CN105440160A - Preparation method for dalteparin sodium - Google Patents
Preparation method for dalteparin sodium Download PDFInfo
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- CN105440160A CN105440160A CN201510880058.4A CN201510880058A CN105440160A CN 105440160 A CN105440160 A CN 105440160A CN 201510880058 A CN201510880058 A CN 201510880058A CN 105440160 A CN105440160 A CN 105440160A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method for dalteparin sodium. The preparation method comprises the steps of (1) degradation, wherein heparin sodium is dissolved and degraded to obtain heparin sodium degradation liquid; (2) reduction, wherein the heparin sodium degradation liquid is reduced with a reducing agent to obtain reduction liquid; (3) enzymolysis, wherein, the pH of the reduction liquid is regulated with a hydrochloric acid, and after a certain temperature is reached, enzyme is added, and the temperature is kept for a certain time of period; (4) ethanol precipitation, wherein ethanol is added, and the liquid is stirred continuously; (5) ultrafiltration, wherein ethanol is precipitated and dissolved, and dissolution liquid is ultrafiltered through an ultramicro filter membrane; (6) ethanol reprecipitation, wherein the pH is regulated with sodium hydroxide, ethanol is added, and the liquid is stirred continuously; (7) dewatering and drying, wherein ethanol is used for dewatering and drying to obtain the dalteparin sodium. The yield of the dalteparin sodium obtained through the method is increased obviously. The method is simple and easy to implement; besides, production time is short, conditions are moderate, cost is low, and the method is suitable for industrial production and has a significant application prospect.
Description
Technical field
The present invention relates to the bulk drug preparation in biomedicine field, it relates to a kind of preparation method of dalteparin sodium.
Background technology
Dalteparin sodium is a kind of Low molecular heparin sodium salt, and dalteparin sodium is low-molecular-weight heparin sodium, is applicable to the pre-anticoagulant of hemodialysis and the treatment of deep venous thrombosis; Unstable coronary artery disease; Prevent the thrombosis relevant with operation.The data presentation of clinical study, DALT to the curative effect of gerontal patient and security and young patient without population differences.With unfractionated heparin sodium ratio, DALT has many advantages in pharmacology and pharmacokinetics, comprising: measurable anticoagulant effect; High bioavailability and long plasma half-life; Dosage is reliable, and security is good.
Domesticly at present on the purification technique of dalteparin sodium, mainly contain ion exchange chromatography, size-exclusion method, and the method such as ultrafiltration.Although the dalteparin sodium quality product that ion exchange chromatography and size-exclusion method obtain is higher, complex operation step, purification cycle is long, and cost is high, is only applicable to a small amount of dalteparin sodium and carries out purifying, cannot realize suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of preparation method of dalteparin sodium, the fine work dalteparin sodium yield adopting the inventive method to obtain significantly improves, and method is simple, and the production used time is few, and cost is low, and suitability for industrialized is produced, and has important application prospect.The object of the invention is to be achieved through the following technical solutions:
A preparation method for dalteparin sodium, this preparation method comprises the following steps:
(1) degrade: heparin sodium dissolved and degrades, obtaining heparin sodium degradation solution;
(2) reduce: heparin sodium degradation solution reductive agent is reduced, obtains reduced liquid;
(3) enzymolysis: above-mentioned reduced liquid hydrochloric acid soln is adjusted pH, adds enzyme after being raised to certain temperature and start held for some time;
(4) alcohol settling: add ethanol, constantly stirs;
(5) ultrafiltration: dissolved by ethanol pellet, lysate supermicro filtration membrane carries out ultrafiltration;
(6) ethanol redeposition: regulate pH with sodium hydroxide, add ethanol, constantly stir;
(7) dehydrate: dry with ethanol dehydration, obtain fine work dalteparin sodium.
In step (1), in 10-20 minute, rapid temperature increases is to 80-90 DEG C, and keeps 30-60 minute, constantly stirs.Heparin sodium is degraded more complete, and shorten the production used time.
In step (2), in heparin sodium degradation solution, adding sodium hydroxide to pH is that 11-12 stops DeR, add reductive agent V-Brite B or Sodium Pyrosulfite or both again and mix reduction 3-5 hour, then PH to 6.0-8.0 is regulated, namely obtain reduced liquid, the amount of reductive agent is the 0.5-1.0% of heparin sodium weight.Reduce the consumption of reductive agent.
In step (3), above-mentioned reduced liquid hydrochloric acid soln is adjusted pH7.5-8.5, be warmed up to after between 55-60 DEG C and add trypsinase 4-8g/ hundred million unit, then add 8-16g/ hundred million unit stomach en-, 55-60 DEG C of insulation 3-5 hour.
Ultrafiltrated volume 2-3 95% ethanol redeposition 10-14 hour is doubly added in step (5).
The invention provides a kind of preparation method of dalteparin sodium, its beneficial effect mainly had is:
The present invention makes heparin sodium fully be degraded by being rapidly heated, and shorten and produce the used time, and heparin sodium yield significantly improves, dalteparin sodium quality is significantly improved, and method is simple.
In addition, the method production used time is few, and mild condition, low for equipment requirements, cost is low, and the number of chemical reagent used in method, all lower than the consumption in existing industrial production and cost, is applicable to being applied in suitability for industrialized production, has important application prospect very much.
Embodiment
A preparation method for dalteparin sodium, this preparation method comprises the following steps:
(1) degrade: heparin sodium dissolved and degrades, obtaining heparin sodium degradation solution; (2) reduce: heparin sodium degradation solution reductive agent is reduced, obtains reduced liquid; (3) enzymolysis: above-mentioned reduced liquid hydrochloric acid soln is adjusted pH, adds enzyme after being raised to certain temperature and start held for some time; (4) alcohol settling: add ethanol, constantly stirs; (5) ultrafiltration: dissolved by ethanol pellet, lysate supermicro filtration membrane carries out ultrafiltration; (6) ethanol redeposition: regulate pH with sodium hydroxide, add ethanol, constantly stir; (7) dehydrate: dry with ethanol dehydration, obtain fine work dalteparin sodium.
Embodiment:
1. in retort, add heparin sodium 30kg, then add purified water 100L and make it entirely molten, regulate PH to 6.5 with the acetic acid of 1mol/L, control temperature, at about 35 DEG C, adds 100g Sodium Nitrite.Heating, rapid temperature increases to 80 DEG C, keep 30 minutes, and constantly stir, logical water of condensation is cooled to room temperature, obtains heparin sodium degradation solution;
2. in heparin sodium degradation solution, add sodium hydroxide is 11 termination DeRs to pH, then adds reductive agent Sodium Pyrosulfite 200g and reduce 3 hours, then regulates PH to 6.5, namely obtains reduced liquid;
3. above-mentioned reduced liquid hydrochloric acid soln is adjusted pH8.0, be warmed up to after between 55 DEG C and add trypsinase 400g, then add 800g stomach en-, 55 DEG C are incubated 4 hours;
4. in reduced liquid, add 95% alcohol settling is 65% to ethanol degree, precipitates;
5., by above-mentioned precipitate dissolves, lysate carries out ultrafiltration with supermicro filtration membrane again;
6. after ultrafiltration, ultrafiltrated regulates pH to 6.5, adds 95% alcohol settling 10 hours of the ultrafiltrated volume 3 times that ultrafiltration obtains, obtains fine work dalteparin sodium 27.8kg with ethanol dehydration drying.Weight-average molecular weight is 5800 after testing, and the anti-IIa ratio of anti-Xa/ is 2:1, meets production requirement.
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (8)
1. a preparation method for dalteparin sodium, is characterized in that: this preparation method comprises the following steps:
(1) degrade: heparin sodium dissolved and degrades, obtaining heparin sodium degradation solution;
(2) reduce: heparin sodium degradation solution reductive agent is reduced, obtains reduced liquid;
(3) enzymolysis: above-mentioned reduced liquid hydrochloric acid soln is adjusted pH, adds enzyme after being raised to certain temperature and start held for some time;
(4) alcohol settling: add ethanol, constantly stirs;
(5) ultrafiltration: alcohol settling is dissolved again, lysate ultra-filtration membrane carries out ultrafiltration, obtains ultrafiltrated;
(6) ethanol redeposition: regulate pH with sodium hydroxide, add ethanol, constantly stir;
(7) dehydrate: dry in suitable temperature with ethanol dehydration, obtain dalteparin sodium.
2. preparation method according to claim 1, it is characterized in that: in step (1), with the water of 3-5 times amount, heparin sodium is all dissolved, regulate PH to 6.0-8.0, at 25-35 DEG C, add Sodium Nitrite, this Sodium Nitrite is the 0.1-0.3% of heparin sodium weight, in 10-20 minute, rapid temperature increases is to 80-90 DEG C, and keeps 30-40 minute, constantly stirs, be cooled to room temperature, obtain heparin sodium degradation solution.
3. preparation method according to claim 1, it is characterized in that: in step (2), in heparin sodium degradation solution, adding sodium hydroxide to pH is that 11-12 stops DeR, add reductive agent V-Brite B or Sodium Pyrosulfite or both again and mix reduction 3-5 hour, then PH to 6.0-8.0 is regulated, namely obtain reduced liquid, the amount of reductive agent is the 0.5-1.0% of heparin sodium weight.
4. preparation method according to claim 1, it is characterized in that: above-mentioned reduced liquid hydrochloric acid soln is adjusted pH7.5-8.5 by step (3), be warmed up to after between 55-60 DEG C and add trypsinase 4-8g/ hundred million unit, then add 8-16g/ hundred million unit stomach en-, 55-60 DEG C of insulation 3-5 hour.
5. preparation method according to claim 1, is characterized in that: adding 95% alcohol settling to ethanol degree in step (4) is 65%-75%.
6. preparation method according to claim 1, is characterized in that: in step (5) ethanol pellet molten again after, carry out ultrafiltration with the supermicro filtration membrane of the molecular weight that can retain 10000, obtain ultrafiltrated.
7. preparation method according to claim 1, is characterized in that: first regulate pH to 6.0-8.0 with sodium hydroxide in step (6), is adding ultrafiltrated volume 2-3 95% alcohol settling 10-14 hour doubly.
8. preparation method according to claim 1, is characterized in that: in step (7), ethanol dehydration thing is at 55-70 DEG C of dry 4-6 hour, obtains dalteparin sodium.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510880058.4A CN105440160A (en) | 2015-12-06 | 2015-12-06 | Preparation method for dalteparin sodium |
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| CN201510880058.4A CN105440160A (en) | 2015-12-06 | 2015-12-06 | Preparation method for dalteparin sodium |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107236057A (en) * | 2017-05-19 | 2017-10-10 | 南京健友生化制药股份有限公司 | A kind of biodegrading process for obtaining Dalteparin Sodium |
| WO2019159092A1 (en) | 2018-02-14 | 2019-08-22 | Biological E Limited | Improved process for the preparation of dalteparin sodium |
| CN111560087A (en) * | 2020-06-28 | 2020-08-21 | 揭阳市润达肠衣有限公司 | Purification method of high-quality heparin sodium |
-
2015
- 2015-12-06 CN CN201510880058.4A patent/CN105440160A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107236057A (en) * | 2017-05-19 | 2017-10-10 | 南京健友生化制药股份有限公司 | A kind of biodegrading process for obtaining Dalteparin Sodium |
| WO2019159092A1 (en) | 2018-02-14 | 2019-08-22 | Biological E Limited | Improved process for the preparation of dalteparin sodium |
| US11492421B2 (en) | 2018-02-14 | 2022-11-08 | Biological E Limited | Process for the preparation of Dalteparin sodium |
| CN111560087A (en) * | 2020-06-28 | 2020-08-21 | 揭阳市润达肠衣有限公司 | Purification method of high-quality heparin sodium |
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