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Preparation of high quality nadroparin calcium

A high-quality technology of nadroparin calcium, applied in the field of preparation of high-quality nadroparin calcium, can solve the problems of ultrafiltration membrane separation loss yield, backward technology, low molecular sieve efficiency, etc., and achieve industrialized mass production and automation The effect of high degree and high product yield

Inactive Publication Date: 2019-06-28
WUXI GALAK CHROMATOGRAPHIC TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the existing molecular weight control methods such as alcohol fractionation precipitation (CN 106986954 A), ultrafiltration membrane separation (CN 104072638 A, CN 104804110 A), molecular sieves, etc., the alcohol fractionation precipitation technology is backward, and the ultrafiltration membrane separation loses a lot of yield and is difficult to separate Fragments with a narrow molecular weight distribution range, molecular sieve efficiency is low, and traditional anion exchange chromatography only plays a role in calcium transformation (CN 104072639 A), but fails to separate fragments that meet the molecular weight distribution of nadroparin calcium
The method provided by CN104163878 A is difficult to ensure the quality of heparin sodium in the heparin sodium removal step, and also uses highly toxic barium chloride, which causes the risk of product safety and increases the pressure on environmental protection
The methods of CN 103275246A, CN 103382232 A and CN 103408676 A have relatively complicated procedures and cumbersome operations. At the same time, the anti-Xa / anti-IIa ratio of the product is generally low and needs to be further improved. The proportion of components less than 2000Da in the molecular weight distribution is high, which affects the Overall Quality of Dropparin Calcium

Method used

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  • Preparation of high quality nadroparin calcium

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] The preparation method of the high-quality nadroparin calcium of the present embodiment comprises the following steps:

[0018] The first step, cracking of heparin sodium: use pure water to make 1000g of heparin sodium solid raw material into a heparin solution with a mass concentration of 9%, adjust the pH value to 2.5 with hydrochloric acid solution; Sodium nitrite solution, the solid mass ratio of sodium nitrite to heparin sodium is 32g:1000g, the temperature is controlled at 23°C, stirred and reacted for 1.5h, and then the pH value is adjusted to 8.5 with calcium oxide to terminate the cracking reaction;

[0019] The second step, the reduction of the lysate: add 10g of sodium borohydride to the lysate, control the temperature at 30°C, react for 2 hours and then lower the temperature to below 20°C; adjust the pH value to 2.5 with hydrochloric acid, stir the reaction for 15min, and then use hydrogen Adjust the pH value to 6.5 with sodium oxide, flow the solution throu...

Embodiment 2

[0024] The preparation method of the high-quality nadroparin calcium of the present embodiment comprises the following steps:

[0025] The first step, cracking of heparin sodium: use pure water to make 1000g of heparin sodium solid raw material into a heparin solution with a mass concentration of 10%, adjust the pH value to 2.7 with hydrochloric acid solution; Sodium nitrite solution, the solid mass ratio of sodium nitrite to heparin sodium is 30g:1000g, the temperature is controlled at 24°C, stirred and reacted for 2.0h, and then the pH value is adjusted to 8.8 with calcium oxide to terminate the cracking reaction;

[0026] The second step, the reduction of the lysate: add 12g of sodium borohydride to the lysate, control the temperature at 35°C, react for 3 hours and then lower the temperature to below 20°C; adjust the pH value to 2.7 with hydrochloric acid, stir for 18 minutes, and then use hydrogen Adjust the pH value to 6.8 with sodium oxide, flow the solution through a UV...

Embodiment 3

[0031] The preparation method of the high-quality nadroparin calcium of the present embodiment comprises the following steps:

[0032] The first step, cracking of heparin sodium: use pure water to make 1000g of heparin sodium solid raw material into a heparin solution with a mass concentration of 11%, adjust the pH value to 3.0 with hydrochloric acid solution; Sodium nitrite solution, the solid mass ratio of sodium nitrite to heparin sodium is 28g:1000g, the temperature is controlled at 25°C, stirred and reacted for 2.5h, and then the pH value is adjusted to 9.0 with calcium oxide to terminate the cracking reaction;

[0033]The second step, the reduction of the lysate: add 15g of sodium borohydride to the lysate, control the temperature at 40°C, react for 4 hours and cool down to below 20°C; adjust the pH value to 3.0 with hydrochloric acid, stir the reaction for 20min, and then use hydrogen Adjust the pH value to 7.0 with sodium oxide, flow the solution through a UV lamp irra...

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Abstract

The invention relates to the field of biomedicines and in particular relates to a preparation method of high quality nadroparin calcium. The preparation method comprises the steps of degradation, reduction, ethanol precipitation, weak anion exchange chromatographic grading and calcium conversion and filtration, precipitation and dehydration to obtain the high quality nadroparin calcium by taking heparin sodium as a raw material. Compared with the prior art, the molecular weight distribution is controlled more precisely. The anti-Xa factor / anti-II factor potency ratio of a product is higher, and the preparation method is simpler to operate and high in yield and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a method for preparing high-quality nadroparin calcium. Background technique [0002] Nadroparin calcium is a low-molecular-weight heparin calcium salt, which is generally obtained by fractionating heparin derived from porcine intestinal mucosa with nitrous acid, and selectively removing most sugar chains with a molecular weight less than 2000 Da. Nadroparin calcium is composed of a series of complex oligosaccharides, the non-reducing end is mainly composed of 2-O-thio-α-L-iduronic acid, and the reducing end is mainly composed of 6-O-thio-2,5-anhydro- Composed of D-mannitol, its weight-average molecular weight should be 3600-5000, the anti-Xa factor activity should be 95 IU / mg-130 IU / mg, and the ratio of anti-Xa factor potency to anti-IIa factor potency should be 2.5-4.0. Nadroparin calcium can be used clinically to prevent venous thromboembolic diseases, treat existing deep vein thro...

Claims

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Application Information

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IPC IPC(8): C08B37/10
Inventor 孙国威阮必武穆宁
Owner WUXI GALAK CHROMATOGRAPHIC TECH
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