CN102633906A - Method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium - Google Patents
Method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium Download PDFInfo
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- CN102633906A CN102633906A CN2011100895732A CN201110089573A CN102633906A CN 102633906 A CN102633906 A CN 102633906A CN 2011100895732 A CN2011100895732 A CN 2011100895732A CN 201110089573 A CN201110089573 A CN 201110089573A CN 102633906 A CN102633906 A CN 102633906A
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- heparin sodium
- alcohol precipitation
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- desorption liquid
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- 229920000669 heparin Polymers 0.000 title claims abstract description 36
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 title claims abstract description 28
- 229960001008 heparin sodium Drugs 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 239000012043 crude product Substances 0.000 title abstract 5
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical class FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 title abstract 4
- 229920001287 Chondroitin sulfate Polymers 0.000 title abstract 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 76
- 238000001556 precipitation Methods 0.000 claims abstract description 28
- 239000007788 liquid Substances 0.000 claims description 21
- 229920002567 Chondroitin Polymers 0.000 claims description 20
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims description 20
- 238000003795 desorption Methods 0.000 claims description 17
- 239000006228 supernatant Substances 0.000 claims description 11
- 239000002244 precipitate Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 3
- 235000019441 ethanol Nutrition 0.000 description 30
- 239000003814 drug Substances 0.000 description 10
- 230000018044 dehydration Effects 0.000 description 9
- 238000006297 dehydration reaction Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 8
- 229960002897 heparin Drugs 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 239000003055 low molecular weight heparin Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- -1 sulfuric acid ester Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium, which can be used for removing the oversulfated chondroitin sulfate in a way of graded alcohol precipitation in the production process of the crude product heparin sodium, so that the crude product heparin sodium which does not contain the oversulfated chondroitin sulfate can be produced. The method is simple in operation and obvious in effect, and can be directly carried out in the production process without treating the crude product heparin sodium again.
Description
Technical field
The present invention relates to heparin sodium purification field, specifically is a kind of removal method of desorption liquid being carried out chondroitin polysulfate in the crude heparin sodium production process that alcohol precipitation handles that is mainly.
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.The heparin sodium incident that took place in 2008, analysis expert maybe with the chondroitin polysulfate that contains in the heparin sodium.
Summary of the invention
The objective of the invention is to adopt method simple to operate and capable of being industrialized to remove the chondroitin polysulfate in the heparin sodium crude.
Technical scheme of the present invention is:
The removal method of chondroitin polysulfate in a kind of crude heparin sodium production process; Be mainly desorption liquid is carried out the alcohol precipitation processing; It is characterized in that: to regulating 15 °-20 ° of desorption liquid salinity before the desorption liquid alcohol precipitation; Said alcohol precipitation is realized at twice: alcohol precipitation for the first time adds the 90%-98% concentration ethanol earlier to desorption liquid and leaves standstill 8h at least, to isolating supernatant layer; Alcohol precipitation adds the 90%-98% concentration ethanol and leaves standstill 8h at least in supernatant for the second time.
Further, in the said first time alcohol precipitation, the 90%-98% concentration ethanol be the desorption liquid volume 0.05-0.12 doubly.
Further, in the said second time alcohol precipitation, to the 90%-98% of middle adding concentration ethanol be precipitate for the first time gained supernatant the 0.05-0.7 volume doubly.
Adopt this method to remove the principle of chrondroitin: to be based on the molecular weight ratio heparin sodium of chondroitin polysulfate big for the alcohol precipitation method of removing chondroitin polysulfate at twice; In general molecular weight solute is big more; By organic solvent deposit, it is just low more that the needed organic solvent concentration of deposition takes place more easily.
The invention has the advantages that: the removal method of the chondroitin polysulfate of report is mainly extraction, IX and rapid precipitation method before this.Compare with method before, this method is simple to operate, and effect is obvious, can carry out suitability for industrialized production.
Embodiment
Adopt gradation alcohol precipitation settle out chondroitin polysulfate and heparin of alcohol respectively, the concrete operations 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.
B. alcohol precipitation for the first time: add the 90%-98% concentration ethanol of 0.05-0.12 times of desorption liquid volume, stir, leave standstill more than the 8h.
C. to the first time alcohol precipitation appearance centrifugal, chondroitin polysulfate is stayed in the deposition, gets supernatant and carries out the alcohol precipitation second time.
D. alcohol precipitation for the second time: add the 90%-98% concentration ethanol of 0.05-0.7 times of desorption liquid volume in the alcohol precipitation clear liquid again to the first time, stir, leave standstill more than the 8h.
E. to the second time alcohol precipitation appearance centrifugal, collecting precipitation is gone into the dehydration bucket.
F. in dehydration bucket, add absolute ethyl alcohol, stir and make solid precipitation and high concentration ethanol thorough mixing even.It is centrifugal to adopt supercentrifuge that dehydration appearance is carried out, and collects solid precipitation, promptly gets the heparin sodium crude that does not contain (or containing minute quantity) chondroitin polysulfate after the oven dry below 65 ℃.
Embodiment 1
A desorption liquid 2000ml that picks up the car gets supernatant after centrifugal, complements to 2000ml with purified water, and fluid temperature records salinity when being 30 ℃ be 17 °, adds 93% edible ethanol 200ml, stirs, and leaves standstill 8h.Centrifugal, 55 ℃ of oven dry of gained solid, the staple of gained sample is a chondroitin polysulfate.Add 93% the edible ethanol of 1000ml again to the clear liquid of centrifugal gained the inside, stir, leave standstill 8h.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 19.47g tires and is the heparin sodium crude of 86U/mg, wherein chondroitin polysulfate content is 0.4% (area normalization calculating).
Embodiment 2
A desorption liquid 3000ml that picks up the car gets supernatant after centrifugal, complements to 3000ml with purified water, and fluid temperature records salinity when being 24 ℃ be 19 °, adds 93% edible ethanol 300ml, stirs, and leaves standstill 8h.Centrifugal, 55 ℃ of oven dry of gained solid, the staple of gained sample is a chondroitin polysulfate.Add 93% the edible ethanol of 1510ml again to the clear liquid of centrifugal gained the inside, stir, leave standstill 8h.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 27.81g tires and is the heparin sodium crude of 68U/mg, wherein chondroitin polysulfate content is 0.5% (area normalization calculating).
Embodiment 3
A desorption liquid 2500ml that picks up the car gets supernatant after centrifugal, complements to 2500ml with purified water, and fluid temperature records salinity when being 28 ℃ be 17 °, adds 93% edible ethanol 300ml, stirs, and leaves standstill 8h.Centrifugal, 55 ℃ of oven dry of gained solid, the staple of gained sample is a chondroitin polysulfate.Add 93% the edible ethanol of 1310ml again to the clear liquid of centrifugal gained the inside, stir, leave standstill 8h.Centrifugal, in the gained solid, add the absolute ethanol washing dehydration.Dehydration appearance is carried out centrifugal, 55 ℃ of dryings, 22.30g tires and is the heparin sodium crude of 71U/mg, wherein chondroitin polysulfate content is 0.3% (area normalization calculating).
Claims (3)
1. the removal method of chondroitin polysulfate in the crude heparin sodium production process; Be mainly desorption liquid is carried out the alcohol precipitation processing; It is characterized in that: to regulating 15 °-20 ° of desorption liquid salinity before the desorption liquid alcohol precipitation; Said alcohol precipitation is realized at twice: alcohol precipitation for the first time adds the 90%-98% concentration ethanol earlier to desorption liquid and leaves standstill 8h at least, to isolating supernatant layer; Alcohol precipitation adds the 90%-98% concentration ethanol and leaves standstill 8h at least in supernatant for the second time.
2. according to the removal method of chondroitin polysulfate in a kind of crude heparin sodium production process described in the claim 1, it is characterized in that: in the said first time alcohol precipitation, the 90%-98% concentration ethanol be the desorption liquid volume 0.05-0.12 doubly.
3. according to the removal method of chondroitin polysulfate in a kind of crude heparin sodium production process described in the claim 1; It is characterized in that: in the said second time alcohol precipitation, to the 90%-98% of middle adding concentration ethanol be precipitate for the first time gained supernatant the 0.05-0.7 volume doubly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100895732A CN102633906A (en) | 2011-04-11 | 2011-04-11 | Method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100895732A CN102633906A (en) | 2011-04-11 | 2011-04-11 | Method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102633906A true CN102633906A (en) | 2012-08-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100895732A Pending CN102633906A (en) | 2011-04-11 | 2011-04-11 | Method for removing oversulfated chondroitin sulfate in production process of crude product heparin sodium |
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| CN (1) | CN102633906A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102830150A (en) * | 2012-07-09 | 2012-12-19 | 东营天东制药有限公司 | High sensitivity detection method of oversulfated chondroitin sulfate in liquaemin |
| CN103864958A (en) * | 2013-11-24 | 2014-06-18 | 青岛九龙生物医药有限公司 | Method of preparing high-purity heparin sodium |
| CN104479049A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Pretreatment method for analysis of impurities in heparin sodium crude products |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101824098A (en) * | 2010-02-12 | 2010-09-08 | 淮安麦德森化学有限公司 | Method for quickly precipitating and separating oversulfated chondroitin sulfate in sodium heparin |
-
2011
- 2011-04-11 CN CN2011100895732A patent/CN102633906A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101824098A (en) * | 2010-02-12 | 2010-09-08 | 淮安麦德森化学有限公司 | Method for quickly precipitating and separating oversulfated chondroitin sulfate in sodium heparin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102830150A (en) * | 2012-07-09 | 2012-12-19 | 东营天东制药有限公司 | High sensitivity detection method of oversulfated chondroitin sulfate in liquaemin |
| CN103864958A (en) * | 2013-11-24 | 2014-06-18 | 青岛九龙生物医药有限公司 | Method of preparing high-purity heparin sodium |
| CN104479049A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Pretreatment method for analysis of impurities in heparin sodium crude products |
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Application publication date: 20120815 |