CN102911290A - 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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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 the mucopolysaccharide field of biological pharmacy.
Background technology
Heparin sodium is mucopolysaccharide sulfuric acid ester anticoagulant, and Recent study proof heparin sodium also has reducing blood lipid.Suleparoid is the subcomponent of heparin, is present in the unsegregated heparin.Compare with heparin sodium, Suleparoid has the advantage that anticoagulating active relaxes.Suleparoid is used for anti-bolt, anti-inflammatory, reducing blood-fat and kidney of diabetic patients protection, is the hottest mucopolysaccharide biochemical drug of Recent study.
From the process of pig intestinal mucosa through ion-exchange and fractionation precipitation production heparin, produced 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 to some extent differences of specific rotation of by product.But because active substance separation difficulty wherein, so generally these by products are abandoned or store behind the production heparin, perhaps only do simple process, mainly be purification Suleparoid and dermatan sulfate from heparin byproduct such as traditional technology, heparin sodium then discards, and causes certain loss.Suleparoid and dermatan sulfate similar performance adopt common ion exchange chromatography and organic solvent fractionation precipitation method to be difficult to the Suleparoid purifying.In the prior art, utilize Suleparoid to realize both separation with dermatan sulfate with the special reaction of Benedicts reagent, but in the Suleparoid solution that separation obtains, 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 reduce resin life easily, and be difficult to cupric ion is eliminated, so that the Suleparoid crude product is still with light blue, through atomic absorption spectroscopy determination, content of copper ion surpasses 30ppm.
Summary of the invention
The purpose of this invention is to provide a kind of method of isolating simultaneously 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.
Purpose of the present invention can reach by following measures:
A kind of from heparin byproduct the method for separating-purifying heparin sodium and Suleparoid, it is characterized in that according to the following steps:
1.. the raw material heparin byproduct is dissolved in to obtain concentration in the purified water be 5-20%(w/v) solution, add Potassium ethanoate, make that the content of Potassium ethanoate reaches 30-60%(w/v in the solution), with the pH value of acetic acid regulator solution to 5-7, precipitation is 20-80 hour under 18-20 ℃, 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 the purified water dissolving, add dehydrated alcohol and precipitate; The throw out that obtains repeats the step of purified water dissolving and dehydrated alcohol precipitation, last collecting precipitation, and drying obtains heparin sodium;
4.. 1. in the supernatant liquor of gained, add the Benedicts 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, after 20-25 ℃ of lower precipitation, precipitation separation and supernatant liquor;
5.. the step 4. supernatant liquor of gained adds sodium sulphite, staticly settles 1-3 hour, adds to filter after gac stirs again;
6.. add 1-5 times of purified water dilution in the clear liquid that 5. step obtains, and then the pH value of regulator solution add the anionite-exchange resin whip attachment to 5-7, discard adsorption liquid, resin drains;
7.. the sodium chloride solution washing resin of elder generation take concentration as 0.1-0.5mol/L, resin drains;
8.. the sodium chloride solution wash-out resin take concentration as 2.0-4.0mol/L again, collect elutriant, filter and add dehydrated alcohol behind the elutriant and precipitate, the collecting precipitation thing repeats the step that purified water dissolving and dehydrated alcohol precipitate, last collecting precipitation thing, drying obtains Suleparoid.
Step 1. in, the raw material heparin byproduct can adopt produce by product (wet feed) that heparin sodium obtains 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 the content of Potassium ethanoate is preferably 30-40% in the solution, and the precipitation process time is preferably 20-50 hour.
Step 2. in, collect the 1. precipitation of gained of step, re-start be dissolved in the purified water, add Potassium ethanoate, with the operation of vinegar acid for adjusting pH value, precipitation and separation, its condition is with step 1..
Step 3. in, the consumption of purified water is take complete dissolution precipitation thing as good, the consumption of dehydrated alcohol so that no longer continue in the solution to produce be precipitated as good.
Step 4. in, can adopt mode precipitation separation and the supernatant liquors such as centrifugal or filtration in this step, 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).Churning time behind the adding gac is generally 5-100 minute, preferred 10-30 minute.
Step 6. in, described anionite-exchange resin is the acrylic acid or the like strongly basic anion exchange resin.Wherein the middle anionite-exchange resin whip attachment time is 1-20 hour, preferred 2-6 hour.
Step 7. in, the sodium chloride solution washing resin time take concentration as 0.1-0.5mol/L is generally 1-5 hour.
Step 8. in, the general 2-10 hour sodium chloride solution wash-out resin time take 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 characteristics, add Potassium ethanoate and make heparin sodium precipitate and separate from heparin byproduct, add again the Potassium ethanoate precipitation behind the resolution of precipitate, collecting precipitation, precipitate through the dehydrated alcohol multiple fractionation after the dissolving, and then make the higher heparin sodium of purity; Supernatant liquor is by adding Benedicts reagent and saturated sodium hydroxide solution, the centrifugal solution that obtains containing Suleparoid, remove cupric ion with decoppering agent, filter after adding charcoal absorption precipitation and decolouring, by anionite-exchange resin absorption and wash-out, separate obtaining highly purified Suleparoid, through atomic absorption spectroscopy determination again, the content of cupric ion is no more than 8ppm in the Suleparoid, can effectively remove cupric ion.Present method can directly obtain refined heparin sodium and Suleparoid product elaboration.
After the invention solves supernatant liquor adding Benedicts reagent and saturated sodium hydroxide solution, through the problem of ion exchange column very obstinate cupric ion.This law uses decoppering agent that cupric ion is removed by filter with precipitation forms before anionite-exchange resin absorption Suleparoid, because precipitation is tiny, free settling not, refilter after using sorbent material to stir, prepared Suleparoid has higher purity, and do not need follow-up again steps for copper removal, can directly be used as the bulk drug of Suleparoid.
The present invention can be simultaneously from the by product of producing heparin sodium Re-isolation obtain highly purified heparin sodium and Suleparoid, 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, namely save great amount of cost, created again value.
Embodiment
Embodiment one
(1) raw material is the by product 260kg that heparin sodium is produced, and the optical value that records is-34.5 °, with material dissolution in purified water, making material concentration is 5% (g/mL), adds Potassium ethanoate, and the content that makes Potassium ethanoate is 30%, regulate pH to 6, under temperature 18-20 ℃, left 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, leaves standstill 24 hours under temperature 18-20 ℃.
(3) centrifugal collecting precipitation after the purified water dissolving, adds the dehydrated alcohol precipitation, again with the purified water dissolving, precipitates with dehydrated alcohol behind the centrifugal collecting precipitation.Collecting precipitation also dehydrates, and gets heparin sodium 18.6kg.
The optically-active that records refined heparin sodium is 55 °, and anticoagulation is tired and is 176USP u/mg.
(4) step (1) gained supernatant liquor adds 0.2 times of Benedicts reagent and 0.5 times of saturated sodium hydroxide solution, and precipitation is 30 minutes under the room temperature, centrifugation precipitation and supernatant liquor.
(5) step (4) gained supernatant liquor adds an amount of sodium sulphite to make its concentration is 10% (g/mL), after the stirring, staticly settles 1.5 hours, and adding proper amount of active carbon, to make its concentration be 10% (g/mL), stirs filtration after 60 minutes.
(6) step (5) is filtered the 1 times of purified water dilution of clear liquid adding that obtains, and 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, again use the sodium chloride solution washing resin 1 hour of 0.1mol/L after draining.Resin drains.
(8) resin is added the sodium chloride solution wash-out 6 hours of 4.0mol/L, again use the sodium chloride solution wash-out 2 hours of 4.0mol/L behind the separation eluent, merge 2 times elutriant.Add the dehydrated alcohol precipitation, add the rear dehydrated alcohol precipitation that adds of purified water dissolving behind the collecting precipitation.Collecting precipitation obtains white powder 32kg with dehydrated alcohol dehydration and oven dry, is Suleparoid.The optically-active that records the Suleparoid elaboration is 38 °, and anticoagulation is tired as 52USP u/mg, and through atomic absorption spectroscopy determination, the content of cupric ion is 6ppm in the Suleparoid.
Embodiment two
(1) raw material is the by product 254kg that heparin sodium is produced, and the optical value that records is-1.7 °, with material dissolution in purified water, making material concentration is 15% (g/mL), adds Potassium ethanoate, and the content that makes Potassium ethanoate is 45%, regulate pH to 5, under temperature 18-20 ℃, left 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, leaves standstill 48 hours under temperature 18-20 ℃.
(3) centrifugal collecting precipitation after the purified water dissolving, adds the dehydrated alcohol precipitation, again with the purified water dissolving, precipitates with dehydrated alcohol behind the centrifugal collecting precipitation.Collecting precipitation also dehydrates, and gets heparin sodium 36.6kg.
The optically-active that records refined heparin sodium is 51 °, and anticoagulation is tired and is 172USP u/mg.
(4) step (1) gained supernatant liquor adds 1.2 times of Benedicts reagents and 0.8 times of saturated sodium hydroxide solution, and precipitation is 30 minutes under the room temperature, centrifugation precipitation and supernatant liquor.
(5) step (4) gained supernatant liquor adds an amount of sodium sulphite to make its concentration is 8% (g/mL), after the stirring, staticly settles 3 hours, and adding proper amount of active carbon, to make its concentration be 15% (g/mL), stirs filtration after 30 minutes.
(6) step (5) is filtered the 3 times of purified water dilutions of clear liquid adding that obtain, and 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 the sodium chloride solution wash-out 6 hours of 3.0mol/L, add the dehydrated alcohol precipitation, add the dehydrated alcohol precipitation after adding the purified water dissolving behind the collecting precipitation.Collecting precipitation obtains white powder 48kg with dehydrated alcohol dehydration and oven dry, is Suleparoid.The optically-active that records the Suleparoid elaboration is 40 °, and anticoagulation is tired as 52USP u/mg, and through atomic absorption spectroscopy determination, the content of cupric ion is 5ppm in the Suleparoid.
Embodiment three
(1) raw material is the by product 197kg that heparin sodium is produced, the optical value that records is 15.2 °, with 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, leaves standstill 72 hours under temperature 18-20 ℃.
(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, leaves standstill 72 hours under temperature 18-20 ℃.
(3) centrifugal collecting precipitation after the purified water dissolving, adds the dehydrated alcohol precipitation, again with the purified water dissolving, precipitates with dehydrated alcohol behind the centrifugal collecting precipitation.Collecting precipitation also dehydrates, and gets heparin sodium 34.2kg.
The optically-active that records refined heparin sodium is 48 °, and anticoagulation is tired and is 167USP u/mg.
(4) step (1) gained supernatant liquor adds 0.7 times of Benedicts reagent and 0.1 times of saturated sodium hydroxide solution, and precipitation is 30 minutes under the room temperature, centrifugation precipitation and supernatant liquor.
(5) step (4) gained supernatant liquor adds an amount of sodium sulphite to make its concentration is 15% (g/mL), after the stirring, staticly settles 1 hour, and adding proper amount of active carbon, to make its concentration be 8% (g/mL), stirs filtration after 10 minutes.
(6) step (5) is filtered the 5 times of purified water dilutions of clear liquid adding that obtain, and 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 the sodium chloride solution wash-out 4 hours of 3.0mol/L, elutriant adds the dehydrated alcohol precipitation, adds the dehydrated alcohol precipitation after adding the purified water dissolving behind the collecting precipitation.Collecting precipitation obtains white powder 52.8kg with dehydrated alcohol dehydration and oven dry, is Suleparoid.The optically-active that records the Suleparoid elaboration is 42 °, and anticoagulation is tired as 55USP u/mg, and through atomic absorption spectroscopy determination, the content of cupric ion is 8ppm in the Suleparoid.
Claims (7)
1. the method for separating-purifying heparin sodium and Suleparoid from a heparin byproduct is characterized in that according to the following steps:
1.. the raw material heparin byproduct is dissolved in to obtain concentration in the purified water be 5-20%(w/v) solution, add Potassium ethanoate, make that the content of Potassium ethanoate reaches 30-60%(w/v in the solution), with the pH value of acetic acid regulator solution to 5-7, precipitation is 20-80 hour under 18-20 ℃, 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 the purified water dissolving, add dehydrated alcohol and precipitate; The throw out that obtains repeats the step of purified water dissolving and dehydrated alcohol precipitation, last collecting precipitation, and drying obtains heparin sodium;
4.. 1. in the supernatant liquor of gained, add the Benedicts 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, after 20-25 ℃ of lower precipitation, precipitation separation and supernatant liquor;
5.. the step 4. supernatant liquor of gained adds sodium sulphite, staticly settles 1-3 hour, adds to filter after gac stirs again;
6.. add 1-5 times of purified water dilution in the clear liquid that 5. step obtains, and then the pH value of regulator solution add the anionite-exchange resin whip attachment to 5-7, discard adsorption liquid, resin drains;
7.. the sodium chloride solution washing resin of elder generation take concentration as 0.1-0.5mol/L, resin drains;
8.. the sodium chloride solution wash-out resin take concentration as 2.0-4.0mol/L again, collect elutriant, filter and add dehydrated alcohol behind the elutriant and precipitate, the collecting precipitation thing repeats the step that purified water dissolving and dehydrated alcohol precipitate, last collecting precipitation thing, drying obtains Suleparoid.
2. method according to claim 1 is characterized in that the add-on of sodium sulphite was 8-15%(w/v during step 5.).
3. method according to claim 1 is characterized in that the add-on of gac was 8-15%(w/v during step 5.).
4. method according to claim 1 is characterized in that the anionite-exchange resin described in step 6. is the acrylic acid or the like strongly basic anion exchange resin.
5. method according to claim 1 is characterized in that 6. the middle anionite-exchange resin whip attachment time is 1-20 hour to step.
6. method according to claim 1 is characterized in that step 7. the sodium chloride solution washing resin time 1-5 take concentration as 0.1-0.5mol/L hour.
7. method according to claim 1 is characterized in that 8. 2-10 hour sodium chloride solution wash-out resin time take concentration as 2.0-4.0mol/L of step.
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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 |
| CN104163878A (en) * | 2014-08-13 | 2014-11-26 | 南京健友生化制药股份有限公司 | Method for producing nadroparin calcium from heparin sodium crude product |
| 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 |
| CN105037584A (en) * | 2015-07-02 | 2015-11-11 | 杭州惠顺生物科技有限公司 | Method for separating heparitin from heparin by-product waste protein |
| 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 |
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| 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 |
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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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| 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 |
| CN115448993A (en) * | 2022-09-15 | 2022-12-09 | 中盐金坛盐化有限责任公司 | Coated salt product and preparation method and application thereof |
| 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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