CN1724533A - Method of extracting deydrokaividing and solubilizing injection agent from rock gold thread total alkaloid - Google Patents
Method of extracting deydrokaividing and solubilizing injection agent from rock gold thread total alkaloid Download PDFInfo
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- CN1724533A CN1724533A CN 200510037754 CN200510037754A CN1724533A CN 1724533 A CN1724533 A CN 1724533A CN 200510037754 CN200510037754 CN 200510037754 CN 200510037754 A CN200510037754 A CN 200510037754A CN 1724533 A CN1724533 A CN 1724533A
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Abstract
The invention relates to a method for purifying dehydrocavidine from Corydalis saxicola Bunting total alkaloid and method for solubilization its injection preparation, wherein a pH graded phase transition method, or column chromatography separation method, or the combination of the two methods are employed for the segregation and purification of dehydrocavidine, then acidic materials are used directly for solubiliziation the dehydrocavidine and preparing injection through intra-vascular instillation, the purity of the dehydrocavidine can reach above 99.00%.
Description
Technical field
The present invention relates to a kind of purification, solubilizing method of deydrokaividing, particularly a kind of from total alkaloids of meadowrueleaf corydalis root the solubilizing method of purification deydrokaividing and injection formulations thereof.
Background technology
Deydrokaividing claims Dihydrocavidine again, is present in the bloodroot, is the effective ingredient of treatment hepatitis disease in the bloodroot Root of Meadowrue Corydalis.
Before the present invention, the injection formulations of using for intramuscular injection has been arranged.Owing to can only obtain total alkaloids of meadowrueleaf corydalis root at present, and contained deydrokaividing is water-soluble very little, can't make water miscible pharmaceutical preparation, adds tensio-active agent such as Polysorbate 80 so intramuscular injectable formulations adopts, make its solubilising, make intramuscular injectable formulations then.This is the method that adopts at present.
But this solubilizing method or technology exist many defectives, and wherein Zui Da defective one is to make intramuscular injectable formulations, and the medication effect of intramuscular injectable formulations far is inferior to intravenous formulations; The 2nd, used tensio-active agent Polysorbate 80 has hemolytic action, and sizable side effect is arranged during clinical application, is unfavorable for that patient body recovers and health.In addition, this extract that contains deydrokaividing is the crude extract of total alkaloids of meadowrueleaf corydalis root, and itself result of treatment also is limited.So existing intramuscular injectable formulations all can not effectively be guaranteed in curative effect and security.
Summary of the invention
Purpose of the present invention just is to overcome above-mentioned defective, develops a kind of solubilizing method or technology of extracting the purifying deydrokaividing and can be used for intravenous formulations.
Technical scheme of the present invention is:
Purification deydrokaividing and injection formulations solubilizing method from total alkaloids of meadowrueleaf corydalis root, step comprises: pH value classification phase transfer method:
(1) gets 1 part of total alkaloids of meadowrueleaf corydalis root, add 2～50 parts of mixing of purified water or deionized water;
(2) add 10% acidic substance solution, regulate pH value in 2～4;
(3) heating, stirring make it dissolving;
(4) clarification filtration, filtrate is lower than 10% alkaline substance solution with concentration, regulates pH value;
(5) when pH value is 7, carries out the PH gradient and regulate;
(6) adopt organic solvent to carry out phase transition, consumption is 1～10 times of total alkaloids, extracts 3～5 times;
(7) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, will have the part of maximum absorption to keep at the 347nm place, merge;
(8) decompression, evaporate to dryness organic solvent;
The deydrokaividing dissolving that (9) 40～100% alcoholic solutions reflux phase transition is obtained;
(10) cold putting more than 8 hours makes and separates out the deydrokaividing crystallization;
(11) filter,, more than 4 hours, get the high purity deydrokaividing 20～80 ℃ of dryings with water for injection washing several and after draining.
Or column chromatography for separation method:
(1) 90% alcoholic solution with 2～20 times of volumes of amount of solid refluxes, and makes it dissolving;
(2) chromatography column adopts column chromatographic isolation and purification on the alcoholic solution;
(3) adopt gradient alcohol liquid wash-out, Fractional Collections elutriant;
(4) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, the part that is rich in deydrokaividing is separated, separates out, merged;
(5) pressure reducing and steaming partial solvent, cold putting more than 8 hours makes the deydrokaividing crystallization of separating out complete;
(6) filter,, more than 4 hours, get the high purity deydrokaividing 20～80 ℃ of dryings with water for injection washing several and after draining.
Or pH value classification phase transfer method, the combination of column chromatography for separation method:
(1) total alkaloids of meadowrueleaf corydalis root is 1 part, adds 2～50 parts of mixing of purified water or deionized water;
(2) add 10% acidic substance solution, regulate pH value in 2～4;
(3) heating, stirring make it dissolving;
(4) clarification filtration, filtrate is lower than 10% alkaline substance solution with concentration, regulates pH value;
(5) when pH value is 7, carries out the PH gradient and regulate;
(6) adopt organic solvent to carry out phase transition, consumption is 5～10 times of total alkaloids, extracts 3～5 times;
(7) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, will have the part of maximum absorption to keep at the 347nm place, merge;
(8) decompression, evaporate to dryness organic solvent;
(9) 90% alcoholic solution with 2～20 times of volumes of amount of solid refluxes, and makes it dissolving;
(10) chromatography column adopts column chromatographic isolation and purification on the alcoholic solution;
(11) adopt gradient alcohol liquid wash-out, Fractional Collections elutriant;
(12) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, the part that is rich in deydrokaividing is separated, merged;
(13) pressure reducing and steaming partial solvent, cold putting more than 8 hours makes the deydrokaividing crystallization of separating out;
(14) filter,, more than 4 hours, get the high purity deydrokaividing 80 ℃ of dryings with water for injection washing several and after draining.
Further technical scheme of the present invention is:
The deydrokaividing of purifying is suspended in water, join in the acidic substance solution with acidic substance solution or with deydrokaividing and to make salify, regulate between the pH value 3～6.5, do not stop to stir and make dissolving, preparation process or method are made injection formulations routinely then, comprise injection with small volume, freeze-dried type injection, subpackage type powder injection, sodium-chlor or glucose etc. ooze transfusion type injection.
Advantage of the present invention and effect are to adopt PH classification phase transfer method, or column chromatography for separation method, or the two method that combines is separated the purification deydrokaividing, directly deydrokaividing is carried out solubilising then with acidic substance, but make the injection formulations of intravenous drip, its result of treatment is far above intramuscular injection.Solved in the past and just can make the limitation of intramuscular injectable formulations, and avoided adding the haemolysis side effect that the tensio-active agent Polysorbate 80 brings, thereby helped the healthy and recovery of patient body with adding tensio-active agent.Technology of the present invention is simple, cost is low, good effect, and deydrokaividing purity is up to more than 99.00%.
Embodiment
Embodiment 1:
PH value classification phase transfer method:
Get 1 part of total alkaloids of meadowrueleaf corydalis root, add 35 parts of mixing of purified water or deionized water; The hydrochloric acid soln of adding 10% is regulated pH value 3.5; Heating, stirring make it dissolving; Clarification filtration, filtrate is regulated pH value with 8% sodium carbonate solution; When pH value is 7, carry out the PH gradient and regulate, promptly PH is 7, PH is 9, PH is 11, PH is 13 o'clock, adopts chloroform or ethyl acetate to carry out phase transition respectively; Consumption is 8 times of total alkaloids, divides and extracts for 3～5 times; Merge every grade phase transition extract, be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, will have the part of maximum absorption to keep at the 347nm place, merge; Decompression, evaporate to dryness organic solvent, make dissolving with 90% alcohol reflux after, add 1% activated carbon decolorizing, filtering decarbonization; Cold putting more than 8 hours makes and separates out the deydrokaividing crystallization; Filter, filter cake more than 4 hours, gets the high density deydrokaividing 80 ℃ of dryings with water for injection washing several and after draining.
Embodiment 2:
The combination of column chromatography for separation method:
90% alcoholic solution with 5 times of volumes of amount of solid refluxes, and makes it dissolving; Silica gel column chromatography adopts column chromatographic isolation and purification on the alcoholic solution; Adopt gradient alcohol liquid wash-out, the determining alcohol of each gradient 15% is poor, from 0～100% Fractional Collections elutriant; Be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, the part that is rich in deydrokaividing isolated the back merge,, suitably concentrate this part solution activated carbon decolorizing, filtration; Cold putting more than 24 hours makes the deydrokaividing crystallization of separating out yellowish brown; Filter,, more than 4 hours, get the high purity deydrokaividing 80 ℃ of dryings with water for injection washing leaching cake several and after draining.
Embodiment 3:
PH value classification phase transfer method, the combination of column chromatography for separation method:
Get 1 part of total alkaloids of meadowrueleaf corydalis root, add 30 parts of purified water or deionized waters, mix, make its dispersion; Comprise inorganic or organic acid with 10% acidic substance solution, mineral acid comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid comprises acetate, propionic acid, butyric acid, Citric Acid etc., specifically mineral acid hydrochloric acid in this example, adjusting pH value to 3 (about), and heated and stirred, make it dissolving; Clarification, filter, filtrate is with the pH value of 10% alkaline substance solution yellow soda ash (but also sodium hydroxide or ammonium hydroxide) regulator solution; From pH value is 7, carries out the pH value gradient and regulates, and every grade of 2 pH values are poor; Use organic solvent ether (or chloroform, ethyl acetate) to carry out phase transition again, make it to form immiscible two-phase with water, and deydrokaividing is changeed be dissolved in the organic solvent ether, obtain free alkaloid, consumption is 8 times of total alkaloids, extracts 3 to 5 times; This step, also available salting-out process replaced; Then, be aided with thin-layer chromatography and/or high-efficient liquid phase analysis again, will have the part of maximum absorption to keep and merge at the 347nm place; Evaporated under reduced pressure organic solvent again; Reflux and make it dissolving with 90% methyl alcohol (or ethanol) of 15 times of volumes of amount of solid; Alcoholic solution upper strata post is analysed and is carried out column chromatography for separation, purifying, and column chromatography for separation comprises ion exchange resin column chromatography, macroporous resin column chromatography, silica gel column chromatography, alumina column chromatography, polyamide column chromatography separation etc., and what adopt in this example is silica gel column chromatography; Gradient alcoholic solution wash-out, every grade 15% concentration difference is from 0～100%; Then, the Fractional Collections elutriant is aided with thin-layer chromatography and/or high-efficient liquid phase analysis, and the deydrokaividing composition is isolated, and its concentration can be more than or equal to 99.0%, and the repeated upper prop that does not reach separates, until reaching; After the elutriant that will contain highly purified deydrokaividing more suitably concentrates, be placed on cold place 24 hours or more than, just have a large amount of yellowish brown needle crystals to separate out, filter; Filter cake with water for injection washing for several times and drain, under 80 ℃ of temperature dry 4 hours or more than, get final product the high purity deydrokaividing; Deydrokaividing is suspended in water, use acidic solution (comprising organic acids such as mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or acetate, propionic acid, butyric acid, methylsulfonic acid, Citric Acid, tartrate, liquor epinephrinae bitartratis ophthalmicus, fumaric acid, lactic acid, phenylformic acid, Whitfield's ointment, toxilic acid, Sorbic Acid, L-glutamic acid, xitix) hydrochloric acid conditioning solution pH value again between 3～6.5, do not stop to stir, can appropriateness heat in case of necessity, and then get the water-soluble salt solution of deydrokaividing with the promotion dissolving; Again routinely preparation process be made into the medicament that is fit to injection such as injection with small volume, freeze-dried type injection, subpackage type powder injection, high-capacity injection promptly contain sodium-chlor or glucose etc. ooze transfusion type injection.
The extraction of total alkaloids of meadowrueleaf corydalis root be according to the meadowrueleaf corydalis root extract method for making of the national drug standards that are numbered WS-1149 (2D-1149)-2002 (try) announcement of promulgation in National Drug Administration of the People's Republic of China (PRC) on November 16th, 2002 extract obtain.
Total alkaloids of meadowrueleaf corydalis root comprises deydrokaividing, dextrorotation tetrahydropalmatine, Berberine and the ugly element of YANHUSU.
Protection scope of the present invention and explanation are not limited only to the description of present embodiment.
Claims (3)
1. purification deydrokaividing and injection formulations solubilizing method from total alkaloids of meadowrueleaf corydalis root, step comprises: pH value classification phase transfer method:
(1) gets 1 part of total alkaloids of meadowrueleaf corydalis root, add 2～50 parts of mixing of purified water or deionized water;
(2) add 10% acidic substance solution, regulate pH value in 2～4;
(3) heating, stirring make it dissolving;
(4) clarification filtration, filtrate is lower than 10% alkaline substance solution with concentration, regulates pH value;
(5) when pH value is 7, carries out the PH gradient and regulate;
(6) adopt organic solvent to carry out phase transition, consumption is 1～10 times of total alkaloids, extracts 3～5 times;
(7) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, will have the part of maximum absorption to keep at the 347nm place, merge;
(8) decompression, evaporate to dryness organic solvent;
The deydrokaividing dissolving that (9) 40～100% alcoholic solutions reflux phase transition is obtained;
(10) cold putting more than 8 hours separated out the deydrokaividing crystallization;
(11) filter,, more than 4 hours, get the high purity deydrokaividing 20～80 ℃ of dryings with water for injection washing several and after draining.Or column chromatography for separation method:
(1) 90% alcoholic solution with 2～20 times of volumes of amount of solid refluxes, and makes it dissolving;
(2) chromatography column adopts column chromatographic isolation and purification on the alcoholic solution;
(3) adopt gradient alcohol liquid wash-out, Fractional Collections elutriant;
(4) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, the part that is rich in deydrokaividing is separated, separated out, merge;
(5) pressure reducing and steaming partial solvent, cold putting more than 8 hours makes the deydrokaividing crystallization of separating out complete;
(6) filter,, more than 4 hours, get the high purity deydrokaividing 20～80 ℃ of dryings with water for injection washing several and after draining.Or pH value classification phase transfer method, the combination of column chromatography for separation method:
(1) total alkaloids of meadowrueleaf corydalis root is 1 part, adds 2～50 parts of mixing of purified water or deionized water;
(2) add 10% acidic substance solution, regulate pH value in 2～4;
(3) heating, stirring make it dissolving;
(4) clarification filtration, filtrate is lower than 10% alkaline substance solution with concentration, regulates pH value;
(5) when pH value is 7, carries out the PH gradient and regulate;
(6) adopt organic solvent to carry out phase transition, consumption is 5～10 times of total alkaloids, extracts 3～5 times;
(7) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, will have the part of maximum absorption to keep at the 347nm place, merge;
(8) decompression, evaporate to dryness organic solvent;
(9) 90% alcoholic solution with 2～20 times of volumes of amount of solid refluxes, and makes it dissolving;
(10) chromatography column adopts column chromatographic isolation and purification on the alcoholic solution;
(11) adopt gradient alcohol liquid wash-out, Fractional Collections elutriant;
(12) be aided with thin-layer chromatography and/or high-efficient liquid phase analysis, the part that is rich in deydrokaividing is separated, merged;
(13) pressure reducing and steaming partial solvent, cold putting more than 8 hours makes the deydrokaividing crystallization of separating out;
(14) filter,, more than 4 hours, get the high purity deydrokaividing 80 ℃ of dryings with water for injection washing several and after draining.
2. according to claim 1 from total alkaloids of meadowrueleaf corydalis root purification deydrokaividing and injection formulations solubilizing method, it is characterized in that the acidic substance solution in pH value classification phase transfer method step (2), pH value classification phase transfer method and the column chromatography for separation method integrating step (2) can be organic acidity substance solution or mineral acid substance solution.
3. according to claim 1 from total alkaloids of meadowrueleaf corydalis root purification deydrokaividing and injection formulations solubilizing method, it is characterized in that the deydrokaividing of will purify suspends in water, join in the acidic substance solution with acidic substance solution or with deydrokaividing and to make salify, regulate between the pH value 3～6.5, do not stop to stir and make dissolving, preparation process or method are made injection formulations routinely then, comprise injection with small volume, freeze-dried type injection, subpackage type powder injection, sodium-chlor or glucose etc. ooze transfusion type injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100377545A CN100491376C (en) | 2005-02-04 | 2005-02-04 | Method of extracting deydrokaividing and solubilizing injection agent from rock gold thread total alkaloid |
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| CNB2005100377545A CN100491376C (en) | 2005-02-04 | 2005-02-04 | Method of extracting deydrokaividing and solubilizing injection agent from rock gold thread total alkaloid |
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| CN1724533A true CN1724533A (en) | 2006-01-25 |
| CN100491376C CN100491376C (en) | 2009-05-27 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600247A (en) * | 2012-04-11 | 2012-07-25 | 宁波德沃生物科技有限公司 | Corydalis saxicola bunting alkaloid extract and preparation method thereof, as well as extraction method of dehydrocavidine |
| CN103919743A (en) * | 2014-04-14 | 2014-07-16 | 广州一品红制药有限公司 | Pharmaceutical composition containing cavidine total alkali and preparation method of pharmaceutical composition |
| CN106667906A (en) * | 2017-03-22 | 2017-05-17 | 中国人民解放军第三军医大学第二附属医院 | Coptisine injection as well as preparation method and application thereof |
| CN114191467A (en) * | 2021-12-06 | 2022-03-18 | 广西师范大学 | Method for extracting high-purity alkaloid from corydalis saxicola bunting |
| CN116813611A (en) * | 2023-08-24 | 2023-09-29 | 云南省农业科学院生物技术与种质资源研究所 | Preparation method and application of isoquinoline alkaloid |
-
2005
- 2005-02-04 CN CNB2005100377545A patent/CN100491376C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600247A (en) * | 2012-04-11 | 2012-07-25 | 宁波德沃生物科技有限公司 | Corydalis saxicola bunting alkaloid extract and preparation method thereof, as well as extraction method of dehydrocavidine |
| CN102600247B (en) * | 2012-04-11 | 2014-02-05 | 宁波德沃生物科技有限公司 | Corydalis saxicola bunting alkaloid extract and preparation method thereof |
| CN103919743A (en) * | 2014-04-14 | 2014-07-16 | 广州一品红制药有限公司 | Pharmaceutical composition containing cavidine total alkali and preparation method of pharmaceutical composition |
| CN103919743B (en) * | 2014-04-14 | 2015-06-17 | 广州一品红制药有限公司 | Pharmaceutical composition containing cavidine total alkali and preparation method of pharmaceutical composition |
| CN106667906A (en) * | 2017-03-22 | 2017-05-17 | 中国人民解放军第三军医大学第二附属医院 | Coptisine injection as well as preparation method and application thereof |
| CN114191467A (en) * | 2021-12-06 | 2022-03-18 | 广西师范大学 | Method for extracting high-purity alkaloid from corydalis saxicola bunting |
| CN116813611A (en) * | 2023-08-24 | 2023-09-29 | 云南省农业科学院生物技术与种质资源研究所 | Preparation method and application of isoquinoline alkaloid |
| CN116813611B (en) * | 2023-08-24 | 2023-12-01 | 云南省农业科学院生物技术与种质资源研究所 | Preparation method and application of isoquinoline alkaloid |
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| CN100491376C (en) | 2009-05-27 |
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