CN102558393A - Preparation process of dalteparin sodium - Google Patents
Preparation process of dalteparin sodium Download PDFInfo
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- CN102558393A CN102558393A CN2011104579823A CN201110457982A CN102558393A CN 102558393 A CN102558393 A CN 102558393A CN 2011104579823 A CN2011104579823 A CN 2011104579823A CN 201110457982 A CN201110457982 A CN 201110457982A CN 102558393 A CN102558393 A CN 102558393A
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- 229940018872 dalteparin sodium Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229920000669 heparin Polymers 0.000 claims abstract description 23
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims abstract description 17
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 17
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
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- 239000007788 liquid Substances 0.000 claims description 16
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- 238000003756 stirring Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003055 low molecular weight heparin Substances 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 238000005516 engineering process Methods 0.000 claims description 7
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- 150000002978 peroxides Chemical class 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
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- 238000000034 method Methods 0.000 abstract description 17
- 239000000047 product Substances 0.000 abstract description 17
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 abstract description 7
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- 208000029078 coronary artery disease Diseases 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 208000004043 venous thromboembolism Diseases 0.000 abstract description 3
- 206010014522 Embolism venous Diseases 0.000 abstract description 2
- 230000002785 anti-thrombosis Effects 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
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- 208000007536 Thrombosis Diseases 0.000 description 2
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- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
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- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
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- 229930195725 Mannitol Natural products 0.000 description 1
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- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
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- 238000011027 product recovery Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- 210000000813 small intestine Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention discloses a preparation process of dalteparin sodium. The preparation process comprises the following steps: preparing a heparin sodium solution, a heparin degradation fluid, a reducing solution and a crude product, refining, freeze-drying and the like. The average molecular weight of the obtained product is 5,500 to 6,500, the peak molecular weight is 3,500 to 6,000, a component with the molecular weight of less than 3,000 is not greater than 13% , a component with the molecular weight of greater than 8,000 is not greater than 15%, anti-Xa activity is more than or equal to 130IU/mg. The invention has the advantages of rich source of raw materials, high yield, stable and reliable quality, high purity, low cost, simple process, easiness in operation and no waste discharge. The dalteparin sodium has the anticoagulant, antithrombotic, anti-tumor, anti-inflammatory, anti-allergy and blood lipid regulating effects, thereby having a significant curative effect. The dalteparin sodium can be used for preventing preoperative and postoperative thrombosis of general surgery, orthopedic surgery and neurosurgery, effectively preventing venous thromboembolism of ischemic stroke patients, greatly reducing the risk of stroke, effectively preventing the solidification caused by extracorporeal circulation of blood, effectively preventing the instable coronary heart disease, and having a wide usable range.
Description
Technical field
The present invention relates to the dalteparin sodium production technique.
Background technology
Dalteparin sodium is low molecular sodium salt, and it is mainly used in prevention blood coagulation and Treatment of Deep-Vein Thrombosis, the treatment of instability mode coronary artery disease and the prevention thrombosis relevant with operation in the hemodialysis.Heparin (heparin) extensively is present in a kind of glycosaminoglycan in the tissue such as animal organ and mucous membrane of small intestine, lung, has multiple pharmacologically actives such as anti-freezing, anti-inflammatory, antianaphylaxis, antiviral, anticancer, regulating blood fat.
Low molecular heparin uses as the anti-freezing medicine except that possessing the whole pharmacological actions of unfractionated heparin, short-term medication usually, and therapeutic index is high.U.S. FDA has been ratified the prophylactic of dalteparin sodium after as low level limbs displacement technique.
The method of the product of domestic production Low molecular heparin class degraded at present mainly contains methods such as Sodium Nitrite edman degradation Edman, hydrogen peroxide degradation method, enzyme liberating method.But hydrogen peroxide degradation possibly introduced foreign matter, and quality is not easy control; Enzyme liberating product end has unsaturated group, poor stability, and cost is high; On the removal of impurities decoloring method, present domestic mainly contain potassium permanganate and ydrogen peroxide 50 secondary oxidation method or hydrogen peroxide oxidation process under condition of different pH.The shortcoming of potassium permanganate and ydrogen peroxide 50 secondary oxidation method be the Manganse Dioxide that produces difficulty leach, and Manganse Dioxide has adsorption to portioned product, and product recovery rate is reduced; Technical at purifying products, the domestic methods such as gel chromatography, ultrafiltration that mainly contain although the quality product that gel chromatography obtains is higher, be difficult to large-scale production, and cost are higher.
Summary of the invention
The present invention aims to provide a kind of dalteparin sodium production technique, and prepare with this technology reach heparin and quality standard thereof, to overcome the defective that prior art exists.
For realizing the object of the invention, dalteparin sodium production technique of the present invention comprises the following steps:
1., preparation heparin sodium aqua
After in heparin sodium, adding 5～8 quality purified water doubly, stir dissolving after 4～6 hours at normal temperatures;
2., preparation depolymerized heparin liquid
After the pH value 2～3 of the heparin sodium aqua that 1. obtains with the hydrochloric acid regulating step, adding weight is the Sodium Nitrite of heparin sodium 1.5%～2.5%, then at 10～30 ℃ of following stirring reaction 2～5h, obtains depolymerized heparin liquid after leaving standstill 20～24h again;
3., preparation reduced liquid
Regulate the pH value 9～11 of above-mentioned depolymerized heparin liquid with sodium hydroxide solution after, add 0.6%～1.0% times of heparin sodium weight sodium borohydride reduction 10～16h, and then regulate pH value to 6.5～7.0 with sodium hydroxide solution, obtain reduced liquid;
4., preparation precipitate reduction thing
In above-mentioned reduced liquid, add the ethanol that 2～4 volumes are doubly measured, fully stir the back collection and obtain the precipitate reduction thing;
5., preparation dalteparin sodium bullion
After in the precipitate reduction thing of collecting, adding the pure water stirring and dissolving; The ydrogen peroxide 50 that adding 0.2%～1.0% volume is doubly measured is at 25～35 ℃ of following oxidation 10～24h; And then add the ethanol that 2～4 volumes are doubly measured, fully stir back collecting precipitation thing and obtain the dalteparin sodium bullion;
6., preparation dalteparin sodium elaboration
The dalteparin sodium bullion of above-mentioned collection deposition is added the solution that purified water is dissolved into 1%～2% (w/w), and using the molecular weight cutoff respectively is that 3000 and 8000 ultra-filtration membrane carries out ultrafiltration, after Sterile Filtration, obtains dalteparin sodium elaboration solution again;
7., freeze-drying
The dalteparin sodium solution that above-mentioned steps is made promptly obtains the dalteparin sodium finished product-25～-35 ℃ of following freeze-drying.
The relevant comparative data of product of the present invention with the domestic and imported standard
The technical progress that the present invention obtains:
1, owing to adopts production technique of the present invention; With application of membrane separation technology in separating the different molecular weight section; The solvent precipitation classification and expensive gel molecular sieve method that fall behind have been changed; Obtained anti-Xa and tired >=130IU/mg, specific activity is 2.0～3.0, and the MWD of main ingredient is the dalteparin sodium product of 5500～6500D.
2, to obtain molecular-weight average be that the dalteparin sodium product of 5500～6500D can effectively prevent VTE for production technique of the present invention; Can be used for preventing before the art of general surgery, orthopedics, Neurological Surgery and the thrombosis of postoperative; Can effectively prevent the venous thromboembolism of Ischemic Apoplexy Patients; Can reduce the risk that suffers stroke greatly, what can prevent effectively that the blood extracorporeal circulation from causing solidifies, and can effectively prevent unstable coronary heart disease; Can effectively solve be prone to behind the unfraction heparin life-time service hemorrhage, osteoporosis, induced platelet minimizing etc., have broad application prospects.
3, the present invention and existing dalteparin sodium preparation technology are relatively; Productive rate is up to 85%～95%, and weight-average molecular weight is 5500～6500D, and peak molecular weight is 3500～6000; Molecular weight is not more than 13% less than 3000 component, and molecular weight is not more than 15% greater than 8000 component; Anti-xa activity >=130IU/mg, quality reaches the quality standard of European Pharmacopoeia regulation.The structure of product compound reducing end is the N.F,USP MANNITOL of dehydration, and has abundant, high, the stable and reliable product quality of productive rate of raw material sources, and purity is high; Cost is low, adopts the Sodium Nitrite degraded to make technology simple, and is easy to operate; Production process is controlled easily, steady quality, reaction temperature with; Product color is better, does not have characteristics such as " three wastes " discharging.The product dalteparin sodium has the effect of effects such as anticoagulation, antithrombotic, antitumor, anti-inflammatory, antianaphylaxis and regulating blood fat, and evident in efficacy, use range is extensive, can be used as the raw material of products such as injection, capsule, ointment, is convenient to scale prodn.
Description of drawings
Fig. 1 is a process flow sheet of the present invention.
Embodiment
Embodiment 1: as shown in Figure 1, at first:
1., take by weighing respectively behind 3Kg heparin sodium, 45g Sodium Nitrite, the 30g Peng Qinghuana subsequent use;
2., in 15～24L purified water retort, add the 3Kg heparin sodium after, stir at normal temperatures that dissolving obtains heparin sodium aqua after 4～6 hours;
3., regulate pH=2～3 of above-mentioned heparin sodium aqua with hydrochloric acid after, under whipped state, add the 45g Sodium Nitrite that is taken by weighing, then 10～30 ℃ of insulations, react 2～5h under stirring, obtain depolymerized heparin liquid after leaving standstill 20～24h again;
4., regulate the pH value 9～11 of above-mentioned depolymerized heparin liquid with sodium hydroxide solution after, add 30g sodium borohydride reduction 10～16h, regulate pH value to 6.5～7.0 with sodium hydroxide solution again after reaction finishes, obtain reduced liquid;
5., in above-mentioned reduced liquid, add the ethanol that 2～4 volumes are doubly measured, collection precipitate reduction thing after fully stirring;
6., in the precipitate reduction thing of collecting, add the pure water stirring and dissolving after; Add 0.2%～1.0% volume ydrogen peroxide 50 doubly at 25～35 ℃ of following oxidation 10～24h; Add the ethanol that 2～4 volumes doubly measure after oxidation finishes again and precipitate, fully stir the back and collect and obtain dalteparin sodium throw out bullion;
7., above-mentioned dalteparin sodium bullion deposition is added pure water 150L～200L, be dissolved into the solution of 1～2% concentration after, be respectively 3000 and 8000 ultra-filtration membrane with the molecular weight cutoff and carry out ultrafiltration, after the degerming processing, obtain dalteparin sodium solution again;
8., the dalteparin sodium solution that above-mentioned steps is made obtains dalteparin sodium finished product 2.7Kg after-25～-35 ℃ of following freeze-drying.
Embodiment 2: present embodiment and embodiment 1 difference are that heparin sodium is 10Kg, and Sodium Nitrite is 150g, and Peng Qinghuana is 100g, obtains dalteparin sodium finished product 9Kg after the freeze-drying.
Embodiment 3: present embodiment and embodiment 1 difference are that heparin sodium is 30Kg, and Sodium Nitrite is 450g, and Peng Qinghuana is 300g, obtains dalteparin sodium finished product 27Kg after the freeze-drying.
Claims (1)
1. dalteparin sodium preparation technology is characterized in that it may further comprise the steps:
1., preparation heparin sodium aqua
After in heparin sodium, adding 5～8 quality purified water doubly, stir dissolving after 4～6 hours at normal temperatures;
2., preparation depolymerized heparin liquid
After the pH value 2～3 of the heparin sodium aqua that 1. obtains with the hydrochloric acid regulating step, adding weight is the Sodium Nitrite of heparin sodium 1.5%～2.5%, then at 10～30 ℃ of following stirring reaction 2～5h, obtains depolymerized heparin liquid after leaving standstill 20～24h again;
3., preparation reduced liquid
Regulate the pH value 9～11 of above-mentioned depolymerized heparin liquid with sodium hydroxide solution after, add 0.6%～1.0% times of heparin sodium weight sodium borohydride reduction 10～16h, and then regulate pH value to 6.5～7.0 with sodium hydroxide solution, obtain reduced liquid;
4., preparation precipitate reduction thing
In above-mentioned reduced liquid, add the ethanol that 2～4 volumes are doubly measured, fully stir the back collection and obtain the precipitate reduction thing;
5., preparation dalteparin sodium bullion
After in the precipitate reduction thing of collecting, adding the pure water stirring and dissolving; The ydrogen peroxide 50 that adding 0.2%～1.0% volume is doubly measured is at 25～35 ℃ of following oxidation 10～24h; And then add the ethanol that 2～4 volumes are doubly measured, fully stir back collecting precipitation thing and obtain the dalteparin sodium bullion;
6., preparation dalteparin sodium elaboration
The dalteparin sodium bullion of above-mentioned collection deposition is added the solution that purified water is dissolved into 1%～2% (w/w), and using the molecular weight cutoff respectively is that 3000 and 8000 ultra-filtration membrane carries out ultrafiltration, after Sterile Filtration, obtains dalteparin sodium elaboration solution again;
7., freeze-drying
The dalteparin sodium solution that above-mentioned steps is made promptly obtains the dalteparin sodium finished product-25～-35 ℃ of following freeze-drying.
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214596A (en) * | 2013-05-14 | 2013-07-24 | 枣庄赛诺康生化股份有限公司 | Method for directly producing low-molecular weight heparin sodium through heparin sodium crude product |
| CN103408676A (en) * | 2013-07-15 | 2013-11-27 | 河北常山生化药业股份有限公司 | Nadroparin calcium preparation technology |
| CN104045744A (en) * | 2014-06-26 | 2014-09-17 | 常州千红生化制药股份有限公司 | Preparation method for dalteparin sodium |
| CN104045743A (en) * | 2014-06-26 | 2014-09-17 | 常州千红生化制药股份有限公司 | Method for preparing high-quality dalteparin sodium |
| CN104072635A (en) * | 2014-03-07 | 2014-10-01 | 常山生化药业（江苏）有限公司 | Method for preparing dalteparin sodium in purifying manner by using anion exchange resin |
| CN104098716A (en) * | 2014-07-16 | 2014-10-15 | 南京健友生化制药股份有限公司 | Production method of dalteparin sodium fine product |
| CN104262510A (en) * | 2014-10-11 | 2015-01-07 | 枣庄赛诺康生化股份有限公司 | Preparation method for low molecular weight heparin sodium with ultralow free sulfate group content |
| CN104262508A (en) * | 2014-09-19 | 2015-01-07 | 东营天东制药有限公司 | Preparation technique of tinzaparin sodium |
| CN105294885A (en) * | 2015-11-23 | 2016-02-03 | 山东大学 | Preparation method of novel source of low molecular weight heparin from nitrous acid degradation |
| CN105884934A (en) * | 2014-10-17 | 2016-08-24 | 北京海吉星医疗科技有限公司 | Preparation method of dalteparin sodium |
| CN107141373A (en) * | 2017-07-01 | 2017-09-08 | 湖北亿诺瑞生物制药有限公司 | A kind of preparation technology of new Dalteparin Sodium |
| 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 |
| CN113024689A (en) * | 2021-05-21 | 2021-06-25 | 江西浩然生物制药有限公司 | Method for controlling molecular weight of dalteparin sodium |
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Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214596A (en) * | 2013-05-14 | 2013-07-24 | 枣庄赛诺康生化股份有限公司 | Method for directly producing low-molecular weight heparin sodium through heparin sodium crude product |
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| CN104045744A (en) * | 2014-06-26 | 2014-09-17 | 常州千红生化制药股份有限公司 | Preparation method for dalteparin sodium |
| CN104098716A (en) * | 2014-07-16 | 2014-10-15 | 南京健友生化制药股份有限公司 | Production method of dalteparin sodium fine product |
| CN104098716B (en) * | 2014-07-16 | 2015-04-22 | 南京健友生化制药股份有限公司 | Production method of dalteparin sodium fine product |
| CN104262508A (en) * | 2014-09-19 | 2015-01-07 | 东营天东制药有限公司 | Preparation technique of tinzaparin sodium |
| CN104262510A (en) * | 2014-10-11 | 2015-01-07 | 枣庄赛诺康生化股份有限公司 | Preparation method for low molecular weight heparin sodium with ultralow free sulfate group content |
| CN104262510B (en) * | 2014-10-11 | 2016-08-17 | 山东万邦赛诺康生化制药股份有限公司 | A kind of preparation method of the low molecular weight heparin sodium of ultralow free sulphur acidic group |
| CN105884934A (en) * | 2014-10-17 | 2016-08-24 | 北京海吉星医疗科技有限公司 | Preparation method of dalteparin sodium |
| CN105294885A (en) * | 2015-11-23 | 2016-02-03 | 山东大学 | Preparation method of novel source of low molecular weight heparin from nitrous acid degradation |
| 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 |
| CN107141373A (en) * | 2017-07-01 | 2017-09-08 | 湖北亿诺瑞生物制药有限公司 | A kind of preparation technology of new Dalteparin Sodium |
| WO2019159092A1 (en) | 2018-02-14 | 2019-08-22 | Biological E Limited | Improved process for the preparation of dalteparin sodium |
| JP2021513593A (en) * | 2018-02-14 | 2021-05-27 | バイオロジカル イー リミテッド | An improved way to prepare dalteparin sodium |
| US11492421B2 (en) | 2018-02-14 | 2022-11-08 | Biological E Limited | Process for the preparation of Dalteparin sodium |
| CN113024689A (en) * | 2021-05-21 | 2021-06-25 | 江西浩然生物制药有限公司 | Method for controlling molecular weight of dalteparin sodium |
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