Preparation method of high-FXa-resistant low-FIIa-resistant low-molecular heparin sodium

A low-molecular-weight heparin sodium and low-resistance technology, which is applied in the field of preparation of low-molecular-weight heparin sodium, can solve problems such as the reduction of anticoagulant activity, and achieve the effect of mild degradation conditions and high anticoagulant activity of the product

Inactive Publication Date: 2012-07-11
王芃
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a method for degrading unfractionated heparin by β-elimination in an organic solvent, so as to solve the technical problem that the anticoagulant activity of the product is reduced when the aqueous solution is degraded, thereby providing a kind of degradation condition that is mild and the product anticoagulant Preparation method of low molecular weight heparin sodium with high activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Dissolve 1 kg of high-quality heparin sodium in 7 liters of water, then add 4.5 liters of 50% (W / V) aqueous solution of benzethonium chloride under rapid stirring, after 2 hours of reaction, add 10 liters of water, settle still, and pour to the upper part Clear the night, add water to wash, then filter, wash with water, and dry to obtain about 2.7 kg of heparin quaternary ammonium salt.

[0016] Take 10 grams of the heparin quaternary ammonium salt obtained by the above reaction and dissolve it in 30 ml of dichloromethane, add 5 ml of DBU at room temperature, and react for 12 hours, add 60 ml of 10% sodium acetate methanol solution, and stir for 1 hour. Sediment under refrigeration (0-4°C), filter, wash with methanol, and dry to obtain crude low-molecular-weight heparin sodium.

[0017] Dissolve the obtained crude low-molecular-weight heparin sodium in 50 ml of water, add 1M sodium hydroxide to adjust the pH to 9.5, add 30% hydrogen peroxide to a concentration of 0.5%, ...

Embodiment 2

[0021] Repeat Example 1, the difference is: heparin quaternary ammonium salt was dissolved in 30 ml of dimethylformamide (DMF), 2 g of sodium methoxide was added at 45 ° C, stirred for 8 hours, cooled to room temperature, and then 10 % sodium acetate methanol solution.

[0022] This embodiment finally obtains 2.5 grams of high-quality low-molecular-weight heparin sodium, with an average molecular weight of 4700 Da, 4.5% of those with a molecular weight greater than 8000 Da, 18% of those with a molecular weight of less than 2500 Da, and 77.5% of those with a molecular weight of 2500-8000 Da; the anti-FXa value is 151IU / mg , the anti-FIIa value was 27IU / mg.

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Abstract

The invention provides a preparation method of high-FXa-resistant low-FIIa-resistant low-molecular heparin sodium. Common heparin is subjected to beta- elimination degradation in an organic solvent to reduce the falling of sulfonic groups from heparin, so that the preparation method has the advantages of mild degradation conditions and high anticoagulating activity of the product. The FXa-resistant titer of the low-molecular heparin sodium is 120-160IU / mg, the FIIa-resistant titer is 10-30IU / mg, and the average molecular weight is 3500-5000Da.

Description

technical field [0001] The invention relates to a preparation method of low molecular weight heparin sodium (Low Molecular Weight Heparin, LMWH), in particular to a production process of low molecular weight heparin sodium with high anti-FXa and low anti-FIIa. Background technique [0002] Heparin is a mucopolysaccharide extracted from animal intestinal mucosa, lungs and other organs. It is used in medicine to prevent and treat thromboembolic diseases such as thrombosis and venous thrombosis caused by surgery, and has a wide range of uses. Low-molecular-weight heparin is degraded from unfractionated heparin, its average molecular weight is less than 8000Da, and the content of components with a molecular weight less than 8000Da should not be less than 60%. Calculated on a dry basis, the anti-Xa titer ≥ 70IU / mg, anti-Xa / anti-IIa ≥1.5. [0003] Low-molecular-weight heparin has the advantages of high bioavailability and long plasma half-life, especially the significant reductio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
Inventor 王芃
Owner 王芃
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