CN109232773A - The preparation method of heparin lithium - Google Patents
The preparation method of heparin lithium Download PDFInfo
- Publication number
- CN109232773A CN109232773A CN201811440914.4A CN201811440914A CN109232773A CN 109232773 A CN109232773 A CN 109232773A CN 201811440914 A CN201811440914 A CN 201811440914A CN 109232773 A CN109232773 A CN 109232773A
- Authority
- CN
- China
- Prior art keywords
- heparin
- lithium
- heparin lithium
- preparation
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Sustainable Development (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to biochemical pharmacy fields, disclose a kind of preparation method of heparin lithium, using heparin sodium as raw material, heparin lithium is converted to by ion exchange under low temperature, the heparin lithium concentrate obtained by ultrafiltration, under control appropriate solution concentration, temperature and ionic strength conditions, organic solvent, which is added, using compartment in batches makes heparin lithium in colloidal precipitation, gained heparin lithium product purity is high, quality is stablized, at low cost；Preparation method of the invention forms heparin lithium colloidal precipitation and avoids the viscous glutinous equipment inner wall of product, improves production efficiency.Process conditions environmental protection；Cation resin method dynamic ion-exchange process carries out under cryogenic, and reduction has heparin activity loss, and the rate of recovery reaches 97% or more, and product potency reaches 180IU/mg or more.
Description
Technical field
The present invention relates to biochemical pharmacy field, in particular to a kind of preparation method of heparin lithium.
Background technique
Heparin is mainly extracted from intestinal mucosa, is one kind by gucosamine, L- idose aldehyde glycosides, N-Acetyl-D-glucosamine
The glutinous Alginic Sodium Diester alternately formed with D-Glucose aldehydic acid.Heparin is a kind of natural anticoagulative substance, by with anticoagulation
Enzyme III, which is combined, makes it expose arginine reaction center, its inactivation is made in conjunction with the coagulation factor of activation, main to inactivate Xa and IIa
The factor.Heparin is mainly used for preventing and treating thrombotic disease, as myocardial infarction, pulmonary embolism, cerebral vessels embolism, periphery are quiet
Arteries and veins thrombus etc., can anti-tampon formation and expansion.Can also be used in DIC early stage and other inside and outsides it is anticoagulant.
Heparin lithium has better anticoagulating active than heparin sodium, has unique value in clinical examination, is widely used in urgency
Examine biochemical analysis, the acquisition of blood preparation of lectin from hemolymph inspection and anticoagulant.Serum is precipitated since blood is retracted to solidification from human body
The time for generally requiring one hour or more seriously affects emergency treatment result report time, therefore clinical emergency often uses heparin anti-coagulating
Slurry carries out biochemical analysis.When examining the sodium ion in blood specimen, to avoid influencing testing result, commonly uses heparin lithium and replace.This
Outside, heparin lithium or the ideal anti-coagulants of erythrocyte infiltration test.
Currently, the preparation of heparin lithium is prepared as raw material, by sodium ion with exchanging for lithium ion using heparin sodium, ion
Heparin lithium solution after exchange generallys use freeze-drying or intermediate processing obtains product.And desivac is at high cost and is unsuitable for scale life
It produces.Since lithium ion molecular weight is small in the precipitation method, density, viscosity are small, and heparin lithium is assembled when organic solvent is added in heparin lithium solution
Settling velocity is slower, and needs to be added the organic solvent compared with high magnification numbe, and impurity is easy Precipitation, therefore influences product quality,
And heparin lithium molecular weight, in 3000 ~ 50000 dalton, the heparin lithium aggregate and precipitate of each segment molecule amount is inconsistent.Simultaneously precipitating by
In having viscosity, causes precipitating to be easy to stick at production equipment inner wall, influence production efficiency.
Summary of the invention
Goal of the invention: aiming at the problems existing in the prior art, the present invention provides a kind of preparation method of heparin lithium, it is intended to
The preparation cost for reducing heparin lithium promotes the quality and yield of product, improves production efficiency.
Technical solution: the present invention provides a kind of preparation methods of heparin lithium, which comprises the following steps:
S1: at 0 ~ 5 DEG C, by heparin sodium aqua by cation exchange resin column, acid efflux is collected；S2: it is adjusted using LiOH
The pH of the acidity efflux is 6 ~ 7, obtains heparin lithium solution；S3: the heparin lithium solution is concentrated by ultrafiltration, and chlorination is added
Lithium or lithium acetate, which are sufficiently stirred, dissolves to obtain heparin lithium salt solution；S4: slow into the heparin lithium salt solution at interval of 0.5 ~ 3h
The organic solvent of 1 ~ 2 times of its volume is added in stirring, until the final additional amount of the organic solvent is 3 ~ 10 times of its volume, obtains
Mixed liquor；S5: the mixed liquor is stood into 2 ~ 12h, removes upper layer mother liquor, isolates heparin lithium colloidal precipitation；S6: to the liver
The organic solvent is added in plain lithium colloidal precipitation to be dehydrated, 60 ~ 70 DEG C dry to obtain High-purity heparin lithium finished product.
Preferably, in the S1, the mass concentration of the heparin sodium aqua is 10 ~ 20%.
Preferably, in the S1, the resin cation is 732 resin cations, is h type resin.
Preferably, in the S2, the mass fraction of the LiOH is 10 ~ 30%.
Preferably, in the S3, mass fraction of the heparin lithium solution after being concentrated by ultrafiltration is 5 ~ 20%.
Preferably, in the S3, the volume that the lithium chloride or lithium acetate is added is the 5 of the heparin lithium liquor capacity
~15%。
Preferably, in the S4, the heparin lithium salt solution is first warming up to 30 ~ 50 DEG C, then thereto described in addition
Organic solvent.
Preferably, the organic solvent be it is following any one or combinations thereof: ethyl alcohol, methanol, acetone, isopropanol.
The utility model has the advantages that the advantages of present invention has compared with prior art are as follows: the present invention is using heparin sodium as raw material, under low temperature
Be converted to heparin lithium by ion exchange, the heparin lithium concentrate obtained by ultrafiltration, control appropriate solution concentration, temperature and
Under ionic strength conditions, organic solvent, which is added, using compartment in batches makes the heparin lithium of different molecular weight section be in colloidal precipitation,
The higher heparin lithium of molecular weight is initially formed colloidal precipitation.Dispersion should be avoided to have been formed as far as possible when organic solvent is added in stirring
Heparin lithium colloid, gained heparin lithium product purity is high, quality is stablized, at low cost；Preparation method of the invention forms heparin lithium
Colloidal precipitation is gathered in device bottom in fluid state, avoids the viscous glutinous equipment inner wall of product, improves production efficiency.Process conditions
Environmental protection；Cation resin method dynamic ion-exchange process carries out at low temperature, and reduction has heparin activity loss, and the rate of recovery reaches
97% or more, product potency reaches 180IU/mg or more.
Specific embodiment
The present invention is described in detail With reference to embodiment.
Embodiment 1:
It takes 100 grams of heparin sodiums to be dissolved in 1000ml purified water, is sufficiently stirred and dissolves to obtain heparin sodium aqua；By gained heparin sodium aqua
2 DEG C are cooled to, by 732 type cation exchange resin columns under low temperature, the pH of acid efflux starts to collect less than 5,2 DEG C of purifying
Water cleans resin, and acid efflux pH stops collecting when being greater than 5, and the LiOH that acid efflux mass fraction is 30% adjusts pH
To 6 ~ 7, heparin lithium solution is obtained；Heparin lithium solution is concentrated by ultrafiltration to 500ml, and 25 grams lithium chlorides are added, is sufficiently stirred molten
Solve heparin lithium salt solution；Heparin lithium salt solution is warming up to 30 DEG C, is added with stirring the ethyl alcohol of 500ml 95%, stands 0.5h
Obtain mixed liquor 1；Then it is slowly stirred the ethyl alcohol that 500ml 95% is slowly added in lower continuation into mixed liquor 1, is stood after mixing
0.5h obtains mixed liquor 2；Such recurrence interval formula operation makes heparin lithium in colloidal form until the ethyl alcohol of 5000ml 95% is added
Precipitating, obtains mixed liquor N；Mixed liquor N is stood into 12h, removes upper layer mother liquor, isolates heparin lithium colloidal precipitation；To heparin lithium glue
It is added ethanol dehydration 2 times in body precipitating, 60 DEG C dry to obtain 89 grams of High-purity heparin lithium finished product.
The performance indexes of heparin lithium finished product obtained by present embodiment are as follows: potency 192IU/mg, lithium content 3.6%, no sulphur
The impurity such as sour dermatan, chondroitin and chondroitin polysulfate.
Embodiment 2:
It takes 100 grams of heparin sodiums to be dissolved in 1000ml purified water, is sufficiently stirred and dissolves to obtain heparin sodium aqua；By gained heparin sodium aqua
5 DEG C are cooled to, by 732 type cation exchange resin columns under low temperature, the pH of acid efflux starts to collect less than 5,5 DEG C of purifying
Water cleans resin, and acid efflux pH stops collecting when being greater than 5, and the LiOH that acid efflux mass fraction is 10% adjusts pH
To 6 ~ 7, heparin lithium solution is obtained；Heparin lithium solution is concentrated by ultrafiltration to 900ml, and 90 grams lithium chlorides are added, is sufficiently stirred molten
Solve heparin lithium salt solution；Heparin lithium salt solution is warming up to 40 DEG C, is added with stirring the ethyl alcohol of 1350ml95%, 1h is stood and obtains
Mixed liquor 1；Then it is slowly stirred the ethyl alcohol that 1350ml 95% is slowly added in lower continuation into mixed liquor 1, is stood after mixing
1h obtains mixed liquor 2；Such recurrence interval formula operation makes heparin lithium sink in colloidal form until the ethyl alcohol of 7200ml 95% is added
It forms sediment, obtains mixed liquor N；Mixed liquor N is stood into 12h, removes upper layer mother liquor, isolates heparin lithium colloidal precipitation；To heparin lithium colloid
It is added in precipitating ethanol dehydration 2 times, 60 DEG C dry to obtain 91 grams of High-purity heparin lithium finished product.
The performance indexes of heparin lithium finished product obtained by present embodiment are as follows: potency 189IU/mg, lithium content 3.8%, no sulphur
The impurity such as sour dermatan, chondroitin and chondroitin polysulfate.
Embodiment 3:
It takes 100 grams of heparin sodiums to be dissolved in 1000ml purified water, is sufficiently stirred and dissolves to obtain heparin sodium aqua；By gained heparin sodium aqua
3 DEG C are cooled to, by 732 type cation exchange resin columns under low temperature, the pH of acid efflux starts to collect less than 5,3 DEG C of purifying
Water cleans resin, and acid efflux pH stops collecting when being greater than 5, and the LiOH that acid efflux mass fraction is 20% adjusts pH
To 6 ~ 7, heparin lithium solution is obtained；Heparin lithium solution is concentrated by ultrafiltration to 600ml, and 90 grams lithium chlorides are added, is sufficiently stirred molten
Solve heparin lithium salt solution；Heparin lithium salt solution is warming up to 50 DEG C, is added with stirring the ethyl alcohol of 600ml 95%, 3h is stood and obtains
Mixed liquor 1；Then it is slowly stirred the ethyl alcohol that 600ml 95% is slowly added in lower continuation into mixed liquor 1, stands 3h after mixing
Obtain mixed liquor 2；Such recurrence interval formula operation precipitates heparin lithium in colloidal form until the ethyl alcohol of 3000ml 95% is added,
Obtain mixed liquor N；Mixed liquor N is stood into 12h, removes upper layer mother liquor, isolates heparin lithium colloidal precipitation；To heparin lithium colloidal precipitation
Middle addition ethanol dehydration 2 times, 70 DEG C dry to obtain 91.5 grams of High-purity heparin lithium finished product.
The performance indexes of heparin lithium finished product obtained by present embodiment are as follows: potency 190IU/mg, lithium content 3.9%, no sulphur
The impurity such as sour dermatan, chondroitin and chondroitin polysulfate.
The technical concepts and features of above embodiment only to illustrate the invention, its object is to allow be familiar with technique
People cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done, should be covered by the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of heparin lithium, which comprises the following steps:
S1: at 0 ~ 5 DEG C, by heparin sodium aqua by cation exchange resin column, acid efflux is collected；
S2: the pH that the acid efflux is adjusted using LiOH is 6 ~ 7, obtains heparin lithium solution；
S3: the heparin lithium solution is concentrated by ultrafiltration, and be added lithium chloride or lithium acetate be sufficiently stirred dissolve heparin lithium salts is molten
Liquid；
S4: being slowly stirred the organic solvent that 1 ~ 2 times of its volume is added at interval of 0.5 ~ 3h into the heparin lithium salt solution, until
The final additional amount of the organic solvent is 3 ~ 10 times of its volume, obtains mixed liquor；
S5: the mixed liquor is stood into 2 ~ 12h, removes upper layer mother liquor, isolates heparin lithium colloidal precipitation；
S6: being added the organic solvent into the heparin lithium colloidal precipitation and be dehydrated, and 60 ~ 70 DEG C dry to obtain High-purity heparin
Lithium finished product.
2. the preparation method of heparin lithium described according to claim 1, which is characterized in that in the S1, the heparin sodium is molten
The mass fraction of liquid is 10 ~ 20%.
3. the preparation method of heparin lithium described according to claim 1, which is characterized in that in the S1, the cation tree
Rouge is 732 resin cations, is h type resin.
4. the preparation method of heparin lithium described according to claim 1, which is characterized in that in the S2, the matter of the LiOH
Measuring score is 10 ~ 30%.
5. the preparation method of heparin lithium according to claim 1, which is characterized in that in the S3, the heparin lithium is molten
Mass fraction of the liquid after being concentrated by ultrafiltration is 5 ~ 20%.
6. the preparation method of heparin lithium according to claim 1, which is characterized in that in the S3, the chlorination is added
The volume of lithium or lithium acetate is the 5 ~ 15% of the heparin lithium liquor capacity.
7. the preparation method of heparin lithium described according to claim 1, which is characterized in that in the S4, first by the heparin
Lithium salt solution is warming up to 30 ~ 50 DEG C, then the organic solvent is added thereto.
8. the preparation method of heparin lithium according to any one of claim 1 to 7, which is characterized in that the organic solvent
For it is following any one or combinations thereof: ethyl alcohol, methanol, acetone, isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811440914.4A CN109232773A (en) | 2018-11-29 | 2018-11-29 | The preparation method of heparin lithium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811440914.4A CN109232773A (en) | 2018-11-29 | 2018-11-29 | The preparation method of heparin lithium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109232773A true CN109232773A (en) | 2019-01-18 |
Family
ID=65073747
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811440914.4A Withdrawn CN109232773A (en) | 2018-11-29 | 2018-11-29 | The preparation method of heparin lithium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109232773A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580789A (en) * | 1993-01-27 | 1996-12-03 | American Home Products Corporation | Method for collecting blood |
| CN1760215A (en) * | 2005-11-21 | 2006-04-19 | 武汉理工大学 | Exchange method of ionic equilibriom for heparin lithium |
| CN102617756A (en) * | 2012-03-23 | 2012-08-01 | 武汉博锐通科技有限公司 | Preparation method of heparin lithium |
| CN102952203A (en) * | 2011-08-25 | 2013-03-06 | 苏州鸿洋医药科技有限公司 | Method for preparing heparin lithium by ion-exchange resin method |
| CN103209997A (en) * | 2010-09-14 | 2013-07-17 | 国立大学法人宫崎大学 | High purity heparin and production method therefor |
| CN103601820A (en) * | 2013-10-31 | 2014-02-26 | 安徽工贸职业技术学院 | Preparation method of heparin lithium |
-
2018
- 2018-11-29 CN CN201811440914.4A patent/CN109232773A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580789A (en) * | 1993-01-27 | 1996-12-03 | American Home Products Corporation | Method for collecting blood |
| CN1760215A (en) * | 2005-11-21 | 2006-04-19 | 武汉理工大学 | Exchange method of ionic equilibriom for heparin lithium |
| CN103209997A (en) * | 2010-09-14 | 2013-07-17 | 国立大学法人宫崎大学 | High purity heparin and production method therefor |
| CN102952203A (en) * | 2011-08-25 | 2013-03-06 | 苏州鸿洋医药科技有限公司 | Method for preparing heparin lithium by ion-exchange resin method |
| CN102617756A (en) * | 2012-03-23 | 2012-08-01 | 武汉博锐通科技有限公司 | Preparation method of heparin lithium |
| CN103601820A (en) * | 2013-10-31 | 2014-02-26 | 安徽工贸职业技术学院 | Preparation method of heparin lithium |
Non-Patent Citations (1)
| Title |
|---|
| 周东坡等: "《生物制品学（第1版）》", 31 May 2007, 化学工业出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102775523B (en) | Process for preparing high-purity low-molecular heparin sodium | |
| JP5848240B2 (en) | Crystalline sulfated cellulose II and its production from sulfuric acid hydrolysis of cellulose | |
| CN102050888B (en) | Method for preparing enoxaparin sodium | |
| CN101182495B (en) | Joint production process for producing alkaline phosphatase and heparin sodium with pig small intestine as raw material | |
| WO2017032276A1 (en) | Bovine intestinal mucosa enoxaparin sodium, preparation method therefor, and application thereof | |
| CN101735336A (en) | Oligomeric fucosylated glycosaminoglycan and preparation method thereof | |
| CN106589167B (en) | The preparation method and its process units of high-titer crude heparin sodium | |
| CN105399867A (en) | Preparation method for heparin sodium | |
| CN107759712A (en) | The LMWHs in sheep source and preparation method and application | |
| CN106883321B (en) | A method of extracting Sulodexide bulk pharmaceutical chemicals from heparin sodium by-product | |
| US20100151438A1 (en) | Methods and kits for enhancing sedimentation and recovery of cells in a sample | |
| CN112940150A (en) | Method for preparing heparin calcium from heparin sodium | |
| RU2670767C1 (en) | Method for producing low molecular weight heparin | |
| CN102952203A (en) | Method for preparing heparin lithium by ion-exchange resin method | |
| CN104829750A (en) | Refining process of heparin lithium | |
| CN109232773A (en) | The preparation method of heparin lithium | |
| CN1308351C (en) | Exchange method of ionic equilibriom for heparin lithium | |
| US7396923B2 (en) | Method for the sulfonation of compounds comprising free hydroxyl (OH) groups or primary or secondary amines | |
| CN101605549A (en) | The heparin, its preparation and the purposes that comprise the covalent bond of at least one and biotin or biotin derivative | |
| CN104004109B (en) | Ocean Sulfation glycosaminoglycans SE-3 and preparation method thereof | |
| CN102603910B (en) | Preparation method of pachyman sulfate | |
| CN113754795B (en) | Sulfonated hyaluronic acid compound, preparation method and application thereof | |
| CN109734824A (en) | A kind of N- succinyl group chitosan C-6 selective oxidation derivative and its preparation method and application | |
| CN109485749A (en) | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium | |
| CN102585034B (en) | Method for sulfonating pectin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20190118 |
|
| WW01 | Invention patent application withdrawn after publication |