CN103804520A - Method for improving test index of heparin sodium competitive product 260nm absorbancy - Google Patents
Method for improving test index of heparin sodium competitive product 260nm absorbancy Download PDFInfo
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Abstract
The invention discloses a method for improving test index of heparin sodium competitive product 260nm absorbancy. By utilizing the method, the standard request of Chinese pharmacopoeia and United States pharmacopoeia that heparin sodium competitive product 260nm absorbancy is less than 0.2 is met, the request of United States client that the 260nm absorbancy is less than 0.1 is met, the technical scheme aims at the test index of 260nm light absorption and the level of hybrid protein and nucleic acid content of representative products, and the key of research and development is how to remove hybrid protein and nucleic acid farthest. By adopting heparin sodium refining process, proper pH value and ethanol precipitation degree are selected to carry out separation and purification on heparin sodium, impurities of acid protein, alkali protein, peptide, nucleic acid, and the like can be removed farthest, and quality standard is in line with various indexes specified by Chinese pharmacopoeia, United States pharmacopoeia, British pharmacopoeia and Western Europe pharmacopoeia.
Description
Technical field
The present invention relates to biological technical field, relate in particular to and remove to greatest extent foreign protein and nucleic acid, improve refined heparin sodium 260nm absorbance detection and refer to calibration method.
Background technology
Heparin sodium is a kind of biochemical drug extracting from pig intestinal mucosa, be operation in irreplaceable, 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 is developed into hydrogen peroxide oxidation method by potassium permanganate oxidation method, in conjunction with alcohol wash partition method, a large amount of impurity is taken away with ethanol, develops into finally enzymolysis process impurity and is further removed.In heparin sodium, Research Emphasis is how to remove to greatest extent foreign protein and nucleic acid.Chinese Pharmacopoeia and American Pharmacopeia are <0.2 to heparin sodium finished product 260nm absorbancy standard-required, and client is higher to this requirement, require the necessary <0.1 of 260nm absorbancy, for meeting market user's requirement, promote export, domestic heparin enterprise updates to meet the need of market to this Technology.
Summary of the invention
The invention provides a kind of PH of tune and ethanol precipitation number method and remove the method for foreign protein and nucleic acid in heparin sodium, in order to meet the necessary <0.1 of customer requirement refined heparin sodium 260nm absorbancy, utilize in heparin sodium refining step, select suitable pH value, the ethanol precipitation number of degrees, heparin sodium is carried out to separation and purification, can remove to greatest extent the impurity such as acid albumin, basonuclin, peptide, nucleic acid, to reach refined heparin sodium purifying to greatest extent, make refined heparin sodium 260nm absorbancy <0.1.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions:
Regulate method to remove a method for foreign protein and nucleic acid in heparin sodium, it is characterized in that: adopt and regulate PH and ethanol precipitation number that foreign protein in heparin sodium and nucleic acid are removed.
In the technical scheme of invention, also there is following technical characterictic: described adjusting 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, add while stirring, in raw material and tap water 1:(6-7) ratio dissolving, stir after 5-10 hour, with whether all dissolving stirring rod examination bottom;
2, salt solution-enzymolysis:
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid soln, while being warming up between 50-55 ℃, add stomach en-5-10g/ hundred million units, add again 10-20g/ hundred million unit pancreatin, 50-55 ℃ of insulation 2-4 hour, then add sodium-chlor, the amount of regulatory enzyme and sodium-chlor repeatedly.
3, the temperature that rises suddenly:
Previous step salt solution-enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, in the time that temperature is down to 50-55 ℃, with 2-6mol/L sodium hydroxide solution tune 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, filtrate is adjusted to PH10.0-12.0 with hydrochloric acid, add concentration while stirring 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, adjust solution PH 6.0-7.0 with hydrochloric acid soln, add concentration while stirring 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, solution is adjusted to PH6.0-7.0 with hydrochloric acid soln, 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, 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, add ethanol while stirring, make alcohol concn is 45-50% in the time of 20 ℃, precipitation 10-12 hour,
8,, after throw out is pressed to 2-5L/ hundred million units and dissolved by purified water, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, precipitate with ethanol, make alcohol concn reach 75-80%, add the sodium chloride solution of 23-26%, every 1 liter of solution adds 6-10ml sodium chloride solution, quiescent setting 10-12 hour again;
9, upper strata ethanol is discarded, add dehydrated alcohol dehydration, add while stirring, making alcohol concn is 97-99%, and static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in product, remains ethanol with vacuum pump by pipeline and filter flask handle and drain, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, heat with recirculated water, 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; 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 PH and the ethanol precipitation number method of regulating that adopt, a large amount of impurity is taken away with ethanol, its fine work absorbancy <0.1, amount to Chinese Pharmacopoeia and American Pharmacopeia to refined heparin sodium 260nm absorbancy standard-required <0.2, met the necessary <0.1 of U.S. customer requirement 260nm absorbancy, its quality standard meets the indices of Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia and West Europe pharmacopeia defined.
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 a certain amount of tap water, then heparin sodium crude is joined in retort, add while stirring, in raw material and tap water 1:(6-7) ratio dissolving, stir after 5-10 hour, with whether all dissolving stirring rod examination bottom;
2, salt solution-enzymolysis:
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid soln, while being warming up between 50-55 ℃, add stomach en-5-10g/ hundred million units, add again 10-20g/ hundred million unit pancreatin, 50-55 ℃ of insulation 2-4 hour, then add sodium-chlor, the amount of regulatory enzyme and sodium-chlor repeatedly.
3, the temperature that rises suddenly:
Previous step salt solution-enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, in the time that temperature is down to 50-55 ℃, with 2-6mol/L sodium hydroxide solution tune 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, filtrate is adjusted to PH10.0-12.0 with hydrochloric acid, add concentration while stirring 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, adjust solution PH 6.0-7.0 with hydrochloric acid soln, add concentration while stirring 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, solution is adjusted to PH6.0-7.0 with hydrochloric acid soln, 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, 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, add ethanol while stirring, make alcohol concn is 45-50% in the time of 20 ℃, precipitation 10-12 hour,
8,, after throw out is pressed to 2-5L/ hundred million units and dissolved by purified water, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, precipitate with ethanol, make alcohol concn reach 75-80%, add the sodium chloride solution of 23-26%, every 1 liter of solution adds 6-10ml sodium chloride solution, quiescent setting 10-12 hour again;
9, upper strata ethanol is discarded, add dehydrated alcohol dehydration, add while stirring, making alcohol concn is 97-99%, and static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in product, remains ethanol with vacuum pump by pipeline and filter flask handle and drain, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, heat with recirculated water, 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.
The above, be only preferred embodiment of the present invention, is not the restriction of the present invention being made to 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. improve refined heparin sodium 260nm absorbance detection and refer to a calibration method, it is characterized in that: adopt suitable pH value and the ethanol precipitation number of degrees to make heparin sodium finished product 260nm absorbancy meet standard-required, step is as follows:
One, extract
1, dissolving crude product:
Open water valve, add a certain amount of tap water, then heparin sodium crude is joined in retort, add while stirring, in raw material and tap water 1:(6-7) ratio dissolving, stir after 5-10 hour, with whether all dissolving stirring rod examination bottom;
2, salt solution-enzymolysis:
By previous step lysate, first adjust PH7.0-8.0 with hydrochloric acid soln, while being warming up between 50-55 ℃, add stomach en-5-10g/ hundred million units, add again 10-20g/ hundred million unit pancreatin, 50-55 ℃ of insulation 2-4 hour, then add sodium-chlor, the amount of regulatory enzyme and sodium-chlor repeatedly.
3, the temperature that rises suddenly:
Previous step salt solution-enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, and static 10-30 minute, opens stirring, passes into circulating water cooling, in the time that temperature is down to 50-55 ℃, with 2-6mol/L sodium hydroxide solution tune 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, filtrate is adjusted to PH10.0-12.0 with hydrochloric acid, add concentration while stirring 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, adjust solution PH 6.0-7.0 with hydrochloric acid soln, add concentration while stirring 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, solution is adjusted to PH6.0-7.0 with hydrochloric acid soln, 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, 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, add ethanol while stirring, make alcohol concn is 45-50% in the time of 20 ℃, precipitation 10-12 hour,
8,, after throw out is pressed to 2-5L/ hundred million units and dissolved by purified water, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, precipitate with ethanol, make alcohol concn reach 75-80%, add the sodium chloride solution of 23-26%, every 1 liter of solution adds 6-10ml sodium chloride solution, quiescent setting 10-12 hour again;
9, upper strata ethanol is discarded, add dehydrated alcohol dehydration, add while stirring, making alcohol concn is 97-99%, and static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in product, remains ethanol with vacuum pump by pipeline and filter flask handle and drain, to be dried;
10, the product of draining is evenly placed in Stainless Steel Disc, is placed in vacuum drying oven and vacuumizes, heat with recirculated water, 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.
2. the method for adjusting pH value according to claim 1 and ethanol precipitation number, it is characterized in that: heparin sodium refining step, select suitable pH value, the ethanol precipitation number of degrees, heparin sodium is carried out to separation and purification, can remove to greatest extent the impurity such as acid albumin, basonuclin, peptide, nucleic acid, thereby obtain the refined heparin sodium of high quality, high yield, make refined heparin sodium 260nm absorbancy <0.1.
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Cited By (4)
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| CN104017101A (en) * | 2014-06-18 | 2014-09-03 | 中国科学院过程工程研究所 | Preparation method of rehmanniae polysaccharide |
| CN104530261A (en) * | 2014-12-24 | 2015-04-22 | 青岛九龙生物医药有限公司 | Method for reducing absorbancy of heparin sodium at 260nm |
| CN104650263A (en) * | 2014-12-25 | 2015-05-27 | 青岛九龙生物医药有限公司 | Method for improving stability of refined heparin sodium 10% water solution by virtue of stabilizer adding process |
| CN115286725A (en) * | 2022-08-31 | 2022-11-04 | 山东万邦赛诺康生化制药股份有限公司 | Preparation method of high-purity low-molecular-weight heparin |
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| CN104650263A (en) * | 2014-12-25 | 2015-05-27 | 青岛九龙生物医药有限公司 | Method for improving stability of refined heparin sodium 10% water solution by virtue of stabilizer adding process |
| CN115286725A (en) * | 2022-08-31 | 2022-11-04 | 山东万邦赛诺康生化制药股份有限公司 | Preparation method of high-purity low-molecular-weight heparin |
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Application publication date: 20140521 |