Synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium

A technology of enoxaparin sodium and a synthesis method, which is applied in the preparation and application field of enoxaparin sodium preparation, can solve the problems of no mention of impurity removal method, environmental hazards, large amount of organic solvent used, etc., and achieves high quality Stable and controllable, improve quality, realize the effect of industrialized production

Active Publication Date: 2014-02-05
江西浩然生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, firstly, the amount of organic solvent used in the preparation process disclosed by the above-mentioned patent is large, which has serious harm to the environment; secondly, there is almost no mention in the above-mentioned patent of the structural analogues of heparin sodium, dermatan sulfate and polysulfuric acid. The removal method of impurities such as chondroitin, the presence of impurities in heparin will have a direct impact on the subsequent preparation process such as the depolymerization sequence of heparin and the molecular weight distribution of enoxaparin sodium products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1. Synthesis of affinity precipitation medium:

[0029] Weigh 1350g of ES-100 and stir it with 2.7LN,N-dimethylformamide to dissolve it, add the dissolved ES-100 solution into the reactor, stir with nitrogen gas at the bottom, then add N,N-diisopropyl 3.78g of carbodiimide and 4.05g of 1-hydroxybenzotriazole were used to activate ES-100 for 3 minutes. After activation, 100g of protamine was added for coupling reaction for 2.5 hours. After the coupling reaction is completed, use 8mol / L acetic acid to adjust the pH value of the reaction solution to 3.5. After the reaction product is completely precipitated, the reaction solution is taken out, and the precipitate is washed 3 times with 0.1mol / L, pH4.0 acetic acid-sodium acetate buffer solution. Remove the buffer to obtain the affinity precipitation medium.

[0030] 2. Purification of crude heparin sodium by affinity precipitation medium:

[0031] Take 120g of crude heparin sodium, dissolve it in 2400mL of purified water,...

Embodiment 2

[0039] 1. Synthesis of affinity precipitation medium:

[0040] Weigh 1350g of polyacrylic acid resin No. Ⅲ and stir it with 13.5LN,N-dimethylformamide to dissolve it, add the dissolved polyacrylic acid resin No. 7.56g of diisopropylcarbodiimide and 8.1g of 1-hydroxybenzotriazole were used to activate ES-100 for 5 minutes. After activation, 200g of thrombin was added for coupling reaction for 3.0 hours. After the coupling reaction is completed, adjust the pH value of the reaction solution to 4.5 with 8 mol / L acetic acid. After the reaction product is completely precipitated, the reaction solution is taken out, and the precipitate is washed 3 times with 0.1 mol / L, pH4.0 acetic acid-sodium acetate buffer solution. Remove the buffer to obtain the affinity precipitation medium.

[0041] 2. Purification of crude heparin sodium by affinity precipitation medium:

[0042] Take 120g of crude heparin sodium, dissolve it in 1200mL of purified water, adjust the pH value to 8.5 with 8mol / ...

Embodiment 3

[0049] Example 3: The difference between this example and Example 1 is that the crude heparin sodium is 2 kg, the amount of affinity precipitation medium is 40 L, and benzethonium chloride is 2 kg.

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Abstract

The invention relates to a synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium. The preparation method is as below: salinizing heparin with benzethonium chloride salt in a heparin sodium solution purified by the affinity precipitation medium; esterifying the heparin benzethonium chloride to generate heparin benzyl ester; carrying out depolymerization on heparin benzyl ester in alkaline conditions; the precipitating by ethanol to obtain an enoxaparin sodium crude product; and oxidizing for decolorization by hydrogen peroxide to obtain the enoxaparin sodium fine product. The invention uses crude heparin sodium as a raw material and employs the affinity precipitation medium for purification, so as to effectively remove impurities bonded or non-boned with the heparin, ensure integrity of the natural structure of heparin, increase the activity yield of heparin and provide the basis for the stability and controllability of the subsequent preparation process of the enoxaparin sodium. The invention reduces the production cost, improves production efficiency, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of enoxaparin sodium, more specifically, the invention relates to the preparation of an affinity precipitation medium and its application in the preparation of enoxaparin sodium. Background technique [0002] Heparin is an acidic mucopolysaccharide with natural anticoagulant activity widely present in human and mammalian tissues. As an anticoagulant drug, heparin has been used clinically for nearly a hundred years, and it is still one of the most important anticoagulant and antithrombotic drugs, and is the drug of choice for preventing and treating embolic diseases such as deep venous thrombosis. In addition, heparin also has various biological functions such as anti-virus, anti-inflammatory, anti-allergic, anti-cancer, and hypolipidemic. During the long-term use of heparin, unforeseen side effects occur, which can easily lead to side effects such as bleeding, thrombocytopenia, and osteoporosis. In order ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
Inventor 杨华英万偲张素芳杨丽琴高铁旦魏超娟
Owner 江西浩然生物制药有限公司
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