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Method for preparing enoxaparin sodium through heparin benzyl ester

A technology of heparin benzyl ester and enoxaparin sodium, which is applied in the field of medicine and pharmaceutical engineering, can solve the problems of rising, difficulty in ensuring the stability of drug efficacy, and failure to find it, so as to achieve the effect of ensuring stability

Inactive Publication Date: 2017-02-22
苏州正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although Zhang Liyun's "Two Low Molecular Weight Heparins (LMWH) Production Processes and Quality Standards Research" reported that the increase of sodium hydroxide concentration and the prolongation of degradation time can increase the content of 1,6-ring, and did experimental research, but did not No more in-depth research on how to adjust the concentration of sodium hydroxide and reaction time according to the esterification rate of heparin benzyl ester, and the control of the degradation process, and did not find out how to keep the 1,6-ring according to the esterification rate of 9.5-14% In the 15-25% way
In actual operation, there are still cases where 1,6-ring is lower than 15% and higher than 25%, which causes the instability of the process and makes it difficult to guarantee the stability of the drug effect

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Preparation of heparin benzyl ester with reference to patent US5389618

[0018] Take by weighing 20g of heparin sodium and add it to 200ml of water and stir to dissolve it, weigh 50g of benzethonium chloride and add it to 250ml of water and stir to dissolve it, add the benzethonium chloride solution to the heparin sodium solution under vigorous stirring, react at room temperature, filter, wash and Dry to obtain 47g of solid, add the solid into 235ml of dichloromethane and stir to dissolve, add 47ml of benzyl chloride, react at room temperature to 35°C for 25 hours, add 285ml of 10% sodium acetate methanol solution, filter, wash with methanol, and dry to obtain 20.3 heparin Benzyl ester, the measured esterification rate is 10.5%.

[0019] Preparation of Enoxaparin Sodium from Heparin Benzyl Ester

[0020] Add 2.7g of 99% sodium hydroxide to 450ml of purified water, stir and dissolve, prepare sodium hydroxide solution, heat the water bath to 62°C and keep it warm for lat...

Embodiment 2

[0023] Preparation of heparin benzyl ester with reference to patent US5389618

[0024] Take by weighing 20g of heparin sodium and add it to 200ml of water and stir to dissolve it, weigh 50g of benzethonium chloride and add it to 250ml of water and stir to dissolve it, add the benzethonium chloride solution to the heparin sodium solution under vigorous stirring, react at room temperature, filter, wash and Dry to obtain 44g of solid, add the solid into 220ml of dichloromethane and stir to dissolve, add 44ml of benzyl chloride, react at room temperature to 35°C for 25 hours, add 265ml of 10% sodium acetate methanol solution, filter, wash with methanol, and dry to obtain 18.4 heparin Benzyl ester, the measured esterification rate is 13.3%.

[0025] Preparation of Enoxaparin Sodium from Heparin Benzyl Ester

[0026] Add 1.4g of 99% sodium hydroxide to 375ml of purified water, stir and dissolve, prepare sodium hydroxide solution, heat the water bath to 62°C and keep it warm for lat...

Embodiment 3

[0029] Preparation of heparin benzyl ester with reference to patent US5389618

[0030] Take by weighing 20g of heparin sodium and add it to 200ml of water and stir to dissolve it, weigh 50g of benzethonium chloride and add it to 250ml of water and stir to dissolve it, add the benzethonium chloride solution to the heparin sodium solution under vigorous stirring, react at room temperature, filter, wash and Dry to obtain 51g of solid, add the solid to 255ml of dichloromethane and stir to dissolve, add 51ml of benzyl chloride, react at room temperature to 35°C for 25 hours, add 310ml of 10% sodium acetate methanol solution, filter, wash with methanol, and dry to obtain 19.5 heparin Benzyl ester, the measured esterification rate is 11.9%.

[0031] Preparation of Enoxaparin Sodium from Heparin Benzyl Ester

[0032] Add 2.2g of 99% sodium hydroxide to 450ml of purified water and stir to dissolve. Prepare sodium hydroxide solution. Heat the water bath to 62°C and keep it warm for lat...

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Abstract

The invention relates to a method for preparing enoxaparin sodium through heparin benzyl ester. The method comprises the following steps of preparing sodium hydroxide with purified water to be a solution with the concentration being 0.06 to 0.2mol / L, and heating to be 62 DEG C, wherein the weight of the purified water is 20 to 30 times of the weight of the heparin benzyl ester; adding the sodium hydroxide solution with the temperature of 62 DEG C and the heparin benzyl ester for twice, and reacting for 1 to 4 hours at the temperature of 62 DEG C; cooling to room temperature, adding hydrochloric acid for adjusting pH(potential of Hydrogen) to be neutral, adding sodium chloride, filtering through a filter membrane, alcohol-precipitating and drying to obtain the enoxaparin sodium. According to the method provided by the invention, the concentration of the sodium hydroxide solution is adjusted according to the esterification rate of the benzyl ester, and the product 1,6-cyclo is ensured to keep between 15 percent to 25 percent specified by Pharmacopeia EP8.0 through controlling sequences of material adding and temperature rising, alkalifying and degrading for twice, and regulating degradation time during a degradation process, so that the stability of a pharmacological function is ensured.

Description

technical field [0001] The invention relates to the technical field of medicine and pharmaceutical engineering, in particular to a method for preparing enoxaparin sodium from heparin benzyl ester. Background technique [0002] Enoxaparin Sodium (Enoxaparin Sodium) is an anticoagulant used for the prevention and treatment of deep vein thrombosis or pulmonary embolism. The mechanism is to play an anticoagulant effect by binding to antithrombin AT-III and inhibiting IIa and Xa. Most of its components have a 4-enopyranuronic acid structure at the non-reducing end of the sugar chain, and Its active action site is a unique 1,6-anhydrous ring structure at the reducing end of the sugar chain, which makes it have different pharmacological effects from other low molecular weight heparins. The European Pharmacopoeia (EP8.0) stipulates that 15-25% of the components in its structure have a 1,6-anhydrous ring structure at the reducing end. [0003] At present, there are many patent repo...

Claims

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Application Information

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IPC IPC(8): C08B37/10
CPCC08B37/0075C08B37/0003
Inventor 段世英刘中华张为成
Owner 苏州正济药业有限公司
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