CN1850865A - Production method for purifying enoxaparin sodium - Google Patents
Production method for purifying enoxaparin sodium Download PDFInfo
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- CN1850865A CN1850865A CN 200610051609 CN200610051609A CN1850865A CN 1850865 A CN1850865 A CN 1850865A CN 200610051609 CN200610051609 CN 200610051609 CN 200610051609 A CN200610051609 A CN 200610051609A CN 1850865 A CN1850865 A CN 1850865A
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Abstract
The invention relates to a purifying manufacture method for Yino sodium heparin that adopts long chain quaternary ammonium salt salinization heparin, after taking benzyl chloride esterification, gaining the raw Yino heparin raw product. After taking decoloration by active carbon and macropore adsorptive resin, the sodium heparin product could be gained. The invention is easy to realize industrializing producing.
Description
Technical field
The present invention relates to a kind of production method for purifying of low molecular sodium heparin, especially, relate to a kind of production method for purifying of Enoxaparin Sodium.
Background of invention
The English enoxaparin sodium by name of Enoxaparin Sodium, according to the definition of European Pharmacopoeia 4, its chemical structural formula is as follows:
Wherein, n is the integer of 1-21, and R is H or SO
3Na, R ' are H or SO
3Na or CO-CH
3, R3 is CO when R2 is H
2Na or when R2 be CO
2R3 is H during Na.
Regulation according to European Pharmacopoeia 4, Enoxaparin Sodium belongs to a member in the Low molecular heparin family, system is with the Calciparine/sodium salt that extracts in the chitling mucous membrane alkaline depolymerization and getting after the benzyl esterification, molecular-weight average is about 4500 dalton, and principal character has a 4-enol pyranose aldehydic acid structure for the non-reducing end at molecule.
The main mechanism of enoxaparin is this product by combining with Antithrombin III and mixture thereof, and reinforcement is to the restraining effect of Xa factor and zymoplasm (the IIa factor).But because this product molecular chain is shorter, the antagonism xa activity is strong and for a long time, to the zymoplasm restraining effect a little less than, anti-thrombosis activity is better than anticoagulant active.Compare with unfractionated heparin, this product has that anti thrombotic action is strong, and hemorrhage risk is little, the bioavailability height, and long half time, advantage such as easy to use, thereby favored by doctor and patient.Have maximum indications in the present global heparin class pharmaceutical market of enoxaparin, comprising:
Due to illness and the degree of depth phlebothrombosis that the moving limited patient of activation is taken place (though this indication just gets the Green Light in the U.S. to calendar year 2001 late, this class patient number is estimated up to about annual 13000000 people) (1) prevention;
(2) there is the degree of depth phlebothrombosis that the patient of thromboembolic complication risk is taken place in the prevention abdominal postoperative;
(3) degree of depth phlebothrombosis of prevention hip displacement postoperative patient generation;
(4) degree of depth phlebothrombosis of prevention knee replacement postoperative patient generation;
(5) share the arterial thrombus (this type of patient's number whole world estimates at 2,000,000 people) of preventing unstable angina pectoris and non-q wave myocardial infarction patient to take place with acetylsalicylic acid (aspirin);
(6) share the venothrombotic inpatient of the acute degree of depth that is used to have or do not have pulmonary infarction with warfarin (warfarin);
(7) share the venothrombotic out-patient of the acute degree of depth who is used to not have pulmonary infarction with warfarin.
In addition, An Wante (Aventis) company comes China to apply for that two enoxaparins are at the process patent for the treatment of cerebrum ischemia (CN01803471.3) and prevention and treatment central nervous system trauma (CN98805489.2).
The method of producing low molecular sodium heparin at present in the world has physical fractionation method (FR2440376, US4692435, FR2453875 etc.), chemical cracking method (EP14184, EP37319, EP347588, US4629699, EP380943 etc.) and enzyme process (EP64452, US4826827, EP244236 etc.).Enoxaparin is because its special structure, employing be alkaline lysis.The production technique of relevant enoxaparin, existing many pieces of bibliographical informations.For example, US4692435 discloses the preparation technology in early stage of heparin, is mainly used in the chondroitin sulfate of removing in the heparin raw material.US4440926 has reported the production technique of utilizing quaternary ammonium salt esterification heparin.US5389618 has reported a kind of production technique of enoxaparin, main process comprise pre-treatment, the heparin sodium quaternary ammonium salt of heparin sodium preparation, heparin benzyl ester preparation (degree of esterification is between the 9.5%-14%) and under alkaline condition depolymerization heparin benzyl ester derivative obtain the enoxaparin finished product.
But all not mentioned important production technique problem of above-mentioned document promptly can produce some foreign pigments in the enoxaparin production process, the structure of matter of present not clear these impurity, and be difficult to isolate these foreign pigments with conventional means.And the pigment problem of Enoxaparin Sodium is the important indicator that influences the Enoxaparin Sodium final product quality, the color of drug solution and can reflect the purity of medicine to a certain extent with the difference of specified color.The solution colour of European Pharmacopoeia 4 regulation enoxaparin 10% aqueous solution (weightmeasurement ratio) is No. 5 look ((regulations of related standards look of yellow standard, can be with reference to the relevant regulations in the 2.2.2 joint " degree of coloration of liquids " among the European Pharmacopoeia 4), this production technique to Enoxaparin Sodium proposes higher requirement.Because enoxaparin is the wetting ability polysaccharide, although general purifying process such as charcoal absorption can be taken off partial pigment, residual pigment can't further separate again, can't reach the standard of European Pharmacopoeia 4; And the chemical decolorization rule is destroyed the structure of enoxaparin easily, thereby influences the quality of enoxaparin finished product.Therefore, need to adopt new purifying process to solve this technical barrier.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of production method for purifying of Enoxaparin Sodium is provided, use the regulation that Enoxaparin Sodium that this method produces meets European Pharmacopoeia 4.
Purpose of the present invention is achieved through the following technical solutions:
In being situated between, hydrophily uses long chain quaternary salinization heparin, the benzyl esterification is above-mentioned by the heparin of salinization, control its degree of esterification between 9.5%-14%, the heparin of the above-mentioned degree of esterification of depolymerization between 9.5%-14% under alkaline condition obtains the Enoxaparin Sodium crude product then.
According to the Enoxaparin Sodium crude product of above-mentioned prepared, its color is a tawny, need decolour.The contriver finds that through comparative study resin column on the Enoxaparin Sodium crude product is decoloured can effectively solve the pigment problem of Enoxaparin Sodium, and especially the macroporous adsorbent resin decolorizing effect is obvious.Decolorizing effect kind such as Rhom and Hass (Rohm Haas) the AMBERLITE series of producing preferably in the macroporous adsorbent resin is as polar macroporous poly-alkane ester polymeric adsorbent XAD-7HP, nonpolar macroporous polystyrene adsorption resin XAD-1600 etc.; Nonpolar macroporous polystyrene adsorption resin H1020, H103 that Chemical Plant of Nankai Univ. produces and D4006 etc., wherein preferred nonpolar macroporous polystyrene adsorption resin H103.
Further, resin decolorization and activated carbon decolorizing can be combined, can the pigment in the Enoxaparin Sodium effectively be separated.For example, earlier crude product is adsorbed with gac, upper prop decolours with macroporous adsorbent resin again; Perhaps crude product elder generation upper prop decolours with macroporous adsorbent resin, decolours with charcoal absorption again.
The invention has the beneficial effects as follows, utilize gac and macroporous adsorbent resin combined method that Enoxaparin Sodium is decoloured, can effectively separate foreign pigment, the Enoxaparin Sodium finished product is reached or be better than No. 5 looks of yellow standard of European Pharmacopoeia 4 regulation, and ordinary method is as only making the Enoxaparin Sodium finished product reach No. 5 looks of yellow standard that European Pharmacopoeia 4 is stipulated with activated carbon decolorizing; In addition, this method is economical and practical, is easy to realize suitability for industrialized production, and can not produce the structure of Enoxaparin Sodium and destroy, and this is than superior many of chemical decolorization method.
Embodiment
Heparin sodium at first needs to become the Enoxaparin Sodium crude product of molecular-weight average between 3500-5500 dalton through depolymerization, its technical scheme is: heparin sodium passes through ethanol sedimentation earlier, utilize impurity different, the content of chondroitin sulfate and Suleparoid in the minimizing heparin sodium raw material with heparin sodium resolution of precipitate degree in ethanol.Then, in water medium,, generate heparin sodium season with long-chain tetravalence ammonium salt (for example Benzethonium) salinization heparin sodium
The ammonium salt precipitation.The heparin sodium quaternary ammonium salt is in methylene dichloride and benzyl chloride generation esterification, the control degree of esterification is between 9.5%-14%, the mensuration of esterification yield can be with reference to the capable method of US5389618 specification sheets the 5th hurdle 44-48, promptly get the hydrolysis of m gram heparin benzyl ester, measuring the phenylcarbinol content that generates is the n gram, the ratio of n/m gained is esterification yield, obtains the heparin benzyl ester after precipitation, filtration, washing, drying.The heparin benzyl ester is water-soluble, add an amount of sodium hydroxide, in 60-65 ℃ of reaction 1-3 hour,, add sodium-chlor with the hydrochloric acid neutralization, behind the ethanol sedimentation, filtration drying promptly gets the Enoxaparin Sodium crude product, and its color is isabelline.
According to this production technique, the Enoxaparin Sodium that obtains at last is different types of mixture of heparin sulfate polysaccharide, the polysaccharide chain molecular weight that basic composition is 9%-20% of mixture is less than 2000 dalton, the polysaccharide chain molecular weight of 5%-20% is greater than 8000 dalton, the molecular weight of the polysaccharide chain of 60%-86% is between 2000-8000 dalton, and its molecular-weight average is between 3500-5500 dalton.
Further, according to European Pharmacopoeia 4 standards, the polysaccharide chain molecular weight that basic composition is 12%-20% of mixture is less than 2000 dalton in the preferred Enoxaparin Sodium, the molecular weight of the polysaccharide chain of 68%-88% is between 2000-8000 dalton, and its molecular-weight average is between 3500-5500 dalton.
According to the Enoxaparin Sodium that above-mentioned explained hereafter goes out, inevitably understand the chromogenesis problem.Decolouring can adopt activated carbon decolorizing method and the combination of resin decolorization method to carry out.After Enoxaparin Sodium is dissolved in water,, go up resin column again, after the freeze-drying, can obtain meeting the Enoxaparin Sodium finished product of European Pharmacopoeia 4 standards through activated carbon decolorizing; Perhaps the enoxaparin sodium sample is gone up resin column earlier, after collecting target components, precipitation, filtration, again through activated carbon decolorizing, after the precipitation freeze-drying, can obtain meeting the Enoxaparin Sodium finished product of European Pharmacopoeia 4 standards, the detection of every index can be with reference to the relevant regulations of European Pharmacopoeia 4 enoxaparin standards.
Above-mentioned resin can be selected in the macroporous adsorbent resin decolorizing effect kind preferably for use, AMBERLITE series as Rhom and Hass (Rohm Haas) production, as polar macroporous poly-alkane ester polymeric adsorbent XAD-7HP, nonpolar macroporous polystyrene adsorption resin XAD-1600 etc.; Nonpolar macroporous polystyrene adsorption resin H1020, H103 that Chemical Plant of Nankai Univ. produces and D4006 etc.Wherein, the nonpolar macroporous polystyrene adsorption resin H103 that preferred Chemical Plant of Nankai Univ. produces, its every technical parameter is as follows:
| Resin structure | Crosslinked-Polystyrene |
| Polarity | Nonpolar |
| Outward appearance | The dark-brown spherical particle |
| Particle size range (mm) | 0.3~1.25 |
| Water content (%) | 45~50 |
| Wet true density (g/ml) | 1.05~1.07 |
| Wet volume density (g/ml) | 0.70~0.75 |
| Specific surface (m 2/g) | 1000~1100 |
| Apparent density (g/ml) | 0.53~0.57 |
| Skeletal density (g/ml) | 1.20~1.24 |
| Mean pore size () | 85~95 |
| Porosity (%) | 55~59 |
| Pore volume (ml/g) | 1.08~1.12 |
For further illustrating the present invention, provide the following example that utilizes macroporous adsorbent resin and gac that Enoxaparin Sodium is decoloured.
The preparation of embodiment 1, Enoxaparin Sodium
1.1 in hydrophily is situated between, use long chain quaternary salinization heparin
Take by weighing heparin raw material 100g and 20g sodium-chlor is dissolved in 1L water, slowly add the ethanol of 800ml 95% under the room temperature, after precipitation is spent the night, remove supernatant, precipitation adds the 1L water dissolution.The Benzethonium that takes by weighing 250g is dissolved in the 1L water, and it is slowly added in the heparin solution, stirs.After sedimentation and filtration, water cleaned, filtering drying obtained the heparin sodium quaternary ammonium salt of 327g approximately.
1.2 benzyl esterification heparin
Above-mentioned heparin sodium quaternary ammonium salt is dissolved in the 1.2L methylene dichloride, slowly adds the 350ml benzyl chloride, stirred 25 hours down at 35 ℃.Take by weighing the 200g sodium-acetate in addition and be dissolved in the 2L methyl alcohol, slowly join in the above-mentioned dichloromethane solution, treat that precipitation is separated out after, filter, with washed with methanol 2 times, filtering drying obtains 116g heparin benzyl ester approximately, according to aforesaid method, recording its esterification yield is 13.4%.
1.3 depolymerization under the alkaline condition
116g heparin benzyl ester is dissolved in the 2.5L water, is heated to 62 ℃, add 10.8g sodium hydroxide, stir cracking 1.5 hours, cool to 20 ℃, add hydrochloric acid conditioning solution pH to 7.0.Adding sodium-chlor then, to make final concentration be 10%, adds 8L methyl alcohol, stirred 30 minutes, treat that precipitation is separated out after, filter, usefulness methyl alcohol diafiltration twice, vacuum-drying, the gained sample is isabelline, weighing is about 43.6g.After testing, weight-average molecular weight is 4718, wherein molecular weight is 12.6% less than 2000 daltonian polysaccharide molecule content, and the polysaccharide molecule content of molecular weight between 2000-8000 dalton is 74.5%, and molecular weight is 12.8% greater than 8000 daltonian polysaccharide molecule content
Embodiment 2, decoloring method one
Take by weighing 23 gram enoxaparin crude products, be dissolved in water, colorimetric is equivalent to No. 3 looks of yellow of European Pharmacopoeia 4 regulations.Add gac, 100rpm stirred 40 minutes, removed gac with filter paper filtering earlier, and then removed remaining gac with filtering with microporous membrane, and colorimetric is between No. 4 looks of yellow of European Pharmacopoeia 4 definition and No. 5 looks.With the nonpolar macroporous polystyrene adsorption resin post of H103 on the enoxaparin sodium solution (Chemical Plant of Nankai Univ.'s production), column volume 150ml, the water wash-out is collected target peak.Collect liquid upper prop wash-out 2 times again, collect target peak, colorimetric is better than No. 5 looks of yellow of European Pharmacopoeia 4 regulations, approaches yellow No. 6 looks.To collect the liquid ethanol sedimentation, after filtration, after the freeze-drying, weigh 18.8 grams.After testing, the every index of gained Enoxaparin Sodium finished product is as follows:
Weight-average molecular weight: 4604;
Molecular weight distribution: molecular weight is 13.8% less than 2000 daltonian polysaccharide molecule content, and the polysaccharide molecule content of molecular weight between 2000-8000 dalton is 75.1%.
The anti-II:4.1 of anti-Xa/;
Anti-Xa:108IU/mg;
231nm absorption value: 14.06.
Embodiment 3: decoloring method two
Take by weighing 30 gram enoxaparin crude products, be dissolved in water, colorimetric approaches No. 3 looks of yellow of European Pharmacopoeia 4 regulations.With the polar macroporous poly-alkane ester adsorption resin column of XAD-7HP on the enoxaparin solution (production of Rohm Haas company), column volume is 120ml, and the water wash-out is collected target peak.The upper prop wash-out is 2 times again, collects target peak, and colorimetric is No. 4 looks of yellow of European Pharmacopoeia 4 definition.Add gac, 100rpm stirred 40 minutes, removed gac with filter paper filtering earlier, and then removed remaining gac with filtering with microporous membrane, and colorimetric is better than No. 5 looks of yellow of European Pharmacopoeia 4 regulations.Collect liquid through ethanol sedimentation, filter, after the freeze-drying, weigh 26.4 grams.After testing, the every index of gained Enoxaparin Sodium finished product is as follows:
Weight-average molecular weight: 4653;
Molecular weight distribution: molecular weight is 13.4% less than 2000 daltonian polysaccharide molecule content, and the polysaccharide molecule content of molecular weight between 2000-8000 dalton is 75.8%.
The anti-II:4.3 of anti-Xa/;
Anti-Xa:112.4IU/mg;
231nm absorption value: 14.56.
The foregoing description is used for the present invention that explains, rather than limits the invention, and in the protection domain of spirit of the present invention and claim, any modification and change to the present invention makes all fall into protection scope of the present invention.
Claims (6)
1, a kind of production method for purifying of Enoxaparin Sodium is characterized in that, comprises the steps:
(1) in being situated between, hydrophily uses long chain quaternary salinization heparin.
(2) the benzyl esterification is above-mentioned by the heparin of salinization, and its degree of esterification is between 9.5%-14%.
(3) heparin of the above-mentioned degree of esterification of depolymerization between 9.5%-14% under the alkaline condition makes the Enoxaparin Sodium crude product.
(4) above-mentioned depolymerization gained Enoxaparin Sodium crude product is decoloured through gac and macroporous adsorbent resin.
2, the production method for purifying of Enoxaparin Sodium according to claim 1 is characterized in that, in the described step (1), described long chain quaternary is a Benzethonium.
3, the production method for purifying of Enoxaparin Sodium according to claim 1 is characterized in that, in the described step (4), Enoxaparin Sodium through the charcoal absorption decolouring, decolours through macroporous adsorbent resin earlier again.
4, the production method for purifying of Enoxaparin Sodium according to claim 1 is characterized in that, in the described step (4), Enoxaparin Sodium through the macroporous adsorbent resin decolouring, decolours through charcoal absorption earlier again.
5, according to the production method for purifying of claim 3 or 4 described Enoxaparin Sodiums, it is characterized in that described macroporous adsorbent resin is polar macroporous poly-alkane ester polymeric adsorbent XAD-7HP, nonpolar macroporous polystyrene adsorption resin XAD-1600, nonpolar macroporous polystyrene adsorption resin H1020, nonpolar macroporous polystyrene adsorption resin H103 or nonpolar macroporous polystyrene adsorption resin D4006.
6, the production method for purifying of Enoxaparin Sodium according to claim 5 is characterized in that, described macroporous adsorbent resin is nonpolar macroporous polystyrene adsorption resin H103.
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| CN102040672A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102040673A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Refining and purification method of enoxaparin |
| CN102050888A (en) * | 2010-12-13 | 2011-05-11 | 河北常山生化药业股份有限公司 | Method for preparing enoxaparin sodium |
| CN102924629A (en) * | 2012-12-03 | 2013-02-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| WO2013044793A1 (en) * | 2011-09-26 | 2013-04-04 | Xu Meiying | High-purity heparin benzyl ester salt, preparation method therefor and application thereof |
| CN103175925A (en) * | 2013-03-20 | 2013-06-26 | 山东辰中生物制药有限公司 | Method for detecting esterification rate of heparin benzyl ester in production process of enoxaparin sodium |
| CN103804523A (en) * | 2013-11-24 | 2014-05-21 | 青岛九龙生物医药有限公司 | Method for preparing high-purity enoxaparin |
| 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 |
| CN104086674A (en) * | 2014-07-28 | 2014-10-08 | 常州千红生化制药股份有限公司 | Process for preparing enoxaparin sodium |
| CN107586350A (en) * | 2017-08-03 | 2018-01-16 | 淮安麦德森制药有限公司 | The preparation method of Enoxaparin |
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| CN1749284A (en) * | 2005-09-19 | 2006-03-22 | 南京健友生物化学制药有限公司 | Purifying method for low molecule heparin |
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| CN102040673A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Refining and purification method of enoxaparin |
| CN102040672B (en) * | 2010-10-11 | 2012-09-05 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102040672A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102050888A (en) * | 2010-12-13 | 2011-05-11 | 河北常山生化药业股份有限公司 | Method for preparing enoxaparin sodium |
| WO2013044793A1 (en) * | 2011-09-26 | 2013-04-04 | Xu Meiying | High-purity heparin benzyl ester salt, preparation method therefor and application thereof |
| CN102924629B (en) * | 2012-12-03 | 2013-11-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| CN102924629A (en) * | 2012-12-03 | 2013-02-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| CN103175925A (en) * | 2013-03-20 | 2013-06-26 | 山东辰中生物制药有限公司 | Method for detecting esterification rate of heparin benzyl ester in production process of enoxaparin sodium |
| CN103804523A (en) * | 2013-11-24 | 2014-05-21 | 青岛九龙生物医药有限公司 | Method for preparing high-purity enoxaparin |
| CN103804523B (en) * | 2013-11-24 | 2016-08-17 | 青岛九龙生物医药有限公司 | Preparation high-purity Yi Nuo heparin method |
| 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 |
| CN104086674A (en) * | 2014-07-28 | 2014-10-08 | 常州千红生化制药股份有限公司 | Process for preparing enoxaparin sodium |
| CN107586350A (en) * | 2017-08-03 | 2018-01-16 | 淮安麦德森制药有限公司 | The preparation method of Enoxaparin |
| US11299558B2 (en) | 2017-12-11 | 2022-04-12 | Biological E Limited | Process for the preparation of low molecular weight heparin |
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