CN106084090A - A kind of preparation method of refined heparin sodium - Google Patents
A kind of preparation method of refined heparin sodium Download PDFInfo
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- CN106084090A CN106084090A CN201610501525.2A CN201610501525A CN106084090A CN 106084090 A CN106084090 A CN 106084090A CN 201610501525 A CN201610501525 A CN 201610501525A CN 106084090 A CN106084090 A CN 106084090A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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Abstract
The invention discloses the preparation method of a kind of refined heparin sodium, belong to heparin sodium preparing technical field.Expanded perlite is loaded compound enzyme and obtains making enzyme preparation by oneself by the present invention, with its pretreatment crude heparin sodium, then can be prepared by refined heparin sodium through hydrogen peroxide once oxidation.Example proves, the inventive method uniqueness is novel, not only avoid the generation of by-product in conventional refining method, from at utmost reducing Product Activity loss, and simplify purification step, it is effectively increased titer and the titer response rate of refined heparin sodium so that titer is up to 160～170u/mg, and the response rate reaches more than 98%.
Description
Technical field
The invention discloses the preparation method of a kind of refined heparin sodium, belong to heparin sodium preparing technical field.
Background technology
Heparin sodium (Heparin Sodium) is mucopolysaccharide sulfuric acid ester anticoagulant.Heparin sodium is to be glued by the intestinal of pig or cattle
The sodium salt of the CSSO3 extracted in film, belongs to mucopolysaccharide material.It is respectively provided with blood coagulation resisting function in vivo and in vitro, is current
The anticoagulation medicine of main flow.But the bioavailability of unfractionated heparin sodium is low, side effect is big, it is found that heparin sodium cracked later
The sodium salt of the CSSO3 fragment obtained, mean molecule quantity is 4000～6000 dalton, referred to as low molecular sodium heparins.
Low molecular heparin sodium injection regulating liver-QI element sodium injection equally belongs to antithrombin Ⅲ (AT III) dependency thrombin inhibitor.But
Compared with heparin sodium injection, have that the half-life is longer, antithrombotic effect good, bleeding tendency is more weak, convenient drug administration, but price ratio
More expensive.And DALT is one of which.Dalteparin sodium injection is mainly used in the treatment of acute deep venous thrombosis, acute renal
Exhaustion or chronic renal insufficiency person prevent from occurring in extracorporeal circulation system blood coagulation during carrying out hemodialysis and blood filtration, no
Stable coronary heart disease, such as unstable angina pectoris and non-Q-wave mode myocardial infarction, prevents the thrombosis relevant with operation.It it is mesh
The anti-thrombotic drugs of front main flow.
The subtractive process of heparin mainly carries out removing protein purification and decolouring to crude heparin sodium, reaches state-promulgated pharmacopoeia standard
Requirement.Refined at China's heparin use the two of potassium permanganate and hydrogen peroxide two-step penetration method or hydrogen peroxide addition by several times more
Secondary oxidizing process production technology；Also there is document announcement simultaneously, use enzymolysis to combine oxidizing process and refine the record of heparin.But it is above-mentioned several
Plant technique all Shortcomings；There is manganese dioxide and suck heparin in the first potassium permanganate and hydrogen peroxide two-step penetration method, makes liver
Element loss of activity is big, and the response rate is low；Filtration difficulty, the production cycle is long, the shortcomings such as color and luster is bad, of poor quality；The second peroxidating
The Two-step anodization technique that oxygen adds by several times, because product color is preferable, is generally used at present.But this technique is primarily present secondary
Hydrogen oxide processes and damages heparin structure, it is difficult to obtain the deficiency of the fine work heparin product of more efficient valency.
At present heparin sodium extraction technology is of a great variety the most on the market, but need a kind of ensure Product Activity, color and luster same
Time, it is also possible to making raw material production with low cost, technique simply prepares the method for heparin sodium.
Summary of the invention
The technical problem that present invention mainly solves: for commonly using potassium permanganate and hydrogen peroxide two-step penetration method or mistake at present
The Two-step anodization that hydrogen oxide adds by several times produces choice goods heparin sodium, and the loss of consequent Product Activity is big, shade deviation, by-product
Thing manganese dioxide reduces product yield and the low defect of titer, it is provided that a kind of expanded perlite is loaded compound enzyme made by oneself
Enzyme preparation, with its pretreatment crude heparin sodium, then can be prepared by refined heparin sodium through hydrogen peroxide once oxidation.The method is unique
Novelty, not only avoid the generation of by-product in conventional refining method, from utmost reducing Product Activity loss, and simplifies
Purification step, is effectively increased titer and the titer response rate of refined heparin sodium so that titer up to 160～170u/mg, is returned
Yield reaches more than 98%.
In order to solve above-mentioned technical problem, the technical solution adopted in the present invention is:
(1) weigh 40～50g expanded perlites respectively with concentration be 0.5mol/L sulfuric acid solution and 0.3mol/L sodium hydroxide molten
Immersion bubble 3～5h, moves into buchner funnel filtering and washing 20～30min, obtains the expanded perlite of surface modification；
(2) three's cumulative volume 3～5 times are added after to be 5:3:1 in mass ratio mix trypsin, alkaline protease and lipase
Deionized water, proceed to vacuum concentration pot after stirring, under 900～1000Pa pressure, be concentrated into the 1/2 of its original volume
Complex enzyme liquid is 1:3 by solid-to-liquid ratio immerses complex enzyme liquid by the expanded perlite of above-mentioned surface modification, put into sonic oscillation instrument with
200～300W oscillation of power steeped overnight；
(3) filter isolated filtering residue after dipping terminates, at-40～-30 DEG C, after lyophilizing, i.e. obtain self-control with vacuum freeze-drying machine solid
Surely compound enzymic preparation is changed；
(4) weigh 1～2kg crude heparin sodium and be dissolved in its volume 3～5 times of mass concentrations are in 3% sodium chloride solution, stirring 10～
Filtering removal filtering residue after 20min and obtain filtrate, the filtrate that will obtain loads in pottery enzymatic vessel, adds filtrate gross mass 5～10%
Above-mentioned from preparing curable compound enzymic preparation, it is that 0.1mol/L sodium hydroxide solution regulates pH to 7.5～8.5, room temperature enzyme by concentration
Filtering removal filtering residue after solving 5～6h must be without protein enzymatic hydrolyzate；
(5) to above-mentioned be 30% hydrogenperoxide steam generator without protein enzymatic hydrolyzate adds its volume 1/10 mass concentration, at 20～25 DEG C
Filter isolated oxidation solution after lower standing oxidation processes 10～12h, in oxidation solution, add its volume 1～the anhydrous second of 2 times
Alcohol, puts into and staticly settles 6～8h in the ice-water bath of 4～6 DEG C, with horizontal centrifuge with centrifugal point of 3000～5000r/min rotating speeds
Obtain lower sediment after from, after vacuum drying, i.e. obtain refined heparin sodium.
The application process of the present invention is: the refined heparin sodium present invention prepared is prepared according to medical science, by embedding, goes out
The regular injection agent preparation technology such as bacterium, packaging, makes hypodermic injection, during use, injects human body, and every day is sooner or later
Once, each consumption of being grown up is 15～20mg, continuously injection 3～5 days, after testing, as anticoagulant, antithrombotic reagent, treatment effect
Fruit is notable, and the value finally recording anticoagulin a is 160～170IU/mg, and anticoagulation enzyme values is 0.65～0.75IU/mg.
The invention has the beneficial effects as follows:
(1) the inventive method uniqueness is novel, it is to avoid the generation of by-product in conventional refining method, from utmost reducing product
Product loss of activity, and simplify standing step；
(2) present invention is effectively increased titer and the titer response rate of refined heparin sodium so that titer up to 160～170u/mg,
The response rate reaches more than 98%, can be widely applied to medical field.
Detailed description of the invention
First weighing 40～50g expanded perlites is 0.5mol/L sulfuric acid solution and 0.3mol/L hydroxide by concentration respectively
Sodium solution soaks 3～5h, moves into buchner funnel filtering and washing 20～30min, obtains the expanded perlite of surface modification；Then press
Mass ratio is to add three's cumulative volume 3～the deionization of 5 times after trypsin, alkaline protease and lipase are mixed by 5:3:1
Water, proceeds to vacuum concentration pot after stirring, be concentrated into its original volume under 900～1000Pa pressure 1/2 obtains complex enzyme liquid,
It is that the expanded perlite of above-mentioned surface modification is immersed complex enzyme liquid by 1:3 by solid-to-liquid ratio, puts into sonic oscillation instrument with 200～300W
Oscillation of power steeped overnight；Dipping filters isolated filtering residue after terminating, with vacuum freeze-drying machine at-40～-30 DEG C after lyophilizing
I.e. derive from preparing curable compound enzymic preparation；Next weigh 1～2kg crude heparin sodium and be dissolved in its volume 3～5 times of mass concentrations are
In 3% sodium chloride solution, filtering removal filtering residue and obtain filtrate after stirring 10～20min, the filtrate that will obtain loads pottery enzymatic vessel
In, add filtrate gross mass 5～10% above-mentioned from preparing curable compound enzymic preparation, be that 0.1mol/L sodium hydroxide is molten by concentration
Liquid regulation pH to 7.5～8.5, filtering removal filtering residue after room temperature enzymolysis 5～6h must be without protein enzymatic hydrolyzate；Finally to above-mentioned without albumen
Adding its volume 1/10 mass concentration in enzymolysis solution is 30% hydrogenperoxide steam generator, at 20～25 DEG C stand oxidation processes 10～
Filter isolated oxidation solution after 12h, in oxidation solution, add its volume 1～dehydrated alcohol of 2 times, put into the frozen water of 4～6 DEG C
Bath staticly settles 6～8h, with horizontal centrifuge to obtain lower sediment, vacuum after 3000～5000r/min rotating speed centrifugations
I.e. obtain refined heparin sodium after drying.
Example 1
First weigh 40g expanded perlite respectively with concentration be 0.5mol/L sulfuric acid solution and 0.3mol/L sodium hydroxide solution leaching
Bubble 3h, moves into buchner funnel filtering and washing 20min, obtains the expanded perlite of surface modification；The most in mass ratio will for 5:3:1
Add the deionized water of three's cumulative volume 3 times after trypsin, alkaline protease and lipase mixing, proceed to true after stirring
Empty concentration tank, be concentrated into its original volume under 900Pa pressure 1/2 obtains complex enzyme liquid, is that above-mentioned surface is changed by 1:3 by solid-to-liquid ratio
Property expanded perlite immerse complex enzyme liquid, put into sonic oscillation instrument with 200W oscillation of power steeped overnight；Impregnate mistake after terminating
Filter isolated filtering residue, i.e. derives from preparing curable compound enzymic preparation with vacuum freeze-drying machine at-40 DEG C after lyophilizing；Next weigh
It is in 3% sodium chloride solution that 1kg crude heparin sodium is dissolved in 3 times of mass concentrations of its volume, filters removal filtering residue and obtain after stirring 10min
Filtrate, loads the filtrate obtained in pottery enzymatic vessel, adds filtrate gross mass 5% above-mentioned from preparing curable compound enzymic preparation,
Being that 0.1mol/L sodium hydroxide solution regulates pH to 7.5 by concentration, filtering removal filtering residue after room temperature enzymolysis 5h must be without proteolysis
Liquid；Finally to above-mentioned be 30% hydrogenperoxide steam generator without protein enzymatic hydrolyzate adds its volume 1/10 mass concentration, quiet at 20 DEG C
Filter isolated oxidation solution after putting oxidation processes 10h, in oxidation solution, add the dehydrated alcohol of its volume 1 times, put into 4 DEG C
Ice-water bath staticly settles 6h, with horizontal centrifuge to obtain lower sediment after 3000r/min rotating speed centrifugation, after vacuum drying
Obtain refined heparin sodium.
This example operation is easy, and the refined heparin sodium present invention prepared is prepared according to medical science, by embedding, sterilizing, bag
The regular injection agent preparation technologies such as dress, make hypodermic injection, during use, inject human body, every day morning and evening the most once,
Each consumption of being grown up is 15mg, and injection 3 days, after testing, are used as anticoagulant, antithrombotic reagent continuously, and therapeutic effect is notable, finally
The value recording anticoagulin a is 160IU/mg, and anticoagulation enzyme values is 0.65IU/mg.
Example 2
First weigh 45g expanded perlite respectively with concentration be 0.5mol/L sulfuric acid solution and 0.3mol/L sodium hydroxide solution leaching
Bubble 4h, moves into buchner funnel filtering and washing 25min, obtains the expanded perlite of surface modification；The most in mass ratio will for 5:3:1
Add the deionized water of three's cumulative volume 4 times after trypsin, alkaline protease and lipase mixing, proceed to true after stirring
Empty concentration tank, be concentrated into its original volume under 950Pa pressure 1/2 obtains complex enzyme liquid, is that above-mentioned surface is changed by 1:3 by solid-to-liquid ratio
Property expanded perlite immerse complex enzyme liquid, put into sonic oscillation instrument with 250W oscillation of power steeped overnight；Impregnate mistake after terminating
Filter isolated filtering residue, i.e. derives from preparing curable compound enzymic preparation with vacuum freeze-drying machine at-35 DEG C after lyophilizing；Next weigh
It is in 3% sodium chloride solution that 1.5kg crude heparin sodium is dissolved in 4 times of mass concentrations of its volume, filters and remove filtering residue after stirring 15min
Obtaining filtrate, the filtrate that will obtain loads in pottery enzymatic vessel, adds filtrate gross mass 8% above-mentioned from preparing curable compound enzyme system
Agent, is that 0.1mol/L sodium hydroxide solution regulates pH to 8.0 by concentration, and filtering removal filtering residue after room temperature enzymolysis 5.5h must be without albumen
Enzymolysis solution；Finally to above-mentioned be 30% hydrogenperoxide steam generator without protein enzymatic hydrolyzate adds its volume 1/10 mass concentration, at 23 DEG C
Filter isolated oxidation solution after lower standing oxidation processes 11h, in oxidation solution, add the dehydrated alcohol of its volume 1.5 times, put
Enter in the ice-water bath of 5 DEG C and staticly settle 7h, with horizontal centrifuge to obtain lower sediment after 4000r/min rotating speed centrifugation, very
Sky i.e. obtains refined heparin sodium after drying.
This example operation is easy, and the refined heparin sodium present invention prepared is prepared according to medical science, by embedding, sterilizing, bag
The regular injection agent preparation technologies such as dress, make hypodermic injection, during use, inject human body, every day morning and evening the most once,
Each consumption of being grown up is 18mg, and injection 4 days, after testing, are used as anticoagulant, antithrombotic reagent continuously, and therapeutic effect is notable, finally
The value recording anticoagulin a is 165IU/mg, and anticoagulation enzyme values is 0.7IU/mg.
Example 3
First weigh 50g expanded perlite respectively with concentration be 0.5mol/L sulfuric acid solution and 0.3mol/L sodium hydroxide solution leaching
Bubble 5h, moves into buchner funnel filtering and washing 30min, obtains the expanded perlite of surface modification；The most in mass ratio will for 5:3:1
Add the deionized water of three's cumulative volume 5 times after trypsin, alkaline protease and lipase mixing, proceed to true after stirring
Empty concentration tank, be concentrated into its original volume under 1000Pa pressure 1/2 obtains complex enzyme liquid, is that 1:3 is by above-mentioned surface by solid-to-liquid ratio
Modified expanded perlite immerses complex enzyme liquid, puts into sonic oscillation instrument with 300W oscillation of power steeped overnight；After dipping terminates
Filter isolated filtering residue, at-30 DEG C, after lyophilizing, i.e. derive from preparing curable compound enzymic preparation with vacuum freeze-drying machine；Next claim
Take 2kg crude heparin sodium being dissolved in 5 times of mass concentrations of its volume is in 3% sodium chloride solution, filters and remove filtering residue after stirring 20min
Obtaining filtrate, the filtrate that will obtain loads in pottery enzymatic vessel, adds filtrate gross mass 10% above-mentioned from preparing curable compound enzyme system
Agent, is that 0.1mol/L sodium hydroxide solution regulates pH to 8.5 by concentration, and filtering removal filtering residue after room temperature enzymolysis 6h must be without protease
Solve liquid；Finally to above-mentioned be 30% hydrogenperoxide steam generator without protein enzymatic hydrolyzate adds its volume 1/10 mass concentration, at 25 DEG C
Filter isolated oxidation solution after standing oxidation processes 12h, in oxidation solution, add the dehydrated alcohol of its volume 2 times, put into 6 DEG C
Ice-water bath in staticly settle 8h, with horizontal centrifuge with after 5000r/min rotating speed centrifugation lower sediment, vacuum drying
After i.e. obtain refined heparin sodium.
This example operation is easy, and the refined heparin sodium present invention prepared is prepared according to medical science, by embedding, sterilizing, bag
The regular injection agent preparation technologies such as dress, make hypodermic injection, during use, inject human body, every day morning and evening the most once,
Each consumption of being grown up is 20mg, and injection 5 days, after testing, are used as anticoagulant, antithrombotic reagent continuously, and therapeutic effect is notable, finally
The value recording anticoagulin a is 170IU/mg, and anticoagulation enzyme values is 0.75IU/mg.
Claims (1)
1. the preparation method of a refined heparin sodium, it is characterised in that concrete preparation process is:
(1) weigh 40～50g expanded perlites respectively with concentration be 0.5mol/L sulfuric acid solution and 0.3mol/L sodium hydroxide molten
Immersion bubble 3～5h, moves into buchner funnel filtering and washing 20～30min, obtains the expanded perlite of surface modification；
(2) three's cumulative volume 3～5 times are added after to be 5:3:1 in mass ratio mix trypsin, alkaline protease and lipase
Deionized water, proceed to vacuum concentration pot after stirring, under 900～1000Pa pressure, be concentrated into the 1/2 of its original volume
Complex enzyme liquid is 1:3 by solid-to-liquid ratio immerses complex enzyme liquid by the expanded perlite of above-mentioned surface modification, put into sonic oscillation instrument with
200～300W oscillation of power steeped overnight；
(3) filter isolated filtering residue after dipping terminates, at-40～-30 DEG C, after lyophilizing, i.e. obtain self-control with vacuum freeze-drying machine solid
Surely compound enzymic preparation is changed；
(4) weigh 1～2kg crude heparin sodium and be dissolved in its volume 3～5 times of mass concentrations are in 3% sodium chloride solution, stirring 10～
Filtering removal filtering residue after 20min and obtain filtrate, the filtrate that will obtain loads in pottery enzymatic vessel, adds filtrate gross mass 5～10%
Above-mentioned from preparing curable compound enzymic preparation, it is that 0.1mol/L sodium hydroxide solution regulates pH to 7.5～8.5, room temperature enzyme by concentration
Filtering removal filtering residue after solving 5～6h must be without protein enzymatic hydrolyzate；
(5) to above-mentioned be 30% hydrogenperoxide steam generator without protein enzymatic hydrolyzate adds its volume 1/10 mass concentration, at 20～25 DEG C
Filter isolated oxidation solution after lower standing oxidation processes 10～12h, in oxidation solution, add its volume 1～the anhydrous second of 2 times
Alcohol, puts into and staticly settles 6～8h in the ice-water bath of 4～6 DEG C, with horizontal centrifuge with centrifugal point of 3000～5000r/min rotating speeds
Obtain lower sediment after from, after vacuum drying, i.e. obtain refined heparin sodium.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810351A (en) * | 2016-12-23 | 2017-06-09 | 浙江海洋大学 | A kind of method that hydrolyzed aquatic products accessory substance prepares amino acid foliage fertilizer |
| CN107056365A (en) * | 2016-12-23 | 2017-08-18 | 浙江海洋大学 | A kind of amino acid foliage fertilizer preparation method planted for organic vegetable |
| CN107141372A (en) * | 2017-06-06 | 2017-09-08 | 淮安市双宝畜产有限公司 | The method of multiplex-enzyme extraction heparin |
| CN107267572A (en) * | 2017-08-10 | 2017-10-20 | 盐城盛大肠衣食品有限公司 | A kind of combined-enzyme method heparin sodium extracting technique |
| CN108456262A (en) * | 2018-03-13 | 2018-08-28 | 广元市海天实业有限责任公司 | A kind of preparation process of high purity heparin sodium |
| KR20190061322A (en) * | 2017-11-27 | 2019-06-05 | (주)우리비앤비 | Method for producing unfractionated heparin |
| CN111393542A (en) * | 2020-05-16 | 2020-07-10 | 青岛科技大学 | Novel method for refining crude heparin sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106810351A (en) * | 2016-12-23 | 2017-06-09 | 浙江海洋大学 | A kind of method that hydrolyzed aquatic products accessory substance prepares amino acid foliage fertilizer |
| CN107056365A (en) * | 2016-12-23 | 2017-08-18 | 浙江海洋大学 | A kind of amino acid foliage fertilizer preparation method planted for organic vegetable |
| CN107141372A (en) * | 2017-06-06 | 2017-09-08 | 淮安市双宝畜产有限公司 | The method of multiplex-enzyme extraction heparin |
| CN107267572A (en) * | 2017-08-10 | 2017-10-20 | 盐城盛大肠衣食品有限公司 | A kind of combined-enzyme method heparin sodium extracting technique |
| KR20190061322A (en) * | 2017-11-27 | 2019-06-05 | (주)우리비앤비 | Method for producing unfractionated heparin |
| KR102298179B1 (en) | 2017-11-27 | 2021-09-06 | (주)우리비앤비 | Method for producing unfractionated heparin |
| CN108456262A (en) * | 2018-03-13 | 2018-08-28 | 广元市海天实业有限责任公司 | A kind of preparation process of high purity heparin sodium |
| CN111393542A (en) * | 2020-05-16 | 2020-07-10 | 青岛科技大学 | Novel method for refining crude heparin sodium |
| CN111393542B (en) * | 2020-05-16 | 2021-11-05 | 青岛科技大学 | Novel method for refining crude heparin sodium |
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Application publication date: 20161109 |