CN102633905B - 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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- CN102633905B CN102633905B CN201110089571.3A CN201110089571A CN102633905B CN 102633905 B CN102633905 B CN 102633905B CN 201110089571 A CN201110089571 A CN 201110089571A CN 102633905 B CN102633905 B CN 102633905B
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- heparin sodium
- ethanol
- 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 a kind of mode that adopts alcohol precipitation is not near being degraded by nitrous acid and go out the material removal method at peak heparin sodium retention time in heparin sodium.
Background technology
Heparin sodium (Heparin Sodium) is mucopolysaccharide sulfuric acid ester anticoagulant.Heparin sodium is the sodium salt of the CSSO3 extracted in the intestinal mucosa of pig, ox or sheep, belongs to mucopolysaccharide material.At present heparin is in the world the most effectively and the anticoagulation medicine of quantity maximum, is mainly used in cardiovascular and cerebrovascular diseases and hemodialysis, and it is unique effective specific medicament in hemodialysis.Clinical application and studies show that, heparin, except having blood coagulation resisting function, also has other multiple biological activity and clinical applications, comprise reducing blood lipid, anti-in film smooth muscle cell (SMC) hyperplasia, promote the effects such as fibrinolysis.In addition, Low molecular heparin is the antithrombotic medicine of a large class being further processed into as raw material by heparin bulk drug, there is clinical medicine purposes more widely, become the choice drug of the diseases such as treatment Acute Venous thrombus and acute coronary artery syndrome (stenocardia, myocardial infarction).
Heparin is the known the most complicated compound of molecular structure up to now in the world, and in a short time cannot artificial chemistry synthetic, 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 heparin sodium crude, its extraction can only be derived from the mucous membrane of small intestine of healthy live pig, owing to containing the impurity such as a large amount of impurity albumen, impurity nucleic acid, microorganism, need to extract sepn process through physics and chemistry, orientation is obtained the heparin sodium that natural structure group is complete, thereby makes heparin sodium bulk drug.Heparin sodium bulk drug is unique effective constituent of standard heparin preparation and the production starting point of Low molecular heparin raw material, and this makes heparin sodium bulk drug need very large purity.After heparin events 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 check 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 object of the invention is in order to meet the requirement of related substance check item in new edition heparin sodium European Pharmacopoeia standard, remove in heparin sodium and there is the impurity of but not degraded by nitrous acid with heparin sodium similar quality.
Technical scheme of the present invention is:
Near the removal of not degraded and go out the material at peak heparin sodium retention time by nitrous acid in a kind of heparin sodium
Method, is characterized in that: step is as follows:
A. the desorption liquid in workshop is carried out centrifugally, supernatant liquor is squeezed into Alcohol-settling tank, regulate 15 °-20 ° of salinity, add
The ethanol of 90-98% mass body volume concentrations, standing at least 8h, controlling alcohol precipitation ethanol final concentration is 10-45%;
B. by vacuum, pump Alcohol-settling tank middle and upper part clear liquid, bottom adopts whizzer centrifugal, and solid sediment enters alcohol cask washing,
The pre-prepd temperature that adds 5-20 doubly to precipitate bulking value is 10-70 ℃, and the warm ethanol that concentration is 15-50% carries out alcohol wash, and churning time 10-60min makes solid precipitation fully mix with warm ethanol;
C. adopt supercentrifuge to carry out alcohol wash sample centrifugal, collect solid precipitation and enter dehydration barrel;
D. to the ethanol that adds 90%-98% in dehydration barrel, stir solid precipitation and high concentration ethanol are fully mixed all
Even;
E. adopt supercentrifuge to carry out dehydration sample centrifugal, collect solid precipitation, after 65 ℃ of following oven dry, obtain and do not contain
By nitrous acid, do not degraded and near heparin sodium retention time, 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 the action site that can be degraded by nitrous acid, the molecular weight that is this material is less than heparin, so can remove this material by controlling alcohol precipitation concentration.
Advantage of the present invention:
Report in the past does not all relate to the removal method of this type of impurity, and the present invention can effectively remove this impurity, can meet in the new edition heparin sodium European Pharmacopoeia standard in the end of the year 2009 and after nitrous acid degraded, not go out peak near heparin sodium retention time in related substance detection.This method is simple to operate, and successful can carry out suitability for industrialized production.
Embodiment
Embodiment 1
The about 2000ml of a desorption liquid that picks up the car, gets supernatant liquor after centrifugal, by purified water, complements to 2000ml, and fluid temperature records salinity while being 24 ℃ be 17 °, adds 93% edible ethanol 1540ml, stir, and standing 8h.Centrifugal, precipitation is stirred with 45% the ethanol of 30 ℃, alcohol wash.Centrifugal, in gained solid, add absolute ethanol washing dehydration.Dehydration sample is carried out centrifugal, 55 ℃ dry, obtains 20.9g and tire as the heparin sodium crude of 79U/mg.
Embodiment 2
The about 2750ml of a desorption liquid that picks up the car, gets supernatant liquor after centrifugal, by purified water, complements to 3000ml, and fluid temperature records salinity while being 19 ℃ be 17 °, adds 93% edible ethanol 1050ml, stir, and standing 8h.Centrifugal, precipitation is stirred with 35% the ethanol of 30 ℃, alcohol wash.Centrifugal, in gained solid, add absolute ethanol washing dehydration.Dehydration sample is carried out centrifugal, 55 ℃ dry, obtains 17.1g and tire as the heparin sodium crude of 82.6U/mg.
Embodiment 3
The about 3000ml of a desorption liquid that picks up the car, gets supernatant liquor after centrifugal, by purified water, complements to 3000ml, and fluid temperature records salinity while being 17 ℃ be 17 °, adds 93% edible ethanol 1950ml, stir, and standing 8h.Centrifugal, precipitation is stirred with 40% the ethanol of 30 ℃, alcohol wash.Centrifugal, in gained solid, add absolute ethanol washing dehydration.Dehydration sample is carried out centrifugal, 55 ℃ dry, obtains 39g and tire as the heparin sodium crude of 75U/mg.
Claims (1)
1. in heparin sodium, by nitrous acid, do not degraded and near heparin sodium retention time, go out the removal method of the material at peak, it is characterized in that: step is as follows:
A. the desorption liquid in workshop is carried out centrifugally, supernatant liquor is squeezed into Alcohol-settling tank, regulate 15 °-20 ° of salinity, adding volumetric concentration is the ethanol of 90-98%, the standing 8h that is no less than, and controlling alcohol precipitation ethanol final volume concentration is 10-45%;
B. by vacuum, pump Alcohol-settling tank middle and upper part clear liquid, bottom adopts whizzer centrifugal, solid sediment enters alcohol cask washing, the pre-prepd temperature that adds 5-20 times of precipitation volume is 10-70 ℃, volumetric concentration is that the warm ethanol of 15-50% carries out alcohol wash, churning time 10-60min, makes solid precipitation fully mix with warm ethanol;
C. adopt supercentrifuge to carry out alcohol wash sample centrifugal, collect solid precipitation and enter dehydration barrel;
D. to adding volumetric concentration in dehydration barrel, be the ethanol of 90%-98%, stir solid precipitation and high concentration ethanol are fully mixed;
E. adopt supercentrifuge to carry out dehydration sample centrifugal, collect solid precipitation, after 65 ℃ of following oven dry, obtain and do not contain near the heparin sodium of not degraded by nitrous acid and going out the material at peak heparin sodium retention time.
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 CN102633905A (en) | 2012-08-15 |
| CN102633905B true CN102633905B (en) | 2014-10-08 |
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Family Applications (1)
| 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 |
Country Status (1)
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| CN (1) | CN102633905B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2704861B1 (en) * | 1993-05-07 | 1995-07-28 | Sanofi Elf | Purified heparin fractions, process for obtaining them and pharmaceutical compositions containing them. |
| CN101762668B (en) * | 2009-12-24 | 2013-06-19 | 山东海科化工集团有限公司 | Method for quantitatively detecting dermatan sulfate in heparin |
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2011
- 2011-04-11 CN CN201110089571.3A patent/CN102633905B/en not_active Expired - Fee Related
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| CN102633905A (en) | 2012-08-15 |
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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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| EC01 | Cancellation of recordation of patent licensing contract |
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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| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141008 Termination date: 20160411 |