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Method for producing enoxaparin sodium by using crude sodium heparin products

A technology for enoxaparin sodium and heparin sodium, which is applied in the field of biochemical raw material drug production, can solve problems such as unfavorable obtaining of high-quality final products, cumbersome steps, etc., and achieve the effects of low energy consumption, concise preparation process and simple process.

Active Publication Date: 2015-04-29
NORTH CHINA PHARMA HUAKUN HEBEI BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The heparin sodium removal step in this method only relies on the use of organic solvents and oxidation, which is not conducive to obtaining high-quality final products; when preparing enoxaparin sodium from the heparin sodium precipitate, the sulfate group can be removed in the alcohol precipitation step, However, the patent uses resin to remove sulfate radicals, and the steps are cumbersome

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  • Method for producing enoxaparin sodium by using crude sodium heparin products

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Effect test

Embodiment 1

[0034] Take 1kg of crude heparin sodium, dissolve it in 8L of purified water, add 80g of sodium chloride, raise the temperature to 50°C, and at the same time adjust the pH value to 8.5 with 1mol / L sodium hydroxide solution, and perform salt hydrolysis for 2 hours under this condition. The salt solution was centrifuged to obtain heparin sodium pretreatment solution. Lower the temperature of the heparin sodium pretreatment solution to 28°C, add hydrogen peroxide, the volume of which is 1% of the heparin sodium pretreatment solution, stir evenly, add to a resin column equipped with 15L OC1074 resin for adsorption, and control the adsorption rate to 0.05BV / h, the resin after adsorption is first washed with 5.5% sodium chloride solution, the flow rate is 0.5BV / h, and washed to absorbance A 260nm ≤0.20,A 280nmWhen ≤0.20, use 12% sodium chloride solution to elute, the elution rate is 0.05BV / h, detect the refraction of the column liquid, start collecting the eluate when the refracti...

Embodiment 2

[0036] Take 1kg of crude heparin sodium, dissolve it in 10L of purified water, add 200g of sodium chloride, raise the temperature to 60°C, and adjust the pH value to 9.0 with 3mol / L sodium hydroxide solution, and perform salt solution for 3 hours under this condition , and the salt solution was centrifuged to obtain a heparin sodium pretreatment solution. Lower the temperature of the heparin sodium pretreatment solution to 32°C, add hydrogen peroxide, the volume of which is 2% of the heparin sodium pretreatment solution, stir evenly, add to a resin column equipped with 15L FPA98 resin for adsorption, and control the adsorption rate to 0.06BV / h, the resin after adsorption is first washed with 6% sodium chloride solution, the flow rate is 0.5BV / h, and washed to absorbance A 260nm ≤0.20,A 280nm When ≤0.20, elute with 12% sodium chloride solution, the elution rate is 0.06BV / h, detect the refraction of the column liquid, and start collecting the eluate when the refraction is grea...

Embodiment 3

[0038] Take 1kg of crude heparin sodium, dissolve it in 10L of purified water, add 200g of sodium chloride, raise the temperature to 50°C, and at the same time adjust the pH value to 8.5 with 6mol / L sodium hydroxide solution, and perform salt hydrolysis for 2 hours under this condition. The salt solution was centrifuged to obtain heparin sodium pretreatment solution. Lower the temperature of the heparin sodium pretreatment solution to 30°C, add hydrogen peroxide, the volume of which is 1.5% of the heparin sodium pretreatment solution, stir evenly, add to a resin column equipped with 15L FPA98 resin for adsorption, and control the adsorption rate to 0.05BV / h, the resin after adsorption is first washed with 5.5% sodium chloride solution, the flow rate is 0.5BV / h, and washed to absorbance A 260nm ≤0.20,A 280nm When ≤0.20, use 12% sodium chloride solution to elute, the elution rate is 0.05BV / h, detect the refraction of the column liquid, start collecting the eluate when the refr...

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Abstract

The invention discloses a method for producing enoxaparin sodium by using crude sodium heparin products. The method is implemented by taking crude sodium heparin products as a raw material through the steps of pretreating the crude sodium heparin products by using a salt hydrolysis process; sequentially carrying out oxidation, ion exchange resin adsorption, washing and elution on the obtained object; sequentially carrying out ultrafiltration and freeze-drying on the obtained product so as to obtain a fine sodium heparin product; and sequentially carrying out salifying, esterification, depolymerization, oxidation, alcoholic precipitation, and freeze-drying treatment on the fine sodium heparin product, so that enoxaparin sodium is obtained. The method disclosed by the invention has the advantages that the quality of enoxaparin sodium is controlled from the aspects of source and process, the production cycle is short, the energy consumption of production is low, and the quality of products is high, therefore, the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of production of biochemical raw materials, in particular to a method for producing enoxaparin sodium from crude heparin sodium. Background technique [0002] Enoxaparin sodium is a low molecular weight heparin sodium salt obtained by alkaline depolymerization of benzyl ester derivatives of heparin derived from porcine intestinal mucosa. It is composed of a series of complex oligosaccharides that cannot be fully characterized. The non-reducing end is mainly composed of 4-enol-pyriduronic acid, and 15% to 25% of the components contain 1,6-anhydro derivatives at the reducing end. structure. Its weight average molecular weight is 3800-5000. Calculated on dry basis, the anti-Xa factor activity titer is 90IU / mg~125IU / mg, the anti-IIa factor titer is 20.0IU / mg~35.0IU / mg, and the ratio of anti-Xa factor titer to anti-IIa factor titer is 3.3 ~5.3. The anticoagulant effect of enoxaparin sodium is equal to or bett...

Claims

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Application Information

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IPC IPC(8): C08B37/10
Inventor 刘建芬任风芝张雪霞段宝玲李宁魏松波陈书红李丽红张静岩高任龙
Owner NORTH CHINA PHARMA HUAKUN HEBEI BIOTECH
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