CN109280092A - A kind of method of purification of crude heparin sodium - Google Patents
A kind of method of purification of crude heparin sodium Download PDFInfo
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- CN109280092A CN109280092A CN201810465704.4A CN201810465704A CN109280092A CN 109280092 A CN109280092 A CN 109280092A CN 201810465704 A CN201810465704 A CN 201810465704A CN 109280092 A CN109280092 A CN 109280092A
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- 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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Abstract
The invention discloses a kind of methods of purification of crude heparin sodium, its object is to solve often to contain more impurity in existing crude heparin sodium, purity is lower, product quality is not high, it patent medicine is further purified increases difficulty to subsequent with heparin sodium, cause pharmaceutical heparin sodium product obtained often poor quality, it is difficult to the problem of meeting the requirements.The present invention dissolves crude heparin sodium, adsorbs, elutes, precipitates and is dried using pure physical method, is purified with cleaning to crude heparin sodium.For the present invention to crude heparin sodium good impurity removing effect, the crude heparin sodium purity after removal of impurities is higher, reduces the subsequent difficulty that patent medicine heparin sodium is further purified, it is ensured that final pharmaceutical heparin sodium product purity obtained is high, and quality is good.Operation is simple and reliable for purification process of the invention, at low cost, is suitble to industrialized production.
Description
Technical field
The present invention relates to heparin sodium purification technical field, in particular to a kind of method of purification of crude heparin sodium.
Background technique
Heparin sodium is also known as heparin, is a kind of natural anticoagulative substance of the acid mucopolysaccharides containing sulfate.Heparin sodium is
White or off-white powder, odorless, tasteless, have draw it is moist, it is soluble easily in water, it is organic molten insoluble in ethyl alcohol, acetone, dioxane etc.
Agent.
Heparin sodium is widely present in mammal liver, lung, in intestinal mucosa, and complex presence is mostly combined into protein.Enzyme
It solves albumen and separates heparin sodium, heparin sodium is the mucopolysaccharide of sulfur acid, amino, glycuronic acid.It is negatively charged in pH8-9, it can be with
Anionite carries out ion exchange, carries out crude separation, it is consummate that polysaccharide liquid precipitates progress in high concentration ethanol.Heparin sodium is
Best anti-coagulants in blood chemistry measurement.Heparin sodium is a kind of glutinous polysaccharide of sulfur-bearing acid groups, and molecular weight is 1.5 ten thousand,
Its anticoagulant mechanism be with anticoagulant enzyme II together, the effect between low concentration energy inhibiting factor Ⅸ a, VIII and PF3, and capable of reinforcing anti-
Fibrin ferment III inactivates serine protease, so that fibrin ferment be prevented to be formed；There are also inhibit fibrin ferment self catalysis and inhibit because
The effect of sub- X.
Currently, the crude heparin sodium of domestic production, wherein often containing more impurity, purity is lower, and product quality is not
Height, however the difficulty that these impurity remove in crude heparin sodium is larger, this increases the subsequent patent medicine heparin sodium that is further purified
Difficulty is added, pharmaceutical heparin sodium product obtained is often poor quality, it is difficult to meet the requirements.
A kind of crude heparin sodium of the disclosure of the invention of CN1844165A isolates and purifies the method for high purity heparin sodium, with thick
Product heparin sodium is raw material, produces high-purity by ion-exchange chromatography, potassium permanganate oxidation, ultrafiltration and organic solvent fractional precipitation
Heparin sodium bulk pharmaceutical chemicals.This method purifies crude heparin sodium using chemically treated method, this will destroy the molecule knot of heparin sodium
Structure, cause porcine heparin and ox, sheep heparin sodium etc. cannot be distinguished, and ox, the price of sheep heparin sodium and effectiveness often can not and pig
The price and effectiveness of heparin sodium compare favourably, and finally will be a greater impact to the medicinal effects of product in this way.
Summary of the invention
It is an object of the invention to solve often containing more impurity in existing crude heparin sodium, purity is lower, product
It is of low quality, it patent medicine is further purified increases difficulty to subsequent with heparin sodium, lead to pharmaceutical heparin sodium product obtained
It is often poor quality, it is difficult to which that the problem of meeting the requirements provides a kind of method of purification of crude heparin sodium, and the present invention uses pure object
Reason method cleans to crude heparin sodium, good impurity removing effect, and the crude heparin sodium purity after removal of impurities is higher, reduce it is subsequent into
The difficulty of one step purifying patent medicine heparin sodium, it is ensured that final pharmaceutical heparin sodium product purity obtained is high, and quality is good.The present invention
Method of purification operation is simple and reliable, it is at low cost, be suitble to industrialized production.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of method of purification of crude heparin sodium, specific step is as follows for the method for purification:
(1) it dissolves
The water of 10-12 times of crude heparin sodium weight is first added in dissolving tank, opens steam valve, heating, slurry is stirred in unlatching,
Crude heparin sodium dissolution is put into, temperature is controlled during dissolution at 60 DEG C hereinafter, crude heparin sodium must expect after being completely dissolved
Liquid；Crude heparin sodium is commercial product；
(2) it adsorbs
The pH value of feed liquid is adjusted in 7.0-7.5, then controls the temperature of feed liquid at 50-60 DEG C, adjust the salinity of feed liquid to
2.5-3.0 °, ROHM AND HAAS resin is added into feed liquid, adds 4.5-6kg ROHM AND HAAS tree by every hundred million international units crude heparin sodium
Rouge, after stirring and adsorbing 6 hours, the content of heparin sodium, detected value are less than 1.5U/ml, put in the feed liquid after sample detection absorption
Material collects resin；
Continue to adsorb if detected value is in 1.5U/ml or more；ROHM AND HAAS resin is specially ROHM AND HAAS FPA98 type tree
Rouge belongs to acrylic compounds strong-base anion-exchange resin；
(3) it elutes
The resin that step (2) are collected is poured into elution tank, 21 ± 1 ° of salinity of sodium chloride solution, sodium chloride solution is added
Additional amount be 1.2-1.5L sodium chloride solution is added in every kilogram resin meter, elution 3 more than hour is received under stirring condition
Collect eluent, is eluted 3-5 times according to the above elution action；
(4) it precipitates
Merge the eluent that step (3) are collected into, pours into settling tank, alcoholic strength is added under stirring condition into settling tank
85 ° or more of alcohol, alcohol dosage are subject to the alcoholic strength for surveying mixed liquor in settling tank to 50 ° -55 °, staticly settle 8-10
Hour, collect sediment；
(5) dry
The alcohol that the sediment that step (4) obtains is added 90 ° of alcoholic strength or more carries out suction filtration dehydration, does at drying after being filtered dry
Reason.
Inventor has found by long term production: being obtained using pig intestinal mucosa as raw material using salt solution, enzymatic isolation method thick
Product heparin sodium often contains more impurity, and purity is low, and usually in 70-80U/mg, such crude heparin sodium is difficult to potency
Meet requirement of the pharmaceutical heparin sodium manufacturing enterprise (pharmaceutical factory) to crude heparin sodium raw material.Since there are more in crude heparin sodium
Impurity, is the impurity that some conventional means are difficult to remove by it, and pharmaceutical heparin sodium manufacturing enterprise is past using conventional means of purification
Toward be difficult to obtain purity good, potency high pharmaceutical heparin sodium product, such larger impact product matter of pharmaceutical heparin sodium product
Amount, the medicinal effects of product are undesirable.Therefore pharmaceutical heparin sodium manufacturing enterprise proposes crude heparin sodium raw material higher
It is required that.
Inventor is the study found that the principal element for influencing the purification of pharmaceutical heparin sodium manufacturing enterprise is existed in crude heparin sodium
2.3 peak impurity, which gains the name because being shown in the position of 2.3ppm or so on nuclear magnetic resonance map.Either crude product liver
Plain sodium raw materials manufacturing enterprise or pharmaceutical heparin sodium manufacturing enterprise often not can be removed 2.3 peak impurity using conventional method,
The larger impact quality of pharmaceutical heparin sodium product in this way.
In technical solution of the present invention, the control of salinity is extremely crucial, and temperature lowers the salinity of material-saving liquid extremely at 50-60 DEG C
2.5-3.0 °, be influence removal of impurities success one of key factor, too high in salinity and it is too low all cannot be effective by 2.3 peak impurity
It removes.
Optimization of the present invention through inventor's years of researches and technology path is effectively removed using the method for pure physics
2.3 peak impurity present in crude heparin sodium, substantially increases the quality of crude heparin sodium, and the potency of crude heparin sodium is reachable
140U/mg or more, so that pharmaceutical heparin sodium manufacturing enterprise can be obtained the pharmaceutical heparin of high-quality under conventional purifying technique
Sodium product, improves drug effect and economic benefit.
Preferably, being reused after resin activated processing in step (2) absorption, it is activated are as follows: resin is with 50-60 DEG C
It is rinsed well and is drained with clear water after warm water immersion 20 hours or more, added the sodium hydroxide solution that mass concentration is 10% and stir
It is more than hour to mix 1, it is neutral for finally being rinsed with clear water to washing lotion pH, and the additional amount of the sodium hydroxide solution is every kilogram of tree
The meter of rouge addition 1L sodium hydroxide solution.Resin activated processing is conducive to improve adsorption effect, using activation of the invention
Method is conducive to acquisition preferably adsorption effect, the regeneration treatment simultaneously for resin and is also relatively easy to.
Preferably, resin adsorption after 2-3 time using needing to do regeneration treatment, regeneration treatment in step (2) absorption are as follows: set
The sodium hydroxide solution that rouge mass concentration is 10% impregnates and it is more than hour to stir 1, is finally rinsed with clear water to washing lotion pH
Drained and standby for neutrality, the additional amount of the sodium hydroxide solution is the meter that 1L sodium hydroxide solution is added in every kilogram resin.
Preferably, the resin after regeneration treatment can temporarily be immersed in (resin guarantor spare in 5 ° of salinity of salt water (sodium chloride solution)
It supports, making it when in use has optimal adsorption effect).
Preferably, during step (5) is dry, time of dehydration is filtered at 1 more than hour, the temperature of drying and processing is
60-70 DEG C, the time is 18 ± 2 hours.
The beneficial effects of the present invention are: the present invention purifies crude heparin sodium using pure physical method, impurity-eliminating effect
Good, the crude heparin sodium purity after removal of impurities is higher, reduces the subsequent difficulty that patent medicine heparin sodium is further purified, it is ensured that final
Pharmaceutical heparin sodium product purity obtained is high, and quality is good.Operation is simple and reliable for method of purification of the invention, at low cost, is suitble to
Industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance map before crude heparin sodium removal of impurities；
Fig. 2 is the enlarged drawing of Fig. 1；
Fig. 3 is the nuclear magnetic resonance map after crude heparin sodium removal of impurities.
Specific embodiment
Below by specific embodiment, and in conjunction with attached drawing, technical scheme of the present invention will be further explained in detail.
In the present invention, if not refering in particular to, used raw material and equipment etc. are commercially available or commonly used in the art.
Method in following embodiments is unless otherwise instructed the conventional method of this field.
Resin activated processing:
By new ROHM AND HAAS FPA98 type resin (commercially available import resin, the limited public affairs of dealer Beijing Bo Saisi biotechnology
Department) impregnated 20 hours with 50 DEG C of warm water after rinsed well and drained with clear water, add mass concentration as 10% sodium hydroxide
It is more than hour to stir 1 for solution, and it is neutral for finally being rinsed with clear water to washing lotion pH, and the additional amount of the sodium hydroxide solution is every
The meter of kilogram resin addition 1L sodium hydroxide solution.Studies have shown that the warm water temperature used in resin activated processing is in 50-60
Between DEG C, soaking time between 16-24 hours, the activation processing effect to resin be it is equivalent, do not do repeat one by one herein.
Embodiment 1:
(1) it dissolves
10 times of weight of crude heparin sodium (commercially available, Hangzhou Longyang Biotechnology Co., Ltd.'s production) is first added in dissolving tank
Water, open steam valve, heating, slurry is stirred in unlatching, and investment crude heparin sodium dissolution, control temperature is 60 during dissolution
DEG C hereinafter, crude heparin sodium be completely dissolved after feed liquid.
(2) it adsorbs
The pH value of feed liquid is adjusted 7.0, then controls the temperature of feed liquid at 50 DEG C, adjusts the salinity of feed liquid about to 3.0 °,
ROHM AND HAAS FPA98 type resin is added into feed liquid, adds 4.5kg ROHM AND HAAS FPA98 by every hundred million international units crude heparin sodium
Type resin, after stirring and adsorbing 6 hours, the content of heparin sodium, detected value are less than 1.5U/ in the feed liquid after sample detection absorption
Ml, blowing collect resin.If detected value in 1.5U/ml or more, continues to adsorb, until detected value is less than 1.5U/ml, then blowing is received
Collect resin, such separating effect is best.
(3) it elutes
The resin that step (2) are collected is poured into elution tank, 21 ± 1 ° of salinity of sodium chloride solution, sodium chloride solution is added
Additional amount be 1.2L sodium chloride solution is added in every kilogram resin meter, about 4 hours are eluted under stirring condition, collect elution
Liquid elutes 3 times according to the above elution action.
(4) it precipitates
Merge the eluent that step (3) are collected into, pours into settling tank, alcoholic strength is added under stirring condition into settling tank
85 ° or more of alcohol, alcohol dosage are subject to the alcoholic strength for surveying mixed liquor in settling tank to 50 ° or so, it is small to staticly settle 8
When, collect sediment.
(5) dry
The alcohol that the sediment that step (4) obtains is added 90 ° of alcoholic strength or more carries out filtering dehydration about 1 hour, after being filtered dry,
It is sent into an oven, is dried 16 hours at about 60 DEG C of temperature.
Through detecting, the potency > 140U/mg of the crude heparin sodium after present invention removal of impurities.
Embodiment 2:
(1) it dissolves
12 times of crude heparin sodium weight of water is first added in dissolving tank, opens steam valve, heating, slurry is stirred in unlatching, throws
Enter crude heparin sodium dissolution, temperature is controlled during dissolution at 60 DEG C hereinafter, crude heparin sodium obtains feed liquid after being completely dissolved.
(2) it adsorbs
The pH value of feed liquid is adjusted 7.5, then controls the temperature of feed liquid at 60 DEG C, adjusts the salinity of feed liquid about to 2.5 °,
ROHM AND HAAS FPA98 type resin is added into feed liquid, adds 6kg ROHM AND HAAS FPA98 type by every hundred million international units crude heparin sodium
Resin, after stirring and adsorbing 6 hours, the content of heparin sodium, detected value are less than 1.5U/ml in the feed liquid after sample detection absorption,
Blowing collects resin.If detected value in 1.5U/ml or more, continues to adsorb, until detected value is less than 1.5U/ml, then blowing is collected
Resin, such separating effect are best.
(3) it elutes
The resin that step (2) are collected is poured into elution tank, 21 ± 1 ° of salinity of sodium chloride solution, the addition of salt water is added
Amount is the meter that 1.5L salt water is added in every kilogram resin, and about 3 hours are eluted under stirring condition, eluent is collected, according to above
Elution action elutes 5 times.
(4) it precipitates
Merge the eluent that step (3) are collected into, pours into settling tank, alcoholic strength is added under stirring condition into settling tank
85 ° or more of alcohol, alcohol dosage are subject to the alcoholic strength for surveying mixed liquor in settling tank to 55 ° or so, it is small to staticly settle 10
When, collect sediment.
(5) dry
The alcohol that the sediment that step (4) obtains is added 90 ° of alcoholic strength or more carries out filtering dehydration about 1.5 hours, is filtered dry
Afterwards, it is sent into an oven, is dried 20 hours at about 70 DEG C of temperature.
Through detecting, the potency > 140U/mg of the crude heparin sodium after present invention removal of impurities.
Embodiment 3:
(1) it dissolves
11 times of crude heparin sodium weight of water is first added in dissolving tank, opens steam valve, heating, slurry is stirred in unlatching, throws
Enter crude heparin sodium dissolution, temperature is controlled during dissolution at 60 DEG C hereinafter, crude heparin sodium obtains feed liquid after being completely dissolved.
(2) it adsorbs
The pH value of feed liquid is adjusted 7.2, then controls the temperature of feed liquid at 55 DEG C, adjusts the salinity of feed liquid about to 3.0 °,
ROHM AND HAAS FPA98 type resin is added into feed liquid, adds 5kg ROHM AND HAAS FPA98 type by every hundred million international units crude heparin sodium
Resin, after stirring and adsorbing 6 hours, the content of heparin sodium, detected value are less than 1.5U/ml in the feed liquid after sample detection absorption,
Blowing collects resin.If detected value in 1.5U/ml or more, continues to adsorb, until detected value is less than 1.5U/ml, then blowing is collected
Resin, such separating effect are best.
(3) it elutes
The resin that step (2) are collected is poured into elution tank, 21 ± 1 ° of salinity of sodium chloride solution, the addition of salt water is added
Amount is the meter that 1.3L salt water is added in every kilogram resin, and about 3 hours are eluted under stirring condition, eluent is collected, according to above
Elution action elutes 3 times.
(4) it precipitates
Merge the eluent that step (3) are collected into, pours into settling tank, alcoholic strength is added under stirring condition into settling tank
85 ° or more of alcohol, alcohol dosage are subject to the alcoholic strength for surveying mixed liquor in settling tank to 52 ° or so, it is small to staticly settle 9
When, collect sediment.
(5) dry
The alcohol that the sediment that step (4) obtains is added 90 ° of alcoholic strength or more carries out filtering dehydration about 1 hour, after being filtered dry,
It is sent into an oven, is dried 18 hours at about 65 DEG C of temperature.
Through detecting, the potency > 140U/mg of the crude heparin sodium after present invention removal of impurities.
In technique of the invention, resin adsorption (does regeneration treatment after 2 times or 3 times using regeneration treatment is done after 2 times or 3 times
Effect is equivalent), regeneration treatment are as follows: the sodium hydroxide solution that resin mass concentration is 10% impregnates and it is more than hour to stir 1,
It is neutral for finally being rinsed with clear water to washing lotion pH, and drained and standby, the additional amount of sodium hydroxide solution is that 1L is added in every kilogram resin
The meter of sodium hydroxide solution.
Nuclear magnetic resonance map of the crude heparin sodium before removal of impurities and after removal of impurities is shown in Fig. 1 and Fig. 3 (parameter setting of nuclear magnetic resonance
Are as follows: frequency: 500MHz, pulse: no less than 16, pulse width: 90 degree,
Sampling time: at least 1 second, the pulse spacing: 20 seconds, spectral window: 8000Hz), find out from Fig. 1, Fig. 2, crude product
Obviously in the position of 2.3ppm or so, there are impurity peaks (having 2.3 peak impurity) before removal of impurities for heparin sodium, and from Fig. 3
Out, after technique removal of impurities of the invention, 2.3 peaks of crude heparin sodium are disappeared, i.e., 2.3 peak impurity effectively remove.
Crude product compared with the potency of existing commercially available crude heparin sodium 70-80U/mg, after technique removal of impurities of the invention
Titer of heparin sodium is in 140U/mg or more, good impurity removing effect of the invention, reduces the subsequent patent medicine heparin sodium that is further purified
Difficulty, it is ensured that final pharmaceutical heparin sodium product purity obtained is high, and quality is good.Method of purification of the invention is easy to operate can
It leans on, it is at low cost, it is suitble to industrialized production.
Above-mentioned embodiment is only a preferred solution of the present invention, not the present invention is made in any form
Limitation, there are also other variations and modifications on the premise of not exceeding the technical scheme recorded in the claims.
Claims (3)
1. a kind of method of purification of crude heparin sodium, it is characterised in that: specific step is as follows for the method for purification:
(1) it dissolves
The water of 10-12 times of crude heparin sodium weight is first added in dissolving tank, opens steam valve, heating, slurry is stirred in unlatching, puts into
Crude heparin sodium dissolution controls temperature at 60 DEG C hereinafter, crude heparin sodium obtains feed liquid after being completely dissolved during dissolution；
(2) it adsorbs
The pH value of feed liquid is adjusted in 7.0-7.5, then controls the temperature of feed liquid at 50-60 DEG C, adjusts the salinity of feed liquid to 2.5-
3.0 °, ROHM AND HAAS resin is added into feed liquid, adds 4.5-6kg ROHM AND HAAS resin by every hundred million international units crude heparin sodium,
After stirring and adsorbing 6 hours, the content of heparin sodium in the feed liquid after sample detection absorption, detected value is less than 1.5U/ml, and blowing is received
Collect resin；
(3) it elutes
The resin that step (2) are collected is poured into elution tank, 21 ± 1 ° of salinity of sodium chloride solution is added, sodium chloride solution adds
Entering amount is the meter that 1.2-1.5L sodium chloride solution is added in every kilogram resin, and more than hour, collection is washed for elution 3 under stirring condition
De- liquid, elutes 3-5 times according to the above elution action；
(4) it precipitates
Merge the eluent that step (3) are collected into, pour into settling tank, is added 85 ° of alcoholic strength under stirring condition into settling tank
Above alcohol, alcohol dosage are subject to the alcoholic strength for surveying mixed liquor in settling tank to 50 ° -55 °, it is small to staticly settle 8-10
When, collect sediment；
(5) dry
The alcohol that the sediment that step (4) obtains is added 90 ° of alcoholic strength or more carries out suction filtration dehydration, and drying and processing is done after being filtered dry i.e.
It can；The time being dehydrated is filtered at 1 more than hour, the temperature of drying and processing is 60-70 DEG C, and the time is 18 ± 2 hours.
2. the method for purification of crude heparin sodium according to claim 1, it is characterised in that: in step (2) absorption, resin is living
It reuses, is activated after change processing are as follows: resin is rinsed well and dripped with clear water after being impregnated 16-24 hours with 50-60 DEG C of warm water
It is dry, it adds the sodium hydroxide solution that mass concentration is 10% and it is more than hour to stir 1, finally rinsed with clear water to washing lotion pH and be
Neutrality, the additional amount of the sodium hydroxide solution are the meter that 1L sodium hydroxide solution is added in every kilogram resin.
3. the method for purification of crude heparin sodium according to claim 1, it is characterised in that: in step (2) absorption, resin is inhaled
It needs to do regeneration treatment, regeneration treatment after attached use 2-3 times are as follows: the sodium hydroxide solution that resin mass concentration is 10% impregnates simultaneously
It is more than hour to stir 1, finally being rinsed with clear water is neutral, drained and standby, the addition of the sodium hydroxide solution to washing lotion pH
Amount is the meter that 1L sodium hydroxide solution is added in every kilogram resin.
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| CN201810465704.4A CN109280092A (en) | 2018-05-16 | 2018-05-16 | A kind of method of purification of crude heparin sodium |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810465704.4A CN109280092A (en) | 2018-05-16 | 2018-05-16 | A kind of method of purification of crude heparin sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276473A (en) * | 2020-09-27 | 2022-04-05 | 上海帕尼生物科技有限公司 | Refined heparin sodium product and extraction method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891842A (en) * | 2010-07-16 | 2010-11-24 | 杭州龙扬生物科技有限公司 | Process for producing heparin sodium |
| CN102746421A (en) * | 2012-05-23 | 2012-10-24 | 杭州龙扬生物科技有限公司 | Impurity removing technology of crude heparin sodium |
| CN104072635A (en) * | 2014-03-07 | 2014-10-01 | 常山生化药业（江苏）有限公司 | Method for preparing dalteparin sodium in purifying manner by using anion exchange resin |
| CN107216412A (en) * | 2017-08-10 | 2017-09-29 | 如皋市永兴肠衣有限公司 | The Hydrolysis kinetics technology of liquaemin in pig intestinal mucosa |
-
2018
- 2018-05-16 CN CN201810465704.4A patent/CN109280092A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891842A (en) * | 2010-07-16 | 2010-11-24 | 杭州龙扬生物科技有限公司 | Process for producing heparin sodium |
| CN102746421A (en) * | 2012-05-23 | 2012-10-24 | 杭州龙扬生物科技有限公司 | Impurity removing technology of crude heparin sodium |
| CN104072635A (en) * | 2014-03-07 | 2014-10-01 | 常山生化药业（江苏）有限公司 | Method for preparing dalteparin sodium in purifying manner by using anion exchange resin |
| CN107216412A (en) * | 2017-08-10 | 2017-09-29 | 如皋市永兴肠衣有限公司 | The Hydrolysis kinetics technology of liquaemin in pig intestinal mucosa |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276473A (en) * | 2020-09-27 | 2022-04-05 | 上海帕尼生物科技有限公司 | Refined heparin sodium product and extraction method and application thereof |
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