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Method for removing bacterial endotoxin in low-molecular-weight heparin

A technology of low molecular weight heparin and bacterial endotoxin, applied in the field of biomedicine, to achieve the effect of easy production and amplification, simple and quick method, and thorough removal

Active Publication Date: 2022-08-05
SHENZHEN SCIPROGEN BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, there is no other relevant literature on the removal of bacterial endotoxin in heparin and low molecular weight heparin

Method used

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  • Method for removing bacterial endotoxin in low-molecular-weight heparin
  • Method for removing bacterial endotoxin in low-molecular-weight heparin
  • Method for removing bacterial endotoxin in low-molecular-weight heparin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1, the removal method of bacterial endotoxin in nadroparin calcium

[0031] Step S1: take 1kg of sodium heparin, add 5kg of water to dissolve, adjust the pH to 2.6, add 27g of sodium nitrite for cracking for 2h, adjust the pH to neutrality, add 20g of sodium borohydride for reduction, add 3kg of calcium chloride to convert it into a calcium salt to obtain Nadroparin calcium crude solution, the volume is about 6L;

[0032] Step S2: add 1.2L n-butanol-butyl acetate mixed solution to the nadroparin calcium crude product solution in step S1, the volume ratio of n-butanol and butyl acetate in the n-butanol-butyl acetate mixed solution is 7 : 1, stirred for 20min, left standstill for 40min, discarded the upper organic phase, and repeated extraction with n-butanol-butyl acetate mixed solution, a total of 5 times, n-butanol and acetic acid in the n-butanol-butyl acetate mixed solution The volume ratio of butyl ester is 7:1, and the organic phase is discarded. At thi...

Embodiment 2

[0034] Embodiment 2, the removal method of bacterial endotoxin in dalteparin sodium

[0035] Step S1: take 1kg of sodium heparin, add 5kg of water to dissolve, adjust the pH to 2.6, add 22g of sodium nitrite to crack for 2h, adjust the pH to neutrality, add 16g of sodium borohydride for reduction, and obtain a crude heparin sodium solution with a volume of about 6L;

[0036] Step S2: add 1.8L n-butanol-butyl acetate mixed solution to the dalteparin sodium crude product solution in step S1, the volume ratio of n-butanol and butyl acetate in the described n-butanol-butyl acetate mixed solution is 10: 1. Stir for 30 minutes, let stand for 60 minutes, discard the upper organic phase, and repeat the extraction with n-butanol-butyl acetate mixed solution for a total of 4 times. In the n-butanol-butyl acetate mixed solution, n-butanol and butyl acetate The volume ratio of the ester is 10:1, and the organic phase is discarded. At this time, most of the bacterial endotoxin has been rem...

Embodiment 3

[0038] Embodiment 3, the removal method of bacterial endotoxin in enoxaparin sodium

[0039]Step S1: take 1kg of sodium heparin, dissolve it in 10kg of water, add it to 12.5kg and 20% benzethonium chloride, stir and heat up to 55°C for 2h, cool down, filter and dry to obtain 3.1kg of ammonium salt; Dissolve an appropriate amount of N,N-dimethylformamide, heat up to 50°C, add benzyl chloride for esterification for 20h, then cool down, precipitation in alcohol, filter, and dry to obtain 1.2kg of esterified product; dissolve the esterified product with appropriate amount of water, heat up To 60 ℃, add an appropriate amount of lye for cracking, cooling, and oxidation to obtain a crude enoxaparin sodium solution with a volume of about 9.5L;

[0040] Step S2: Add 1.9L of n-butanol-butyl acetate mixed solution to the enoxaparin sodium crude product solution in step S1, and the volume ratio of n-butanol to butyl acetate in the n-butanol-butyl acetate mixed solution is 9 : 1, stir for...

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Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a method for removing bacterial endotoxin in low-molecular-weight heparin. According to the method for removing the bacterial endotoxin in the low-molecular-weight heparin, the bacterial endotoxin is removed through an n-butyl alcohol-butyl acetate extraction method, after extraction is completed, purified water is supplemented for equal-volume ultrafiltration, and a residual solvent can be effectively removed. The method for removing bacterial endotoxin in low-molecular-weight heparin provided by the invention has the characteristics of simplicity, convenience, rapidness, thorough endotoxin removal, small product loss, easiness in production amplification and the like, and the quality of a final product meets EP standard requirements.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a method for removing bacterial endotoxin in low molecular weight heparin. Background technique [0002] Heparin is a sulfated glycosaminoglycan compound extracted from mammalian tissues (such as small intestinal mucosa, lung, and liver). It has rapid anticoagulant effects both in vivo and in vitro. It is mainly used clinically for prevention and treatment. Treatment of thromboembolic disease and anticoagulation in hemodialysis. The molecular weight of unfractionated heparin ranges from 3kd to 30kd, and the molecular structure is extremely complex. At present, only heparin derived from porcine intestinal mucosa can be used for clinical treatment. Low molecular weight heparin is prepared by chemical or enzymatic cleavage of unfractionated heparin. It has a higher anti-FXa / anti-FIIa titer ratio than unfractionated heparin, which can greatly reduce the bleeding tend...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
CPCC08B37/0075
Inventor 郑华淦廖冬杨艳群吴园园
Owner SHENZHEN SCIPROGEN BIO PHARMA
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