CN1384090A - Extraction process of tanshin general phenolic acid and its prepn and use - Google Patents
Extraction process of tanshin general phenolic acid and its prepn and use Download PDFInfo
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- CN1384090A CN1384090A CN 01142288 CN01142288A CN1384090A CN 1384090 A CN1384090 A CN 1384090A CN 01142288 CN01142288 CN 01142288 CN 01142288 A CN01142288 A CN 01142288A CN 1384090 A CN1384090 A CN 1384090A
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- salviae miltiorrhizae
- radix salviae
- total phenolic
- phenolic acids
- miltiorrhizae total
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- 238000000605 extraction Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 18
- 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 14
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 5
- 235000009048 phenolic acids Nutrition 0.000 claims description 106
- 239000007924 injection Substances 0.000 claims description 46
- 238000002347 injection Methods 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
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- 229920005989 resin Polymers 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
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- QKBTVDSMJGHBJC-UHFFFAOYSA-K [Fe](Cl)(Cl)Cl.[Fe](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K].[K].[K] Chemical compound [Fe](Cl)(Cl)Cl.[Fe](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K].[K].[K] QKBTVDSMJGHBJC-UHFFFAOYSA-K 0.000 claims description 6
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- SOXUSBQFIOBYJU-VPIXDIMLSA-N (2r)-2-[(e)-3-[2-[(e)-3-[(1r)-1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]-1-(3,4-dihydroxyphenyl)-3-oxoprop-1-en-2-yl]-3,4-dihydroxyphenyl]prop-2-enoyl]oxy-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C(=C(O)C(O)=CC=1)\C(=C/C=1C=C(O)C(O)=CC=1)C(=O)O[C@H](CC=1C=C(O)C(O)=CC=1)C(O)=O)C1=CC=C(O)C(O)=C1 SOXUSBQFIOBYJU-VPIXDIMLSA-N 0.000 description 2
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Landscapes
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to extraction process of total tanshin phenolic acid, the preparation process and application of its preparation. The total tanshin phenolic acid and its preparation may use in preparing medicine for preventing and treating cardiac and cerebral vascular diseases, senile dementia and hypomnesia caused by cerebral ischemia. The total tanshin phonelic acid prepared based on the process of the present invention has rich active components of tanshin and obvious pharmacological effect, stable performance and les stoxicity and is safety and reliable.
Description
Technical field
The present invention relates to a kind of processing method of Radix Salviae Miltiorrhizae total phenolic acids and preparation method of preparation thereof of from salviamiltiorrhizabung, extracting, and the Radix Salviae Miltiorrhizae total phenolic acids and the application of preparation in pharmacy field thereof that utilize the inventive method to obtain, the particularly application in the medicines such as damage in learning and memory that preparation control cardiovascular and cerebrovascular diseases, senile dementia and treatment cerebral ischemia cause.
Background technology
The red sage root and various preparation thereof are clinical treatment cardiovascular and cerebrovascular disease Chinese medicine commonly used.We carry out systematic study to the water soluble component of the red sage root and congener thereof since the eighties, separate to obtain salvianolic acid A (1), B (2), C (3), D (4), E (5), F (8), G (9), H (11) I (12), J (13), rosmarinic acid (6), alkannic acid (7), different salvianolic acid C (10), the glycoside of rosmarinic acid phenolic acid compounds such as (14).(Lian-Niang?Li，J.Chinese?PharmaceuticalSciences?1997，6，57-64)。The pharmacological results illustrates that these phenolic acid compounds have very strong anti peroxidation of lipid, antithrombotic, improve effects such as blood circulation.Wherein the activity of salvianolic acid A and B is the strongest, and the brain that hypoxic-ischemic, ischemia-reperfusion are caused, core cell damage have obvious provide protection, the damage in learning and memory effect of having clear improvement that cerebral ischemia re-pouring is caused.(institute of Materia Medica,Chinese Academy of Medical Sciences is write, combined publication society of China Concord Medical Science University of Beijing Medical University, 498～522 pages for herbal medicine modern study, second volume).
At present, the extracting method of salvianolic acid compounds mostly is water and carries the back resin column of crossing.1989, the extracting method of the salvianolate of reports such as Takashi Tanaka is: red sage root hot water extraction, behind the concentrating under reduced pressure by with vinylbenzene being the macroporous resin MCl-CHP-20P of framework material, after washing with water, use 50% methanol-eluted fractions again, promptly get the salvianolate (Chemical Pharmaceutical Bulletin, 1989 that mainly contain salvianolic acid B magnesium, 37 (2), 340～344).Thereafter, Koji Hase etc. (Planta Medica, 1997,63,22～26), Xu Yaming etc. (Chinese patent CN1247855A, 2000 open) also adopt to use the same method and extract phenolic acid compound from the reds sage root.Above method is owing to be that impurity is more with resin column on the aqueous extract of the red sage root, and the resin regeneration utilization ratio is low, and the content of gained salvianolic acid compounds is also lower.Aspect preparation, because salvianolic acid compounds instability, in preparation and storage process, easily decompose rotten, therefore various Danshen root injections, the contained composition of danshen powder injection of present clinical usefulness are mainly active more weak Salvianic acidA and rancinamycin IV, and active other very strong salvianolic acid constituents, as salvianolic acid B, then because of decomposing rotten remaining little, pharmacologically active is had a greatly reduced quality.
Summary of the invention
The objective of the invention is defective and deficiency, a kind of method that can extract the Radix Salviae Miltiorrhizae total phenolic acids of stable performance from salviamiltiorrhizabung is provided at above-mentioned prior art existence.
Another object of the present invention provides a kind of preparation method of Radix Salviae Miltiorrhizae total phenolic acids preparation.
Further aim of the present invention provides above-mentioned Radix Salviae Miltiorrhizae total phenolic acids and the application of preparation in pharmacy field thereof, particularly the application in the damage in learning and memory medicine that preparation control cardiovascular and cerebrovascular diseases medicament, senile dementia prevention and cure medicine and preparation treatment cerebral ischemia cause.
The present invention is implemented by following technical proposals.
The present invention relates to a kind of method of from salviamiltiorrhizabung, extracting Radix Salviae Miltiorrhizae total phenolic acids, it is characterized in that this method comprises the following steps: successively
(1) add deionized water after danshen powder is broken into meal, be heated to 60～100 ℃ of extractions, extracting solution merges;
(2) amalgamation liquid carries out alcohol precipitation at 30～60 ℃ of following concentrating under reduced pressure after the cooling, leaves standstill, and filters to get filtrate;
(3) filtrate decompression concentrates the back and goes up macroporous adsorbent resin, and being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 30～90% ethanol elutions to elutriant and does not have tangible phenolic hydroxyl group reaction.Elutriant is at concentrating under reduced pressure below 30～60 ℃, and cold filtration is regulated pH value 5.0～7.0 after drying with sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids.
Specifically, the method that the present invention extracts Radix Salviae Miltiorrhizae total phenolic acids is a hot water extraction, and alcohol precipitation purifies, and uses purification with macroreticular resin, in the elutriant and postlyophilization, obtains Radix Salviae Miltiorrhizae total phenolic acids.Its this method may further comprise the steps:
(1). add deionized water after danshen powder is broken into meal, be heated to 60～100 ℃, can repeat to extract 2～4 times, extracting solution merges, and at 30～60 ℃, is preferably 40～50 ℃ of following concentrating under reduced pressure;
(2). after the spissated extracting solution cooling, adding ethanol is 45%～80% to containing the alcohol amount, is preferably 70%, leaves standstill, and filters to get filtrate;
(3). filtrate decompression concentrates the back and goes up macroporous adsorbent resin, be preferably styrene tyle macroporous adsorption resin, being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 30～90% ethanol elutions to elutriant and does not have tangible phenolic hydroxyl group reaction.Elutriant is preferably 30～45 ℃ of following concentrating under reduced pressure at 30～60 ℃, and cold filtration is regulated pH value to 5.0～7.0 postlyophilizations with sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids.
The invention still further relates to the preparation method of Radix Salviae Miltiorrhizae total phenolic acids preparation, Radix Salviae Miltiorrhizae total phenolic acids is 1: 0.3～1 with the ratio of employed propping agent in this method, and employed protective material is 2.0%～10% of a Radix Salviae Miltiorrhizae total phenolic acids.
Specifically, consumption proportion (weight ratio): Radix Salviae Miltiorrhizae total phenolic acids is 1: 0.3～1 with the ratio of employed propping agent, and its preferred propping agent is a N.F,USP MANNITOL; Employed protective material is 2.0%～10% of a Radix Salviae Miltiorrhizae total phenolic acids, and its preferred protective material is the strange land hydrochlorate.
The Radix Salviae Miltiorrhizae total phenolic acids that utilizes the inventive method to obtain can be used for preparing said preparation on any pharmaceutics.For example, be used for to make forms such as corresponding tablet, granule or capsule when oral; Can also make powder injection, also can make the forms such as solution of injection.
When the Radix Salviae Miltiorrhizae total phenolic acids that utilizes the inventive method to obtain prepares the various formulation of required medicine, can be according to the conventional production method preparation of pharmaceutical field.The Radix Salviae Miltiorrhizae total phenolic acids that utilizes the inventive method to obtain is mixed with one or more carriers, make corresponding dosage forms then.
Radix Salviae Miltiorrhizae total phenolic acids powder injection preparation method involved in the present invention also can use method same as the prior art.
This shows that it is simple to extract the Radix Salviae Miltiorrhizae total phenolic acids technological process with the inventive method, does not need High Temperature High Pressure and specific installation, safety, easy handling, and cost is low.The present invention adopts the method for crossing resin column behind the first alcohol precipitation, be promptly to carry out alcohol precipitation after the cooling of red sage root aqueous extract, can remove destarching, polysaccharide, impurity such as protein, filtrate concentrates the back can further remove the oligosaccharides of solubility by macroporous adsorbent resin (styrene type), impurity such as resin, compared with prior art, not only can reduce pollution to resin column, the resin column manipulation of regeneration is simple and increase regeneration of resin and utilize number of times, and the content height of Radix Salviae Miltiorrhizae total phenolic acids in the final extract, impurity is few, its total phenolic content is more than 85%, and wherein the content of salvianolic acid B accounts for 40%～80% of total phenolic acid, and physiologically active is strong.In order to keep the stable of salvianolic acid compounds, the temperature of concentrating under reduced pressure is controlled at 30～60 ℃, preferable range be 40～50 ℃ to prevent that active stronger salvianolic acid B etc. from transforming to activity more weak Salvianic acidA and rancinamycin IV.Whether subtracting property of acid, the height of the temperature when handling and the length in treatment time etc. stable and solution all have bigger relation to the salvianolic acid compounds, so regulate pH value to 5.0～7.0 postlyophilizations with sodium hydroxide solution, increased the stability of salvianolic acid compounds, laid a good foundation for the gained Radix Salviae Miltiorrhizae total phenolic acids is applied to various preparations.
The Radix Salviae Miltiorrhizae total phenolic acids powder injection that makes with the inventive method has overcome the salvianolic acid compounds and easily decomposed rotten defective in preparation and storage process, guarantee the stability of salvianolic acid effective constituents, thereby guaranteed the quality and the curative effect of Radix Salviae Miltiorrhizae total phenolic acids powder injection.
Utilize not only steady quality of Radix Salviae Miltiorrhizae total phenolic acids that the inventive method obtains, and be rich in the activeconstituents of salviamiltiorrhizabung, have excellent anti-cerebral ischemia, resist myocardial ischemia, pharmacological action such as anti-apoptotic, therefore can be used for preparing degradation medicine under the learning memory that good effect, safe and reliable control cardiovascular and cerebrovascular diseases, senile dementia prevention and cure and treatment cerebral ischemia re-pouring cause.The pharmacodynamics test of following Radix Salviae Miltiorrhizae total phenolic acids has proved that fully Radix Salviae Miltiorrhizae total phenolic acids and powder injection thereof have good pharmacological action.
Embodiment
The following examples can help those skilled in the art more fully to understand the present invention.But do not limit the present invention in any way.
Embodiment 1 extracts Radix Salviae Miltiorrhizae total phenolic acids from salviamiltiorrhizabung
Red sage root 5kg is ground into meal and adds deionized water 100 ℃ of heating extractions 3 times.For the first time add 30L water, heated 1 hour; Second and third time respectively adds 15L water and heated respectively 1/2 hour.Extracting solution is evaporated to 5L at 60 ℃, adds 95% ethanol 14L after the cooling, and standing over night is filtered.Decompression filtrate recycling ethanol, (chemical industry seven factories in Beijing produce the gained concentrated solution by RA type macroporous adsorbent resin, with vinylbenzene, toluylene is a main body, dried resin amount 2kg), being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 50% ethanol elution to elutriant and does not have bright existing phenolic hydroxyl group reaction.Elutriant is placed on refrigerator overnight at 60 ℃ of following concentrating under reduced pressure, filters promptly to get the Radix Salviae Miltiorrhizae total phenolic acids extracting solution, regulates pH value to 7 postlyophilization with 2% sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids dry powder 115g.Its dry powder contains total phenolic acid 87.39% after testing, and salvianolic acid B is 54.93%.
The detection method of Radix Salviae Miltiorrhizae total phenolic acids and salvianolic acid B: (1) salvianolic acid B: measure with the HPLC method, detect wavelength 288nm, the standard substance salvianolic acid B is provided by institute of Materia Medica,Chinese Academy of Medical Sciences, purity 98.0%.(2) Radix Salviae Miltiorrhizae total phenolic acids: content=F (A-B)+B
Wherein: A is that spectrophotometry is total phenolic content that contrast is calculated with the salvianolic acid B
B is the content of danshinolic acid B of high effective liquid chromatography for measuring
F is that correction factor 0.626 Radix Salviae Miltiorrhizae total phenolic acids is except salvianolic acid B (molecular weight 718), also contain rancinamycin IV (molecular weight 138), salvianolic acid E (molecular weight 718), rosmarinic acid (molecular weight 360), alkannic acid (molecular weight 538), salvianolic acid A phenolic acid compounds such as (molecular weight 494), the molecular weight between them differs bigger.Being that contrast is higher with total phenolic content result of spectrophotometry with the salvianolic acid B, mainly is because the molecular weight of other phenolic acid compounds is lower than due to the molecular weight of salvianolic acid B.Therefore, with the ratio of above-mentioned 5 phenolic acid compound molecular-weight average and salvianolic acid B molecular weight as correction factor, the Radix Salviae Miltiorrhizae total phenolic acids content after proofreading and correct with this with measure 6 phenolic acid compound content sum basically identicals such as rancinamycin IV respectively with the HPLC method.Rancinamycin IV is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute, and salvianolic acid E, rosmarinic acid, alkannic acid, salvianolic acid A are by being provided by institute of Materia Medica,Chinese Academy of Medical Sciences.
Embodiment 2 extracts Radix Salviae Miltiorrhizae total phenolic acids from salviamiltiorrhizabung
Red sage root 5kg is ground into meal and adds deionized water 70 ℃ of heating extractions 4 times.For the first time add 30L water, then respectively add 15L water at every turn, be 1.2 hours heat-up time for the first time, is extracted as 1 hour for the second time, and is extracted as 0.8 hour third and fourth time.Extracting solution is evaporated to 5L at 30 ℃, adds 70% ethanol 14L after the cooling, and standing over night is filtered.Decompression filtrate recycling ethanol, (chemical industry seven factories in Beijing produce the gained concentrated solution by RA type macroporous adsorbent resin, with vinylbenzene, toluylene is a main body, dried resin amount 2kg), being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 30% ethanol elution to elutriant and does not have bright existing phenolic hydroxyl group reaction.Elutriant is placed on refrigerator overnight at 30 ℃ of following concentrating under reduced pressure, filters promptly to get the Radix Salviae Miltiorrhizae total phenolic acids extracting solution, regulates pH value to 6.5 postlyophilization with 2% sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids 114g.
Embodiment 3 extracts Radix Salviae Miltiorrhizae total phenolic acids from salviamiltiorrhizabung
Red sage root 5kg is ground into meal and adds deionized water 80 ℃ of heating extractions 4 times.For the first time add 30L water, heated 1 hour; Second and third time and respectively add 15L water for the 4th time and heated respectively 1/2 hour.Extracting solution is evaporated to 5L at 50 ℃, adds 80% ethanol 14L after the cooling, and standing over night is filtered.Decompression filtrate recycling ethanol, (chemical industry seven factories in Beijing produce the gained concentrated solution by RA type macroporous adsorbent resin, with vinylbenzene, toluylene is a main body, dried resin amount 2kg), being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 70% ethanol elution to elutriant and does not have bright existing phenolic hydroxyl group reaction.Elutriant is placed on refrigerator overnight at 30 ℃ of following concentrating under reduced pressure, filters promptly to get the Radix Salviae Miltiorrhizae total phenolic acids extracting solution, regulates pH value to 5.0 postlyophilization with 2% sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids 113.5g.
The preparation method of embodiment 4 Radix Salviae Miltiorrhizae total phenolic acids powder injection
Radix Salviae Miltiorrhizae total phenolic acids 100 grams; N.F,USP MANNITOL 30 grams; Calcium Disodium Edetate 5 grams; Water for injection adds to 5000 milliliters.After above-mentioned substance mixed, adopt conventional powder injection preparation method, can make 1000 injection lyophilized powders.
The pharmacodynamics test and the toxicity test of experimental example 1 Radix Salviae Miltiorrhizae total phenolic acids
The anti-cerebral ischemia test and the result of Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection
With galvanocautery method blocking-up intraluminal middle cerebral artery occlusion in rats (MCAO), cause the focal cerebral ischemia model, observe the provide protection of Radix Salviae Miltiorrhizae total phenolic acids and powder injection thereof to cerebral ischemia, the result is as follows.
(1) Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are to the influence of MCAO rat cerebral infarction area
As shown in table 1, the Radix Salviae Miltiorrhizae total phenolic acids 20, the 10mg/Kg that adopt embodiment 1 to obtain, the Radix Salviae Miltiorrhizae total phenolic acids powder injection 27 that embodiment 4 obtains, intravenous drip (iv) for 13.5mg/Kg (containing Radix Salviae Miltiorrhizae total phenolic acids 20,10mg), can significantly dwindle the cerebral infarct size behind the rat MCAO24 h, compare with control group, there were significant differences.And the two effect quite, no significance difference.Radix Salviae Miltiorrhizae total phenolic acids 10mg/Kg, Radix Salviae Miltiorrhizae total phenolic acids powder injection 13.5mg/Kg and compound injection of red sage root 2g/kg effect are suitable.
Table 1. Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are to the influence of MCAO rat cerebral infarction area
Group dosage (mg/Kg) cerebral infarct size (%)
Control group 7.25 ± 3.16
Radix Salviae Miltiorrhizae total phenolic acids powder injection 27 3.81 ± 1.03**
13.5 4.67±1.29*
6.75 5.75±1.33
Radix Salviae Miltiorrhizae total phenolic acids 20 3.82 ± 1.07**
10 4.67±1.44*
5 5.76±1.37
Compound injection of red sage root 2,000 4.59 ± 1.18*
1000 5.91±1.46
* n=10 is compared with control group in p＜0.05**p＜0.01
(2) Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are to the influence of MCAO rat neural function symptom
The appearance of hemiplegia sample symptom is promptly arranged after control rats anesthesia is regained consciousness, mainly show as and receive, take on inward turning, the decline of muscle of anterior limb tension force in the operation offside forelimb, resistance descends when the operation offside promotes.Radix Salviae Miltiorrhizae total phenolic acids 20,10mg/Kg, Radix Salviae Miltiorrhizae total phenolic acids injection 27,13.5mg/Kg can significantly improve the neural function symptom, compare with control group, and there were significant differences, and the two effect is quite, no significance difference.Radix Salviae Miltiorrhizae total phenolic acids 10mg/Kg, Radix Salviae Miltiorrhizae total phenolic acids powder injection 13.5mg/Kg and compound injection of red sage root 2g/Kg effect are suitable.
Table 2. Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are to the influence of MCAO rat neural function symptom
Group dosage (mg/kg) symptom score
Sham operated rats 3.46 ± 1.44***
Control group 7.18 ± 1.75
Radix Salviae Miltiorrhizae total phenolic acids powder injection 27 3.97 ± 1.76**
13.5 5.10±1.30*
6.75 5.98±0.98
Radix Salviae Miltiorrhizae total phenolic acids 20 3.98 ± 1.92**
10 5.05±1.62*
5 6.01±1.26
Compound injection of red sage root 2,000 4.99 ± 1.71
1000 6.08±1.74
* p＜0.05, * * p＜0.01 and control group relatively, n=10
(3) Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are as shown in table 3 to the influence of MCAO rat brain water content, behind the blocking-up rat one side medium sized artery 24h, the brain water content of control group is 82.82 ± 1.29, and the brain water content of sham operated rats is 80.91 ± 0.79, the two has compared marked difference, behind the prompting blocking-up one side medium sized artery 24h, blocking-up side brain hemisphere has formed serious oedema.Radix Salviae Miltiorrhizae total phenolic acids 20,10mg/Kg, Radix Salviae Miltiorrhizae total phenolic acids powder injection 27,13.5mg/kg can significantly alleviate ischemic cerebral edema, and the two effect quite, no significance difference.Radix Salviae Miltiorrhizae total phenolic acids 10mg/Kg, Radix Salviae Miltiorrhizae total phenolic acids powder injection 13.5mg/Kg are suitable with compound injection of red sage root injection 2g/Kg effect.
Table 3. Radix Salviae Miltiorrhizae total phenolic acids and Radix Salviae Miltiorrhizae total phenolic acids powder injection are to the influence of MCAO rat brain water content
Group dosage (mg/kg) brain water content (%)
Sham operated rats 80.91 ± 0.79**
Control group 82.82 ± 1.29
Radix Salviae Miltiorrhizae total phenolic acids powder injection 27 80.99 ± 0.90**
13.5 81.52±1.07*
6.75 82.01±0.85
Radix Salviae Miltiorrhizae total phenolic acids 20 81.00 ± 0.86**
10 81.50±0.87*
5 82.07±1.02
Compound injection of red sage root 2,000 81.55 ± 0.61*
1000 82.42±0.92
* p＜0.05, * * p＜0.01 and control group relatively, n=10
Experiment showed, that the Radix Salviae Miltiorrhizae total phenolic acids that utilizes the inventive method to obtain has good provide protection to cerebral ischemia.
Experimental example 2 Radix Salviae Miltiorrhizae total phenolic acidss are irritated the provide protection of arrhythmia again to the rat heart muscle ischemic
Ischemic is irritated control animals major part generation chamber speed (VT) in irritating at once to one and half more again, the time length major part reaches 1～2 minute, the total incidence of ventricular arrhythmia is 87.5%, and the Radix Salviae Miltiorrhizae total phenolic acids that adopts embodiment 2 to obtain (20mg/kg 40mg/kg) does not all have ventricular arrhythmia again and takes place between flush phase.The compound injection of red sage root group again between flush phase the ventricular arrhythmia incidence be 16.7%.(seeing Table 4)
Table 4 Radix Salviae Miltiorrhizae total phenolic acids is to the influence of rat myocardial ischemia and reperfusion arrhythmia
Animal dosage
Group
Number I.V. VP (%) VT (%) irregular pulse
Physiological saline 81 (12.5) 6 (75) 7 (87.5)
Radix Salviae Miltiorrhizae total phenolic acids 5 20mg/kg 0 0*** 0***
Radix Salviae Miltiorrhizae total phenolic acids 7 40mg/kg 0 0*** 0***
The compound Salviae Miltiorrhizae injection
Liquid 6 2.4g/kg 01 (16.7) * * 1 (16.7) * *
Compare with the physiological saline group: * * P＜0.05, * * *＜0.01
Experimental results show that the Radix Salviae Miltiorrhizae total phenolic acids that utilizes the inventive method to obtain has significant protective effect to the myocardial ischemia-reperfusion arrhythmia.Experimental example 3 Radix Salviae Miltiorrhizae total phenolic acidss are to the handicapped improvement effect of cerebral ischemia re-pouring learning and memory of little mouse
This paper adopts diving tower method and head-breaking, and the research salvianolic acid is to the effect of the damage in learning and memory of ischemia-reperfusion mouse and the influence of hypoxia-bearing capability.Result such as table 5 and table 6.The amnemonic provide protection that table 5. salvianolic acid and compound injection of red sage root iv cause the mouse brain ischemical reperfusion injury
Group dosage number of animals reaction times (second) training period errors number latent period (second) the phase errors number of resurveying
(mg/ (only) (second) (second)
kg)
Sham operated rats 9 7.2 ± 5.5** 2.9 ± 1.5* 249.8 ± 99.7** 0.4 ± 1.0**
Control group NS 10 24.1 ± 15.3 6.2 ± 3.5 91.4 ± 114.7 2.5 ± 1.7
Compound Salviae Miltiorrhizae is injected 50 9 8.8 ± 7.3*, 2.7 ± 1.4* 175.4 ± 97.2 1.3 ± 1.0
Compound Salviae Miltiorrhizae is injected 200 10 20.1 ± 16.4 2.8 ± 2.2*, 249.8 ± 67.3**, 0.5 ± 0.7**
Compound Salviae Miltiorrhizae is injected 2,000 11 6.5 ± 4.3**, 1.4 ± 1.3***, 252.8 ± 66.7***
Radix Salviae Miltiorrhizae total phenolic acids 3 11 11.4 ± 8.7* 3.7 ± 2.5 195.5 ± 78.3*, 0.9 ± 0.5**
Radix Salviae Miltiorrhizae total phenolic acids 6 10 17.6 ± 15.1 3.5 ± 3.3 243.9 ± 86.2**, 0.5 ± 0.7**
Radix Salviae Miltiorrhizae total phenolic acids 10 12 4.9 ± 2.8*** 3.4 ± 2.6* 245.3 ± 81.1** 0.7 ± 1.0**
* p＜0.05 * * p＜0.01 * * * p＜0.001 VS. control group table 6. salvianolic acid and compound injection of red sage root iv are to the influence of cerebral ischemia re-pouring mouse hypoxia-bearing capability
Group dosage (mg/kg) number of animals (only) is breathed the time length (second)
Sham operated rats 10 17.3 ± 1.77*
Control group NS 10 15.1 ± 2.0
Compound injection of red sage root 50 10 21.0 ± 2.8***
Compound injection of red sage root 200 10 21.6 ± 2.1***
Compound injection of red sage root 2,000 10 22.0 ± 1.8***
Radix Salviae Miltiorrhizae total phenolic acids 3 11 21.1 ± 2.2***
Radix Salviae Miltiorrhizae total phenolic acids 6 12 21.9 ± 2.0***
Radix Salviae Miltiorrhizae total phenolic acids 10 12 21.1 ± 2.6***
* p＜0.05 * * p＜0.01 * * * p＜0.001 VS. control group
The above results explanation Radix Salviae Miltiorrhizae total phenolic acids 3mg/kg, 6mg/kg, 10mg/kg can improve the damage in learning and memory of cerebral ischemia re-pouring mouse, significantly improves its hypoxia-bearing capability, and the effect of the effect of salvianolic acid 10mg/kg and compound injection of red sage root 2g/kg is suitable.The toxicity test of experimental example 4. Radix Salviae Miltiorrhizae total phenolic acidss
Acute toxicity: mouse mainline medium lethal dose (LD50) is 1858.82mg/kg; Abdominal injection medium lethal dose (LD50) is 1994.34mg/kg.The long term toxicity safe dose of rat and dog is respectively 60mg/kg and 30mg/kg.As seen the toxicity of Radix Salviae Miltiorrhizae total phenolic acids is very little.
Claims (16)
1. a method of extracting Radix Salviae Miltiorrhizae total phenolic acids from salviamiltiorrhizabung is characterized in that this method comprises the following steps: successively
(1) add deionized water after danshen powder is broken into meal, be heated to 60～100 ℃ of extractions, extracting solution merges;
(2) amalgamation liquid carries out alcohol precipitation at 30～60 ℃ of following concentrating under reduced pressure after the cooling, leaves standstill, and filters to get filtrate;
(3) filtrate decompression concentrates the back and goes up macroporous adsorbent resin, and being washed till effluent liquid with deionized water does not have alphanaphthol reaction, continues to add iron trichloride Tripotassium iron hexacyanide reagent with 30～90% ethanol elutions to elutriant and does not have tangible phenolic hydroxyl group reaction.Elutriant is at 30～60 ℃ of following concentrating under reduced pressure, and cold filtration is regulated pH value 5.0～7.0 after drying with sodium hydroxide solution, promptly gets Radix Salviae Miltiorrhizae total phenolic acids.
2. extracting method according to claim 1 is characterized in that employed organic solvent is preferably ethanol in this method.
3. extracting method according to claim 1 is characterized in that the temperature of concentrating under reduced pressure in this method is controlled at 40～50 ℃.
4. extracting method according to claim 1, concentration of ethanol is 45%～80% when it is characterized in that in this method steps (2) alcohol precipitation.
5. extracting method according to claim 4, concentration of ethanol is 70% when it is characterized in that in this method steps (2) alcohol precipitation.
6. extracting method according to claim 1 is characterized in that employed macroporous adsorbent resin is preferably styrene type in this method steps (3).
7. extracting method according to claim 1 is characterized in that the middle elutriant of this method steps (3) is 50% ethanol.
8. extracting method according to claim 1 is characterized in that the pH value transfers to 5.0～6.5 in this method steps (3).
9. extracting method according to claim 1 is characterized in that the drying means in this method steps (3) is lyophilize.
10. the Radix Salviae Miltiorrhizae total phenolic acids that extracting method according to claim 1 obtains.
11. Radix Salviae Miltiorrhizae total phenolic acids according to claim 10 is characterized in that this Radix Salviae Miltiorrhizae total phenolic acids can be to be used for preparing said preparation on any pharmaceutics.
12. a powder injection preparation method who contains the described Radix Salviae Miltiorrhizae total phenolic acids of claim 10, the weight ratio that it is characterized in that Radix Salviae Miltiorrhizae total phenolic acids and employed propping agent is 1: 0.3～1, and employed protective material is 2.0%～10% of a Radix Salviae Miltiorrhizae total phenolic acids.
13. the powder injection preparation method of Radix Salviae Miltiorrhizae total phenolic acids according to claim 12 is characterized in that preferred propping agent is a N.F,USP MANNITOL, preferred protective material is an edetate.
14. the application of Radix Salviae Miltiorrhizae total phenolic acids in preparation control cardiovascular and cerebrovascular diseases.
15. the application of Radix Salviae Miltiorrhizae total phenolic acids in preparation senile dementia prevention and cure medicine.
16. join the application of total phenolic acid in the damage in learning and memory medicine that preparation treatment cerebral ischemia causes.
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| WO2005051404A1 (en) | 2003-09-23 | 2005-06-09 | Tianjin Tasly Pharmaceutical Co., Ltd. | Pharmaceutical composition for the treatment of cardiovascular and cerebrovascular diseases |
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| CN100420665C (en) * | 2006-04-21 | 2008-09-24 | 王国振 | Method for extracting 'Danfen' phenolic acid-A |
| CN1884558B (en) * | 2006-05-30 | 2010-09-08 | 天津大学 | Method for intensively extracting red-rooted salvia polyphenol acids using composite enzyme hydrolyzing red-rooted salvia |
| CN101210002B (en) * | 2006-12-27 | 2011-04-20 | 中国科学院大连化学物理研究所 | Method for separating and preparing salvianolic acid B chemical reference substance |
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