CN101006984A - An injection preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application - Google Patents
An injection preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application Download PDFInfo
- Publication number
- CN101006984A CN101006984A CN 200710003036 CN200710003036A CN101006984A CN 101006984 A CN101006984 A CN 101006984A CN 200710003036 CN200710003036 CN 200710003036 CN 200710003036 A CN200710003036 A CN 200710003036A CN 101006984 A CN101006984 A CN 101006984A
- Authority
- CN
- China
- Prior art keywords
- radix notoginseng
- salvianolic acid
- danshen root
- root salvianolic
- preparation
- 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.)
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- YMGFTDKNIWPMGF-AGYDPFETSA-N 3-(3,4-dihydroxyphenyl)-2-[(e)-3-[2-[(e)-2-(3,4-dihydroxyphenyl)ethenyl]-3,4-dihydroxyphenyl]prop-2-enoyl]oxypropanoic acid Chemical compound C=1C=C(O)C(O)=C(\C=C\C=2C=C(O)C(O)=CC=2)C=1/C=C/C(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 YMGFTDKNIWPMGF-AGYDPFETSA-N 0.000 title claims abstract description 352
- YMGFTDKNIWPMGF-QHCPKHFHSA-N Salvianolic acid A Natural products OC(=O)[C@H](Cc1ccc(O)c(O)c1)OC(=O)C=Cc2ccc(O)c(O)c2C=Cc3ccc(O)c(O)c3 YMGFTDKNIWPMGF-QHCPKHFHSA-N 0.000 title claims abstract description 352
- 238000002360 preparation method Methods 0.000 title claims abstract description 284
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- -1 panaxadiol saponin Chemical class 0.000 claims abstract description 230
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Abstract
The invention discloses a salvianolic acid A and notoginseng extract preparation for injection, its preparing process and use thereof, characterized in that the preparation comprises salvianolic acid A and Notoginsen triterpenes by a weight ratio of 1:1-10, preferably 1:3, the weight ratio of salvianolic acid A and notoginseng panaxadiol saponin is 1:1-5, the weight ratio of salvianolic acid A and notoginseng panaxadiol saponin Rb1 is 1:0.5-5. The preparation has good pharmaceutical actions.
Description
Technical field
The present invention relates to technical field of traditional Chinese medicine pharmacy, be specifically related to ejection preparation of a kind of danshen root salvianolic acid A, Radix Notoginseng extract and its production and application.
Background technology
Salvianolic acid A [salvianolic acid A] is an active best composition in the Radix Salviae Miltiorrhizae; has great pharmacological effects (Du Guanhua [preclinical medicine and clinical; 2000; 20 (5): 10～14] etc. the people has carried out big quantity research to the activity of salvianolic acid A; find that salvianolic acid A has significant protective effect to the isolated rat myocardial ischemia reperfusion injury; the brain injury that the mouse brain ischemia-reperfusion is caused has protective effect; the mouse memory acquired disturbance tool that Anisodine or scopolamine are caused improves significantly; rat galactose-cataract is formed or inhibitory action arranged; therefore in the cardiovascular and cerebrovascular vessel direction good curative effect is arranged; Hu Yiyang [herbal pharmacology journal; 1997,18 (5): 478-480] etc. the people has reported that salvianolic acid A is to the Fibrotic protective effect of hepatic injury regulating liver-QI.) therefore salvianolic acid A is applied to the hope that treatment of diseases is a lot of medical scientific research persons, particularly with the compatibility of salvianolic acid A with pharmaceutically active ingredient in other, one of need difficult problem to be solved especially.
The research of Chinese medicine compatibility rests on the basis of medical material compatibility more, though can make an explanation with theory of Chinese medical science, but there is dispute in its science always, therefore the middle pharmaceutically active ingredient of the Chinese medicine active substance particularly being gone into blood carries out compatibility, admitted by numerous researchers, the proportion relation of this compatibility is its core and soul place, be the characteristic and the advantage of Chinese medicine, it neither simple Chinese medicine medical material using, quantitative addition, the counteracting of toxic reaction that neither be mechanical, but by a series of research (pharmacokinetics, aspects such as pharmacodynamics), on the basis of dialectical method, with legally constituted authority side, cube send medicine, the teacher that system is arranged who combines in order.
Used the preparation of the compatibility of a lot of Radix Salviae Miltiorrhizaes and Radix Notoginseng clinically, it passes through Radix Salviae Miltiorrhizae, the compatibility of Radix Notoginseng reaches the effect of treatment, 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 the compatibility of this Chinese medicine medical material is that the more weak composition of other relativity of Radix Salviae Miltiorrhizae is (such as TANSHINONES, salvianolic acid B etc.) compatibility that carries out with Radix Notoginseng, though this compatibility has played certain therapeutical effect clinically, but the effective ingredient of Radix Salviae Miltiorrhizae and Radix Notoginseng not being brought into play maximum drug effect is applied in the treatment of diseases, has caused the huge waste of resource.
Consult document and patent, the report of danshen root salvianolic acid A and Radix Notoginseng extract compatibility is not arranged.
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, we discover that the danshen root salvianolic acid A half-life short, in the treatment disease, need rechallenge in a short period of time, to reach the purpose of keeping blood drug level, Radix Notoginseng extract (Radix Notoginseng total arasaponins, Radix Notoginseng Panaxadiol saponin, Radix Notoginseng Panaxadiol saponin Rb
1) half-life is longer, after effect far away is obvious, and is suitable long-acting; Though the compatibility of Radix Salviae Miltiorrhizae and Radix Notoginseng has been arranged clinically to be used, but its essence is the effect of the compatibility of other extract of Radix Salviae Miltiorrhizae and Radix Notoginseng extract, salvianolic acid A is trace level in its compatibility, and with whether level salvianolic acid A and Radix Notoginseng extract can need a large amount of research works by compatibility in batches; Therefore danshen root salvianolic acid A and a kind of half-life can be carried out compatibility than long medicine Radix Notoginseng extract, reach collaborative pharmacological action; We are by the research of aspects such as pharmacokinetics, pharmacodynamics, toxicology, find that the salvianolic acid A and the Radix Notoginseng extract of level have certain rules aspect compatibility in batches, this rule is embodied in salvianolic acid A and Radix Notoginseng total arasaponins, Radix Notoginseng Panaxadiol saponin, Radix Notoginseng Panaxadiol saponin Rb1 weight proportion, and the pharmaceutical composition under this ratio has good complementary action.
The present invention is achieved through the following technical solutions.
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng total arasaponins=1: 1-10.
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng total arasaponins=1: 3.
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 1-5.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 0.5-5.
One. process recipes:
The preparation of danshen root salvianolic acid A:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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 chromatography post, 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, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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 chromatography post, and first water, 20-50% alcoholic solution eluting discard eluent, and reuse 50-95% alcoholic solution eluting reclaims ethanol to most; Concentrated solution transfers 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, separates the organic solvent phase, must contain drug solns, concentrate, drying or lyophilization, danshen root salvianolic acid A;
Danshen root salvianolic acid A content is more than or equal to 50% and less than 100%; Preferred danshen root salvianolic acid A content is more than or equal to 80% and less than 100%; More preferably danshen root salvianolic acid A content is more than or equal to 90% and less than 100%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is according to the standard of " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins or can also directly buys Radix Notoginseng extract from the market; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content should be 5%-10%, the ginsenoside Rg
1Content should be 20%-40%, ginsenoside Rb
1Content should be 30%-40%, and the content of its Radix Notoginseng total arasaponins is preferably in more than 80% more than or equal to 60% and less than 100%.No matter be to buy, do not reach above-mentioned content standard, then should make with extra care, make it to meet above-mentioned content standard as purity by prior art for preparing or market.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last macroporous adsorptive resins, macroporous adsorbent resin are D101, AB-8 or NKA, uses earlier 40% ethanol elution, discard eluent, reuse 50% ethanol elution is collected eluent, concentrate, drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content more than or equal to 75% and less than 100%; Preferred content is more than or equal to 80% and less than 100%, and more preferably content is more than or equal to 90% and less than 100%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: the pseudo-ginseng ethanol extraction, extracting solution reclaims ethanol to most, macroporous adsorptive resins on the concentrated solution, macroporous adsorbent resin is D101, AB-8 or NKA, washes with water earlier, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution, collect eluent, reclaim ethanol to most; Macroporous adsorptive resins on the concentrated solution, macroporous adsorbent resin are D101, AB-8 or NKA, use 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Radix Notoginseng Panaxadiol saponin Rb
1Content is more than or equal to 75% and less than 100%; Preferred content is more than or equal to 80% and less than 100%, and more preferably content is more than or equal to 90% and less than 100%.
Preparation consists of: danshen root salvianolic acid A, arasaponin constituents, pharmaceutic adjuvant.
Formulation preparation:
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 5-1000mg in aqueous injection, infusion solution, the lyophilized injectable powder; Be lower than the 5mg clinical practice and do not have drug effect; Be higher than the 1000mg clinical practice and produce certain toxicity.
Prepare wherein that preferred unit dosage is 10-500mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
The invention reside in the ejection preparation that a kind of danshen root salvianolic acid A, Radix Notoginseng extract are provided;
The present invention also is to provide the preparation method of a kind of danshen root salvianolic acid A, Radix Notoginseng extract ejection preparation;
The present invention also is to provide the purposes of the ejection preparation of a kind of danshen root salvianolic acid A, Radix Notoginseng extract preparation.
Two. detection method
1. the check and analysis of danshen root salvianolic acid A
Experimental technique:
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 10: 90 ratio;
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: get the salvianolic acid A sample, add dissolve with methanol and shake up, and be diluted to scale; Or precision measures or takes by weighing preparation, 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. Radix Notoginseng extract check and analysis
(1) Radix Notoginseng total arasaponins check and analysis
Chromatographic column: C18 reversed phase chromatographic column MN 4.6x150mm U.S.A
With octadecylsilane chemically bonded silica is filler, the ODS pre-column.Water: acetonitrile (67: 33) is a mobile phase, flow velocity 1.0ml/min; The detection wavelength is 203nm, 25 ℃ of temperature;
The preparation of reference substance solution: precision takes by weighing ginsenoside Rb respectively
1, the ginsenoside Rg
1, Panax Notoginseng saponin R
1Each 10mg puts in the 10ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, promptly;
The preparation of need testing solution: precision takes by weighing or measures sample or preparation, puts in the 10ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, promptly;
Accurate reference substance solution and the need testing solution injection chromatograph of liquid drawn of algoscopy, the record chromatogram adopts external standard method with calculated by peak area, promptly.
(2) Radix Notoginseng Panaxadiol saponin check and analysis
Chromatographic column: C18 reversed phase chromatographic column MN 4.6x150mm U.S.A
With octadecylsilane chemically bonded silica is filler, the ODS pre-column.Water: acetonitrile (67: 33) is a mobile phase, flow velocity 1.0ml/min; The detection wavelength is 203nm, 25 ℃ of temperature;
The preparation of reference substance solution: precision takes by weighing ginsenoside Rb
1, each 10mg of ginsenoside Rd, put in the 10ml measuring bottle, add dissolve with methanol and be diluted to scale, shake up, promptly;
The preparation of need testing solution: precision takes by weighing or measures sample or preparation, puts in the 10ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, promptly;
Accurate reference substance solution and the need testing solution injection chromatograph of liquid drawn of algoscopy, the record chromatogram adopts external standard method with calculated by peak area, promptly.
(3) Radix Notoginseng Panaxadiol saponin Rb
1Check and analysis
Chromatographic column: C18 reversed phase chromatographic column MN 4.6x150mm U.S.A
With octadecylsilane chemically bonded silica is filler, the ODS pre-column.Water: acetonitrile (67: 33) is a mobile phase, and it is 203nm that flow velocity 1.0ml/min detects wavelength, 25 ℃ of temperature;
The preparation of reference substance solution: precision takes by weighing ginsenoside Rb
110mg puts in the 10ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, promptly;
The preparation of need testing solution: precision takes by weighing or measures sample or preparation, puts in the 10ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, promptly.
Accurate reference substance solution and the need testing solution injection chromatograph of liquid drawn of algoscopy, the record chromatogram adopts external standard method with calculated by peak area, promptly.
The preparation check and analysis: get the application's preparation respectively, carry out check and analysis according to above-mentioned experimental technique, calculate content, experimental result sees Table 1, table 2, table 3:
Table 1 formulation content testing result
| Group | Danshen root salvianolic acid A weight mg | Radix Notoginseng total arasaponins weight is (with ginsenoside Rb 1, the ginsenoside Rg 1, Panax Notoginseng saponin R 1Meter) mg |
| Salvianolic acid A+Radix Notoginseng total arasaponins is the feedstock production aqueous injection | 40.7 | 120.3 |
| Salvianolic acid A+Radix Notoginseng total arasaponins is the feedstock production infusion solution | 39.8 | 119.1 |
| Salvianolic acid A+Radix Notoginseng total arasaponins is the feedstock production lyophilized injectable powder | 39.1 | 119.7 |
Table 2 formulation content testing result
| Group | Danshen root salvianolic acid A weight mg | Radix Notoginseng Panaxadiol saponin weight is (with ginsenoside Rb 1, ginsenoside Rd meter) |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin is the feedstock production aqueous injection | 40.1 | 48.7 |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin is the feedstock production infusion solution | 41.2 | 48.0 |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin is the feedstock production lyophilized injectable powder | 41.0 | 48.1 |
Table 3 formulation content testing result
| Group | Danshen root salvianolic acid A weight mg | Radix Notoginseng Panaxadiol saponin Rb 1Weight mg |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin Rb 1Be the feedstock production aqueous injection | 41.2 | 37.1 |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin Rb 1Be the feedstock production infusion solution | 39.8 | 36.4 |
| Salvianolic acid A+Radix Notoginseng Panaxadiol saponin Rb 1Be the feedstock production lyophilized injectable powder | 39.5 | 37.0 |
Experiment conclusion: show that by above-mentioned experiment the application's preparation has scientific meaning.
Three. pharmacokinetic
Experimental program
Scheme 1: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng total arasaponins=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng total arasaponins=1: 2 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng total arasaponins=1: 3 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng total arasaponins=1: 5 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng total arasaponins=1: 8 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng total arasaponins=1: 10 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng total arasaponins=1: 11 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng total arasaponins;
Experimental technique: 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 l, 0.1% 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, 6 every group, give the medicine group of different schemes through tail vein single, by physiological saline solution, the administration volume is 2ml/kg.2min, 5min, l0min, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h, 6h, 10h, 12h collect blood sample (0.6ml) through rat tail vein before medicine and after the administration, calculate the half-life of the preparation of different schemes, and experimental result sees Table 4:
The investigation of table 4 different schemes half-life
| Group | The T of salvianolic acid A 1/2a (min) | The T of Radix Notoginseng total arasaponins 1/2a (min) | The T of salvianolic acid A 1/2β (min) | The T of Radix Notoginseng total arasaponins 1/2β (min) |
| Scheme 1 | 7.1±1.00 | 17.2±3.10 | 189±7.03 | 321±34 |
| Scheme 2 | 8.0±0.99 | 20.3±4.15 | 197±6.99 | 404±42 |
| Scheme 3 | 9.4±1.06 | 26.6±5.31 | 216±7.94 | 500±58 |
| Scheme 4 | 9.4±1.03 | 26.6±5.38 | 215±7.90 | 499±59 |
| Scheme 5 | 9.0±1.01 | 26.2±5.21 | 208±7.25 | 492±49 |
| Scheme 6 | 9.1±0.98 | 26.3±5.18 | 206±7.21 | 492±49 |
| Scheme 7 | 9.1±1.00 | 26.2±5.10 | 214±7.03 | 497±56 |
| Scheme 8 | 9.1±0.99 | 26.3±5.15 | 214±6.99 | 498±57 |
| Scheme 9 | 11.4±1.06 | 31.6±3.31 | 237±7.94 | 654±72 |
| Scheme 10 | 6.4±1.03 | - | 148±5.21 | - |
| Scheme 11 | - | 14.2±3.21 | - | 751±4.98 |
Annotate: with Radix Notoginseng total arasaponins and Radix Notoginseng Panaxadiol saponin or Radix Notoginseng Panaxadiol saponin Rb
1Replace, experimentize according to above-mentioned experimental technique, its experimental result and above-mentioned experimental result change identical (result of experimental program in the application's scope is good).
Four. hemolytic is investigated
Experimental program:
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1.5 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 2 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 3 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 4 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 5 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 6 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin;
Experimental technique: remove the fibrin rabbit whole blood, add normal saline, shake up, centrifugal, the supernatant that inclines is washed clearly till do not become redness repeatedly, measure erythrocyte, add normal saline and be diluted to 2% suspension, get above-mentioned different schemes medicine group, add 2% red blood cell suspension 2.5ml, add normal saline to 5ml, shake up gently, put in 37 ℃ of waters bath with thermostatic control, observe 3 hours, 4 hours, 6 hours haemolysis situations, experimental result sees Table 5:
Each prescription case haemolysis situation of table 5
| Group | 3 hours | 4 hours | 6 hours |
| Scheme 1 | - | - | - |
| Scheme 2 | - | - | - |
| Scheme 3 | - | - | - |
| Scheme 4 | - | - | - |
| Scheme 5 | - | - | - |
| Scheme 6 | - | - | - |
| Scheme 7 | - | - | - |
| Scheme 8 | - | - | - |
| Scheme 9 | -+ | + | + |
| Scheme 10 | - | - | - |
| Scheme 11 | -+ | + | + |
Annotate :+expression haemolysis;-represent not haemolysis
Annotate: with Radix Notoginseng Panaxadiol saponin and Radix Notoginseng total arasaponins or Radix Notoginseng Panaxadiol saponin Rb
1Replace, experimentize according to above-mentioned experimental technique, its experimental result and above-mentioned experimental result change identical.(result of experimental program in the application's scope is good).
Five. the experiment of drug effect blood
Experiment 1
The cerebrovascular disease pharmacological evaluation
Experimental program:
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.4 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.5 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.8 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 1 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 2 preparation cost application ejection preparations;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 3 preparation cost application ejection preparations;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 4 preparation cost application ejection preparations;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 5 preparation cost application ejection preparations;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 6 preparation cost application ejection preparations;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin Rb
1
Experimental technique: adopt middle cerebral artery occlusion (MACO) to induce the method for focal cerebral ischemia in rats model, inquire into the preventive and therapeutic effect of different schemes to local cerebral ischemia due to the intraluminal middle cerebral artery occlusion in rats obturation.Use normal saline as negative control group, the positive contrast of nimodipine, dosage is 0.4mg/kg, and each scheme group dosage is 16mg/kg, contains aquametry as index with brain, and experimental result sees Table 6:
Table 6 pair MACO rat cerebral tissue water content
| Group | Left hemisphere brain water content % | Right hemisphere brain water content % |
| Matched group | 79.32±0.71 | 82.31±0.72 |
| The nimodipine group | 78.12±0.52 | 80.65±0.49 ** |
| Scheme 1 | 79.01±0.64 | 81.37±0.5 2* |
| Scheme 2 | 78.32±0.50 | 81.20±0.47 * |
| Scheme 3 | 78.27±0.48 | 80.71±0.51 **# |
| Scheme 4 | 78.30±0.55 | 80.57±0.59 **# |
| Scheme 5 | 78.25±0.51 | 80.21±0.54 **# |
| Scheme 6 | 78.21±0.47 | 80.57±0.61 **# |
| Scheme 7 | 78.17±0.52 | 80.26±0.42 **# |
| Scheme 8 | 78.09±0.47 | 80.24±0.50 **# |
| Scheme 9 | 78.04±0.44 | 81.57±0.62 * |
| Scheme 10 | 78.21±0.48 | 81.34±0.54 * |
| Scheme 11 | 78.17±0.40 | 81.75±0.59 * |
Annotate: compare with matched group
*P＜0.01,
*P＜0.05; Compare #P＜0.05 for 11 groups with scheme 10, scheme.
Experiment 2
Protective effect to the anesthetized rat myocardial ischemia reperfusion injury
Experimental program:
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.4 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.5 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.8 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 1 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 2 preparation cost application ejection preparations;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 3 preparation cost application ejection preparations;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 4 preparation cost application ejection preparations;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 5 preparation cost application ejection preparations;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 6 preparation cost application ejection preparations;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin Rb
1
Experimental technique:
Get the healthy SD rat, body weight 240-260g is divided into group at random: 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, the assistant upwards pushes away thymus with the ophthalmology tweezer, finds ligation sign blood vessel great cardiac vein between left auricle and pulmonary conus, 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, give corresponding medicinal liquid through the tail vein, 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, and record pours into electrocardiogram at once again, removes in the thoracic cavity layer-by-layer suture thoracic wall behind the hematocele, removes respirator, animal recovery autonomous respiration, and incision of trachea does not process.Irritate again at once, 10min, 20min, 40min, 1h, 2h, 3h recording ecg respectively.Irritated 3 hours, through abdominal aortic blood, 4000rpm is centrifugal, and 10min gets serum again, and dissection is cored dirty, 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 detection index is respectively, myocardial infarct size.Experimental result sees table 7 for details:
Myocardial ischemia myocardial infarct size due to table 7 pair ligation/logical again rat ramus descendens anterior arteriae coronariae sinistrae
Influence (%) (x ± s)
| Group | Myocardial infarct size (%) |
| Matched group | 24.33±11.64 |
| The diltiazem hydrochloride injection | 7.99±2.52 ** |
| Scheme 1 | 14.28±7.34 * |
| Scheme 2 | 8.48±1.22 **# |
| Scheme 3 | 8.40±1.34 **# |
| Scheme 4 | 8.38±1.27 **# |
| Scheme 5 | 8.35±1.19 **# |
| Scheme 6 | 8.34±1.20 **# |
| Scheme 7 | 8.38±1.17 **# |
| Scheme 8 | 8.40±1.29 **# |
| Scheme 9 | 15.37±4.30 * |
| Scheme 10 | 15.78±4.97 * |
| Scheme 11 | 15.89±4.85 * |
Annotate: compare with matched group
*P＜0.01,
*P＜0.05; Compare #P＜0.05 for 11 groups with scheme 10, scheme.
Experiment 3
Anti-ageing year dementia pharmacological evaluation
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1.5 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 2 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 3 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 4 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 5 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 6 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin;
Experimental technique: the normal rat of the diving tower method of learning from else's experience and the screening of eight arm maze methods adopts intracerebroventricular injection β-AP
25-35, make Alzheimer (AD) rat model, use space learning and memory ability that diving tower method and eight arms electricity maze method is judged administration front and back rat; Adopt chemical colorimetry to measure acetylcholinesterase (AchE) activity in the cerebral tissue, each scheme group dosage is 16mg/kg.
Experimental result: compare with the group of solvents rat, rat model eight arms electricity labyrinth errors number obviously increases (P＜0.05), and diving tower learning and memory errors number obviously increases (P＜0.01).Before and after the rat modeling behind the continuous quiet notes administration 21d, the above-mentioned behavioristics of scheme 3-8 group rat index be improved significantly (P＜0.01), active reduce (P＜0.01) of cerebral tissue AchE.The result shows that the application's preparation is to β-AP
25-35Rat space learning and dysmnesia have significant prevention and therapeutical effect due to the intracerebroventricular injection, and the AchE activity is dependency in this effect and the reduction cerebral tissue.Other group effect is not too obvious, does not have significant difference with model group.
Experiment 4
Anti-organ fibrosis experiment
Scheme 1: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng total arasaponins=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng total arasaponins=1: 2 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng total arasaponins=1: 3 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng total arasaponins=1: 5 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng total arasaponins=1: 8 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng total arasaponins=1: 10 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng total arasaponins=1: 11 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng total arasaponins;
Experimental technique: cause the rat liver fibrosis model with 40% carbon tetrachloride complex factors.Treated with the scheme group simultaneously.Detect liver function, III procollagen type (pcIII), hyaluronic acid (HA) during off-test, separate hepatic tissue and detect liver hydroxyproline content and the variation of electron microscopic observation hepatic tissue pathology, each scheme group dosage is 16mg/kg.
Experimental result: scheme 3-8 group can obviously be improved the liver function of hepatic fibrosis rats, reduces serum pCIII, HA content and the hepatic tissue hydroxyproline is obviously descended; Obviously alleviate the deposition of fat-storing cell hypertrophy and collagen.Other group effect is not too obvious, does not have significant difference with model group.
Experiment 5
The microcirculation pharmacological evaluation
Experimental program:
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 1.5 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 2 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 3 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 4 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 5 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin=1: 6 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin;
Experimental technique: each scheme group of micro tv amplification system quantitative observation is to auricular microcirculation obstacle microcirculation of mouse auricle influence due to normal and the norepinephrine (NA); The multiple CAL of blood plasma is measured anticoagulation, and each scheme group dosage is 24mg/kg.
Experimental result: scheme 3-8 group can significantly promote or improve the microcirculation that normally reaches auricular microcirculation obstacle Mice Auricle due to the NA; Also can prolong the blood plasma recalcification time.Scheme 1, scheme 9, scheme 10 effects are not too obvious, do not have significant difference with model group.
Experiment 6
Anti-tumor experiment
Experimental program:
Scheme 1: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.5 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng total arasaponins=1: 0.9 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng total arasaponins=1: 1 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng total arasaponins=1: 2 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng total arasaponins=1: 3 preparation cost application ejection preparation;
Scheme 6: salvianolic acid A: Radix Notoginseng total arasaponins=1: 5 preparation cost application ejection preparation;
Scheme 7: salvianolic acid A: Radix Notoginseng total arasaponins=1: 8 preparation cost application ejection preparation;
Scheme 8: salvianolic acid A: Radix Notoginseng total arasaponins=1: 10 preparation cost application ejection preparation;
Scheme 9: salvianolic acid A: Radix Notoginseng total arasaponins=1: 11 preparation cost application ejection preparation;
Scheme 10: salvianolic acid A;
Experimental technique: with the antimutagenic effect of mouse Bone marrow cells micronucleus experiment and each scheme group of testicular chromosome distortion laboratory observation, observe the antitumous effect of each scheme group with S-180 and H-22 transplanted tumor, each scheme group dosage is 24mg/kg.
Experimental result: scheme 3-8 group all has 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 3-8 group ejection preparation all has protective effect to the DNA damage of somatic cell and sexual cell, also has certain tumor-inhibiting action to mice transplanted tumor.And case 1, scheme 2, scheme 9, scheme 10, scheme 11 effects are not too obvious, do not have significant difference with model group.
Pharmacological evaluation brief summary: show that by above-mentioned pharmacological evaluation preparation in the application's scope and matched group have great pharmacological effects (P＜0.01); Relatively have significant difference (P＜0.05) with danshen root salvianolic acid A, arasaponin constituents, illustrate that the two combination has good complementary action.
Six. toxicological experiment
Scheme 1: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.4 preparation cost application ejection preparation;
Scheme 2: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.5 preparation cost application ejection preparation;
Scheme 3: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 0.8 preparation cost application ejection preparation;
Scheme 4: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 1 preparation cost application ejection preparation;
Scheme 5: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 2 preparation cost application ejection preparations;
Scheme 6: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 3 preparation cost application ejection preparations;
Scheme 7: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 4 preparation cost application ejection preparations;
Scheme 8: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 5 preparation cost application ejection preparations;
Scheme 9: salvianolic acid A: Radix Notoginseng Panaxadiol saponin Rb
1=1: 6 preparation cost application ejection preparations;
Scheme 10: salvianolic acid A;
Scheme 11: Radix Notoginseng Panaxadiol saponin Rb
1
Experimental technique: the pharmaceutical composition of above-mentioned different schemes and preparation, carry out toxicological experiment, measure the LD of mice single intravenously administrable acute toxicity
50, experimental result sees Table 7:
The LD of table 8 different schemes
50Value
| Group | LD 50Value mg/kg |
| Scheme 1 | 298.7 |
| Scheme 2 | 284.3 |
| Scheme 3 | 266.1 |
| Scheme 4 | 258.3 |
| Scheme 5 | 254.2 |
| Scheme 6 | 237.8 |
| Scheme 7 | 243.7 |
| Scheme 8 | 246.3 |
| Scheme 9 | 234.2 |
| Scheme 10 | 437.8 |
| Scheme 11 | 192.6 |
Experiment conclusion: by above-mentioned half-life investigation, hemolytic investigation, pharmacodynamic experiment, toxicological experiment, we determine that danshen root salvianolic acid A and Radix Notoginseng total arasaponins weight ratio are 1: 1-10, preferred danshen root salvianolic acid A and Radix Notoginseng total arasaponins weight ratio are 1: 3, danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin weight ratio are 1: 1-5, the weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb1 is 1: 0.5-5.
Seven. preparation embodiment
Embodiment 1
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-30 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is the standard according to " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 5%, the ginsenoside Rg
1Content is 20%, ginsenoside Rb
1Content is 30%, and the content of its Radix Notoginseng total arasaponins is more than 60%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last D101 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 75%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng 30% ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the AB-8 macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; D101 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Radix Notoginseng Panaxadiol saponin Rb
175.2%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 1, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 40 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 1, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 40 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 0.5, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
120 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, freeze-dried excipient, require to be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the lyophilized injectable powder pharmaceutics is conventional.
Prepare wherein that unit dose is 1000mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 2
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 or transfers pH value, 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%.
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Directly buy Radix Notoginseng extract from the market; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 10%, the ginsenoside Rg
1Content is 40%, ginsenoside Rb
1Content is 40%, and the content of its Radix Notoginseng total arasaponins is more than 95%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last NKA macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 99.3%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the NKA macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; NKA macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Radix Notoginseng Panaxadiol saponin Rb1 content 99.3%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 10, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 400 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 5, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 200 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 5, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
1200 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, freeze-dried excipient, require to be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the lyophilized injectable powder pharmaceutics is conventional.
Prepare wherein that unit dose is 1000mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 3
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 5.5,115 ℃ of temperature, gauge pressure 0.07MPa 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is the standard according to " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 8%, the ginsenoside Rg
1Content is 30%, ginsenoside Rb
1Content is 35%, and the content of its Radix Notoginseng total arasaponins is more than 90%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last AB-8 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 80.3%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, AB-8 macroporous adsorptive resins on the concentrated solution, wash with water earlier, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; AB-8 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content 80.4%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 3, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 120 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 3, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 120 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 3, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
1120 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, freeze-dried excipient, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, freeze-dried excipient, require to be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the lyophilized injectable powder pharmaceutics is conventional.
Prepare wherein that unit dose is 160mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 4
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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Directly buy Radix Notoginseng extract from the market; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 9%, the ginsenoside Rg
1Content is 38%, ginsenoside Rb
1Content is 39%, and the content of its Radix Notoginseng total arasaponins is more than 92%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last D101 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 95.2%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the D101 macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; D101 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content is 92.7%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 2, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 80 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 2, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 80 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 2, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
180 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 10mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 5
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 0.09MPa 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is the standard according to " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 6%, the ginsenoside Rg
1Content is 25%, ginsenoside Rb
1Content is 30%, and the content of its Radix Notoginseng total arasaponins is more than 70%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last AB-8 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 76%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the NKA macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; D101 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content 75.1%
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 4, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 160 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 4, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 160 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 4, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
1160 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 500mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 6
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 4.0,130 ℃ of temperature, gauge pressure 0.17MPa 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is the standard according to " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 10%, the ginsenoside Rg
1Content is 25%, ginsenoside Rb
1Content is 30%, and the content of its Radix Notoginseng total arasaponins is more than 80%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last D101 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 80.3%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the D101 macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; D101 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content is 80.1%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 6, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 240 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 2, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 80 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 0.8, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
132 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 10mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
Embodiment 7
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 5.5,110 ℃ of temperature, gauge pressure 0.05MPa 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Directly buy Radix Notoginseng extract from the market; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 8%, the ginsenoside Rg
1Content is 30%, ginsenoside Rb
1Content is 35%, and the content of its Radix Notoginseng total arasaponins is more than 90%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last AB-8 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 80.3%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, AB-8 macroporous adsorptive resins on the concentrated solution, wash with water earlier, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; AB-8 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content 80.4%.
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 8, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 320 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 4.5, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 180 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 4.5, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
1180 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 400mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
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 4.0,115 ℃ 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%;
Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins; Its standard is the standard according to " National Drug Administration's national drug standards " (WS3-B-3590-2001 (Z)) Radix Notoginseng total arasaponins; Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content is 6%, the ginsenoside Rg
1Content is 25%, ginsenoside Rb
1Content is 30%, and the content of its Radix Notoginseng total arasaponins is more than 70%.
The Radix Notoginseng Panaxadiol saponin: Radix Notoginseng total arasaponins is dissolved in water fully, and last AB-8 macroporous adsorptive resins is used 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin; The Radix Notoginseng Panaxadiol saponin is with ginsenoside Rb
1, the ginsenoside Rd counts content 76%.
Radix Notoginseng Panaxadiol saponin Rb
1Preparation: pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to the greatest extent, and the NKA macroporous adsorptive resins washes with water earlier on the concentrated solution, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; D101 macroporous adsorptive resins on the concentrated solution is used 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1Panax ginsenoside Rb1 content 75.1%
Formulation preparation:
Danshen root salvianolic acid A: Radix Notoginseng total arasaponins=1: 7, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng total arasaponins 280 grams;
The weight ratio of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin=1: 2.5, promptly danshen root salvianolic acid A 40 restrains, Radix Notoginseng Panaxadiol saponin 100 grams.
Danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 3.5, i.e. danshen root salvianolic acid A 40 grams, Radix Notoginseng Panaxadiol saponin Rb
1140 grams.
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose infusion solutions according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into 1000 bottles of unit dose lyophilized injectable powders according to the conventional requirement of lyophilized injectable powder pharmaceutics.
Prepare wherein that unit dose is 700mg in aqueous injection, infusion solution, the lyophilized injectable powder.
Wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, diabetic complications, chronic nephritis, chronic gastritis, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
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 (14)
1. the ejection preparation of a danshen root salvianolic acid A, Radix Notoginseng extract is characterized in that comprising danshen root salvianolic acid A, arasaponin constituents, wherein the weight ratio of danshen root salvianolic acid A and Radix Notoginseng total arasaponins=1: 1-10.
2. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 1, Radix Notoginseng extract, wherein danshen root salvianolic acid A and Radix Notoginseng total arasaponins weight ratio=1: 3.
3. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 1, Radix Notoginseng extract is characterized in that weight ratio=1 of danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin: 1-5.
4. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 1, Radix Notoginseng extract is characterized in that danshen root salvianolic acid A and Radix Notoginseng Panaxadiol saponin Rb
1Weight ratio=1: 0.5-5.
5. according to the ejection preparation of each described a kind of danshen root salvianolic acid A of claim 1-4, Radix Notoginseng extract, wherein the danshen root salvianolic acid A preparation method is:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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.
6. according to the ejection preparation of each described a kind of danshen root salvianolic acid A of claim 1-4, Radix Notoginseng extract, wherein the danshen root salvianolic acid A preparation method is:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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 chromatography post, 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.
7. according to the ejection preparation of each described a kind of danshen root salvianolic acid A of claim 1-4, Radix Notoginseng extract, wherein the danshen root salvianolic acid A preparation method is:
Radix Salviae Miltiorrhizae water or alcoholic solution extract and obtain aqueous extract or alcohol extract, alcohol extract concentrates ethanol to most, the accent pH value is to 7.5-9.0,30-80 ℃ temperature, heating 1-6 hour or transfer pH value to 3.5-6.0,110-130 ℃ temperature, gauge pressure 0.05MPa-0.17MPa pressure, heats 1-6 hour; 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 chromatography post, and first water, 20-50% alcoholic solution eluting discard eluent, and reuse 50-95% alcoholic solution eluting reclaims ethanol to most; Concentrated solution transfers 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, separates the organic solvent phase, must contain drug solns, concentrate, drying or lyophilization, danshen root salvianolic acid A.
8. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 1 and 2, Radix Notoginseng extract, wherein Radix Notoginseng total arasaponins is the standard extract Radix Notoginseng total arasaponins, Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins
1Content should be 5%-10%, the ginsenoside Rg
1Content should be 20%-40%, ginsenoside Rb
1Content should be 30%-40%, and the content of its Radix Notoginseng total arasaponins is more than or equal to 60% and less than 100%.
9. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 3, Radix Notoginseng extract, wherein Radix Notoginseng Panaxadiol saponin preparation method is:
Radix Notoginseng total arasaponins is dissolved in water fully, and last macroporous adsorptive resins, macroporous adsorbent resin are D101, AB-8 or NKA, uses 40% ethanol elution earlier, discards eluent, and reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains the Radix Notoginseng Panaxadiol saponin.
10. the ejection preparation of a kind of danshen root salvianolic acid A according to claim 4, Radix Notoginseng extract, wherein Radix Notoginseng Panaxadiol saponin Rb
1Preparation method is:
Pseudo-ginseng ethanol extraction, extracting solution reclaim ethanol to most, and macroporous adsorptive resins on the concentrated solution, macroporous adsorbent resin are D101, AB-8 or NKA, wash with water earlier, discard water lotion, reuse 40% ethanol elution discards eluent, reuse 50% ethanol elution is collected eluent, reclaims ethanol to most; Macroporous adsorptive resins on the concentrated solution, macroporous adsorbent resin are D101, AB-8 or NKA, use 40% ethanol elution earlier, and eluent discards; Reuse 50% ethanol elution is collected eluent, concentrates, and drying obtains Radix Notoginseng Panaxadiol saponin Rb
1
11. according to the ejection preparation of each described a kind of danshen root salvianolic acid A of claim 1-4, Radix Notoginseng extract, wherein formulation preparation method is:
Aqueous injection preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose aqueous injection according to the conventional requirement of aqueous injection pharmaceutics;
Infusion solution preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose infusion solution according to the conventional requirement of infusion solution pharmaceutics;
Lyophilized injectable powder preparation: get danshen root salvianolic acid A, Radix Notoginseng total arasaponins, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics; Or get danshen root salvianolic acid A, Radix Notoginseng Panaxadiol saponin Rb
1, be prepared into the unit dose lyophilized injectable powder according to the conventional requirement of lyophilized injectable powder pharmaceutics.
12. a kind of danshen root salvianolic acid A according to claim 11, Radix Notoginseng extract ejection preparation prepare wherein that unit dose is 5-1000mg in aqueous injection, infusion solution, the lyophilized injectable powder.
13. a kind of danshen root salvianolic acid A according to claim 11, Radix Notoginseng extract ejection preparation prepare wherein that unit dose is 10-500mg in aqueous injection, infusion solution, the lyophilized injectable powder.
14. a kind of danshen root salvianolic acid A according to claim 11, Radix Notoginseng extract ejection preparation, wherein aqueous injection, infusion solution, lyophilized injectable powder are used in aspect preparation treatment cardiovascular and cerebrovascular disease, microcirculation disturbance, alzheimer disease, organ fibrosis or tumor disease medicine.
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|---|---|---|---|
| CN200710003036A CN101006984B (en) | 2007-02-01 | 2007-02-01 | An injection preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application |
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|---|---|---|---|
| CN200710003036A CN101006984B (en) | 2007-02-01 | 2007-02-01 | An injection preparation containing salvianolic acid A and extract of panax natoginseng, and its preparation method and application |
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| WO2009135433A1 (en) * | 2008-05-05 | 2009-11-12 | 天津天士力制药股份有限公司 | Use of total salvianolic acid, panax notoginsenosides and combination thereof in treating septicemia |
| CN101574392B (en) * | 2008-05-05 | 2012-07-04 | 天津天士力制药股份有限公司 | Prevention and treatment of diseases induced by microcirculation disturbance with total salvianolic acid |
| US20120251634A1 (en) * | 2009-12-17 | 2012-10-04 | Tasly Pharmaceutical Group Co., Ltd. | Traditional chinese drug comprising danshen extracts and sanqi extracts and use thereof |
| CN114470035A (en) * | 2022-03-23 | 2022-05-13 | 暨南大学 | A composition containing Chinese medicinal extract, its preparation method and application in preparing product with antioxidant effect |
| CN116585335A (en) * | 2023-06-07 | 2023-08-15 | 广东植肤生物科技有限公司 | A skin external composition for inhibiting TYR activity and MC1R expression |
Family Cites Families (3)
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| CN1470255A (en) * | 2002-07-22 | 2004-01-28 | 王智民 | Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use |
| CN100404040C (en) * | 2003-09-19 | 2008-07-23 | 天津天士力制药股份有限公司 | A kind of pharmaceutical composition for treating heart disease and its preparation method and application |
| CN100420665C (en) * | 2006-04-21 | 2008-09-24 | 王国振 | Method for extracting 'Danfen' phenolic acid-A |
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2007
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| WO2009135433A1 (en) * | 2008-05-05 | 2009-11-12 | 天津天士力制药股份有限公司 | Use of total salvianolic acid, panax notoginsenosides and combination thereof in treating septicemia |
| CN101574392B (en) * | 2008-05-05 | 2012-07-04 | 天津天士力制药股份有限公司 | Prevention and treatment of diseases induced by microcirculation disturbance with total salvianolic acid |
| US20120251634A1 (en) * | 2009-12-17 | 2012-10-04 | Tasly Pharmaceutical Group Co., Ltd. | Traditional chinese drug comprising danshen extracts and sanqi extracts and use thereof |
| US9034398B2 (en) * | 2009-12-17 | 2015-05-19 | Tasly Pharmaceutical Group Co., Ltd. | Traditional Chinese drug comprising Danshen extracts and Sanqi extracts and use thereof |
| CN114470035A (en) * | 2022-03-23 | 2022-05-13 | 暨南大学 | A composition containing Chinese medicinal extract, its preparation method and application in preparing product with antioxidant effect |
| CN114470035B (en) * | 2022-03-23 | 2023-02-21 | 暨南大学 | A composition containing Chinese medicine extract, its preparation method and its application in the preparation of products with antioxidant effect |
| CN116585335A (en) * | 2023-06-07 | 2023-08-15 | 广东植肤生物科技有限公司 | A skin external composition for inhibiting TYR activity and MC1R expression |
| 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 |
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