CN102911290B - Method for separating and purifying heparin sodium and heparan sulfate from heparin byproducts - Google Patents
Method for separating and purifying heparin sodium and heparan sulfate from heparin byproducts Download PDFInfo
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- CN102911290B CN102911290B CN201210424451.9A CN201210424451A CN102911290B CN 102911290 B CN102911290 B CN 102911290B CN 201210424451 A CN201210424451 A CN 201210424451A CN 102911290 B CN102911290 B CN 102911290B
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Abstract
The invention discloses a method for separating and purifying heparin sodium and heparan sulfate from heparin byproducts. The method comprises the steps of dissolving raw heparin byproducts, adding potassium acetate to precipitate and separate heparin sodium, adding potassium acetate to precipitate heparin sodium after precipitating and dissolving heparin sodium, collecting a precipitate, dissolving and then conducting fractional precipitation repeatedly with anhydrous alcohol to prepare the heparin sodium with a higher purity, adding a benedict reagent and a saturated sodium hydroxide solution to supernate, centrifuging to obtain a solution containing the heparan sulfate, removing copper ions with a decoppering agent, adding active carbon to absorb the precipitate, decolorizing and filtering, and then absorbing and eluting with anion exchange resin to obtain the high-purity heparan sulfate by separation. According to the method, the high-purity heparin sodium and heparan sulfate can be separated again from the byproducts used for producing the heparin sodium, so that financial resources and material resources required for storing or discarding a large number of heparin byproducts can be saved, wastes can be changed into valuables, the byproducts are recycled, the cost is saved greatly, and a value is created.
Description
Technical field
The present invention relates to a kind of from heparin byproduct the method for separating-purifying heparin sodium and Suleparoid, belong to mucopolysaccharide field of biological pharmacy.
Background technology
Heparin sodium is mucopolysaccharide sulfuric acid ester anticoagulant, and Recent study proves that heparin sodium also has reducing blood lipid.Suleparoid is the subcomponent of heparin, is present in unsegregated heparin.Compared with heparin sodium, Suleparoid has advantages of that anticoagulating active relaxes.Suleparoid, for anti-bolt, anti-inflammatory, reducing blood-fat and kidney of diabetic patients protection, is the hottest mucopolysaccharide biochemical drug of Recent study.
Process from pig intestinal mucosa through ion-exchange and fractionation precipitation production heparin, produce a large amount of by products, it is heparin byproduct, wherein chief component is Suleparoid, dermatan sulfate and heparin sodium, and its content is because of the different difference to some extent of specific rotation of by product.But due to active substance separation difficulty wherein, therefore generally these by products are abandoned or are stored after production heparin, or only do simple process, if traditional technology is mainly purify from heparin byproduct Suleparoid and dermatan sulfate, heparin sodium discards, and causes certain loss.Suleparoid is similar with dermatan sulfate character, adopts common ion exchange chromatography and organic solvent fractionation precipitation method to be difficult to Suleparoid purifying.In prior art, utilize Suleparoid to realize both separation with dermatan sulfate with the special reaction of Benedict's reagent, but in the Suleparoid solution obtaining in separation, contain a large amount of cupric ions.Patent (200910039359.9) is removed cupric ion by absorption and the washing of ion exchange column, not only easily reduce resin life, and be difficult to cupric ion to eliminate, make Suleparoid crude product still with light blue, through atomic absorption spectroscopy determination, content of copper ion exceedes 30ppm.
Summary of the invention
The object of this invention is to provide a kind of method of simultaneously isolating stay-in-grade highly purified heparin sodium and Suleparoid from heparin byproduct, this method is suitable for industrial production, low production cost, and technique is simple.
Object of the present invention can reach by following measures:
A method for separating-purifying heparin sodium and Suleparoid from heparin byproduct, is characterized in that according to the following steps:
1.. raw material heparin byproduct is dissolved in in purified water, to obtain concentration be 5-20%(w/v) solution, add Potassium ethanoate, make the content of Potassium ethanoate in solution reach 30-60%(w/v), by the pH value of acetic acid regulator solution to 5-7, at 18-20 DEG C, precipitate 20-80 hour, centrifugation precipitation and supernatant liquor;
2.. collect the 1. precipitation of gained of step, be precipitated as the operation 1. of raw material repeating step with this;
3.. collect the 2. precipitation of gained of step, after dissolving by purified water, add dehydrated alcohol to precipitate; The throw out obtaining repeats the step that purified water is dissolved and dehydrated alcohol precipitates, and last collecting precipitation is dry, obtains heparin sodium;
4.. 1. in the supernatant liquor of gained, add the Benedict's reagent of 0.2-1.2 times of volume and the saturated sodium hydroxide solution of 0.1-0.8 times of volume to step, at 20-25 DEG C after precipitation, precipitation separation and supernatant liquor;
5.. the step 4. supernatant liquor of gained adds sodium sulphite, staticly settles 1-3 hour, then filters after adding gac to stir;
6.. in the clear liquid that 5. step obtains, add 1-5 times of purified water dilution, and the pH value of regulator solution is to 5-7, then adds anionite-exchange resin whip attachment, discards adsorption liquid, resin drains;
7.. the first sodium chloride solution washing resin taking concentration as 0.1-0.5mol/L, resin drains;
8.. the sodium chloride solution wash-out resin taking concentration as 2.0-4.0mol/L again, collect elutriant, after filtration elutriant, add dehydrated alcohol to precipitate, collecting precipitation thing, repeats the step that purified water is dissolved and dehydrated alcohol precipitates, last collecting precipitation thing, dry, obtain Suleparoid.
Step 1. in, raw material heparin byproduct can adopt produce the by product (wet feed) that obtains of heparin sodium dehydrate and weigh after be raw material so that subsequent disposal and calculating.The difference of raw material heparin byproduct specific rotation has embodied the content difference of its main component Suleparoid, dermatan sulfate and heparin sodium.The concentration of the heparin byproduct aqueous solution in this step is preferably 5-10%, and in solution, the content of Potassium ethanoate is preferably 30-40%, and the precipitation process time is preferably 20-50 hour.
Step 2. in, collect the step 1. precipitation of gained, re-start and be dissolved in purified water, add Potassium ethanoate, operation with vinegar acid for adjusting pH value, precipitation and separation, its condition is with step 1..
Step 3. in, the consumption of purified water is taking complete dissolution precipitation thing as good, the consumption of dehydrated alcohol so that in solution, no longer continue to produce be precipitated as good.
Step 4. in, in this step, can adopt mode precipitation separation and the supernatant liquors such as centrifugal or filtration, preferably adopt centrifugation.
Step 5. in, the add-on of sodium sulphite is preferably 10-12%(w/v).The add-on of gac is 9-11%(w/v).Add the churning time after gac to be generally 5-100 minute, preferably 10-30 minute.
Step 6. in, described anionite-exchange resin is acrylic acid or the like strongly basic anion exchange resin.Wherein the middle anionite-exchange resin whip attachment time is 1-20 hour, preferably 2-6 hour.
Step 7. in, the sodium chloride solution washing resin time taking concentration as 0.1-0.5mol/L is generally 1-5 hour.
Step 8. in, the general 2-10 hour of sodium chloride solution wash-out resin time taking concentration as 2.0-4.0mol/L.
Beneficial effect of the present invention:
The inventive method utilizes their solubleness in water to there are differences this feature, add Potassium ethanoate to make heparin sodium precipitate and separate from heparin byproduct, after resolution of precipitate, add again Potassium ethanoate precipitation, collecting precipitation, after dissolving, precipitate through dehydrated alcohol multiple fractionation, and then make the heparin sodium that purity is higher; Supernatant liquor is by adding Benedict's reagent and saturated sodium hydroxide solution, the centrifugal solution that contains Suleparoid of obtaining, remove cupric ion with decoppering agent, add charcoal absorption to precipitate and decolour rear filtration, adsorb and wash-out by anionite-exchange resin again, separate and obtain highly purified Suleparoid, through atomic absorption spectroscopy determination, in Suleparoid, the content of cupric ion is no more than 8ppm, can effectively remove cupric ion.Present method can directly obtain refined heparin sodium and Suleparoid product fine work.
The invention solves supernatant liquor adds after Benedict's reagent and saturated sodium hydroxide solution, through the problem of ion exchange column very obstinate cupric ion.This law is used decoppering agent that cupric ion is removed by filter with precipitation forms before anionite-exchange resin absorption Suleparoid, because precipitation is tiny, not free settling, after using sorbent material to stir, refilter, prepared Suleparoid has higher purity, and do not need follow-up steps for copper removal again, can directly be used as the bulk drug of Suleparoid.
The present invention can again separate and obtain highly purified heparin sodium and Suleparoid simultaneously from the by product of production heparin sodium, solve storage or abandoned the required financial resources of a large amount of heparin byproducts and material resources, and turn waste into wealth, by product is utilized again, save great amount of cost, created again value.
Embodiment
Embodiment mono-
(1) raw material is the by product 260kg that heparin sodium is produced, the optical value recording is-34.5 °, by material dissolution in purified water, making material concentration is 5% (g/mL), add Potassium ethanoate, the content that makes Potassium ethanoate is 30%, regulates pH to 6, at temperature 18-20 DEG C, leaves standstill 24 hours.
(2) centrifugal collecting precipitation, is dissolved as the solution of 5% (g/mL), adds Potassium ethanoate, and the content that makes Potassium ethanoate is 30% (g/mL), with vinegar acid for adjusting pH to 6, at temperature 18-20 DEG C, leaves standstill 24 hours.
(3) centrifugal collecting precipitation, after dissolving, adds dehydrated alcohol precipitation by purified water, after centrifugal collecting precipitation, again dissolves by purified water, precipitates with dehydrated alcohol.Collecting precipitation also dehydrates, and obtains heparin sodium 18.6kg.
The optically-active that records refined heparin sodium is 55 °, and anticoagulation is tired as 176USP u/mg.
(4) step (1) gained supernatant liquor adds 0.2 times of Benedict's reagent and 0.5 times of saturated sodium hydroxide solution, precipitates 30 minutes, centrifugation precipitation and supernatant liquor under room temperature.
(5) to add appropriate sodium sulphite to make its concentration be 10% (g/mL) to step (4) gained supernatant liquor, after stirring, staticly settle 1.5 hours, adding proper amount of active carbon to make its concentration is 10% (g/mL), stirs after 60 minutes and filters.
(6) step (5) is filtered the clear liquid obtaining and is added the dilution of 1 times of purified water, regulates pH to 7 with concentrated hydrochloric acid.Add acrylic acid or the like strongly basic anion exchange resin whip attachment after 2 hours, discard adsorption liquid, drain.
(7), with the sodium chloride solution washing resin of 0.1mol/L 2 hours, after draining, again use the sodium chloride solution washing resin 1 hour of 0.1mol/L.Resin drains.
(8) resin is added to the sodium chloride solution wash-out 6 hours of 4.0mol/L, after separation eluent, again use the sodium chloride solution wash-out 2 hours of 4.0mol/L, merge 2 times elutriant.Add dehydrated alcohol precipitation, add dehydrated alcohol precipitation after adding purified water to dissolve after collecting precipitation.Collecting precipitation dewaters with dehydrated alcohol and dries, and obtains white powder 32kg, is Suleparoid.The optically-active that records Suleparoid fine work is 38 °, and anticoagulation is tired as 52USP u/mg, and through atomic absorption spectroscopy determination, in Suleparoid, the content of cupric ion is 6ppm.
Embodiment bis-
(1) raw material is the by product 254kg that heparin sodium is produced, the optical value recording is-1.7 °, by material dissolution in purified water, making material concentration is 15% (g/mL), add Potassium ethanoate, the content that makes Potassium ethanoate is 45%, regulates pH to 5, at temperature 18-20 DEG C, leaves standstill 48 hours.
(2) centrifugal collecting precipitation, is dissolved as the solution of 15% (g/mL), adds Potassium ethanoate, and the content that makes Potassium ethanoate is 45% (g/mL), with vinegar acid for adjusting pH to 5, at temperature 18-20 DEG C, leaves standstill 48 hours.
(3) centrifugal collecting precipitation, after dissolving, adds dehydrated alcohol precipitation by purified water, after centrifugal collecting precipitation, again dissolves by purified water, precipitates with dehydrated alcohol.Collecting precipitation also dehydrates, and obtains heparin sodium 36.6kg.
The optically-active that records refined heparin sodium is 51 °, and anticoagulation is tired as 172USP u/mg.
(4) step (1) gained supernatant liquor adds 1.2 times of Benedict's reagents and 0.8 times of saturated sodium hydroxide solution, precipitates 30 minutes, centrifugation precipitation and supernatant liquor under room temperature.
(5) step (4) gained supernatant liquor adds appropriate sodium sulphite to make its concentration to be 8% (g/mL), after stirring, to staticly settle 3 hours, and adding proper amount of active carbon to make its concentration is 15% (g/mL), stirs after 30 minutes and filters.
(6) step (5) is filtered the clear liquid obtaining and is added the dilution of 3 times of purified water, regulates pH to 6 with concentrated hydrochloric acid.Add acrylic acid or the like strongly basic anion exchange resin whip attachment after 10 hours, discard adsorption liquid, drain.
(7) with the sodium chloride solution washing resin of 0.5mol/L 2 hours.Resin drains.
(8) resin is added to the sodium chloride solution wash-out 6 hours of 3.0mol/L, add dehydrated alcohol precipitation, add dehydrated alcohol precipitation after adding purified water to dissolve after collecting precipitation.Collecting precipitation dewaters with dehydrated alcohol and dries, and obtains white powder 48kg, is Suleparoid.The optically-active that records Suleparoid fine work is 40 °, and anticoagulation is tired as 52USP u/mg, and through atomic absorption spectroscopy determination, in Suleparoid, the content of cupric ion is 5ppm.
Embodiment tri-
(1) raw material is the by product 197kg that heparin sodium is produced, the optical value recording is 15.2 °, by material dissolution in purified water, making material concentration is 20% (g/mL), add Potassium ethanoate, the content that makes Potassium ethanoate is 60% (g/mL), regulates pH to 7, at temperature 18-20 DEG C, leaves standstill 72 hours.
(2) centrifugal collecting precipitation, is dissolved as the solution of 20% (g/mL), adds Potassium ethanoate, and the content that makes Potassium ethanoate is 60% (g/mL), with vinegar acid for adjusting pH to 7, at temperature 18-20 DEG C, leaves standstill 72 hours.
(3) centrifugal collecting precipitation, after dissolving, adds dehydrated alcohol precipitation by purified water, after centrifugal collecting precipitation, again dissolves by purified water, precipitates with dehydrated alcohol.Collecting precipitation also dehydrates, and obtains heparin sodium 34.2kg.
The optically-active that records refined heparin sodium is 48 °, and anticoagulation is tired as 167USP u/mg.
(4) step (1) gained supernatant liquor adds 0.7 times of Benedict's reagent and 0.1 times of saturated sodium hydroxide solution, precipitates 30 minutes, centrifugation precipitation and supernatant liquor under room temperature.
(5) step (4) gained supernatant liquor adds appropriate sodium sulphite to make its concentration to be 15% (g/mL), after stirring, to staticly settle 1 hour, and adding proper amount of active carbon to make its concentration is 8% (g/mL), stirs after 10 minutes and filters.
(6) step (5) is filtered the clear liquid obtaining and is added the dilution of 5 times of purified water, regulates pH to 5 with concentrated hydrochloric acid.Add acrylic acid or the like strongly basic anion exchange resin whip attachment after 6 hours, discard adsorption liquid, drain.
(7) with the sodium chloride solution washing resin of 0.3mol/L 3 hours.Resin drains.
(8) resin is added to the sodium chloride solution wash-out 4 hours of 3.0mol/L, elutriant adds dehydrated alcohol precipitation, adds dehydrated alcohol precipitation after adding purified water to dissolve after collecting precipitation.Collecting precipitation dewaters with dehydrated alcohol and dries, and obtains white powder 52.8kg, is Suleparoid.The optically-active that records Suleparoid fine work is 42 °, and anticoagulation is tired as 55USP u/mg, and through atomic absorption spectroscopy determination, in Suleparoid, the content of cupric ion is 8ppm.
Claims (5)
1. a method for separating-purifying heparin sodium and Suleparoid from heparin byproduct, is characterized in that according to the following steps:
. raw material heparin byproduct is dissolved in in purified water, to obtain concentration be 5-20%(w/v) solution, add Potassium ethanoate, make the content of Potassium ethanoate in solution reach 30-60%(w/v), by the pH value of acetic acid regulator solution to 5-7, at 18-20 DEG C, precipitate 20-80 hour, centrifugation precipitation and supernatant liquor;
. collect step
the precipitation of gained, is precipitated as raw material repeating step with this
operation;
. collect step
the precipitation of gained, after dissolving, adds dehydrated alcohol to precipitate by purified water; The throw out obtaining repeats the step that purified water is dissolved and dehydrated alcohol precipitates, and last collecting precipitation is dry, obtains heparin sodium;
. to step
in the supernatant liquor of gained, add the Benedict's reagent of 0.2-1.2 times of volume and the saturated sodium hydroxide solution of 0.1-0.8 times of volume, after precipitating at 20-25 DEG C, precipitation separation and supernatant liquor;
. step
the supernatant liquor of gained adds sodium sulphite, staticly settles 1-3 hour, then adds gac to stir filtration after 5-100 minute; Wherein the add-on of sodium sulphite is 8-15w/v%, and the add-on of gac is 8-15 w/v%;
. step
in the clear liquid obtaining, add 1-5 times of purified water dilution, and the pH value of regulator solution is to 5-7, then adds anionite-exchange resin whip attachment, discards adsorption liquid, resin drains;
. the first sodium chloride solution washing resin taking concentration as 0.1-0.5mol/L, resin drains;
. the sodium chloride solution wash-out resin taking concentration as 2.0-4.0 mol/L again, collect elutriant, after filtration elutriant, add dehydrated alcohol to precipitate, collecting precipitation thing, repeats the step that purified water is dissolved and dehydrated alcohol precipitates, last collecting precipitation thing, dry, obtain Suleparoid.
2. method according to claim 1, is characterized in that step
described in anionite-exchange resin be acrylic acid or the like strongly basic anion exchange resin.
3. method according to claim 1, is characterized in that step
the middle anionite-exchange resin whip attachment time is 1-20 hour.
4. method according to claim 1, is characterized in that step
sodium chloride solution washing resin time 1-5 hour taking concentration as 0.1-0.5mol/L.
5. method according to claim 1, is characterized in that step
sodium chloride solution wash-out resin time 2-10 hour taking concentration as 2.0-4.0 mol/L.
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| CN103788232A (en) * | 2013-12-23 | 2014-05-14 | 深圳市海普瑞药业股份有限公司 | Heparitin sulfate decasaccharide as well as preparation method and application thereof |
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| CN104403026A (en) * | 2014-12-24 | 2015-03-11 | 山东辰中生物制药有限公司 | Method for separating heparan sulfate from animal lungs |
| CN105037584B (en) * | 2015-07-02 | 2017-10-31 | 杭州惠顺生物科技有限公司 | A kind of method that heparan is separated in the useless albumen from heparin byproduct |
| CN106905446A (en) * | 2017-04-06 | 2017-06-30 | 山东绅联药业有限公司 | A kind of sheep heparin sodium crude extracts the method that waste liquid prepares Heparan sulfate |
| CN106939056A (en) * | 2017-04-06 | 2017-07-11 | 山东绅联药业有限公司 | A kind of preparation method of Heparan sulfate |
| CN112079941A (en) * | 2019-06-14 | 2020-12-15 | 苏州融析生物科技有限公司 | Method for preparing heparin sodium and heparan sulfate sodium from crude heparin sodium |
| CN111154012A (en) * | 2019-12-31 | 2020-05-15 | 湖北亿诺瑞生物制药有限公司 | Preparation method of ultra-high purity heparan sulfate |
| CN115448993B (en) * | 2022-09-15 | 2024-02-27 | 中盐金坛盐化有限责任公司 | Wrapped salt product and preparation method and application thereof |
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| CN102424659A (en) * | 2011-11-02 | 2012-04-25 | 浙江科技学院 | Synthetic method of D-4-methylsulfonylphenyl serine ethyl ester |
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Effective date of registration: 20190613 Address after: 210061 16 Xuefu Road, hi tech Zone, Nanjing, Jiangsu Co-patentee after: Jian Jin Pharmaceutical Co., Ltd. Patentee after: Nanjing King-friend Biochemical Pharmaceutical Co., Ltd. Address before: 210061 MA010-1, Nanjing High-tech Development Zone, Jiangsu Province Patentee before: Nanjing King-friend Biochemical Pharmaceutical Co., Ltd. |
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