CN100478003C - Rabdosia extraction method - Google Patents
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- CN100478003C CN100478003C CNB2006100017169A CN200610001716A CN100478003C CN 100478003 C CN100478003 C CN 100478003C CN B2006100017169 A CNB2006100017169 A CN B2006100017169A CN 200610001716 A CN200610001716 A CN 200610001716A CN 100478003 C CN100478003 C CN 100478003C
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- 238000000605 extraction Methods 0.000 title claims abstract description 23
- 241001183967 Isodon Species 0.000 title abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 38
- 239000000284 extract Substances 0.000 claims abstract description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000000874 microwave-assisted extraction Methods 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 241001646826 Isodon rubescens Species 0.000 claims description 69
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- 229930004069 diterpene Natural products 0.000 claims description 22
- -1 diterpene chemical compound Chemical class 0.000 claims description 21
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- 239000003480 eluent Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
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- 150000001875 compounds Chemical class 0.000 claims description 9
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a medicament for treating acute and chronic laryngopharyngitis and resisting tumor, whose active constituent being the extract of rabdosia effective portions including rubescensin A and rubescensin B with a content of greater than 55% in the extract. The invention also discloses the extracting method by means of hypercritical extraction and microwave extraction, wherein the extraction solvent for the hypercritical extraction can be CO2 or N2, and the extraction solvent for the microwave extraction can be ethanol, acetone or their mixture.
Description
Technical field
The present invention relates to a kind of treatment acute and chronic pharyngitis, antitumor drug and rabdosia extraction method.
Background technology
Rabdosia rubescens, have another name called Rabdosia rubescens, this product is the crack rice dry aerial parts of inferior RabdosiaRubescens (Hemsl.) of labiate, main product is in Henan, Shanxi, Hebei, Guizhou, include in one one of [Chinese Pharmacopoeia] version in 1977 on ground such as Sichuan, after record again in first of [Drug Standard of Ministry of Public Health of the Peoples Republic of China] Chinese crude drug in 1992.
Rabdosia rubescens was found in the Jiyuan in 1973 first, Henan Province's correlational study departmental cooperation tackling key problem, discover that Rabdosia rubescens has antibacterial and anti-inflammation functions and significant anti-cancer activity widely, be mainly used in treatment acute and chronic pharyngitis, laryngopharynx swelling and pain, tonsillitis, the esophageal carcinoma, carcinoma of gastric cardia, pulmonary carcinoma, hepatocarcinoma, bladder cancer, breast carcinoma etc. are had significant therapeutic effect.
My Henan Province Jiyuan City Jihi Medicine Co., Ltd has been developed relevant dosage forms such as Dong ling cao tablet, 'Donglingcao ' buccal tablets, Rabdosia rubescens syrup, Rabdosia rubescens capsule in succession; formed from raw material planting; the protection of place of origin, sophisticated industrial chain of product development has formed local major industry.
By retrieval, composition, pharmacology and some clinical articles of finding the research Rabdosia rubescens are taken passages as follows:
The molecular configuration research of cancer therapy drug rubescensine A, " chemical journal ", 1992,50 (5)
Crystal Structure of Oridonin, " structural chemistry ".1992，11(6)
Rubescensine A is to the hemodynamic influence of rabbit and mechanism research-Norman Bethune Medical University's journal 1994,20 (2) thereof
Rabdosia rubescens treatment esophageal carcinoma gastric cardia cancer 287 examples-Chinese combination of Chinese and Western medicine surgical magazine-1997,3 (6)
Rabdosia rubescens antitumor action progress-Henan pharmaceutical information, 1998,6 (9)
Progress-Chinese Pharmaceutical Journal of Rabdosia rubescens-1998,33 (10)
The electronic structure of rubescensine B and active anticancer " Henan Medical Univ.'s journal ".1998，33(3)。
Oridonin derivative and preparation method thereof, Chinese patent, application number, 99101179, the applicant, Zhengzhou University, this patent disclosure do not destroying under the active prerequisite of rubescensine A, changing the rubescensine A structure is Oridonin derivative: this Oridonin derivative has higher antitumor cell activity.This invention provides the preparation method of above-claimed cpd.
Journal of Sex Research-the canceration of rubescensine A mutation.Distortion.Sudden change 2001,13 (1)
Rabdosia rubescens leaf Study on extraction " time precious traditional Chinese medical science traditional Chinese medicines " .2001,12 (4), its summary is: inquire into the optimum condition that the Rabdosia rubescens leaf extracted with 95% ethanol (extraction time 4h, twice, add 95% ethanol than 10,1,70 ℃ of extraction temperature).
New technology " Heilungkiang medicine " .2001 of medium pressure column chromatography method extraction separation rubescensine A, 14 (1), the document discloses employing medium pressure column chromatography method extraction separation rubescensine A, it is fast to have elution speed, the separation efficiency height, solvent nontoxic pollution-free, advantage such as safe, inexpensive, as to be easy to get.Reaching 99.28% with tlc scanning determination content behind recrystallization, is a kind of simple and easy to do method that gets.
Dong ling cao tablet treatment acute pharyngitis one example-China is with clinical-2002,2 (3)
The antitumor of Rabdosia rubescens polysaccharide and immunological enhancement-Chinese Journal of Pathophysiology thereof-2002,18 (11)
Rabdosia rubescens intracavity thermochemotherapy primary bladder cancer late result observation-Chinese basic unit medicine-2004,11 (1)
14.Rapid?Communications---Journal?of?Natural?Products，2004，Vol.67，No.1
Novel Mechanism?of?Inhibition?of?Nuclear?Factor-KbDNA-Binding?Activity?by?Diterpenoids?Isolated?from?Isodonrubescens---MOLECULAR?PHARMACOLOGY(68：286---297，2005)---Printed?in?U.S.A
Anticancer pharmacology of Rabdosia rubescens and clinical practice " Chinese medicine medicine for preventing pharmacology and application ", Heilungkiang science tech publishing house.The chief editor, Ji Yubin.
Chinese medicine Rabdosia rubescens effective site antitumor drug extract and preparation method thereof.Chinese patent, application number, 03125250.8, applicant, Baihai Guofa Marine Organism Industry Co., Ltd..This invention belongs to a kind of Chinese medicine preparation, Chinese medicine Rabdosia rubescens active component composition and preparation method thereof particularly, it is after alcohol extraction with the Rabdosia rubescens raw material pulverizing, concentrate, extract, the total terpene crude extract of Rabdosia rubescens, again the dissolving, eluting, freezing or spraying drying powder-forming, get the total terpene of Rabdosia rubescens, get injection and oral agents by drug manufacture then.Medicine of the present invention can be used for treatment and comprises hepatocarcinoma, the esophageal carcinoma, gastric cancer, intestinal cancer, breast carcinoma, pulmonary carcinoma and melanoma, and is evident in efficacy, nontoxic, has no side effect controllable product quality.
From The above results as can be seen, medical institutions and R﹠D institution are clinical observation, the pharmacology of Rabdosia rubescens to the research of Rabdosia rubescens basically; The structure of rubescensine A, pharmacology, pharmacokinetic, extraction separation research and derivant preparation; The structure of rubescensine B and active anticancer; The research of Hamst traditional handicraft, the extraction and the preparation of rabdosia rubescens diterpene and triterpene blending constituent.
But the rabdosia rubescens diterpene effective kind part is not all disclosed on the above-mentioned document, the also unexposed concrete grammar that it extracts purifies and separates is that supercritical extraction (or microwave) extracts, ultrafiltration (molecular filtration), column chromatography, microwave drying, with suitable pharmaceutic adjuvant be processed into certain pharmaceutical preparation, these diterpene-kind compounds are used for the treatment of various malignant tumor such as acute and chronic pharyngitis and the esophageal carcinoma, carcinoma of gastric cardia, pulmonary carcinoma, hepatocarcinoma, bladder cancer, breast carcinoma, obtain better effects.
Summary of the invention
The technical issues that need to address of the present invention just are to provide a kind of treatment of Chinese medicine Rabdosia rubescens effective site acute and chronic pharyngitis, antitumor drug and rabdosia extraction method.
For addressing the above problem, the present invention adopts following technical scheme:
A kind of treatment acute and chronic pharyngitis of the present invention, antitumor drug, described active constituents of medicine is a Chinese medicine Rabdosia rubescens effective part extract, it comprises diterpene-kind compounds such as rubescensine A, rubescensine B, and the rabdosia rubescens diterpene kind compound content is more than 55% in this extract.
Medicine of the present invention can be for adding extract pharmaceutics acceptable drug adjuvant component, make injection, oral agents, external preparation, wherein oral agents comprises capsule, soft capsule, microcapsule, drop pill, dispersible tablet, granule, controlled release agent, targeting preparation, oral liquid and spray; Injection comprises aqueous injection and injectable powder; External preparation comprises suppository and unguentum.
The present invention provides the extracting method of a kind of Rabdosia rubescens simultaneously, and described extracting method is supercritical extraction or microwave extraction.
Preferably, in the extracting method of Rabdosia rubescens of the present invention, the extractant that described supercritical extraction adopted can be CO
2Or N
2, the extraction solvent that the microwave extraction method is adopted can be ethanol, acetone or their mixture.
In the rabdosia extraction method of the present invention, described supercritical extraction comprises the following steps:
The liquid CO of A
2Or N
2Or the Rabdosia rubescens after the pulverizing of mixed solvent supercritical extraction, solvent load is 6-10 a times of raw material, obtains the Rabdosia rubescens crude extract;
B Rabdosia rubescens crude extract is that the 2-5 of extract doubly measures with methanol or dissolve with ethanol, solvent load, and room temperature is placed and spent the night, supernatant adds the methanol or the ethanol of 5-10 amount, coarse filtration, and filtrate reuse molecular weight is less than 100,000 ultrafilter membrane ultrafiltration, concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.03-1.10;
The C column chromatographic isolation and purification: described column chromatographic isolation and purification adopts macroporous resin column chromatography to separate, extract after above-mentioned the concentrating is doubly measured neutral or weakly alkaline macroporous resin adsorption with 3-5,30-50 ℃ of following oven drying at low temperature, the dress post is that mobile phase is carried out eluting with the gradient mixed solvent;
D merges eluent, and concentrating under reduced pressure is removed solvent, and microwave vacuum drying under the 40-55 ℃ of temperature is pulverized, and gets the rabdosia rubescens diterpene chemical compound, perhaps adds the acetone soln recrystallization again, obtains monomeric compounds such as purer rubescensine A, second element.
In the rabdosia extraction method of the present invention, described microwave extraction method is:
A adds 5-10 and doubly measures the extraction solvent, and microwave extraction twice is collected solvent, and decompression and solvent recovery gets the Rabdosia rubescens crude extract;
B Rabdosia rubescens crude extract is with methanol or dissolve with ethanol, solvent load is that the 2-5 of extract doubly measures, room temperature is placed and is spent the night, supernatant adds the methanol or the ethanol of 5-10 amount, coarse filtration, filtrate reuse molecular weight is less than 100,000 ultrafilter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10;
The C column chromatographic isolation and purification: described column chromatographic isolation and purification adopts macroporous resin column chromatography to separate, extract after above-mentioned the concentrating is doubly measured neutral or weakly alkaline macroporous resin adsorption with 3-5,30-50 ℃ of following oven drying at low temperature, the dress post is that mobile phase is carried out eluting with the gradient mixed solvent;
D merges eluent, and concentrating under reduced pressure is removed solvent, and microwave vacuum drying under the 40-55 ℃ of temperature is pulverized, and gets the rabdosia rubescens diterpene chemical compound, perhaps adds the acetone soln recrystallization again, obtains monomeric compounds such as purer rubescensine A, second element.
In the said method, the microwave frequency of described microwave vacuum drying can be the 915-2450 megahertz, and vacuum can be 0.04-0.09Mp.
In the said method, described column chromatographic isolation and purification step can adopt silica gel or neutral alumina column chromatographic isolation and purification.
In the said method, the eluent among the described step C can be ethanol, methanol, chloroform, acetone, petroleum ether or their mixture and aqueous solution.
The diterpene-kind compound impurity that extracting method of the present invention obtains is few, active constituent content is high, and energy saving technology, environmental protection have one's own knack.
The present invention has following distinguishing feature compared with the prior art:
1, supercritical extraction or the environmental protection of microwave extraction method; Extract and do not need fuel, energy-conservation.
2, ultrafiltration: filter and do not need active carbon or other filtering material, loss of effective components is few, and filter material is reusable, and environmental protection is nontoxic; Filtration belongs to molecular level, and impurity is few, improves active constituent content greatly.
3, macroporous resin separates: can further remove impurity, improve the content of effective site, reach the purpose of discarding the dross and selecting the essential.
4, microwave drying: the drying means that is a kind of advanced person, utilize the high-frequency microwave effect that the polar molecule polarization is vibrated at a high speed and swash acute friction generation " heat effect ", so microwave drying, both can save energy and saved time, again because low temperature can guarantee that the Diterpenes effective ingredient is not destroyed, and has guaranteed drug quality.
The specific embodiment
Whether the numerical value of please carefully examining among each embodiment is the scope of claims
Embodiment 1 Rabdosia rubescens supercritical extraction
With the Rabdosia rubescens raw material pulverizing after the purified treatment is 40 purpose coarse powder, through CO
2Supercritical extraction, extracting pressure 30Mp, extract consumption are 6 times of Rabdosia rubescens, separation of C O
2, getting the Rabdosia rubescens crude extract, Rabdosia rubescens crude extract dissolve with methanol, solvent load are 2 times of amounts of extract, room temperature is placed and is spent the night.Supernatant adds the methanol of 5 amounts, coarse filtration, and filtrate reuse molecular weight is less than 100,000 filter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10; Extract after above-mentioned the concentrating is measured neutral macroporous resin adsorption with 3 times, 30 oven drying at low temperatures, dress post, with the gradient mixed solvent is that mobile phase is carried out eluting, and eluent is an ethanol, merges eluent, concentrating under reduced pressure is removed solvent, microwave vacuum drying, 40 ℃, microwave frequency is 915 megahertzes, vacuum 0.5Mp, material is pulverized, and gets the rabdosia rubescens diterpene chemical compound, perhaps add the acetone soln recrystallization again, obtain monomeric compounds such as purer rubescensine A, second element.
Embodiment 2 Rabdosia rubescens supercritical extractions
With the Rabdosia rubescens raw material pulverizing after the purified treatment is 80 purpose coarse powder, through N
2Supercritical extraction, extracting pressure 35Mp, extract consumption are 10 times of Rabdosia rubescens, separate N
2, getting the Rabdosia rubescens crude extract, Rabdosia rubescens crude extract dissolve with ethanol, solvent load are 5 times of amounts of extract, room temperature is placed and is spent the night.Supernatant adds the ethanol of 10 amounts, coarse filtration, and filtrate reuse molecular weight is less than 100,000 filter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10; Extract after above-mentioned the concentrating is measured silica gel adsorption with 5 times, 50 ℃ of oven drying at low temperatures, the dress post is that mobile phase is carried out eluting with the gradient mixed solvent, eluent is a methanol, merge eluent, concentrating under reduced pressure is removed solvent, 55 ℃ of microwave vacuum dryings, microwave frequency is 2450 megahertzes, vacuum 0.9Mp, material is pulverized, and gets the rabdosia rubescens diterpene chemical compound.
Embodiment 3 Rabdosia rubescens microwave extractioies
With the Rabdosia rubescens raw material pulverizing after the purified treatment is 60 purpose coarse powder, adds 5 times of amounts of ethanol, and microwave extraction twice is collected solvent, and decompression and solvent recovery gets the Rabdosia rubescens crude extract.Rabdosia rubescens crude extract dissolve with methanol, solvent load are 3 times of amounts of extract, and room temperature is placed and spent the night.Supernatant adds the methanol of 6 amounts, coarse filtration, and filtrate reuse molecular weight is less than 100,000 ultrafilter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10; Extract after above-mentioned the concentrating is adsorbed 40 ℃ of oven drying at low temperatures, dress post with 4 times of amount neutral aluminas, with the gradient mixed solvent is that mobile phase is carried out eluting, described eluent is the mixture of ethanol, methanol, chloroform, acetone and petroleum ether, merges eluent, and concentrating under reduced pressure is removed solvent, microwave vacuum drying, 50 ℃, microwave frequency is 1500 megahertzes, vacuum 0.06Mp, material is pulverized, and gets the rabdosia rubescens diterpene chemical compound.
Embodiment 4 Rabdosia rubescens microwave extractioies
With the Rabdosia rubescens raw material pulverizing after the purified treatment is 70 purpose coarse powder, adds the ethanol of 10 times of amounts and the mixture of acetone, and microwave extraction twice is collected solvent, and decompression and solvent recovery gets the Rabdosia rubescens crude extract.Rabdosia rubescens crude extract dissolve with ethanol, solvent load are 4 times of amounts of extract, and room temperature is placed and spent the night.Supernatant adds the ethanol of 8 amounts, coarse filtration, and filtrate reuse molecular weight is less than 100,000 ultrafilter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10; Extract after above-mentioned the concentrating is measured neutral macroporous resin adsorption with 4 times, 50 ℃ of oven drying at low temperatures, the dress post, with the gradient mixed solvent is that mobile phase is carried out eluting, described eluent is the mixed aqueous solution of ethanol, methanol, chloroform, acetone and petroleum ether, merge eluent, concentrating under reduced pressure is removed solvent, microwave vacuum drying, 50 ℃, microwave frequency is 2000 megahertzes, vacuum 0.08Mp, material is pulverized, and gets the rabdosia rubescens diterpene chemical compound, perhaps add the acetone soln recrystallization again, obtain monomeric compounds such as purer rubescensine A, second element.
The preparation of embodiment 5 capsules
Take by weighing the 150g diterpene compound, add starch 45g, differential silica gel 5g mixing, adorn 1000 capsules, the 0.2g/ grain.
The preparation of embodiment 6 dispersible tablets
Take by weighing the 150g diterpene compound, add behind carboxymethyl starch sodium 100g, low-substituted hydroxypropyl cellulose 40g, sodium laurylsulfate 5g, the differential silica gel 5g mixing and press 1000.
The preparation of embodiment 7 aqueous injection
Take by weighing rabdosia rubescens diterpene compounds 100g, add sodium alginate, sodium pyrosulfite mix homogeneously, add the ultrafiltration of injection water, fill, sterilization.
Embodiment 8 rabdosia rubescens diterpene chemical compounds are to the treatment of acute/chronic pharyngitis
The treatment of diterpene compound dispersible tablet is used for the pharyngitis of pattern of syndrome such as wind heat is invaded, lung sthenia gastropyrexia, affection by exopathogenic cold-wind outward, and the clinical observation curative effect is better, total effective rate 98.8%, and find no why not very reaction.
Embodiment 9 treatment examples
The rabdosia rubescens diterpene chemical compound has obvious antineoplastic to the human body esophageal carcinoma 109 cell pearls, human hepatocellular BEL-7402 cell pearl, ehrlich carcinoma and S180 etc.
The rabdosia rubescens diterpene chemical compound has tangible lethal effect to the human body esophageal carcinoma 109 cell pearls, human hepatocellular BEL-7402 cell pearl, ehrlich carcinoma and S180, and valid density is that the inhibitory rate of cell growth of this cell pearl of 6ug/ml is respectively 60%, 90%, 81%, 86%.The rabdosia rubescens diterpene chemical compound can obviously reduce S phase cell, delays or block G2 phase cell to enter the M phase, and the M phase is reached all has lethal effect to G0 phase cell.
Embodiment 10
The foregoing description adopts following standard:
1. differentiate: thin layer chromatography (TLC): Rabdosia rubescens control medicinal material methanol ultrasonic extraction concentrated solution and medicine with dissolve with methanol after, use thin-layer developing, developing solvent: chloroform-isopropyl alcohol (20: 2), iodine steam are fumigated and are developed the color.
2. assay: high-efficient liquid phase technique (HPLC): measure rubescensine A content in the rabdosia rubescens diterpene chemical compound, meter being not less than 10% (diterpene total amount in the extract), and tradition is extracted rubescensine A and accounted for 3.8% of diterpene content.
Chromatographic column: C
18Mobile phase: MeOH-H
2O (50: 50); Detect wavelength: 240nm (rubescensine A); 239nm (rubescensine B).
The present invention is not limited to above-mentioned preferred forms, and other any identical with the present invention or akin products that anyone draws under enlightenment of the present invention all drop within protection scope of the present invention.
Claims (2)
1, the extracting method of a kind of Rabdosia rubescens is characterized in that, comprises the following steps:
A adds the extraction solvent that 5-10 doubly measures, and microwave extraction twice is collected solvent, and decompression and solvent recovery gets the Rabdosia rubescens crude extract; The extraction solvent is ethanol, acetone or their mixture;
B Rabdosia rubescens crude extract is with methanol or dissolve with ethanol, solvent load is that the 2-5 of extract doubly measures, room temperature is placed and is spent the night, supernatant adds the methanol or the ethanol of 5-10 amount, coarse filtration, filtrate reuse molecular weight is less than 100,000 ultrafilter membrane ultrafiltration, and the ultrafiltrate concentrating under reduced pressure reclaims solvent, is concentrated into relative density 1.05-1.10;
The C column chromatographic isolation and purification: described column chromatographic isolation and purification adopts macroporous resin column chromatography to separate, extract after above-mentioned the concentrating is doubly measured the macroporous resin adsorption of neutrality or low pole with 3-5,30-50 ℃ of following oven drying at low temperature, the dress post is that mobile phase is carried out eluting with the gradient mixed solvent; The gradient mixed solvent is the mixed aqueous solution of ethanol, methanol, chloroform, acetone and petroleum ether;
D merges eluent, and concentrating under reduced pressure is removed solvent, and microwave vacuum drying under the 40-55 ℃ of temperature is pulverized, and gets the rabdosia rubescens diterpene chemical compound, perhaps adds the acetone soln recrystallization again, obtains purer rubescensine A, the plain monomeric compound of second.
2, extracting method as claimed in claim 1 is characterized in that: the microwave frequency of described microwave vacuum drying is the 915-2450 megahertz, vacuum 0.04-0.09Mp.
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| CN104474011B (en) * | 2014-11-21 | 2018-03-16 | 郑州轻工业学院 | The method of Rabdosia rubescens extract decolouring removal of impurities |
| CN108926525B (en) * | 2018-09-14 | 2021-08-31 | 南方医科大学 | External transdermal absorption preparation for arthritis |
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| 超临界二氧化碳萃取冬凌草甲素的工艺研究. 田宏现.长江电力学院学报，第19卷第3期. 2004 |
| 超临界二氧化碳萃取冬凌草甲素的工艺研究. 田宏现.长江电力学院学报，第19卷第3期. 2004 * |
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Assignee: HENAN JIYUAN JISHI PHARMACEUTICAL CO., LTD. Assignor: Zhang Hai Contract fulfillment period: 2009.5.5 to 2025.5.5 Contract record no.: 2009410000151 Denomination of invention: Rabdosia extraction method Granted publication date: 20090415 License type: Exclusive license Record date: 20090521 |
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