CN103804524A - Method for improving yield of heparin sodium - Google Patents
Method for improving yield of heparin sodium Download PDFInfo
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- CN103804524A CN103804524A CN201310625724.0A CN201310625724A CN103804524A CN 103804524 A CN103804524 A CN 103804524A CN 201310625724 A CN201310625724 A CN 201310625724A CN 103804524 A CN103804524 A CN 103804524A
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Abstract
The invention relates to a method for improving yield of heparin sodium, and discloses an extraction technology for preparing high purity and high yield heparin sodium, belonging to chemical field. The method mainly comprises steps of extracting by acetone and purifying by ethyl alcohol. By adopting the method, the problem that oversulfated chondroitin sulfate is mixed in the existing production process of heparin sodium is solved, the cost is saved, the purity of heparin sodium is improved, and the method is simple, is easy to operate, and is applicable to industrial production.
Description
Technical field
This law explanation relates to a kind of method of extracting synthesis bulk drug, belongs to chemical field, and specifically one is prepared high-purity high-yield refined heparin sodium.
Background technology
Heparin sodium is the sodium salt of the CSSO3 extracted in the intestinal mucosa by pig or ox, belongs to mucopolysaccharide material, exists in animal body mainly with the form of heparin sodium-protein complex.Medically, heparin sodium all has blood coagulation resisting function in vivo and in vitro, can extend the clotting time, prothrombin time and thrombin time.Having clinically anticoagulation, reducing blood-fat, protection endotheliocyte, antiplatelet gathers and discharges, short fibrinolytic, suppresses aortic smooth muscle cell proliferation, reduces the effects such as blood viscosity and anti-inflammatory.
China is maximum in the world heparin sodium production of raw medicine state, and the method for raw materials medicine heparin sodium mainly contains two kinds: biological enzyme, chemical cracking method.Biological enzyme mainly produces heparin sodium with enzyme liberating, method gentleness, but cost is very high, is not suitable for batch production: another kind of chemical cracking method, output is many, but in process, can affect the activity of heparin sodium, is not suitable with medicinal.This technique has been drawn the advantage of above two kinds of techniques, multiple extraction, extraction and ion-exchange techniques, and method gentleness, extracted amount is relatively large, and purity is higher, and can remove to greatest extent the impurity of heparin sodium, such as chondroitin polysulfate.
Summary of the invention
Object of the present invention is in order to improve the deficiencies in the prior art, and a kind of technique of preparing high-purity high-yield heparin sodium is provided; This invention provides a kind of easy high purity heparin sodium technology of preparing, and the heparin sodium making is tired all higher than 180U/mg, the 170U/mg requiring higher than Chinese Pharmacopoeia, and detect according to Chinese Pharmacopoeia heparin sodium examination criteria qualified.
Technical scheme of the present invention is: a kind of technique of preparing high purity heparin sodium, and its step is as follows:
1, crude heparin sodium is dissolved in tap water, stir 5-10 hour, it is all dissolved;
2, by lysate in step 1, adjust PH to 7.0-8.0 with hydrochloric acid soln, while being then warming up between 50-55 ℃, add stomach en-, then add pancreatin, insulation 2-4 hour;
3, enzymolysis solution in step 2 was warming up to 85-90 ℃ in 30～40 minutes, static 10-30 minute, stirs, and then waits while being cooled to 50-55 ℃, with sodium hydroxide solution tune PH to 10.0-12.0, static 20-30 hour, layering, siphon supernatant, filter, stay supernatant liquor to wait to precipitate, it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
4, treat in step 3 that supernatant liquor and centrifugate temperature are down to 20-30 ℃, add sodium-chlor, stirring and dissolving, adjusts PH to 10.0-12.0 with hydrochloric acid, and adding concentration while stirring is 75-80% ethanolic soln, precipitation 10-12 hour;
5, get lower sediment thing purified water in step 4 and dissolve, with sodium hydroxide solution, solution is adjusted to PH to 10.0-12.0, then add hydrogen peroxide oxidation 10-12 hour;
6, solution in step 5 is added to sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, solution is adjusted to PH to 6.0-7.0, add ethanolic soln, precipitation 10-12 hour;
7, get lower sediment thing purified water in step 6 and dissolve, adjust PH to 10.0-12.0 with sodium hydroxide solution, then add volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
8, solution in step 7 is added to sodium-chlor, adjust PH to 10.0-12.0 with hydrochloric acid soln, add concentration while stirring and be 95～97% ethanolic soln, precipitation 10-12 hour;
9, get lower sediment thing purified water in step 8 and dissolve, adjust PH to 10.0-12.0 with sodium hydroxide solution, then add hydrogen peroxide, oxidation 10-12 hour;
10, solution in step 9 is added to sodium-chlor, adjust PH to 6.0-7.0 with hydrochloric acid soln, be then refrigerated to-10 ℃--5 ℃, add acetone while stirring, in-5 ℃-0 ℃, be incubated 24-30 hour, abandoning supernatant, chondroitin polysulfate is taken away by acetone, throw out is dissolved by purified water, add sodium-chlor, adjust PH to 6.0-7.0 with hydrochloric acid soln, add ethanol while stirring, precipitation 10-12 hour;
11, after throw out in step 10 is dissolved by purified water, with micron filter membrane board and frame machine micro-filtration, by ethanol precipitation, then add sodium chloride solution, quiescent setting 10-12 hour, taking precipitate, with dissolve with ethanol, leaves standstill 24-30 hour; Discard upper strata liquid, stainless steel core rod is placed in product, drain with vacuum pump is logical;
12, product in step 11 is placed in vacuum drying oven, dries 70-80 hour, obtain product.
Beneficial effect:
1, the present invention obtains tiring higher than 180U/mg in conjunction with the multiple physical extracting method of intensification oxidation bonding purifying, and yield is higher than 80% high purity heparin sodium.
2, add hydrogen peroxide by intensification and can effectively control heparin sodium oxidation inactivation, and realized oxidation and carried out with decolouring to synchronize.
3, according to the polarity difference of heparin sodium and analog thereof, in sodium chloride solution, with acetone extract, precipitate wash-out with ethanol, finally obtaining heparin sodium product.The acetone extract method of process using, chondroitin polysulfate impurity is extracted, and heparin sodium product has been stayed in low salts solution, precipitate with ethanol, greatly improved yield, the heparin sodium product finally obtaining reaches Chinese Pharmacopoeia standard, and through surveying not containing chondroitin polysulfate composition.
Embodiment
Embodiment 1
(1) 50g crude heparin sodium is dissolved in tap water, stir 5 hours, it is all dissolved;
(2) adjust PH to 7.0 with hydrochloric acid soln, while being then warming up between 50 ℃, add 5g/ hundred million unit stomach en-s, then add 10g/ hundred million unit pancreatin, be incubated 2 hours;
(3) enzymolysis solution was warming up to 85 ℃ in 30 minutes, static 10 minutes, stir, then wait and be cooled at 50 o'clock, with 2mol sodium hydroxide solution tune PH to 10.0, static 20 hours, layering, siphon supernatant, filter, stay supernatant liquor to wait to precipitate, it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
(4) treat that supernatant liquor and centrifugate temperature be down to 20 ℃, add 25g/L sodium-chlor, stirring and dissolving, adjusts PH to 10.0 with hydrochloric acid, and adding concentration while stirring is 75% ethanolic soln, precipitates 10 hours;
(5) take off layer throw out purified water and dissolve, with sodium hydroxide solution, solution is adjusted to PH to 10.0, then add 3% hydrogen peroxide oxidation 10 hours;
(6) solution is added to 20g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, solution is adjusted to PH to 6.0, add ethanolic soln, precipitate 10 hours;
(7) take off layer throw out purified water and dissolve, adjust PH to 10.0 with sodium hydroxide solution, then add volume 3% hydrogen peroxide, be oxidized 10 hours;
(8) solution is added to 20g/L sodium-chlor, adjust PH to 10.0 with hydrochloric acid soln, add concentration while stirring and be 95% ethanolic soln, precipitate 10 hours;
(9) take off layer throw out purified water and dissolve, adjust PH to 10.0 with sodium hydroxide solution, then add 3% hydrogen peroxide, be oxidized 10 hours;
(10) solution is added to 20g/L sodium-chlor, with hydrochloric acid soln tune PH to 6.0, then be refrigerated to-10 ℃, add acetone while stirring, in-5 ℃, be incubated 24 hours, abandoning supernatant, by purified water, throw out is dissolved, add sodium-chlor, with hydrochloric acid soln tune PH to 6.0, add ethanol while stirring, precipitate 10 hours;
(11) after throw out is dissolved by purified water, with micron filter membrane board and frame machine micro-filtration, by ethanol precipitation, then add 20g/L sodium chloride solution, quiescent setting 10 hours, taking precipitate, with dissolve with ethanol, leaves standstill 24 hours;
(12) discard upper strata liquid, stainless steel core rod is placed in product, drain with vacuum pump is logical; Product is placed in vacuum drying oven, dries 70, it is tired as 183U/mg after testing to obtain product, and the rate of recovery is that 80.1% chondroitin sulfate is that 0.09mg/mL dermatan sulfate is 0.01mg/mL, and indices all meets Chinese Pharmacopoeia requirement.
Embodiment 2
(1) crude heparin sodium is dissolved in tap water, stir 5-10 hour, it is all dissolved;
(2) hydrochloric acid soln for lysate is adjusted to PH to 6.5, be then warming up to 52 between time add 7g/ hundred million unit stomach en-s, then add 15g/ hundred million unit pancreatin, be incubated 3 hours;
(3) enzymolysis solution was warming up to 87 ℃ in 35 minutes, static 20 minutes, stir, then wait while being cooled to 52 ℃, with 4mol sodium hydroxide solution tune PH to 11.0, static 25 hours, layering, siphon supernatant, filter, stay supernatant liquor to wait to precipitate, it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
(4) treat that supernatant liquor and centrifugate temperature be down to 25 ℃, add 25g/L25g/L sodium-chlor, stirring and dissolving, adjusts PH to 11.0 with hydrochloric acid, and adding concentration while stirring is 77% ethanolic soln, precipitation 10-12 hour; Take off layer throw out purified water and dissolve, with sodium hydroxide solution, solution is adjusted to PH to 10.0-12.0, then add 4% hydrogen peroxide oxidation 10-12 hour;
(5) solution is added to 25g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, solution is adjusted to PH to 6.5, add ethanolic soln, precipitate 11 hours;
(6) take off layer throw out purified water and dissolve, adjust PH to 11.0 with sodium hydroxide solution, then add volume 4% hydrogen peroxide, be oxidized 11 hours;
(7) solution is added to 25g/L sodium-chlor, adjust PH to 11.0 with hydrochloric acid soln, add concentration while stirring and be 96% ethanolic soln, precipitate 11 hours;
(8) take off layer throw out purified water and dissolve, adjust PH to 10.0-12.0 with sodium hydroxide solution, then add 4% hydrogen peroxide, be oxidized 11 hours;
(9) solution is added to 25g/L sodium-chlor, with hydrochloric acid soln tune PH to 6.5, then be refrigerated to-7, add acetone while stirring, in-3, be incubated 24-30 hour, abandoning supernatant, by purified water, throw out is dissolved, add sodium-chlor, with hydrochloric acid soln tune PH to 6.5, add ethanol while stirring, precipitate 11 hours;
(10) after throw out is dissolved by purified water, with micron filter membrane board and frame machine micro-filtration, by ethanol precipitation, then add 25g/L sodium chloride solution, quiescent setting 10-12 hour, taking precipitate, with dissolve with ethanol, leaves standstill 27 hours;
(11) discard upper strata liquid, stainless steel core rod is placed in product, drain with vacuum pump is logical;
(12) product is placed in vacuum drying oven, dries 75 hours, obtain product.After testing, it is tired as 209U/mg to obtain product, and the rate of recovery is that 89% chondroitin sulfate is that 0.0001mg/mL dermatan sulfate is 0.0005mg/mL, and indices all meets Chinese Pharmacopoeia requirement.
Embodiment 3
(1) crude heparin sodium is dissolved in tap water, stir 10 hours, it is all dissolved;
(2) adjust PH to 8.0 with hydrochloric acid soln, while being then warming up between 50-55 ℃, add 10g/ hundred million unit stomach en-s, then add 20g/ hundred million unit pancreatin, be incubated 4 hours;
(3) enzymolysis solution was warming up to 90 ℃ in 40 minutes, static 30 minutes, stir, then wait while being cooled to 55 ℃, with 6mol sodium hydroxide solution tune PH to 12.0, static 30 hours, layering, siphon supernatant, filter, stay supernatant liquor to wait to precipitate, it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
(4) treat that supernatant liquor and centrifugate temperature be down to 30 ℃, add 30g/L sodium-chlor, stirring and dissolving, adjusts PH to 12.0 with hydrochloric acid, and adding concentration while stirring is 80% ethanolic soln, precipitates 12 hours;
(5) take off layer throw out purified water and dissolve, with sodium hydroxide solution, solution is adjusted to PH to 12.0, then add 5% hydrogen peroxide oxidation 12 hours;
(6) solution is added to 30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, solution is adjusted to PH to 7.0, add ethanolic soln, precipitation 10-12 hour;
(7) take off layer throw out purified water and dissolve, adjust PH to 12.0 with sodium hydroxide solution, then add volume 5% hydrogen peroxide, be oxidized 12 hours;
(8) solution is added to 30g/L sodium-chlor, adjust PH to 12.0 with hydrochloric acid soln, add concentration while stirring and be 97% ethanolic soln, precipitate 12 hours;
(9) take off layer throw out purified water and dissolve, adjust PH to 12.0 with sodium hydroxide solution, then add 5% hydrogen peroxide, be oxidized 12 hours;
(10) solution is added to 30g/L sodium-chlor, adjust PH to 7.0 with hydrochloric acid soln, be then refrigerated to-5 ℃, add acetone while stirring, in 0 ℃, be incubated 30 hours, abandoning supernatant, chondroitin polysulfate is taken away by acetone, throw out is dissolved by purified water, add sodium-chlor, adjust PH to 7.0 with hydrochloric acid soln, add ethanol while stirring, precipitate 12 hours;
(11) after throw out is dissolved by purified water, with micron filter membrane board and frame machine micro-filtration, by ethanol precipitation, then add 30g/L sodium chloride solution, quiescent setting 12 hours, taking precipitate, with dissolve with ethanol, leaves standstill 30 hours;
(12) discard upper strata liquid, stainless steel core rod is placed in product, drain with vacuum pump is logical; Product is placed in vacuum drying oven, dries 80 hours, obtains product.After testing, it is tired as 189U/mg to obtain product, and the rate of recovery is that 89% chondroitin sulfate is that 0.002mg/mL dermatan sulfate is 0.003mg/mL, and indices all meets Chinese Pharmacopoeia requirement.
Claims (7)
1. prepare a technique for high purity heparin sodium, its step is as follows:
(1) crude heparin sodium is dissolved in tap water, stir 5-10 hour, it is all dissolved;
(2) by lysate in step (1), adjust PH to 7.0-8.0 with hydrochloric acid soln, while being then warming up between 50-55 ℃, add stomach en-, then add pancreatin, insulation 2-4 hour;
(3) enzymolysis solution in step (2) was warming up to 85-90 ℃ in 30～40 minutes, static 10-30 minute, stirs, and then waits while being cooled to 50-55 ℃, with sodium hydroxide solution tune PH to 10.0-12.0, static 20-30 hour, layering, siphon supernatant, filter, stay supernatant liquor to wait to precipitate, it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
(4) treat in step (3) that supernatant liquor and centrifugate temperature are down to 20-30 ℃, add sodium-chlor, stirring and dissolving, adjusts PH to 10.0-12.0 with hydrochloric acid, adds ethanolic soln while stirring, precipitation 10-12 hour;
(5) get lower sediment thing purified water in step (4) and dissolve, with sodium hydroxide solution, solution is adjusted to PH to 10.0-12.0, then add hydrogen peroxide oxidation 10-12 hour;
(6) solution in step (5) is added to sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, solution is adjusted to PH to 6.0-7.0, add ethanolic soln, precipitation 10-12 hour;
(7) get lower sediment thing purified water in step (6) and dissolve, adjust PH to 10.0-12.0 with sodium hydroxide solution, then add volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
(8) solution in step (7) is added to sodium-chlor, adjust PH to 10.0-12.0 with hydrochloric acid soln, add concentration while stirring and be 95～97% ethanolic soln, precipitation 10-12 hour;
(9) get lower sediment thing purified water in step (8) and dissolve, adjust PH to 10.0-12.0 with sodium hydroxide solution, then add hydrogen peroxide, oxidation 10-12 hour;
(10) solution in step (9) is added to sodium-chlor, adjust PH to 6.0-7.0 with hydrochloric acid soln, be then refrigerated to-10 ℃--5 ℃, add acetone while stirring, in-5 ℃-0 ℃, be incubated 24-30 hour, abandoning supernatant, chondroitin polysulfate is taken away by acetone, throw out is dissolved by purified water, add sodium-chlor, adjust PH to 6.0-7.0 with hydrochloric acid soln, add ethanol while stirring, precipitation 10-12 hour;
(11) after throw out in step (10) is dissolved by purified water, with micron filter membrane board and frame machine micro-filtration, by ethanol precipitation, then add sodium chloride solution, quiescent setting 10-12 hour, taking precipitate, with dissolve with ethanol, leaves standstill 24-30 hour; Discard upper strata liquid, stainless steel core rod is placed in product, drain with vacuum pump is logical;
(12) product in step (11) is placed in vacuum drying oven, dries 70-80 hour, obtain product.
2. technique according to claim 1, is characterized in that: the pepsin concn in step (1) is 5-10g/ hundred million units, and the concentration of pancreatin is 10-20g/ hundred million units.
3. technique according to claim 1, is characterized in that: in step (2), the concentration of sodium hydroxide is 2-6mol/L.
4. technique according to claim 1, is characterized in that: in step (3), step (6), step (8), step (10) and step (11), the concentration of sodium-chlor is 20-30g/L.
5. technique according to claim 1, is characterized in that: in step (4), the concentration of ethanolic soln is 75%～80%.
6. technique according to claim 1, is characterized in that: the volume fraction of the hydrogen peroxide in step (5) and step (9) is 3-5%.
7. technique according to claim 1, is characterized in that: in step (10), the concentration of acetone is 40-45%.
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| CN201310625724.0A CN103804524A (en) | 2013-11-24 | 2013-11-24 | Method for improving yield of heparin sodium |
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| CN201310625724.0A CN103804524A (en) | 2013-11-24 | 2013-11-24 | Method for improving yield of heparin sodium |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104479046A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Method for increasing yield of chondroitin sulfate |
| CN105001353A (en) * | 2015-08-17 | 2015-10-28 | 江苏联众肠衣有限公司 | Refining optimization technology for crude heparin sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575385A (en) * | 2008-05-09 | 2009-11-11 | 青岛九龙生物医药有限公司 | Method for separating chondroitin polysulfate from heparin sodium by extraction method |
| CN103044578A (en) * | 2012-12-07 | 2013-04-17 | 青岛九龙生物医药有限公司 | Efficient method for refining heparin sodium crude products |
| CN103145878A (en) * | 2012-12-08 | 2013-06-12 | 青岛九龙生物医药有限公司 | Ultralow heparin sodium technical study |
-
2013
- 2013-11-24 CN CN201310625724.0A patent/CN103804524A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575385A (en) * | 2008-05-09 | 2009-11-11 | 青岛九龙生物医药有限公司 | Method for separating chondroitin polysulfate from heparin sodium by extraction method |
| CN103044578A (en) * | 2012-12-07 | 2013-04-17 | 青岛九龙生物医药有限公司 | Efficient method for refining heparin sodium crude products |
| CN103145878A (en) * | 2012-12-08 | 2013-06-12 | 青岛九龙生物医药有限公司 | Ultralow heparin sodium technical study |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104479046A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Method for increasing yield of chondroitin sulfate |
| CN105001353A (en) * | 2015-08-17 | 2015-10-28 | 江苏联众肠衣有限公司 | Refining optimization technology for crude heparin sodium |
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