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Process for preparing and purifying ultra low molecular weight heparin

A technology of molecular weight and heparin, which is applied in the production process of ceramic ultrafiltration membrane separation and purification, and the preparation and purification process of ultra-low molecular weight heparin, can solve the problems of poor anti-microbial erosion ability, poor heat resistance of organic membranes, and high cost of fillers. Achieve the effects of stability, low production cost and high yield

Inactive Publication Date: 2011-05-04
BEIJING GUANHONG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current fractional precipitation separation and purification technology is difficult to separate fragments with a narrow range of molecular weight distribution; the gel filtration chromatography used can separate reasonable fragment distribution, but there are problems such as complicated operation and high packing cost; in recent years, ultrafiltration membrane technology However, due to the poor heat resistance of organic membranes, poor acid, alkali and anti-microbial erosion capabilities, the application in actual production is limited to a certain extent.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]Take 100g of unfractionated heparin sodium (anti-factor IIa titer 140IU / mg), add 500ml of water to dissolve, slowly add 10000ml of 25% benzyl ammonium chloride solution under stirring, the solution gradually becomes turbid, and the filtered filter cake is washed with purified water , and dried at 65°C for 6 hours to obtain 325 g of heparin benzyl ammonium chloride salt.

[0030] Take 200g of heparin benzethonium chloride salt, add 1000ml of dichloromethane and stir to dissolve, slowly add 200ml of benzyl chloride dropwise, react at 40°C for 20h, control the esterification rate to 14.5%, add 1800ml of methanol dissolved in 10% sodium acetate at the end of the reaction , after precipitation, filter. The filter cake was washed with methanol and dried to obtain 71.50 g of heparin benzyl ester.

[0031] Take 50g of heparin benzyl ester, dissolve it in 1500ml of water, heat to 65°C, add 6.4g of sodium hydroxide, stir and depolymerize for 1.25h. After the reaction is complete...

Embodiment 2

[0036] Take 150g of unfractionated heparin sodium (anti-factor II a titer 140IU / mg), add 750ml of water to dissolve, slowly add 15000ml of 25% benzyl ammonium chloride solution under stirring, the solution gradually becomes turbid, and the filtered filter cake is washed with purified water , and dried at 65°C for 6 hours to obtain 477 g of heparin benzyl ammonium chloride salt.

[0037] Take 400g of heparin benzethonium chloride salt, add 2000ml of dichloromethane and stir to dissolve, slowly add 400ml of benzyl chloride dropwise, react at 35°C for 25h, control the esterification rate to 13.8%, add 3500ml of methanol dissolved in 10% sodium acetate at the end of the reaction , after precipitation, filter. The filter cake was washed with methanol and dried to obtain 142 g of heparin benzyl ester.

[0038] Take 100g of heparin benzyl ester, dissolve it in 3000ml of water, heat to 62°C, add 12g of sodium hydroxide, and stir for 1h to depolymerize. After the reaction is complete...

Embodiment 3

[0043] Take 100g of graded heparin sodium (anti-factor II a titer 150IU / mg, dermatan sulfate content less than 2%), add 500ml of water to dissolve, slowly add 10000ml of 25% benzyl ammonium chloride solution under stirring, the solution gradually becomes turbid, filter The final filter cake was washed with purified water and dried at 65°C for 6 hours to obtain 332 g of heparin benzyl ammonium chloride salt.

[0044] Take 300g of heparin benzethonium chloride salt, add 1500ml of dichloromethane and stir to dissolve, slowly add 300ml of benzyl chloride dropwise, react at 40°C for 20h, control the esterification rate to 14.0-14.5%, and add 10% sodium acetate dissolved in it at the end of the reaction Methanol 2700ml, after precipitation, filter. The filter cake was washed with methanol and dried to obtain 115 g of heparin benzyl ester.

[0045] Take 100g of heparin benzyl ester, dissolve it in 3000ml of water, heat to 65°C, add 9g of sodium hydroxide, and stir for 1h to depolyme...

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Abstract

The invention discloses a process for preparing and purifying ultra low molecular weight heparin sodium (calcium), which comprises the following steps of: reacting heparin with organic quaternary ammonium salt to generate heparin quaternary ammonium salt, performing nucleophilic substitution to generate heparin benzyl ester, and degrading under the alkaline condition to obtain a low molecular weight heparin fragment; and separating and purifying by an inorganic ceramic ultrafiltration and hollow fiber ultrafiltration combined method to obtain the ultra low molecular weight heparin sodium (calcium) of which the molecular weight distribution is 2,000 to 2,500D and the average molecular weight is 2,200D. The low molecular weight heparin fragment is obtained by controlling reaction conditions in the esterification process and the degradation time of ester hydrolysis; a ceramic membrane and a hollow fiber ultrafiltration membrane are combined to separate and purify the heparin fragment; and by selecting the pore diameter of the ceramic membrane, operating pressure, feed liquid temperature, and the molecular weight cutoff of the hollow ceramic membrane, the heparin fragment with a reasonable molecular weight distribution range is effectively separated.

Description

technical field [0001] The invention relates to a preparation and purification process of ultra-low molecular weight heparin, in particular, it involves the preparation of ultra-low molecular weight heparin sodium or calcium salt with a molecular weight range of 2000D-2500D by using a β-elimination degradation method, and the use of a ceramic ultrafiltration membrane The production process of separation and purification belongs to the field of biomedicine. Background technique [0002] Heparin is a glycosaminoglycan widely present in animal organs and tissues (such as small intestinal mucosa, lung, etc.), and has anticoagulant, anti-inflammatory, anti-allergic, anti-viral, anti-cancer, and blood lipid regulation functions. Pharmacological activity, but long-term use may cause some adverse reactions, such as bleeding and induction of thrombocytopenia. Low molecular weight heparin (LMWH) is a fragment with a smaller molecular weight obtained by fractionating or degrading hepa...

Claims

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Application Information

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IPC IPC(8): C08B37/10B01D61/14
Inventor 王秀云姬胜利肖佳普
Owner BEIJING GUANHONG TECH
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