CN101575385B - Method for separating chondroitin polysulfate from heparin sodium by extraction method - Google Patents
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Abstract
The invention discloses a method for separating chondroitin polysulfate from heparin sodium by an extraction method, breaking through the conclusion drawn by domestic and international experts, i.e., the chondroitin polysulfate in the heparin sodium is inseparable. The technical scheme is as follows: an acetone extraction method is adopted to remove the chondroitin polysulfate in the heparin sodium and thoroughly separate the chondroitin polysulfate from the heparin sodium by the refinement steps of crude product dissolution, enzymolysis, rapid heating, impurity centrifugation, a plurality of precipitation and oxidation so that the refined product rate of the heparin sodium reaches over 83 percent, the activity valence is over 180 usp/mg and over 200 iu/mg by being converted into the WHO international standard, and the quality standard accords with various indexes specified by Chinese pharmacopoeias, America pharmacopoeias, English pharmacopoeias and Western European pharmacopoeias.
Description
Technical field
The present invention relates to biological technical field, relate in particular to the method for from heparin sodium, isolating chondroitin polysulfate.
Background technology
Heparin sodium is a kind of biochemical drug that extracts from pig intestinal mucosa, be irreplaceable in the operation, save life, market can not be out of stock medicine.From nineteen forties be used for clinical since, its range of application constantly enlarges, 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 heparin sodium to the preventive and therapeutic effect of cancer, and its new purposes constantly increases.
Entered since 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.The production of heparin sodium elaboration develops into hydrogen peroxide oxidation method by potassium permanganate oxidation method, washes partition method in conjunction with alcohol, and a large amount of impurity is taken away with ethanol.On February 11st, 2008, the U.S. is dead because of 4 examples appear in injecting heparin sodium, and 350 many cases untoward reactions become " the heparin sodium incident " that cause a sensation the world.Through being expounded through peer review, above-mentioned death and untoward reaction are owing to contain due to the chondroitin polysulfate in the heparin sodium.Chondroitin polysulfate is a kind of of heparitin, and its character is similar substantially to heparin sodium, and process detects and the difference of heparin sodium is: 1, heparin sodium is the dextrorotation structure; And chondroitin polysulfate is left-handed structure; 2, absolute molecular weight: the chondroitin polysulfate molecular weight than heparin sodium after testing is big; 3, its peakedness ratio heparin sodium of capillary electrophoresis occurs earlier.
The Chinese government attaches great importance to and pays close attention to impact development, April 7, Bureau of Drugs Supervision of country holds " about strengthening heparin sodium quality of production management symposium " national heparin sodium bulk drug and the responsible official of preparation manufacturing enterprise meeting in Beijing, announced in the meeting international expert and U.S. FDA about chondroitin polysulfate in the heparin sodium be artificial add and indissociable identification, and require every heparin sodium that contains chondroitin polysulfate that comes into the market to recall without exception.April 17 to 18 and April 24 to 25 have been held heparin sodium international symposium again in the U.S., May 4, U.S. FDA official website announces, causing death's major cause is exactly a chondroitin polysulfate, May 7,80 many cases death have appearred in the Chinese Central Television (CCTV) report U.S., and so far also not report relevant from heparin sodium with the isolating technology of chondroitin polysulfate.
Summary of the invention
The invention provides the method that a kind of extraction process separates the chondroitin polysulfate in the heparin sodium, be in order to capture domestic and international expert about the indissociable final conclusion of the chondroitin polysulfate in the heparin sodium, utilize the character of chondroitin polysulfate, it is dissolved in the acetone, the acetone that will have chondroitin polysulfate removes then, the sedimentary heparin sodium of the portion of keeping on file, thus realize heparin sodium thoroughly being separated with chondroitin polysulfate with extraction process.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions:
A kind of extraction process separates the method for the chondroitin polysulfate in the heparin sodium, it is characterized in that: adopt the acetone extract method that the chondroitin polysulfate in the heparin sodium is removed.
In the technical scheme of invention, also have following technical characterictic: described acetone extract method comprises the steps:
One, extracts
1, dissolving crude product:
Open water valve, add a certain amount of tap water, again heparin sodium crude is joined in the retort, add while stirring, by raw material and tap water 1: (6-7) ratio dissolving, stirs after 5-10 hour, whether all dissolve bottom trying with stirring rod;
2, enzymolysis:
With the previous step lysate, transfer PH7.0-8.0 with hydrochloric acid soln earlier, add stomach en-5-10g/ hundred million units when being warming up between 50-55 ℃, add 10-20g/ hundred million unit pancreatin again, 50-55 ℃ is incubated 2-4 hour;
3, the temperature that rises suddenly:
The previous step enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, static 10-30 minute, open stirring, feed circulating water cooling, when treating that temperature is reduced to 50-55 ℃, transfer PH10.0-12.0, static layering 20-30 hour with the 2-6mol/L sodium hydroxide solution;
4, the impurity of bottom settlings is centrifugal:
The siphon supernatant filters with 40-100 order filter bag, and the solution after the 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 reduce to 20-30 ℃, add 20-30g/L sodium-chlor, after the stirring and dissolving, with hydrochloric acid filtrate is transferred PH10.0-12.0, add concentration while stirring and be 95～97% ethanolic soln, make concentration of ethanol in the time of 20 ℃, reach 45～50%, precipitate 10-12 hour;
2, oxidation for the first time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
3, precipitate for the second time: solution adds 20-30g/L sodium-chlor, after the stirring and dissolving, transfer solution PH 6.0-7.0, add concentration while stirring and be 95～97% ethanolic soln with hydrochloric acid soln, make concentration of ethanol in the time of 20 ℃, reach 45～50%, precipitate 10-12 hour;
4, oxidation for the second time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
5, precipitation for the third time: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln solution is transferred PH10.0-12.0, adds concentration while stirring and be 95～97% ethanolic soln, makes concentration of ethanol reach 45～50% in the time of 20 ℃, precipitates 10-12 hour;
6, oxidation for the third time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
7, the 4th precipitation: previous step solution is if there is throw out to separate out, then use whizzer centrifugal, do not separate out and then directly add 20-30g/L sodium-chlor, with hydrochloric acid soln solution is transferred PH6.0-7.0, solution put in the freezer is refrigerated to-10 ℃--5 ℃, the limit is stirred Bian Jia-10 ℃--5 ℃ acetone, the quality percentage composition that makes acetone account for solution is 40-45%,-5 ℃-0 ℃ is incubated 24-30 hour, then waste acetone is discarded, chondroitin polysulfate is taken away by acetone, and the portion's throw out of keeping on file dissolves with purified water, and solution adds 20-30g/L sodium-chlor again, transfer solution PH 6.0-7.0 with hydrochloric acid soln, add ethanol while stirring, making alcohol concn is 45-50% in the time of 20 ℃, precipitates 10-12 hour;
8, throw out is pressed 2-5L/ hundred million units dissolvings with purified water after, with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, use ethanol sedimentation, make alcohol concn reach 75-80%, the sodium chloride solution that adds 23-26% again, per 1 liter of solution adds the 6-10ml sodium chloride solution, quiescent setting 10-12 hour;
9, upper strata ethanol is discarded, add the dehydrated alcohol dehydration, add while stirring, making alcohol concn is 97-99%, static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in the product, by pipeline and filter flask residue ethanol is drained with vacuum pump, to be dried;
10, the product of draining evenly is placed in the Stainless Steel Disc, is placed in the vacuum drying oven and vacuumizes, heat, temperature 35-60 ℃, dried 70-80 hour with recirculated water;
11, packing: product is taken out, weigh, make every packing bag 5kg, seal, be placed in the Aluminum Drum to be tested with sealing machine.
In the technical scheme of invention, also have following technical characterictic: the solution of the 4th post precipitation carries out the QA sample examination, surveys absorbancy: 260nm＜0.1; 400nm＜0.02; If defective, if process above continuing to repeat is qualified transfer subsequent processing.
Compared with prior art, advantage of the present invention and positively effect are:
Hydrogen peroxide oxidation method is adopted in heparin sodium elaboration production of the present invention, wash partition method in conjunction with alcohol, a large amount of impurity is taken away with ethanol, with the acetone extract method chondroitin polysulfate in the heparin sodium is removed again, its elaboration yield reaches more than 83%, activity is tired more than 180usp/mg, amounts to the WHO international standard at 200 iu/mg, and its quality standard meets every index of Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia and West Europe pharmacopeia defined.
Heparin sodium thoroughly separates with the chondroitin polysulfate success, for the development of world's biological medicine is made contributions; Promoted national live pig to produce; This product is annual to be exported at 10 more than hundred million, for country's foreign exchange earning is made contributions.Be again a support agriculture-countryside-farmer, turn waste into wealth the good project of environment protection.
Description of drawings
Fig. 1 is the heparin sodium collection of illustrative plates that contains chondroitin polysulfate before separating;
Fig. 2 is the collection of illustrative plates that separates the pure heparin sodium in back;
Fig. 3 is the collection of illustrative plates of pure chondroitin polysulfate.
Embodiment
The invention will be further described below in conjunction with the drawings and specific embodiments.
Embodiment 1
One, extracts
1, dissolving crude product:
Open water valve, add the 900L tap water, again 15,000,000,000 units of heparin sodium crude products are joined in the retort, add, stir after 6 hours, whether all dissolve with stirring rod examination bottom while stirring;
2, enzymolysis:
With the previous step lysate, transfer PH7.5 with hydrochloric acid soln earlier, add stomach en-1500g when being warming up to 53 ℃, add the 3000g pancreatin again, 53 ℃ are incubated 3 hours;
3, the temperature that rises suddenly:
The previous step enzymolysis solution was warming up to 88 ℃ in 35 minutes, static 15 minutes, open stirring, feed circulating water cooling, when treating that temperature is reduced to 50 ℃, transfer PH11.0, static layering 24 hours with the 6mol/L sodium hydroxide solution;
4, the impurity of bottom settlings is centrifugal:
The siphon supernatant filters with 80 order filter bags, and the solution after the 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 reduce to 25 ℃, add 22.5kg sodium-chlor, after the stirring and dissolving, filtrate is transferred PH10.5, add concentration while stirring and be 95～97% ethanolic soln 920L, precipitate 10 hours with hydrochloric acid;
2, oxidation for the first time: discard the upper strata waste ethanol, the lower sediment thing is that product dissolves with the 640L purified water, with sodium hydroxide solution solution is transferred PH11.0, adds the 20L hydrogen peroxide then, oxidation 10 hours;
3, precipitation for the second time: solution adds 12.8kg sodium-chlor, after the stirring and dissolving, transfers solution PH 6.0 with hydrochloric acid soln, adds concentration while stirring and be 95～97% ethanolic soln 640L, precipitates 10 hours;
4, oxidation for the second time: discard the upper strata waste ethanol, the lower sediment thing is transferred PH11.0 with sodium hydroxide solution with solution with the dissolving of 640L purified water, adds the 20L hydrogen peroxide then, oxidation 10 hours;
5, precipitation for the third time: solution adds 1 2.8kg sodium-chlor, with hydrochloric acid soln solution is transferred PH6.0, adds concentration while stirring and be 95～97% ethanolic soln 640L, precipitates 10 hours;
6, oxidation for the third time: discard the upper strata waste ethanol, the lower sediment thing is transferred PH11.0 with sodium hydroxide solution with solution with the dissolving of 640L purified water, adds the 21L hydrogen peroxide then, oxidation 10 hours;
7, the 4th precipitation: previous step solution is if there is throw out to separate out, then use whizzer centrifugal, do not separate out and then directly add 12.8kg sodium-chlor, with hydrochloric acid soln solution is transferred PH6.0, solution put in the freezer be refrigerated to-6 ℃, Bian Jia-10 ℃ acetone 600L is stirred on the 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 with purified water, solution adds 12.8kg sodium-chlor again, transfer solution PH 6.0 with hydrochloric acid soln, add ethanol 640L while stirring, precipitate 10 hours;
8, with after the dissolving of throw out usefulness 300L purified water,, use the 840L ethanol sedimentation, make alcohol concn reach 75-80%, add 26% sodium chloride solution 11L again, quiescent setting 10 hours with aperture 0.3 micron filter membrane board and frame machine micro-filtration;
9, upper strata ethanol is discarded, add the dehydration of 500L dehydrated alcohol, add while stirring, making alcohol concn is 97-99%, static 24 hours, discards upper strata ethanol, stainless steel core rod is placed in the product, by pipeline and filter flask residue ethanol is drained with vacuum pump, to be dried;
10, the product of draining evenly is placed in the Stainless Steel Disc, is placed in the vacuum drying oven and vacuumizes, heat with recirculated water, 50 ℃ of temperature were dried 72 hours;
11, packing: product is taken out, weigh, make every packing bag 5Kg, seal, be placed in the Aluminum Drum to be tested with sealing machine.
As shown in Figure 1, contain before the separation in the heparin sodium collection of illustrative plates of chondroitin polysulfate, the capillary electrophoresis peakedness ratio heparin sodium of chondroitin polysulfate occurs earlier, and than higher.
Fig. 1 compares with Fig. 2, Fig. 3, and the heparin sodium collection of illustrative plates that contains chondroitin polysulfate before promptly separating is compared with the collection of illustrative plates that separates the pure heparin sodium in back and the collection of illustrative plates of pure chondroitin polysulfate, does not have other peak value in the collection of illustrative plates among Fig. 2 and Fig. 3, illustrates that content is purer.
The above only is preferred embodiment of the present invention, is not to be the restriction of the present invention being made 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 break away to any simple modification, equivalent variations and remodeling that above embodiment did, still belongs to the protection domain of technical solution of the present invention according to technical spirit of the present invention.
Claims (3)
1. the method that extraction process separates the chondroitin polysulfate in the heparin sodium is characterized in that: adopt the acetone extract method that the chondroitin polysulfate in the heparin sodium is removed.
2. extraction process according to claim 1 separates the method for the chondroitin polysulfate in the heparin sodium, it is characterized in that described acetone extract method comprises the steps:
One, extracts
1, dissolving crude product:
Open water valve, add a certain amount of tap water, again heparin sodium crude is joined in the retort, add while stirring, by raw material and tap water 1: (6-7) ratio dissolving, stirs after 5-10 hour, whether all dissolve bottom trying with stirring rod;
2, enzymolysis:
With the previous step lysate, transfer PH7.0-8.0 with hydrochloric acid soln earlier, add stomach en-5-10g/ hundred million units when being warming up between 50-55 ℃, add 10-20g/ hundred million unit pancreatin again, 50-55 ℃ is incubated 2-4 hour;
3, the temperature that rises suddenly:
The previous step enzymolysis solution was warming up to 85-90 ℃ in 30～40 minutes, static 10-30 minute, open stirring, feed circulating water cooling, when treating that temperature is reduced to 50-55 ℃, transfer PH10.0-12.0, static layering 20-30 hour with the 2-6mol/L sodium hydroxide solution;
4, the impurity of bottom settlings is centrifugal:
The siphon supernatant filters with 40-100 order filter bag, and the solution after the 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 reduce to 20-30 ℃, add 20-30g/L sodium-chlor, after the stirring and dissolving, with hydrochloric acid filtrate is transferred PH10.0-12.0, add concentration while stirring and be 95～97% ethanolic soln, make concentration of ethanol in the time of 20 ℃, reach 45～50%, precipitate 10-12 hour;
2, oxidation for the first time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
3. precipitate for the second time: solution adds 20-30g/L sodium-chlor, after the stirring and dissolving, transfer solution PH 6.0-7.0, add concentration while stirring and be 95～97% ethanolic soln with hydrochloric acid soln, make concentration of ethanol in the time of 20 ℃, reach 45～50%, precipitate 10-12 hour;
4. oxidation for the second time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
5. precipitation for the third time: solution adds 20-30g/L sodium-chlor, with hydrochloric acid soln solution is transferred PH6.0, adds concentration while stirring and be 95～97% ethanolic soln, makes concentration of ethanol reach 45～50% in the time of 20 ℃, precipitates 10-12 hour;
6. oxidation for the third time: discard the upper strata waste ethanol, the lower sediment thing dissolves with purified water, with sodium hydroxide solution solution is transferred PH10.0-12.0, adds volume 3-5% hydrogen peroxide then, oxidation 10-12 hour;
7. precipitate for the 4th time: previous step solution is if there is throw out to separate out, then use whizzer centrifugal, do not separate out and then directly add 20-30g/L sodium-chlor, with hydrochloric acid soln solution is transferred PH6.0-7.0, solution put in the freezer is refrigerated to-10 ℃--5 ℃, the limit is stirred Bian Jia-10 ℃--5 ℃ acetone, the quality percentage composition that makes acetone account for solution is 40-45%,-5 ℃-0 ℃ is incubated 24-30 hour, then waste acetone is discarded, chondroitin polysulfate is taken away by acetone, and the portion's throw out of keeping on file dissolves with purified water, and solution adds 20-30g/L sodium-chlor again, transfer solution PH 6.0-7.0 with hydrochloric acid soln, add ethanol while stirring, making alcohol concn is 45-50% in the time of 20 ℃, precipitates 10-12 hour;
8. after throw out being pressed the dissolving of 2-5L/ hundred million units with purified water,, use ethanol sedimentation with aperture 0.22-0.3 micron filter membrane board and frame machine micro-filtration, make alcohol concn reach 75-80%, the sodium chloride solution that adds 23-26% again, per 1 liter of solution adds the 6-10ml sodium chloride solution, quiescent setting 10-12 hour;
9. upper strata ethanol is discarded, add the dehydrated alcohol dehydration, add while stirring, making alcohol concn is 97-99%, static 24-30 hour, discards upper strata ethanol, stainless steel core rod is placed in the product, by pipeline and filter flask residue ethanol is drained with vacuum pump, to be dried;
10. the product of draining evenly is placed in the Stainless Steel Disc, is placed in the vacuum drying oven and vacuumizes, heat, temperature 35-60 ℃, dried 70-80 hour with recirculated water;
11. packing: product is taken out, weigh, make every packing bag 5kg, seal, be placed in the Aluminum Drum to be tested with sealing machine.
3. extraction process according to claim 2 separates the method for the chondroitin polysulfate in the heparin sodium, and it is characterized in that: the solution of the 4th post precipitation carries out the QA sample examination, surveys absorbancy: 260nm＜0.1; 400nm＜0.02; If defective, if process above continuing to repeat is qualified transfer subsequent processing.
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| CN101825608A (en) * | 2010-02-12 | 2010-09-08 | 淮安麦德森化学有限公司 | Agarose gel electrophoresis detection method for oversulfated chondroitin sulfate in heparin sodium |
| CN101825607B (en) * | 2010-02-12 | 2012-10-03 | 淮安麦德森化学有限公司 | Method for separating and detecting over-sulfated chondroitin sulfate in heparin sodium |
| EP3144325B1 (en) * | 2010-09-14 | 2020-11-04 | University Of Miyazaki | High purity heparin and production method therefor |
| CN101942040B (en) * | 2010-09-16 | 2012-06-06 | 山东海科化工集团有限公司 | Method for removing oversulfated chondroitin sulfate in heparin sodium |
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| CN103641934A (en) * | 2013-11-21 | 2014-03-19 | 青岛佰众化工技术有限公司 | Chondroitin sulfate preparation method |
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| CN103804522B (en) * | 2013-11-24 | 2016-09-28 | 青岛九龙生物医药有限公司 | A kind of method improving heparin sodium purity |
| CN103804525A (en) * | 2013-11-26 | 2014-05-21 | 青岛九龙生物医药有限公司 | Method for removing organic residual in heparin sodium |
| CN104490793B (en) * | 2014-11-26 | 2017-08-29 | 山东辰中生物制药有限公司 | The method for improving liquaemin heat endurance |
| 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 |
| 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 |
| 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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