CN105461829A - Method for separating high-molecular-weight heparin sodium by enzymolysis process - Google Patents
Method for separating high-molecular-weight heparin sodium by enzymolysis process Download PDFInfo
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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Abstract
The invention discloses a technique for separating high-molecular-weight heparin sodium by an enzymolysis process. By using the method, the molecular weight of the heparin sodium refined product is 15000-19000 Dalton, and the ratio of the heparin sodium with the molecular weight of 8000-16000 Dalton to the heparin sodium with the molecular weight of 16000-24000 Dalton is not less than 1.0. The technical scheme is as follows: the method comprises the following steps: decomposing high-molecular-weight heparin sodium in the heparin sodium by regulating the consumptions of trypsinase and pepsin in the enzymolysis process, and carrying out repeated precipitation-oxidation refinement by using ethanol to thoroughly separate the heparin sodium from other ribonucleic acids and other impurities. The heparin sodium refined product yield reaches 90% or above, the Xa valence/ IIa valence ratio is 0.9-1.1, and all the other quality standards conform to the specifications in Chinese Pharmacopoeia, US Pharmacopoeia, British Pharmacopoeia and Western Europe Pharmacopoeia.
Description
Technical field
The present invention relates to biological technical field, relate in particular to method high molecular weight heparin sodium being decomposed into low molecular weight heparin sodium product.
Background technology
Heparin sodium is a kind of biochemical drug extracted from pig intestinal mucosa, be irreplaceable in operation, save the choice drug that life, market can not be out of stock.From nineteen forties be used for clinical since, its range of application constantly expands, and especially since nineteen nineties, clinical being mainly used in of this product prevents thrombosis, treatment cardiovascular diseases, hemopathy, uremia etc.Western countries have begun one's study the preventive and therapeutic effect of heparin sodium to cancer, and its novelty teabag constantly increases.
Since entering nineteen seventies, China's heparin sodium production technique is updated, and becomes the country that world's heparin sodium output is maximum.The heparin sodium product of world market has more than 70% from China.Refined heparin sodium is produced and is developed into hydrogen peroxide oxidation method by potassium permanganate oxidation method, in conjunction with alcohol wash partition method, is taken away by a large amount of impurity ethanol.On February 11st, 2008, the U.S. is because of the death of injecting heparin sodium appearance 4 example, and 350 many cases untoward reactions, become " the heparin sodium event " that cause a sensation the world.Therefore Bureau of Drugs Supervision of the U.S. is annual all to the standard upgrading of heparin sodium, and next year is by the standard upgrading of heparin sodium molecular weight.
Summary of the invention
The invention provides a kind of method that enzymolysis process decomposes the high component in heparin sodium, the present invention is achieved by the following technical solutions:
Enzymolysis process decomposes a method for the high molecular in heparin sodium, it is characterized in that: regulate trypsinase and pepsic consumption and gradation time to be decomposed by the macromolecule heparin sodium in heparin sodium.
In the technical scheme of invention, also there is following technical characteristic: described method comprises the steps:
One, extract
1, dissolving crude product:
Open water valve, add tap water, then heparin sodium crude is joined in retort, stir while add, in raw material and tap water 1:(6-7) ratio dissolves, and 5-10 is little of whole dissolving in stirring;
2, enzymolysis:
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid soln, stomach en-5-10g/ hundred million unit is added when being warming up between 50-55 DEG C, add 10-20g/ hundred million unit pancreatin again, 50-55 DEG C is incubated 4 hours, after 4 hours, then adds stomach en-3-5g/ hundred million unit, add the trypsinase of 5-10g/ hundred million unit, 50 DEG C are continued insulation 4 hours simultaneously;
3, rise suddenly temperature:
Previous step enzymolysis solution was warming up to 85-90 DEG C in 30 ~ 40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, when temperature is down to 50-55 DEG C, adjusts PH10.0-12.0, static layering 20-30 hour with 2-6mol/L sodium hydroxide solution;
4, the impurity of bottom settlings is centrifugal:
Siphon supernatant, with 40-100 order sock filtration, the solution after filtration is divided into supernatant liquor and lower sediment, and stay supernatant liquor to be precipitated, lower sediment puts centrifuge, stays upper strata centrifugate after centrifugal;
Two, refining
1, first time is precipitated:
Treat that above-mentioned supernatant liquor and centrifugate temperature are down to 20-30 DEG C, add 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted PH10.0-12.0, stir while add the ethanolic soln that concentration is 95 ~ 97%, make the concentration of ethanol reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
2, first time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
3, second time precipitation: solution adds 20-30g/L sodium-chlor, after stirring and dissolving, adjust solution PH 6.0-7.0 with hydrochloric acid soln, stir while add the ethanolic soln that concentration is 95 ~ 97%, the concentration of ethanol is made to reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
4, second time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
5, third time is precipitated: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted PH10.0-12.0, stirs while add the ethanolic soln that concentration is 95 ~ 97%, makes the concentration of ethanol reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
6, third time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
7, 4th precipitation: if previous step solution has throw out to separate out, then use centrifuge, do not separate out and then directly add 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted PH6.0-7.0, solution is let cool in storehouse and is refrigerated to-10 DEG C--5 DEG C, while stir Bian Jia-10 DEG C--the acetone of 5 DEG C, the mass percentage making acetone account for solution is 40-45%,-5 DEG C-0 DEG C insulation 24-30 hour, then waste acetone is discarded, portion's throw out purified water of keeping on file is dissolved, solution adds 20-30g/L sodium-chlor again, adjust solution PH 6.0-7.0 with hydrochloric acid soln, stir while add ethanol, alcohol concn is made to be 45-50% 20 DEG C time, precipitation 10-12 hour,
8, after throw out being pressed the dissolving of 2-5L/ hundred million unit by purified water, with aperture 0.22-0.3 micron membrane filter board and frame machine micro-filtration, with alcohol settling, alcohol concn is made to reach 75-80%, add the sodium chloride solution of 23-26% again, every 1 liter of solution adds 6-10ml sodium chloride solution, quiescent setting 10-12 hour;
9, upper strata ethanol is discarded, add dehydrated alcohol dehydration, stir while add, make alcohol concn be 97-99%, static 24-30 hour, discards upper strata ethanol, stainless steel core rod is put in the product, by pipeline and filter flask, residue ethanol is drained with vacuum pump, to be dried;
10, the product drained evenly is placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, heat with recirculated water, temperature 35-60 DEG C, dry 70-80 hour;
11, pack: product is taken out, weighs, make every packing bag 5kg, with sealing machine sealing, be placed in Aluminum Drum to be tested.
In the technical scheme of invention, also there is following technical characteristic:
1) solution, after the 4th precipitation carries out QA sample examination, survey absorbancy: 260nm < 0.1; 400nm < 0.02;
2), molecular weight between 15000-19000 dalton, and between the daltonian molecular weight ratio of 8000-16000 and 16000-24000 dalton, the ratio of molecular weight ratio is not less than 1.0;
3), refined heparin sodium yield reaches more than 90%;
4), tire ratio of tiring with IIa of Xa is 0.9-1.1;
5), the content of dermatan sulfate is less than 1%.
Compared with prior art, advantage of the present invention and positively effect are:
Refined heparin sodium of the present invention is produced and is adopted hydrogen peroxide oxidation method, in conjunction with alcohol wash partition method, a large amount of impurity ethanol is taken away, with extraction by propanone, the dermatan sulfate in heparin sodium is removed again, its fine work yield reaches more than 90%, tire ratio of tiring with IIa of Xa is 0.9-1.1, and its quality standard meets the indices of Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia and West Europe pharmacopeia defined.
Heparin sodium is successfully thoroughly separated with chondroitin polysulfate, for the development of world's biological medicine is made contributions; The live pig facilitating country produces; This product exports at 10 more than hundred million every year, earns foreign exchange make contributions for national export.Be again a support agriculture-countryside-farmer, turn waste into wealth, the good project of environment protection.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
One, extract
1, dissolving crude product:
Open water valve, add 900L tap water, then 15,000,000,000 units of heparin sodium crude products are joined in retort, stir while add, stir after 6 hours, whether all dissolve with stirring rod examination bottom;
2, enzymolysis:
By previous step lysate, first adjust PH7.5 with hydrochloric acid soln, add stomach en-1500g when being warming up to 53 DEG C, then add 3000g pancreatin, 53 DEG C are incubated 4 hours, then add stomach en-750g and trypsinase 1500g, continue insulation 4 hours;
3, rise suddenly temperature:
Previous step enzymolysis solution is warming up to 88 DEG C in 35 minutes, static 15 minutes, opens stirring, pass into circulating water cooling, when temperature is down to 50 DEG C, adjust PH11.0 with 6mol/L sodium hydroxide solution, static layering 24 hours;
4, the impurity of bottom settlings is centrifugal:
Siphon supernatant, with 80 order sock filtration, the solution after filtration is divided into supernatant liquor and lower sediment, and stay supernatant liquor to be precipitated, lower sediment puts centrifuge, stays upper strata centrifugate after centrifugal;
Two, refining
1, first time is precipitated:
Treat that above-mentioned supernatant liquor and centrifugate temperature are down to 25 DEG C, add 22.5kg sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted PH10.5, stir while add the ethanolic soln 920L that concentration is 95 ~ 97%, precipitate 10 hours;
2, first time oxidation: discard upper strata waste ethanol, lower sediment thing and product 640L purified water are dissolved, and with sodium hydroxide solution, solution are adjusted PH11.0, then add 20L hydrogen peroxide, be oxidized 10 hours;
3, second time precipitation: solution adds 12.8kg sodium-chlor, after stirring and dissolving, adjusts solution PH 6.0 with hydrochloric acid soln, stirs while add the ethanolic soln 640L that concentration is 95 ~ 97%, precipitate 10 hours;
4, second time oxidation: discard upper strata waste ethanol, lower sediment thing 640L purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH11.0, then adds 20L hydrogen peroxide, be oxidized 10 hours;
5, third time is precipitated: solution adds 12.8kg sodium-chlor, with hydrochloric acid soln, solution is adjusted PH6.0, stirs while add the ethanolic soln 640L that concentration is 95 ~ 97%, precipitates 10 hours;
6, third time oxidation: discard upper strata waste ethanol, lower sediment thing 640L purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH11.0, then adds 21L hydrogen peroxide, be oxidized 10 hours;
7, the 4th precipitation: if previous step solution has throw out to separate out, then use centrifuge, does not separate out and then directly adds 12.8kg sodium-chlor, with hydrochloric acid soln, solution is adjusted PH6.0, let cool in storehouse by solution and be refrigerated to-6 DEG C, while stir the acetone 600L of Bian Jia-10 DEG C ,-3 DEG C are incubated 24 hours, then waste acetone is discarded, portion's throw out purified water of keeping on file is dissolved, and solution adds 12.8kg sodium-chlor again, adjusts solution PH 6.0 with hydrochloric acid soln, stir while add ethanol 640L, precipitate 10 hours;
8, after throw out being dissolved by 300L purified water, with aperture 0.3 micron membrane filter board and frame machine micro-filtration, use 840L alcohol settling, make alcohol concn reach 75-80%, then add the sodium chloride solution 11L of 26%, quiescent setting 10 hours;
9, upper strata ethanol is discarded, add the dehydration of 500L dehydrated alcohol, stir while add, make alcohol concn be 97-99%, static 24 hours, discard upper strata ethanol, stainless steel core rod is put in the product, by pipeline and filter flask, residue ethanol is drained with vacuum pump, to be dried;
10, the product drained evenly is placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, heat with recirculated water, temperature 50 C, dry 72 hours;
11, pack: product is taken out, weighs, make every packing bag 5Kg, with sealing machine sealing, be placed in Aluminum Drum to be tested.
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (7)
1. the method for an enzymolysis partition method decomposition high molecular weight heparin sodium, make refined heparin sodium molecular weight between 15000-19000 dalton, and between the daltonian molecular weight ratio of 8000-16000 and 16000-24000 dalton, the ratio of molecular weight ratio is not less than 1.0; It is characterized in that: adopt in enzymolysis process by regulating trypsinase and pepsic consumption and gradation time to be decomposed by the macromolecule heparin sodium in heparin sodium.
2. method according to claim 1, it is characterized in that regulating trypsinase and pepsic consumption to be decomposed by the macromolecule heparin sodium in heparin sodium in enzymolysis process, its step comprises:
One, extract
1), dissolving crude product:
Open water valve, add tap water, then heparin sodium crude is joined in retort, stir while add, in raw material and tap water 1:(6-7) ratio dissolves, and 5-10 is little of whole dissolving in stirring;
2), enzymolysis:
By previous step lysate, first adjust PH to 7.0-8.0 with hydrochloric acid soln, stomach en-5-10g/ hundred million unit is added when being warming up between 50-55 DEG C, add 10-20g/ hundred million unit pancreatin again, 50-55 DEG C is incubated 4 hours, after 4 hours, then adds stomach en-3-5g/ hundred million unit, add the trypsinase of 5-10g/ hundred million unit, 50 DEG C are continued insulation 4 hours simultaneously;
3), rise suddenly temperature:
Previous step enzymolysis solution is warming up to 85-90 DEG C in 30 ~ 40 minutes, static 10-30 minute, starts to stir, pass into circulating water cooling, when temperature is down to 50-55 DEG C, adjust PH10.0-12.0, static layering 20-30 hour with 2-6mol/L sodium hydroxide solution;
4), the impurity of bottom settlings is centrifugal:
Siphon supernatant, with 40-100 order sock filtration, the solution after filtration is divided into supernatant liquor and lower sediment, and stay supernatant liquor to be precipitated, lower sediment puts centrifuge, stays upper strata centrifugate after centrifugal;
Two, refining
1), first time is precipitated:
Treat that above-mentioned supernatant liquor and centrifugate temperature are down to 20-30 DEG C, add 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted PH10.0-12.0, stir while add the ethanolic soln that concentration is 95 ~ 97%, make the concentration of ethanol reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
2), first time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
3), second time precipitation: solution adds 20-30g/L sodium-chlor, after stirring and dissolving, adjust solution PH 6.0-7.0 with hydrochloric acid soln, stir while add the ethanolic soln that concentration is 95 ~ 97%, the concentration of ethanol is made to reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
4), second time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
5), third time is precipitated: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted PH10.0-12.0, stirs while add the ethanolic soln that concentration is 95 ~ 97%, makes the concentration of ethanol reach 45 ~ 50% 20 DEG C time, precipitation 10-12 hour;
6), third time oxidation: discard upper strata waste ethanol, lower sediment thing purified water is dissolved, and with sodium hydroxide solution, solution is adjusted PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
7), 4th precipitation: if previous step solution has throw out to separate out, then use centrifuge, do not separate out and then directly add 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted PH6.0-7.0, solution is let cool in storehouse and is refrigerated to-10 DEG C--5 DEG C, while stir Bian Jia-10 DEG C--the acetone of 5 DEG C, the mass percentage making acetone account for solution is 40-45%,-5 DEG C-0 DEG C insulation 24-30 hour, then waste acetone is discarded, portion's throw out purified water of keeping on file is dissolved, solution adds 20-30g/L sodium-chlor again, adjust solution PH 6.0-7.0 with hydrochloric acid soln, stir while add ethanol, alcohol concn is made to be 45-50% 20 DEG C time, precipitation 10-12 hour,
8), by throw out with purified water press 2-5L/ hundred million unit dissolve after, with aperture 0.22-0.3 micron membrane filter board and frame machine micro-filtration, with alcohol settling, alcohol concn is made to reach 75-80%, add the sodium chloride solution of 23-26% again, every 1 liter of solution adds 6-10ml sodium chloride solution, quiescent setting 10-12 hour;
9), by upper strata ethanol discard, add dehydrated alcohol dehydration, stir while add, make alcohol concn be 97-99%, static 24-30 hour, discards upper strata ethanol, stainless steel core rod is put in the product, by pipeline and filter flask, residue ethanol is drained with vacuum pump, to be dried;
10), by the product drained evenly be placed in Stainless Steel Disc, be placed in vacuum drying oven and vacuumize, heat with recirculated water, temperature 35-60 DEG C, dry 70-80 hour;
11), packaging: product is taken out, weighs, make every packing bag 5kg, with sealing machine sealing, be placed in Aluminum Drum to be tested.
3. enzymolysis process according to claim 2 is separated the method for the high molecular in heparin sodium, it is characterized in that: the solution after the 4th precipitation carries out QA sample examination, surveys absorbancy: 260nm < 0.1; 400nm < 0.02.
4. enzymolysis process according to claim 2 is separated the method for the high molecular in heparin sodium, it is characterized in that: molecular weight is between 15000-19000 dalton, and between the daltonian molecular weight ratio of 8000-16000 and 16000-24000 dalton, the ratio of molecular weight ratio is not less than 1.0.
5. enzymolysis process according to claim 2 is separated the method for the high molecular in heparin sodium, it is characterized in that: refined heparin sodium yield reaches more than 90%.
6. enzymolysis process according to claim 2 is separated the method for the high molecular in heparin sodium, it is characterized in that: tire ratio of tiring with IIa of Xa is 0.9-1.1.
7. enzymolysis process according to claim 2 is separated the method for the high molecular in heparin sodium, it is characterized in that: the content of dermatan sulfate is less than 1%.
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| CN104725531A (en) * | 2013-12-24 | 2015-06-24 | 安徽宝迪肉类食品有限公司 | Production process of effectively extracting heparin sodium |
| CN104650262A (en) * | 2014-12-24 | 2015-05-27 | 青岛九龙生物医药有限公司 | Method for controlling molecular weight of heparin sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1238182A (en) * | 1998-06-05 | 1999-12-15 | 何德惠 | Process for extracting coarse lipo-hepinette from lung of animal |
| 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 |
| CN103030715A (en) * | 2012-12-07 | 2013-04-10 | 青岛九龙生物医药有限公司 | Method for separating purified heparin sodium |
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| CN103044577B (en) * | 2012-12-07 | 2015-05-06 | 青岛九龙生物医药有限公司 | Method for reducing dermatan sulfate content in heparin sodium product |
| CN103145875B (en) * | 2012-12-07 | 2015-11-25 | 青岛九龙生物医药有限公司 | A kind of processing method reducing organic solvent residual in heparin sodium |
| CN103044578B (en) * | 2012-12-07 | 2015-05-06 | 青岛九龙生物医药有限公司 | Efficient method for refining heparin sodium crude products |
| CN103145878B (en) * | 2012-12-08 | 2016-04-13 | 青岛九龙生物医药有限公司 | A kind of ultralow point of heparin sodium technical study |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1238182A (en) * | 1998-06-05 | 1999-12-15 | 何德惠 | Process for extracting coarse lipo-hepinette from lung of animal |
| 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 |
| CN103030715A (en) * | 2012-12-07 | 2013-04-10 | 青岛九龙生物医药有限公司 | Method for separating purified heparin sodium |
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