CN102585037A - Enoxaparin sodium and production purification method thereof - Google Patents
Enoxaparin sodium and production purification method thereof Download PDFInfo
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- CN102585037A CN102585037A CN2012100293234A CN201210029323A CN102585037A CN 102585037 A CN102585037 A CN 102585037A CN 2012100293234 A CN2012100293234 A CN 2012100293234A CN 201210029323 A CN201210029323 A CN 201210029323A CN 102585037 A CN102585037 A CN 102585037A
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Abstract
The invention discloses enoxaparin sodium. The average molecular weight of the enoxaparin sodium is between 3500-5500 dalton, thrombolytic biological activity is 100-125IU/mg, and the ratio value of resistance to Xa and IIa resistance is between 3.3-5.3. A production purification method of the enoxaparin sodium comprises preparation of heparin benzyl chloride ammonium salt, preparation of heparin benzyl ester, purification of heparin benzyl ester, preparation of enoxaparin sodium and purification of enoxaparin sodium. By means of the enoxaparin sodium, the molecular weight and distribution range of a product are controlled, and the quality of a fine enoxaparin sodium product meets the quality standard of the european pharmacopoeia. The enoxaparin sodium adopts a crude product of heparin sodium as an initial raw material and can effectively reduce production cost. The refined heparin benzyl ester stabilizes the final quality of the product. Purification difficulties are simplified, the coloring problem in the production is effectively solved, and the product quality is improved.
Description
Technical field
The present invention relates to a kind of Enoxaparin Sodium and produce purification process.
Background technology
Heparin sodium (Heparin) is the biologically active substance that extensively is present in people and the mammalian tissues; Belong to natural mucopolysaccharide class; Its chemical structure alternately is formed by connecting D-glucose aldehydic acid and D-glucose amine, MWD 5,000-30; 000 dalton (molecular-weight average is 20,000 dalton).Heparin sodium is one of the most complicated organic cpds of human up to now known molecular structures.Heparin sodium has very strong anticoagulation, anti-thrombus function, promptly anti-II a and anti-Xa function.Life-time service unfractionated heparin sodium has induced platelet to reduce the risk (3%) of disease, and thrombocytopenia can cause the increase of thrombosis and mortality ratio.
Enoxaparin Sodium (Enoxaparin Sodium) is Low molecular heparin class (low molecular weight heparin; One of be called for short LMWH) kind; European Pharmacopoeia (EP) 7.0 editions briefly is described as the Enoxaparin Sodium preparation method: Enoxaparin Sodium is a kind of Low molecular heparin sodium salt, and it carries out alkaline hydrolysis through the benzyl ester verivate to heparin and gathers and obtain.β-null method that U.S. Pat 005389618A promptly adopts this alkaline hydrolysis to gather; Its basic step is: with the porcine mucosa heparin is starting raw material; Through the preparation of heparin quaternary ammonium salt preparation, heparin benzyl ester, to heparin benzyl ester carry out alkaline hydrolysis gather, with acid neutralization, alcohol deposition; Refining, decolouring dehydrate, and obtain the Enoxaparin Sodium finished product.
Compare with unfractionated heparin sodium; " Enoxaparin Sodium " has stronger anti-freezing usefulness; Cause that thrombocytopenic spinoff obviously reduces, plurality of advantages such as hemorrhage complication also reduces, the transformation period is long in the subcutaneous injection good absorption, body, share of market accounts for the heparin series products more than 2/3.
Summary of the invention
The objective of the invention is in order to overcome above deficiency, provide a kind of and reduce production costs, improve the quality of products, simplify the Enoxaparin Sodium of production technique and produce purification process.
The present invention realizes through following technical scheme: a kind of Enoxaparin Sodium, the molecular-weight average of Enoxaparin Sodium are between the 3500-5500 dalton, thrombus dissolving biological activity 100-125 IU/mg, and the ratio of anti-Xa and anti-IIa is between 3.3-5.3.Enoxaparin Sodium is different types of mixture; Basic composition is of mixture: the polysaccharide chain molecular weight less than 2000 daltonian be 12%～20%; The polysaccharide chain molecular weight 2000～8000 daltonian be 68%～88%, the polysaccharide chain molecular weight is less than 18% greater than 8000 dalton.
A kind of production purification process of Enoxaparin Sodium may further comprise the steps:
1) under the normal temperature crude heparin sodium of 1 weight part is dissolved in the deionized water of 15～20 weight parts, the benzethonium chloride of 2～3 weight parts is dissolved in mixing and stirring in the deionized water of 4～6 weight parts, the benzethonium chloride aqueous solution is joined in the heparin sodium aqueous solution; Carry out sufficient salinization reaction, the reaction times is 1 hour, and the heparin benzethonium chloride salt of gained is left standstill; Vacuum filtration; Behind the suction filtration solid, again with the solid that obtains with the deionized water agitator treating after suction filtration, wash like this, solid that must be newly behind twice of the suction filtration; With new solid under 40～60 ℃, 1～2KPa vacuum condition dry 20～30 hours, obtain exsiccant heparin benzethonium chloride salt;
2) the heparin benzethonium chloride salt with 1 weight part is dissolved in the exsiccant methylene dichloride of 5～8 weight parts, adds the Benzyl Chloride of 1～3 weight part, under 25～45 ℃ of conditions; Mixed solution is stirred, make it carry out esterification, esterification stopped after 20～30 hours; Reacted solution is a heparin benzyl ester reaction solution, and heparin benzyl ester reaction solution is joined in isopyknic 10% sodium-acetate methanol solution, and solid is separated out; Decompress filter filters twice with the solids that obtains after the suction filtration with the methyl alcohol agitator treating, and solids is freeze-day with constant temperature under 50～60 ℃ of conditions; Get heparin benzyl ester salt bullion, esterification yield 9-14%;
3) with the heparin benzyl ester salt bullion of 1 weight part of above-mentioned preparation under agitation condition; Be dissolved in 10% sodium chloride aqueous solution of 8～12 weight parts, mixed solution joined in the methyl alcohol of 20-30 weight part, solid is separated out; Decompress filter; The solids that obtains filters twice with the methyl alcohol agitator treating, and solid is freeze-day with constant temperature under 50～60 ℃ of conditions, gets pure heparin benzyl ester;
4) the purified heparin benzyl ester with above-mentioned 1 weight part is dissolved in the deionized water of 15～20 weight parts, and 0.2 N aqueous sodium hydroxide solution is added, and under 55～70 ℃ of temperature, carries out DeR; Reaction times is 30～70 minutes, and reacted solution is a reaction solution, and reaction solution is cooled to room temperature; Hydrogen chloride is regulated PH to neutral, adds 15 % sodium-chlor, dissolution filter; Clear liquid is joined in the amount methyl alcohol of 1.6-1.8 weight part, separate out solid, solid is centrifugal, washing; Solid is dry under 45～60 ℃ condition, gets the Enoxaparin Sodium bullion;
5) with the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 40～60 ℃ 8～11 weight parts, regulate pH value to 9～11 of mixed solution with sodium hydroxide, filtration adds 1%～3% ydrogen peroxide 50 of water-soluble liquid measure; Regulate pH value to 9～11 of mixed solution, insulation reaction 1～3 hour adds 10% sodium-chlor, regulates pH value to 6～8; Filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out deposition; Centrifugal, the product spraying drying gets the elaboration Enoxaparin Sodium.
The detected result of the elaboration Enoxaparin Sodium that obtains: molecular-weight average 4240,2000-8000:74.6%, < 2000:14.8%.Anti-Xa:102.6, anti-IIa:23.8.The anti-IIa:4.31 of anti-Xa/>.All the other each items all meet the European Pharmacopoeia standard.
The present invention compared with prior art has the following advantages: the present invention can effectively reduce production cost; Improve the quality of products, simplify production technique, according to this production technique; The elaboration Enoxaparin Sodium that finally obtains is different types of mixture; Meet the European Pharmacopoeia quality standard, yield is with quite external, and the like product quality that the quality of the pharmaceutical preparations is sold than existing market is good.
Description of drawings
Fig. 1 is a process flow diagram of the present invention for the present invention.
Embodiment
In order to deepen to understanding of the present invention, will combine embodiment and accompanying drawing that the present invention is made further detailed description below, this embodiment only is used to explain the present invention, does not constitute the qualification to protection domain of the present invention.
Practical implementation, example one:
Take by weighing the 72g heparin sodium, the 180g benzethonium chloride, the 240g Benzyl Chloride is subsequent use.
1. the preparation of heparin benzethonium chloride salt:
Under the room temperature condition, the heparin sodium of 1 weight part is dissolved in the deionized water of 15 weight parts, the heparin sodium that is about to 72g is dissolved in the deionized water of 1080g; The benzethonium chloride of 180g is dissolved in mixing and stirring in the ionized water of 5.5 weight parts, the benzethonium chloride aqueous solution is joined in the heparin sodium aqueous solution, carry out sufficient salinization reaction; Reaction times is 1 hour, and the heparin benzethonium chloride salt of gained is left standstill vacuum filtration; Get solid behind the suction filtration; Again with the solid that obtains with the deionized water agitator treating after suction filtration, like this behind washing, twice of the suction filtration solid newly, with new solid in 40～60 ℃, 1～2KPa vacuum condition drying 20～30 hours down; Obtaining exsiccant heparin benzethonium chloride salt, is that weight with heparin sodium is fundamental unit in this step;
2. the preparation of heparin benzyl ester bullion:
The heparin benzethonium chloride salt of 1 weight part is dissolved in the exsiccant methylene dichloride of 5～8 weight parts, adds the 240g Benzyl Chloride, under 35 ℃ of conditions; Mixed solution is stirred, make it carry out esterification, esterification stopped after 30 hours; Reacted solution is a heparin benzyl ester reaction solution, and heparin benzyl ester reaction solution is joined in isopyknic 10% sodium-acetate methanol solution, and solid is separated out; Decompress filter filters twice with the solids that obtains after the suction filtration with the methyl alcohol agitator treating, and solids is freeze-day with constant temperature under 50～60 ℃ of conditions; Heparin benzyl ester salt bullion, esterification yield 9-14% is that weight with heparin benzethonium chloride salt is fundamental unit in this step;
3. the purifying of heparin benzyl ester:
The heparin benzyl ester salt bullion of 1 weight part of above-mentioned preparation under agitation condition, is dissolved in 10% sodium chloride aqueous solution of 8～12 weight parts, mixed solution is joined in the methyl alcohol of 20-30 weight part; Solid is separated out; Decompress filter, the solids that obtains filters twice with the methyl alcohol agitator treating, and solid is freeze-day with constant temperature under 50 ℃ of conditions; Pure heparin benzyl ester, be that weight with heparin benzyl ester salt bullion is fundamental unit in this step;
4. the preparation of Enoxaparin Sodium:
The purified heparin benzyl ester of above-mentioned 1 weight part is dissolved in the deionized water of 15～20 weight parts, 0.2 N aqueous sodium hydroxide solution is added, under 55～70 ℃ of temperature, carry out DeR; Reaction times is 30～70 minutes, and reacted solution is a reaction solution, and reaction solution is cooled to room temperature; Hydrogen chloride is regulated PH to neutral, adds 15 % sodium-chlor, dissolution filter; Clear liquid is joined in the amount methyl alcohol of 1.6-1.8 weight part, separate out solid, solid is centrifugal, washing; Solid is dry under 45～60 ℃ condition, the Enoxaparin Sodium bullion, be that weight with purified heparin benzyl ester is fundamental unit in this step;
5. the purifying of Enoxaparin Sodium:
The Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 40～60 ℃ 8～11 weight parts, is regulated pH value to 9～11 of mixed solution, filtration with sodium hydroxide; 1%～3% the ydrogen peroxide 50 that adds water-soluble liquid measure is regulated pH value to 9～11 of mixed solution, insulation reaction 1～3 hour; Add 10% sodium-chlor, regulate pH value to 6～8, filter; Reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out deposition, centrifugal; The product spraying drying, the elaboration Enoxaparin Sodium, be that weight with the Enoxaparin Sodium bullion is fundamental unit in this step.
Practical implementation, example two:
Present embodiment and embodiment one difference are heparin sodium 200g, benzethonium chloride 500g, Benzyl Chloride 667g.
Practical implementation, example three:
Present embodiment and embodiment one difference are heparin sodium 1kg, benzethonium chloride 2.5g, Benzyl Chloride 3.34kg.
The present invention can effectively reduce production cost; Improve the quality of products, simplify production technique, according to this production technique; The elaboration Enoxaparin Sodium that finally obtains is different types of mixture; Meet the European Pharmacopoeia quality standard, yield is with quite external, and the like product quality that the quality of the pharmaceutical preparations is sold than existing market is good.
Claims (3)
1. Enoxaparin Sodium, it is characterized in that: the molecular-weight average of said Enoxaparin Sodium is between the 3500-5500 dalton, thrombus dissolving biological activity 100-125 IU/mg, the ratio of anti-Xa and anti-IIa is between 3.3-5.3.
2. according to the said a kind of Enoxaparin Sodium of claim 1; It is characterized in that: said Enoxaparin Sodium is different types of mixture; Basic composition is of mixture: the polysaccharide chain molecular weight less than 2000 daltonian be 12%～20%; The polysaccharide chain molecular weight 2000～8000 daltonian be 68%～88%, the polysaccharide chain molecular weight is less than 18% greater than 8000 dalton.
3. the production purification process of an Enoxaparin Sodium is characterized in that: may further comprise the steps:
1) under the normal temperature crude heparin sodium of 1 weight part is dissolved in the deionized water of 15～20 weight parts, the benzethonium chloride of 2～3 weight parts is dissolved in mixing and stirring in the deionized water of 4～6 weight parts, the benzethonium chloride aqueous solution is joined in the heparin sodium aqueous solution; Carry out sufficient salinization reaction, the reaction times is 1 hour, and the heparin benzethonium chloride salt of gained is left standstill; Vacuum filtration; Behind the suction filtration solid, again with the solid that obtains with the deionized water agitator treating after suction filtration, wash like this, solid that must be newly behind twice of the suction filtration; With new solid under 40～60 ℃, 1～2KPa vacuum condition dry 20～30 hours, obtain exsiccant heparin benzethonium chloride salt;
2) the heparin benzethonium chloride salt with 1 weight part is dissolved in the exsiccant methylene dichloride of 5～8 weight parts, adds the Benzyl Chloride of 1～3 weight part, under 25～45 ℃ of conditions; Mixed solution is stirred, make it carry out esterification, esterification stopped after 20～30 hours; Reacted solution is a heparin benzyl ester reaction solution, and heparin benzyl ester reaction solution is joined in isopyknic 10% sodium-acetate methanol solution, and solid is separated out; Decompress filter filters twice with the solids that obtains after the suction filtration with the methyl alcohol agitator treating, and solids is freeze-day with constant temperature under 50～60 ℃ of conditions; Get heparin benzyl ester salt bullion, esterification yield 9-14%;
3) with the heparin benzyl ester salt bullion of 1 weight part of above-mentioned preparation under agitation condition; Be dissolved in 10% sodium chloride aqueous solution of 8～12 weight parts, mixed solution joined in the methyl alcohol of 20～30 weight parts, solid is separated out; Decompress filter; The solids that obtains filters twice with the methyl alcohol agitator treating, and solid is freeze-day with constant temperature under 50～60 ℃ of conditions, gets pure heparin benzyl ester;
4) the purified heparin benzyl ester with above-mentioned 1 weight part is dissolved in the deionized water of 15～20 weight parts, and 0.2 N aqueous sodium hydroxide solution is added, and under 55～70 ℃ of temperature, carries out DeR; Reaction times is 30～70 minutes, and reacted solution is a reaction solution, and reaction solution is cooled to room temperature; Hydrogen chloride is regulated PH to neutral, adds 15 % sodium-chlor, dissolution filter; Clear liquid is joined in the amount methyl alcohol of 1.6-1.8 weight part, separate out solid, solid is centrifugal, washing; Solid is dry under 45～60 ℃ condition, gets the Enoxaparin Sodium bullion;
5) with the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 40～60 ℃ 8～11 weight parts, regulate pH value to 9～11 of mixed solution with sodium hydroxide, filtration adds 1%～3% ydrogen peroxide 50 of water-soluble liquid measure; Regulate pH value to 9～11 of mixed solution, insulation reaction 1～3 hour adds 10% sodium-chlor, regulates pH value to 6～8; Filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out deposition; Centrifugal, the product spraying drying gets the elaboration Enoxaparin Sodium.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
| CN103439434A (en) * | 2013-09-12 | 2013-12-11 | 苏州英诺凯生物医药科技有限公司 | Detection method of esterification rate of enoxaparin sodium intermediate |
| CN103554305A (en) * | 2013-10-14 | 2014-02-05 | 南昌市浩然生物医药有限公司 | Synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium |
| CN104558252A (en) * | 2015-02-03 | 2015-04-29 | 华北制药华坤河北生物技术有限公司 | Method for producing enoxaparin sodium by using crude sodium heparin products |
| CN104592421A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | Refining method of enoxaparin sodium |
| CN106243246A (en) * | 2015-08-21 | 2016-12-21 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and preparation method and application |
| CN106699928A (en) * | 2015-08-13 | 2017-05-24 | 烟台东诚药业集团股份有限公司 | Drying method of nadroparin calcium |
| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
| CN111670204A (en) * | 2017-12-11 | 2020-09-15 | 生物E有限公司 | Process for preparing low molecular weight heparin |
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Patent Citations (1)
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| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
| CN103439434A (en) * | 2013-09-12 | 2013-12-11 | 苏州英诺凯生物医药科技有限公司 | Detection method of esterification rate of enoxaparin sodium intermediate |
| CN103554305A (en) * | 2013-10-14 | 2014-02-05 | 南昌市浩然生物医药有限公司 | Synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium |
| CN104592421A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | Refining method of enoxaparin sodium |
| CN104558252A (en) * | 2015-02-03 | 2015-04-29 | 华北制药华坤河北生物技术有限公司 | Method for producing enoxaparin sodium by using crude sodium heparin products |
| CN106699928A (en) * | 2015-08-13 | 2017-05-24 | 烟台东诚药业集团股份有限公司 | Drying method of nadroparin calcium |
| CN106243246A (en) * | 2015-08-21 | 2016-12-21 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and preparation method and application |
| CN106243246B (en) * | 2015-08-21 | 2019-05-24 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and the preparation method and application thereof |
| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
| CN111670204A (en) * | 2017-12-11 | 2020-09-15 | 生物E有限公司 | Process for preparing low molecular weight heparin |
| CN111670204B (en) * | 2017-12-11 | 2022-07-29 | 生物E有限公司 | Process for preparing low molecular weight heparin |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
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Application publication date: 20120718 |