolic acid B in radix salviae miltiorrhizae
CN101006975B (en) An oral medicine preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application
CN101293009A (en) Pharmaceutical composition
CN101292987B (en) Pharmaceutical combination
CN101292986B (en) Pharmaceutical composition
CN111000903A (en) Traditional Chinese medicine composition for treating blood stasis type coronary heart disease angina and preparation method thereof
CN1931233B (en) Medicine composition of red sage and epimedium for treating cardiac and cerebral vascular diseases
CN101019878B (en) Injection medicine composite containing salvianolic acid A and its preparation
CN1994277B (en) Solid preparation of salvianolic acid A of red sage root and preparation process thereof
CN101019824B (en) Preparation method of oral medicine composition containing salvianolic acid
CN101623437A (en) Pulse activating preparation for injection and its preparation method
CN100563647C (en) The Pharmaceutical composition of Herba Erigerontis and sodium tanshinon IIA silate injection
CN101696166B (en) Preparation method for danshen root salvianolic acid A
CN101288705B (en) Medicine composition mainly for adjusting blood fat and its preparation method
CN101974011A (en) New compound methyl brevicate with medical activity
CN101176751B (en) Pharmaceutical composition of red sage root and cassia twig
CN100462072C (en) Medicine composition used for injection and its preparing method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
DD01 Delivery of document by public notice
DD01 Delivery of document by public notice

Addressee: Bencao Tianyuan Pharmaceutical Research Inst., Beijing

Document name: Notification to Pay the Fees

DD01 Delivery of document by public notice
DD01 Delivery of document by public notice

Addressee: Bencao Tianyuan Pharmaceutical Research Inst., Beijing

Document name: Notification of Termination of Patent Right

CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20100908

Termination date: 20180429