CN102633905A - Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium - Google Patents
Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium Download PDFInfo
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- CN102633905A CN102633905A CN2011100895713A CN201110089571A CN102633905A CN 102633905 A CN102633905 A CN 102633905A CN 2011100895713 A CN2011100895713 A CN 2011100895713A CN 201110089571 A CN201110089571 A CN 201110089571A CN 102633905 A CN102633905 A CN 102633905A
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- heparin sodium
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- nitrous acid
- heparin
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Abstract
The invention discloses a removing method for a substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium, and particularly aims to remove a substance A similar to the heparin sodium in characteristics. The substance is resistant to nitrous acid degradation and is not degraded by the nitrous acid in unfractionated heparin sodium degradation. When related substances are checked, on the premise of achieving system suitability, other impurities except for dermatan sulfate, chondroitin sulfate and oversulfated chondroitin sulfate are not allowed to exist in a sample after heparin is degraded by nitrous acid according to requirements of a new edition of European Pharmacopoeia Standards for Heparin Sodium. If the impurity A is mixed in the heparin, when the related substances are detected, the sample degraded by the nitrous acid can have an impurity peak approximate to retention time of original heparin sodium. The substance A can be effectively prevented from being mixed into a heparin sodium crude product by controlling salinity and ethanol final concentration of ethanol precipitation during production of the heparin sodium, adding an ethanol eluting step and improving solid-liquid separation degree during ethanol precipitation, ethanol eluting and dehydration.
Description
Technical field
The present invention relates to the method for purification of heparin sodium, specifically be a kind of mode that adopts alcohol precipitation in the heparin sodium not by the nitrous acid degraded and near the heparin sodium RT, go out the material removal method at peak.
Background technology
Heparin sodium (Heparin Sodium) is a mucopolysaccharide sulfuric acid ester anticoagulant.Heparin sodium is the sodium salt of the CSSO3 that extracts in the intestines mucosa by pig, ox or sheep, belongs to the mucopolysaccharide material.Heparin is the maximum anticoagulation medicine of the most effective and clinical in the world consumption at present, is mainly used in cardiovascular and cerebrovascular diseases and hemodialysis, and it is unique effective specific medicament in hemodialysis.Clinical application and research show that heparin also has other multiple biological activity and clinical applications except that having blood coagulation resisting function, comprise effects such as reducing blood lipid, anti-middle film smooth muscle cell (SMC) hyperplasia, promotion fibrinolysis.In addition; Low molecular heparin is the one big type of antithrombotic medicine that further is processed into as raw material by the heparin bulk drug; Have clinical medicine purposes more widely, become the choice drug of acute phlebothrombosis of treatment and acute coronary artery syndrome diseases such as (stenocardia, myocardial infarctions).
Heparin is the most complicated compound of known molecular structures up to now in the world, in a short time can't artificial chemosynthesis, and the heparin that only derives from pig intestinal mucosa at present can be used in clinical treatment.The raw material of heparin bulk drug is a heparin sodium crude; Its extraction can only be derived from the mucous membrane of small intestine of healthy live pig; Owing to contain impurity such as a large amount of impurity albumen, impurity nucleic acid, mikrobe; Need through physics and chemical extraction sepn process, orientation is obtained the complete heparin sodium of natural structure group, thereby processes the heparin sodium bulk drug.The heparin sodium bulk drug is the unique effective constituent of standard heparin preparation and the production starting point of Low molecular heparin raw material, and this makes the heparin sodium bulk drug need very big purity.After the heparin incidents in 2008; European Pharmacopoeia Commission will improve the original standard of heparin sodium the end of the year 2009; Revised existing new edition heparin sodium European Pharmacopoeia standard, wherein increased related substance inspection item newly, what the present invention is directed to is the glucide that is suspected to be in this related substance.
Summary of the invention
The objective of the invention is to have the impurity of but not degraded in the heparin sodium by nitrous acid with the heparin sodium similar quality in order to satisfy the requirement of related substance inspection item in the new edition heparin sodium European Pharmacopoeia standard, to remove.
Technical scheme of the present invention is:
Near the removal of not degraded and the heparin sodium RT, going out the material at peak in a kind of heparin sodium by nitrous acid
Method is characterized in that: step is following:
A. the desorption liquid in workshop is carried out centrifugally, supernatant is squeezed into Alcohol-settling tank, regulate 15 °-20 ° of salinity, add
The ethanol of 90-98% mass and size concentration leaves standstill 8h at least, and control alcohol precipitation ethanol final concentration is 10-45%;
B. take out Alcohol-settling tank middle and upper part clear liquid with vacuum, the bottom adopts whizzer centrifugal, and solid sediment is gone into pure cask washing,
Adding the pre-prepd temperature that 5-20 doubly precipitates bulking value is 10-70 ℃, and concentration is that the warm ethanol of 15-50% carries out alcohol and washes, and churning time 10-60min makes solid precipitation and warm ethanol thorough mixing even;
C. adopt supercentrifuge that alcohol is washed appearance and carry out centrifugally, collect solid precipitation and go into the dehydration bucket;
D. the ethanol that in dehydration bucket, adds 90%-98% stirs and makes solid precipitation and high concentration ethanol thorough mixing equal
Even;
E. it is centrifugal to adopt supercentrifuge that dehydration appearance is carried out, and collects solid precipitation, promptly gets after the oven dry below 65 ℃ not contain
Not by nitrous acid degraded and near the heparin sodium RT, go out the heparin sodium of the material at peak.
Principle of work: what the present invention removed is similar glucide; Have and the similar structure and properties of heparin; Because it can not be degraded by nitrous acid; So this material and heparin difference are not exist in its structure can be by the action site of nitrous acid degraded, promptly the molecular weight of this material is less than heparin, so can remove this material through the control alcohol precipitation concentration.
Advantage of the present invention:
Report does not in the past all relate to the removal method of this type of impurity, and the present invention can effectively remove this impurity, can satisfy in the new edition heparin sodium European Pharmacopoeia standard in the end of the year 2009 near the heparin sodium RT, not go out the peak after the nitrous acid degraded in the related substance detection.This method is simple to operate, and effect is obvious, can carry out suitability for industrialized production.
Embodiment
Embodiment 1
The about 2000ml of a desorption liquid that picks up the car gets supernatant after centrifugal, complements to 2000ml with purified water, and fluid temperature records salinity when being 24 ℃ be 17 °, adds 93% edible ethanol 1540ml, stirs, and leaves standstill 8h.Centrifugal, 45% the ethanol of deposition with 30 ℃ is stirred, alcohol is washed.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 20.9g tires and is the heparin sodium crude of 79U/mg.
Embodiment 2
The about 2750ml of a desorption liquid that picks up the car gets supernatant after centrifugal, complements to 3000ml with purified water, and fluid temperature records salinity when being 19 ℃ be 17 °, adds 93% edible ethanol 1050ml, stirs, and leaves standstill 8h.Centrifugal, 35% the ethanol of deposition with 30 ℃ is stirred, alcohol is washed.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 17.1g tires and is the heparin sodium crude of 82.6U/mg.
Embodiment 3
The about 3000ml of a desorption liquid that picks up the car gets supernatant after centrifugal, complements to 3000ml with purified water, and fluid temperature records salinity when being 17 ℃ be 17 °, adds 93% edible ethanol 1950ml, stirs, and leaves standstill 8h.Centrifugal, 40% the ethanol of deposition with 30 ℃ is stirred, alcohol is washed.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 39g tires and is the heparin sodium crude of 75U/mg.
Claims (1)
- In the heparin sodium not by the nitrous acid degraded and near the heparin sodium RT, go out the removal method of the material at peak, it is characterized in that: step is following:A. the desorption liquid in workshop is carried out centrifugally, supernatant is squeezed into Alcohol-settling tank, regulate 15 °-20 ° of salinity, add the ethanol of 90-98% mass and size concentration, leave standstill 8h at least, control alcohol precipitation ethanol final concentration is 10-45%;B. take out Alcohol-settling tank middle and upper part clear liquid with vacuum; The bottom adopts whizzer centrifugal; Solid sediment is gone into pure cask washing, and adding the pre-prepd temperature that 5-20 doubly precipitates bulking value is 10-70 ℃, and concentration is that the warm ethanol of 15-50% carries out alcohol and washes; Churning time 10-60min makes solid precipitation and warm ethanol thorough mixing even;C. adopt supercentrifuge that alcohol is washed appearance and carry out centrifugally, collect solid precipitation and go into the dehydration bucket;D. the ethanol that in dehydration bucket, adds 90%-98% stirs and makes solid precipitation and high concentration ethanol thorough mixing even;E. it is centrifugal to adopt supercentrifuge that dehydration appearance is carried out, and collects solid precipitation, promptly gets after the oven dry below 65 ℃ not contain near the heparin sodium of not degraded by nitrous acid and the heparin sodium RT, going out the material at peak.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110089571.3A CN102633905B (en) | 2011-04-11 | 2011-04-11 | Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110089571.3A CN102633905B (en) | 2011-04-11 | 2011-04-11 | Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102633905A true CN102633905A (en) | 2012-08-15 |
| CN102633905B CN102633905B (en) | 2014-10-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110089571.3A Expired - Fee Related CN102633905B (en) | 2011-04-11 | 2011-04-11 | Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599801A (en) * | 1993-05-07 | 1997-02-04 | Choay S.A. | Purified heparin fractions, method for obtaining them and pharmaceutical compositions containing them |
| CN101762668A (en) * | 2009-12-24 | 2010-06-30 | 山东海科化工集团有限公司 | Method for quantitatively detecting dermatan sulfate in heparin |
-
2011
- 2011-04-11 CN CN201110089571.3A patent/CN102633905B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599801A (en) * | 1993-05-07 | 1997-02-04 | Choay S.A. | Purified heparin fractions, method for obtaining them and pharmaceutical compositions containing them |
| CN101762668A (en) * | 2009-12-24 | 2010-06-30 | 山东海科化工集团有限公司 | Method for quantitatively detecting dermatan sulfate in heparin |
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| CN102633905B (en) | 2014-10-08 |
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Application publication date: 20120815 Assignee: Nanjing King-friend Biochemical Pharmaceutical Co., Ltd. Assignor: Nantong Tianlong Animal By-Products Co., Ltd. Contract record no.: 2014320000750 Denomination of invention: Removing method for substance nondegradable by nitrous acid and peaking approximately to heparin sodium retention time in heparin sodium Granted publication date: 20141008 License type: Exclusive License Record date: 20141224 |
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Assignee: Nanjing King-friend Biochemical Pharmaceutical Co., Ltd. Assignor: Nantong Tianlong Animal By-Products Co., Ltd. Contract record no.: 2014320000750 Date of cancellation: 20151215 |
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