CN103342761A - Technology for preparing enoxaparin sodium by membrane separation - Google Patents
Technology for preparing enoxaparin sodium by membrane separation Download PDFInfo
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Abstract
The invention discloses a technology for preparing enoxaparin sodium by membrane separation. The technology is characterized in that the enoxaparin sodium is sequentially subjected to treatments such as quaternary ammonium salt salinization, benzyl esterification and alkalinity degradation so as to realize beta-degradation, oxidation decoloration and filtration edulcoration, and filter liquor is subjected to ultrafiltration treatment to obtain an enoxaparin sodium product which can meet average molecular weight and molecular weight distribution range. According to the technology disclosed by the invention, membranes with different hole diameters are used for realizing ultrafiltration so as to control molecular weight and molecular weight distribution of a control product, and the enoxaparin sodium product with high purity and high activity is prepared; hydrogen peroxide oxidation decoloration and activated carbon filtration edulcoration are adopted, the impurities in a reaction system are effectively removed, and the product chromaticity is remarkably improved; the weight-average molecular weight of the prepared enoxaparin sodium is 3800-5000, the size and distribution range of molecular weight are ideal, the measured anti-FXa resistant / anti-FII a specific value is greater than 3.3, the main factor anti-FII a activity for causing a bleeding danger is greatly reduced, the anti-FXa activity for playing an embolism resisting action is relatively improved, and the validity and security advantages of the product are obvious.
Description
Technical field
The present invention relates to utilize membrane separation technique to prepare the method for Enoxaparin Sodium, belong to technical field of bioengineering.
Technical background
The class long-chain polysaccharide that heparin (heparin) is made up of sulfation glycosamine and hexuronic acid extensively is present in animal organ and tissues such as mucous membrane of small intestine, lung, mainly separates obtaining at present from mammiferous mastocyte.Heparin is by different protein binding with other, can bring into play important biological, have anti-freezing, anti-inflammatory, antianaphylaxis, antiviral, anticancer, transfer various biological function such as blood fat, it can activate antithrombin, accelerate antithrombin and in coagulation cascade, suppress the speed of serine protease, thereby be widely used as a kind of anticoagulant medicine.But life-time service can produce many negative impacts, as side effects such as hemorrhage and induced platelet minimizing, osteoporosises.These drawbacks limit heparin application clinically.Therefore, people have developed the novel anti blood-clotting agent, low molecular weight heparin (LMWH).This class medicine has that chain is short, combining site is few, bioavailability height, and advantage such as long half time, thereby have good medical prospect.
Enoxaparin Sodium is a kind of of Low molecular heparin, is mainly used in antithrombotic, anticoagulation, treatment acute myocardial infarction and unstable angina pectoris etc.Its anti-freezing mechanism complexity, indication is more extensive, and each link of blood coagulation is all had effect.Comprise that the anticoagulant proenzyme changes zymoplasm into, the anticoagulant enzymic activity hinders Fibrinogen to change scleroproein into, prevents platelet aggregation.Enoxaparin Sodium can be by reducing LDL and VLDL, and rising HDL changes blood viscosity, the protection vascular endothelial cell, and pre-preventing thrombosis and atherosclerosis are improved effects such as coronary artery circulation.It is wide that Enoxaparin Sodium has clinical indication, the bioavailability height, and long half time in the body, advantage such as side effect is little, its share of market reaches more than 2/3 of heparin class medicine.
What Enoxaparin Sodium production was mainly adopted at present is β-elimination edman degradation Edman technology, the common problem that this processing method exists is that the target product molecular weight size that obtains is inhomogeneous, need carry out classification to the different molecular weight section, to reach medicinal requirements, and traditional ethanol precipitation processing method step of widespread use is comparatively loaded down with trivial details, and produce a large amount of waste ethanols need the recycling.
Summary of the invention
At the problem that prior art exists, the present invention takes with the film in different apertures soup to be carried out uf processing, and intercepting obtains molecular-weight average and the satisfactory high reactivity Enoxaparin Sodium of range of molecular weight distributions product.
For realizing the object of the invention, this membrane sepn prepares Enoxaparin Sodium technology and may further comprise the steps:
A. quaternary ammonium salt salinization
The heparin sodium aqueous solution is mixed the back with the benzyl rope chlorine aqueous solution with 1/1.5～2.5 volume ratio to react under 45～50 ℃, react after 2～4 hours throw out washing, oven dry are obtained the heparin quaternary ammonium salt, described heparin sodium and benzethonium chloride mass concentration ratio are 1/2.5～3;
B. benzyl esterification
The heparin quaternary ammonium salt is dissolved into 5～7 quality N doubly, in the dinethylformamide organic solvent after, under 25～35 ℃, carry out esterification after adding heparin quaternary ammonium salt 1～4 quality Benzyl Chloride doubly;
C. degraded
Above-mentioned esterification adds esterification reaction product sodium hydroxide again after 20～30 hours reacts under 40～60 ℃, and described sodium hydroxide concentration is 6～12% of esterification reaction product weight;
D. oxidative decoloration
Behind above-mentioned reaction 30～60min, degraded product is added the hydrogen peroxide oxidation decolouring of 30% concentration of 1～1.5%v/v reaction solution volume;
E. filtering and impurity removing
After adding gac with the consumption of 40～80 g/L in the above-mentioned reaction system, under 0.05～0.12MPa, filter;
F. classification ultrafiltration
The filtrate of filtering and impurity removing is used filter membrane ultrafiltration under 0.22～0.28MPa in MWCO8kDa aperture, to remove the heparin sodium degraded product that molecular weight is higher than 8kDa, filtrate is used filter membrane ultrafiltration under 0.18～0.24MPa in MWCO2kDa aperture again, obtains the Enoxaparin Sodium degraded product that molecular weight is lower than 2kDa to hold back.
Beneficial effect of the present invention: this invention is crucial to be to adopt the membrane ultrafiltration technology in different apertures to realize controlling molecular weight and the range of molecular weight distributions of product, prepares high purity, highly active Enoxaparin Sodium product.Production technique of the present invention is to utilize β-null method that common macromole heparin sodium is degraded to low molecular weight heparin sodium under given conditions.The present invention taked the technology of hydrogen peroxide oxidation decolouring and activated carbon filtration removal of impurities, effectively removed the impurity in the reaction system and significantly improved the colourity of product.
Description of drawings
Fig. 1 is Enoxaparin Sodium technological process of production figure of the present invention.
Embodiment
Embodiment 1: as shown in Figure 1,
A. hydrophilic reaction system prepares heparin-benzethonium chloride salt
Add 3kg heparin sodium (injection stage is removed DS) in 30 liters of 30～40 ℃ of purified water, stirring makes it to dissolve fully; Add the 8kg benzethonium chloride in 50 liters of 45～50 ℃ of purified water, stirring makes it to dissolve fully.Heparin sodium aqua with dissolving under agitation slowly joins in the benzethonium chloride solution of dissolving then, adds the back after continuing to stir 30～60min under 45～50 ℃, and the throw out that generates is centrifugal, and abandoning supernatant obtains the heparin salt.Behind 100 liters of purified water washing heparin salts, centrifugal abandoning supernatant, wash centrifugal repetitive operation 3～4 times after, open Hotaircirculatingoven, with the heparin salt after centrifugal in baking oven in 50～60 ℃ dry 18～24 hours down, obtain water content and be lower than 10% heparin salt;
B. the hydrophobic reactant system prepares the heparin benzyl ester
Set 30～35 ℃ of bath temperatures, the heparin salt that drying is good joins to stir in 50 liters of dinethylformamide organic solvents and makes it dissolving, treat to dissolve fully the back and add the 10L Benzyl Chloride, stir the insulation esterification down after 20～30 hours at 25～35 ℃, adding 200 liter of 3%～10% sodium acetate ethanolic soln again stirs, the sodium acetate ethanolic soln agitator treating throw out that under agitation adds 150 liter 3%～10% then, add a small amount of purified water dissolution precipitation thing again, after adding the sodium-chlor stirring and dissolving of liquor capacity 5%～10% again, add 250 liter of 95% ethanol and stir precipitation, left standstill 6 hours after stopping to stir, repeat with salt precipitation operation 2 times;
C. β under the alkaline condition-elimination degraded
Above-mentioned carboxylate precipitation is dissolved into the feed liquid of mass concentration 10% with purified water, during warming-in-water to 40～60 ℃, with 220g sodium hydroxide with after the purified water dissolving, begin degraded in the adding feed liquid, keep 40～60 ℃ of liquid temperature in the degradation process, the pH value is not less than 10.0, surveyed the gentle pH value of a not good liquor in per 10 minutes, logical cooling water temperature behind degraded 30～60min adds hydrochloric acid and is neutralized to pH value 6.0～8.0, again alcohol precipitation behind the vacuum filtration;
D. Enoxaparin Sodium decolouring and removal of impurities
After the dissolving of above-mentioned degraded product adding purified water, added 1%～1.5%(v/v) reaction liquid volume concentrations and be 30% hydrogen peroxide rear oxidation 6～8 hours, reacting liquid temperature control is at 20～30 ℃, and then adding Plate Filtration behind the gac in the reaction system with the consumption of 40～80 g/L, filter pressure is controlled at 0.05～0.12MPa;
E. adopt membrane ultrafiltration that the different molecular weight component is carried out classification
Behind the membrane filtration of the filtrate behind the Plate Filtration through 0.2 μ m aperture, adopt the filter membrane of larger aperture (MWCO 8kDa) in 0.22～0.28MPa, 20～35 ℃ of following ultrafiltration, to remove the heparin sodium degraded product that most of molecular weight is higher than 8kDa, again and then the filtrate that obtains passed through the filter membrane of smaller aperture due (MWCO 2kDa) in 0.18～0.24MPa, 20～35 ℃ of following ultrafiltration, to hold back the heparin sodium degraded product that most of molecular weight is lower than 2kDa.Obtain molecular-weight average and the satisfactory Enoxaparin Sodium product of the present invention of range of molecular weight distributions after smart filter, the lyophilize successively with concentrating the trapped fluid that obtains.Wherein the two times of ultrafiltration model that all adopts Millipore Corp. to produce is the polysulfone membrane of 2KD.
The Enoxaparin Sodium weight-average molecular weight of the present invention's preparation is 3800～5000, the anti-F II of the anti-F X a/ a ratio that records is greater than 3.3, cause the anti-F II of the principal element a activity of hemorrhage risk significantly to reduce, improve relatively and the anti-F X a that brings into play anti-bolt effect is active, validity and the security advantages of product are obvious.Table 1 has been enumerated the Enoxaparin Sodium product of the present invention's preparation and the comparative result of country and imported product standard.
Embodiment 2: the present embodiment difference from Example 1 is:
A. hydrophilic reaction system prepares heparin-benzethonium chloride salt
Add 5kg heparin sodium (injection stage is removed DS) in 50 liters of 30～40 ℃ of purified water, stirring makes it to dissolve fully; Add the 13kg benzethonium chloride in 85 liters of 45～50 ℃ of purified water, stirring makes it to dissolve fully.Heparin sodium aqua with dissolving under agitation slowly joins in the benzethonium chloride solution of dissolving then, adds the back after continuing to stir 30～60min under 45～50 ℃, and the throw out that generates is centrifugal, and abandoning supernatant obtains the heparin salt.Behind 100 liters of purified water washing heparin salts, centrifugal abandoning supernatant, wash centrifugal repetitive operation 3～4 times after, open Hotaircirculatingoven, with the heparin salt after centrifugal in baking oven in 50～60 ℃ dry 18～24 hours down, obtain water content and be lower than 10% heparin salt;
B. the hydrophobic reactant system prepares the heparin benzyl ester
Set 30～35 ℃ of bath temperatures, the heparin salt that drying is good joins 105 liters of N, stir in the dinethylformamide organic solvent and make it dissolving, treat to dissolve fully the back and add 16 liters of Benzyl Chlorides, stir the insulation esterification down after 20～30 hours at 25～35 ℃, adding 500 liter of 3%～10% sodium acetate ethanolic soln again stirs, the sodium acetate ethanolic soln agitator treating throw out that under agitation adds 300 liter 3%～10% then, add a small amount of purified water dissolution precipitation thing again, after adding the sodium-chlor stirring and dissolving of liquor capacity 5%～10% then, add 400 liter of 95% ethanol and stir precipitation, left standstill 6 hours after stopping to stir, repeat with salt precipitation operation 2 times.
C. β under the alkaline condition-elimination degraded
Above-mentioned carboxylate precipitation is dissolved into the feed liquid of mass concentration 10% with purified water, during warming-in-water to 40～60 ℃, after sodium hydroxide with 6%～12% dissolves with purified water, begin degraded in the adding feed liquid, keep 40～60 ℃ of liquid temperature in the degradation process, the pH value is not less than 10.0, surveyed the gentle pH value of a not good liquor in per 10 minutes, behind degraded 30～60min, logical cooling water temperature adds hydrochloric acid and is neutralized to alcohol precipitation behind pH value 6.0～8.0 final vacuum suction filtrations;
D. Enoxaparin Sodium decolouring and removal of impurities
Above-mentioned degraded product is added the purified water dissolving, reacting liquid temperature control is at 20～30 ℃, added 1%～1.5%(v/v) reaction liquid volume concentrations and be 30% hydrogen peroxide oxidation 6～8 hours, add Plate Filtration behind the gac in the reaction system with the consumption of 40～80g/L again, filter pressure is controlled at 0.05～0.12MPa;
E. adopt membrane ultrafiltration that the different molecular weight component is carried out classification
Behind the membrane filtration of the filtrate behind the Plate Filtration through 0.2 μ m aperture, adopt the filter membrane of larger aperture (MWCO 8kDa) in 0.22～0.28MPa, 20～35 ℃ of following ultrafiltration, to remove the heparin sodium degraded product that most of molecular weight is higher than 8kDa, again and then the filtrate that obtains passed through the filter membrane of smaller aperture due (MWCO 2kDa) in 0.18～0.24MPa, 20～35 ℃ of following ultrafiltration, to hold back the heparin sodium degraded product that most of molecular weight is lower than 2kDa.Obtain molecular-weight average and the satisfactory Enoxaparin Sodium product of the present invention of range of molecular weight distributions after smart filter, the lyophilize successively with concentrating the trapped fluid that obtains.Wherein the two times of ultrafiltration model that all adopts Millipore Corp. to produce is the polysulfone membrane of 2KD.
Claims (1)
1. a membrane sepn prepares Enoxaparin Sodium technology, it is characterized in that it may further comprise the steps,
A. quaternary ammonium salt salinization
The heparin sodium aqueous solution is mixed the back with the benzyl rope chlorine aqueous solution with 1/1.5～2.5 volume ratio to react under 45～50 ℃, react after 2～4 hours throw out washing, oven dry are obtained the heparin quaternary ammonium salt, described heparin sodium and benzethonium chloride mass concentration ratio are 1/2.5～3;
B. benzyl esterification
The heparin quaternary ammonium salt is dissolved into 5～7 quality N doubly, in the dinethylformamide organic solvent after, under 25～35 ℃, carry out esterification after adding heparin quaternary ammonium salt 1～4 quality Benzyl Chloride doubly;
C. degraded
Above-mentioned esterification adds esterification reaction product sodium hydroxide again after 20～30 hours reacts under 40～60 ℃, and described sodium hydroxide concentration is 6～12% of esterification reaction product weight;
D. oxidative decoloration
Behind above-mentioned reaction 30～60min, degraded product is added the hydrogen peroxide oxidation decolouring of 30% concentration of 1～1.5%v/v reaction solution volume;
E. filtering and impurity removing
After adding gac with the consumption of 40～80 g/L in the above-mentioned reaction system, under 0.05～0.12MPa, filter;
F. classification ultrafiltration
The filtrate of filtering and impurity removing is used filter membrane ultrafiltration under 0.22～0.28 MPa in MWCO8kDa aperture, to remove the heparin sodium degraded product that molecular weight is higher than 8kDa, filtrate is used filter membrane ultrafiltration under 0.18～0.24MPa in MWCO2kDa aperture again, obtains the Enoxaparin Sodium degraded product that molecular weight is lower than 2kDa to hold back.
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Cited By (11)
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| CN103936889A (en) * | 2014-03-19 | 2014-07-23 | 苏州英诺凯生物医药科技有限公司 | Method for purification of enoxaparin by tangential flow filtration |
| CN106432547A (en) * | 2016-09-14 | 2017-02-22 | 苏州天马精细化学品股份有限公司 | Method for preparing enoxaparin sodium through heparin benzyl ester |
| CN106977627A (en) * | 2017-05-16 | 2017-07-25 | 苏州二叶制药有限公司 | A kind of Enoxaparin production method of sodium |
| CN109293800A (en) * | 2018-08-16 | 2019-02-01 | 山东万邦赛诺康生化制药股份有限公司 | Benzyl chloride taste removes method in a kind of heparin Bian ester production process |
| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| WO2019116217A2 (en) | 2017-12-11 | 2019-06-20 | Biological E Limited | Process for the preparation of low molecular weight heparin |
| WO2020216981A1 (en) | 2019-04-26 | 2020-10-29 | Laboratorios Farmacéuticos Rovi, S.A. | Method for obtaining low-molecular-weight heparins by means of tangential flow filtration |
| CN112673027A (en) * | 2019-04-26 | 2021-04-16 | 罗威制药股份有限公司 | Method for obtaining low molecular weight heparins by tangential flow filtration |
| CN115043959A (en) * | 2022-05-25 | 2022-09-13 | 湖北亿诺瑞生物制药有限公司 | Preparation method of high-yield enoxaparin sodium |
| CN116284499A (en) * | 2022-07-28 | 2023-06-23 | 河北常山生化药业股份有限公司 | Preparation method of sheep-derived low-molecular heparin sodium |
| CN117946294A (en) * | 2023-11-13 | 2024-04-30 | 河北常山凯库得生物技术有限公司 | Preparation method of energy-saving and environment-friendly enoxaparin sodium |
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| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| WO2020216981A1 (en) | 2019-04-26 | 2020-10-29 | Laboratorios Farmacéuticos Rovi, S.A. | Method for obtaining low-molecular-weight heparins by means of tangential flow filtration |
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| CN115043959A (en) * | 2022-05-25 | 2022-09-13 | 湖北亿诺瑞生物制药有限公司 | Preparation method of high-yield enoxaparin sodium |
| CN116284499A (en) * | 2022-07-28 | 2023-06-23 | 河北常山生化药业股份有限公司 | Preparation method of sheep-derived low-molecular heparin sodium |
| CN117946294A (en) * | 2023-11-13 | 2024-04-30 | 河北常山凯库得生物技术有限公司 | Preparation method of energy-saving and environment-friendly enoxaparin sodium |
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Inventor after: Ji Shengli Inventor after: Gao Shuhua Inventor after: Li Wenmao Inventor after: Bai Wenju Inventor after: Cui Jie Inventor before: Ji Shengli Inventor before: Gao Shuhua Inventor before: Li Wenmao |
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Address after: 050800 No.71, Menglong street, South District, Zhengding high tech Industrial Development Zone, Zhengding District, China (Hebei) pilot Free Trade Zone, Shijiazhuang City, Hebei Province Patentee after: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: 050800 No. 9, Fuqiang Road, Zhengding County, Shijiazhuang City, Hebei Province Patentee before: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. |