CN103755835A - Method for stabilizing anti-Xa factor activity of refined heparin sodium by employing ethanol fractional precipitation process - Google Patents
Method for stabilizing anti-Xa factor activity of refined heparin sodium by employing ethanol fractional precipitation process Download PDFInfo
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Abstract
The invention discloses a method for stabilizing anti-Xa factor activity of refined heparin sodium by employing an ethanol fractional precipitation process. American clients put forward that the anti-Xa factor activity must be 100% or more and the tilter should be larger than 180 mu/mg, and in order to satisfy the requirements of the American clients, through effort for technological breakthrough, the employed technical scheme comprise: in the heparin sodium refining process, employing the ethanol fractional precipitation process, adjusting the ethanol precipitation degree, performing different-degree precipitation on the product, and controlling the tilter of the product, so as to reach the purpose of stabilizing the anti-Xa factor activity. The quality standard of refined heparin sodium accords with various indexes prescribed by Chinese pharmacopoeia, American pharmacopeia, British pharmacopeia and Western Europe pharmacopeia.
Description
Technical field
The present invention relates to biological technical field, be specifically related to stablize the method for anti-Xa factor activity in heparin sodium.
Background technology
Heparin sodium is a kind of biochemical drug extracting from pig intestinal mucosa, be irreplaceable in operation, save life, market can not be out of stock choice drug.From nineteen forties, for since clinical, its range of application constantly expands, and especially since nineteen nineties, this product is clinical is mainly used in preventing thrombosis, treatment cardiovascular diseases, hemopathy, uremia etc.The western countries' preventive and therapeutic effect of heparin sodium to cancer that begun one's study, its new purposes constantly increases.
Since entering nineteen seventies, China's heparin sodium production technique is updated, and becomes the country of world's heparin sodium output maximum.The heparin sodium product of world market has more than 70% from China.Refined heparin sodium is produced and by potassium permanganate oxidation method, is developed into hydrogen peroxide oxidation method, in conjunction with alcohol wash partition method, a large amount of impurity is taken away with ethanol.
Summary of the invention
The invention provides a kind of ethanol precipitation method and stablize the method for the anti-Xa factor activity of refined heparin sodium, to propose in order to meet U.S. client Dui Wo company: anti-Xa factor activity must be more than 100%, tire and be greater than the requirement of 180u/mg, the technique that adopts salt solution-enzymolysis to combine, repeatedly regulate the add-on of sodium-chlor and enzyme, refining step, regulate the ethanol precipitation number of degrees, product is carried out separated in various degree, control is tired, thereby realize, by ethanol precipitation method, heparin sodium is carried out separated in various degree, control is tired, stablized the anti-Xa factor of refined heparin sodium active.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions:
Ethanol precipitation method is stablized a method for the anti-Xa factor activity of refined heparin sodium, it is characterized in that: the technique that adopts salt solution-enzymolysis to combine, regulates the add-on of sodium-chlor and enzyme repeatedly, refining step, regulate the ethanol precipitation number of degrees, product is carried out to separation in various degree, control is tired.
In the technical scheme of invention, also there is following technical characterictic: described ethanol precipitation method comprises the steps:
One, extract
1, dissolving crude product:
Open water valve, add a certain amount of tap water, then heparin sodium crude is joined in retort, while stirring, add, by raw material and tap water 1: (6-7) ratio is dissolved, stirs after 5-10 hour, dissolving whether all bottom trying by stirring rod;
2, enzymolysis:
By previous step lysate, first with hydrochloric acid soln, adjust PH7.0-8.0, while being warming up between 50-55 ℃, add stomach en-5-10g/ hundred million units, then add 10-20g/ hundred million unit pancreatin, 50-55 ℃ of insulation 2-4 hour;
3, the temperature that rises suddenly:
Previous step enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, when temperature is down to 50-55 ℃, with 2-6mol/L sodium hydroxide solution, adjusts PH10.0-12.0, static layering 20-30 hour;
4, the impurity of bottom settlings is centrifugal:
Siphon supernatant, filters with 40-100 order filter bag, and the solution after filtration is divided into supernatant liquor and lower sediment, stays supernatant liquor to wait to precipitate, and it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
Two, refining
1, precipitate for the first time:
Treat that above-mentioned supernatant liquor and centrifugate temperature be down to 20-30 ℃, add 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted to PH10.0-12.0, while stirring, add concentration and be 95～97% ethanolic soln, make the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
2, oxidation for the first time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
3, precipitate for the second time: solution adds 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, adjust solution PH 6.0-7.0, while stirring, add concentration and be 95～97% ethanolic soln, make the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
4, oxidation for the second time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
5, precipitation for the third time: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH10.0-12.0, adds concentration and be 95～97% ethanolic soln while stirring, and makes the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
6, oxidation for the third time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
7, the 4th precipitation: if previous step solution has throw out to separate out, use whizzer centrifugal, do not separate out and directly add 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH6.0-7.0, solution is let cool in storehouse and is refrigerated to-10 ℃--5 ℃, Bian Jia-10 ℃ are stirred on limit--the acetone of 5 ℃, the quality percentage composition that makes acetone account for solution is 40-45%,-5 ℃-0 ℃ insulation 24-30 hour, then waste acetone is discarded, chondroitin polysulfate is taken away by acetone, the portion's throw out of keeping on file dissolves by purified water, solution adds 20-30g/L sodium-chlor again, with hydrochloric acid soln, adjust solution PH 6.0-7.0, while stirring, add ethanol, make alcohol concn is 45-50% in the time of 20 ℃, precipitation 10-12 hour,
8, throw out is pressed after the dissolving of 2-5L/ hundred million units by purified water, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, with ethanol, precipitated, make alcohol concn reach 75-80%, the sodium chloride solution that adds again 23-26%, 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, while stirring, add, making alcohol concn is 97-99%, and static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in product, with vacuum pump, by pipeline and filter flask, residue ethanol is drained, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, with recirculated water, heat, temperature 35-60 ℃, dries 70-80 hour;
11, packing: product is taken out, weigh, 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 characterictic: the solution after the 4th precipitation carries out QA sample examination, surveys absorbancy: 260nm < 0.1; 400nm < 0.02; If defective, continue to repeat process above, if qualified transfer subsequent processing.
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 is taken away with ethanol, by acetone extract method, the chondroitin polysulfate in heparin sodium is removed again, its fine work yield reaches more than 90%, activity is tired more than 180usp/mg, amounts to WHO international standard at 200iu/mg, and its quality standard meets the indices of Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia and West Europe pharmacopeia defined.
The anti-Xa factor result of Qingdao Jiulong Bio-Pharmaceutical Co., Ltd.'s product summary sheet
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, while stirring, add, stir after 6 hours, with stirring rod examination bottom, whether all dissolve;
2, enzymolysis:
By previous step lysate, first with hydrochloric acid soln, adjust PH7.5, while being warming up to 53 ℃, add stomach en-1500g, then add 300g pancreatin, 53 ℃ are incubated 3 hours;
3, the temperature that rises suddenly:
Previous step enzymolysis solution was warming up to 88 ℃ in 35 minutes, static 15 minutes, open stirring, pass into circulating water cooling, when temperature is down to 50 ℃, with 6mol/L sodium hydroxide solution, adjust PH11.0, static layering 24 hours;
4, the impurity of bottom settlings is centrifugal:
Siphon supernatant, filters with 80 order filter bags, and the solution after filtration is divided into supernatant liquor and lower sediment, stays supernatant liquor to wait to precipitate, and it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
Two, refining
1, precipitate for the first time:
Treat that above-mentioned supernatant liquor and centrifugate temperature be down to 25 ℃, add 22.5kg sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted to PH10.5, while stirring, add concentration and be 95～97% ethanolic soln 920L, precipitate 10 hours;
2, oxidation for the first time: discard upper strata waste ethanol, lower sediment thing is that product dissolves by 640L purified water, with sodium hydroxide solution, solution is adjusted to PH11.0, then adds 20L hydrogen peroxide, is oxidized 10 hours;
3, precipitation for the second time: solution adds 12.8kg sodium-chlor, after stirring and dissolving, adjusts solution PH 6.0 with hydrochloric acid soln, adds concentration and is 95～97% ethanolic soln 640L while stirring, precipitate 10 hours;
4, oxidation for the second time: discard upper strata waste ethanol, lower sediment thing dissolves by 640L purified water, with sodium hydroxide solution, solution is adjusted to PH11.0, then adds 20L hydrogen peroxide, is oxidized 10 hours;
5, precipitation for the third time: solution adds 12.8kg sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH6.0, adds concentration and be 95～97% ethanolic soln 640L while stirring, and precipitates 10 hours;
6, oxidation for the third time: discard upper strata waste ethanol, lower sediment thing dissolves by 640L purified water, with sodium hydroxide solution, solution is adjusted to PH11.0, then adds 21L hydrogen peroxide, is oxidized 10 hours;
7, the 4th precipitation: if previous step solution has throw out to separate out, use whizzer centrifugal, do not separate out and directly add 12.8kg sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH6.0, solution is let cool in storehouse and be refrigerated to-6 ℃, the acetone 600L of Bian Jia-10 ℃ is stirred on limit,-3 ℃ are incubated 24 hours, then waste acetone is discarded, chondroitin polysulfate is taken away by acetone, and the portion's throw out of keeping on file dissolves by purified water, solution adds 12.8kg sodium-chlor again, with hydrochloric acid soln, adjust solution PH 6.0, while stirring, add ethanol 640L, precipitate 10 hours;
8, after throw out is dissolved by 300L purified water, with 0.3 micron, aperture filter membrane board and frame machine micro-filtration, by 840L ethanol precipitation, make alcohol concn reach 75-80%, then add 26% sodium chloride solution 11L, quiescent setting 10 hours;
9, upper strata ethanol is discarded, add the dehydration of 500L dehydrated alcohol, while stirring, add, making alcohol concn is 97-99%, static 24 hours, discards upper strata ethanol, stainless steel core rod is placed in product, with vacuum pump, by pipeline and filter flask, residue ethanol is drained, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, with recirculated water, heat, temperature 50 C, dries 72 hours;
11, packing: product is taken out, weigh, make every packing bag 5Kg, with sealing machine sealing, be placed in Aluminum Drum to be tested.
The above, be only preferred embodiment of the present invention, is not the present invention to be done to the restriction of other form, and any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not depart from, any simple modification, equivalent variations and the remodeling above embodiment done according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (2)
1. ethanol precipitation method is stablized a method for the anti-Xa factor activity of refined heparin sodium, it is characterized in that: the technique that adopts salt solution-enzymolysis to combine, regulates the add-on of sodium-chlor and enzyme repeatedly, refining step, regulate the ethanol precipitation number of degrees, product is carried out to separation in various degree, control is tired.
2. ethanol precipitation method according to claim 1 is stablized the method for the anti-Xa factor activity of refined heparin sodium, it is characterized in that described ethanol precipitation method comprises the steps:
One, extract
1, dissolving crude product:
Open water valve, add a certain amount of tap water, then heparin sodium crude is joined in retort, while stirring, add, by raw material and tap water 1: (6-7) ratio is dissolved, stirs after 5-10 hour, dissolving whether all bottom trying by stirring rod;
2, enzymolysis:
By previous step lysate, first with hydrochloric acid soln, adjust PH7.0-8.0, while being warming up between 50-55 ℃, add stomach en-5-10g/ hundred million units, then add 10-20g/ hundred million unit pancreatin, 50-55 ℃ of insulation 2-4 hour;
3, the temperature that rises suddenly:
Previous step enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, when temperature is down to 50-55 ℃, with 2-6mol/L sodium hydroxide solution, adjusts PH10.0-12.0, static layering 20-30 hour;
4, the impurity of bottom settlings is centrifugal:
Siphon supernatant, filters with 40-100 order filter bag, and the solution after filtration is divided into supernatant liquor and lower sediment, stays supernatant liquor to wait to precipitate, and it is centrifugal that lower sediment is put whizzer, stays upper strata centrifugate after centrifugal;
Two, refining
1, precipitate for the first time:
Treat that above-mentioned supernatant liquor and centrifugate temperature be down to 20-30 ℃, add 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid, filtrate is adjusted to PH10.0-12.0, while stirring, add concentration and be 95～97% ethanolic soln, make the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
2, oxidation for the first time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
3, precipitate for the second time: solution adds 20-30g/L sodium-chlor, after stirring and dissolving, with hydrochloric acid soln, adjust solution PH 6.0-7.0, while stirring, add concentration and be 95～97% ethanolic soln, make the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
4, oxidation for the second time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
5, precipitation for the third time: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH10.0-12.0, adds concentration and be 95～97% ethanolic soln while stirring, and makes the concentration of ethanol reach 45～50% in the time of 20 ℃, precipitation 10-12 hour;
6, oxidation for the third time: discard upper strata waste ethanol, lower sediment thing dissolves by purified water, with sodium hydroxide solution, solution is adjusted to PH10.0-12.0, then adds volume 3-5% hydrogen peroxide, oxidation 10-12 hour;
7, the 4th precipitation: if previous step solution has throw out to separate out, use whizzer centrifugal, do not separate out and directly add 20-30g/L sodium-chlor, with hydrochloric acid soln, solution is adjusted to PH6.0-7.0, solution is let cool in storehouse and is refrigerated to-10 ℃--5 ℃, Bian Jia-10 ℃ are stirred on limit--the acetone of 5 ℃, the quality percentage composition that makes acetone account for solution is 40-45%,-5 ℃-0 ℃ insulation 24-30 hour, then waste acetone is discarded, chondroitin polysulfate is taken away by acetone, the portion's throw out of keeping on file dissolves by purified water, solution adds 20-30g/L sodium-chlor again, with hydrochloric acid soln, adjust solution PH 6.0-7.0, while stirring, add ethanol, make alcohol concn is 45-50% in the time of 20 ℃, precipitation 10-12 hour,
8, throw out is pressed after the dissolving of 2-5L/ hundred million units by purified water, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, with ethanol, precipitated, make alcohol concn reach 75-80%, the sodium chloride solution that adds again 23-26%, 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, while stirring, add, making alcohol concn is 97-99%, and static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in product, with vacuum pump, by pipeline and filter flask, residue ethanol is drained, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, with recirculated water, heat, temperature 35-60 ℃, dries 70-80 hour;
11, packing: product is taken out, weigh, make every packing bag 5kg, with sealing machine sealing, be placed in Aluminum Drum to be tested.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980387A (en) * | 2014-05-26 | 2014-08-13 | 安徽科宝生物工程有限公司 | Method for preparing heparin sodium by biological enzyme process |
| 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 |
| CN110787866A (en) * | 2019-11-20 | 2020-02-14 | 江苏千牧生物科技股份有限公司 | Vibration grinding device for heparin sodium production and production process thereof |
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| 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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| US20020009782A1 (en) * | 1999-06-03 | 2002-01-24 | Daphna Miron | Heparin and heparan sulfate derived oligosaccharides and a method for their manufacture |
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| CN103980387A (en) * | 2014-05-26 | 2014-08-13 | 安徽科宝生物工程有限公司 | Method for preparing heparin sodium by biological enzyme process |
| 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 |
| CN110787866A (en) * | 2019-11-20 | 2020-02-14 | 江苏千牧生物科技股份有限公司 | Vibration grinding device for heparin sodium production and production process thereof |
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Application publication date: 20140430 |