Preparation and purification process for nadroparin calcium

A technology of heparin calcium and process, applied in the field of preparation and purification process of nadroparin calcium, can solve the problems of difficulty in separating fragments and failing to be separated, and achieve the effect of optimizing conditions

Active Publication Date: 2013-11-06
CHANGSHAN BIOCHEM PHARM JIANGSU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, low-molecular-weight heparin is degraded by chemical methods in China, and its molecular weight ranges from several hundred to nearly 10,000 different molecular weight fragments. Therefore, it is necessary to use effective separation methods for purification. However, it is difficult to separate the range of molecular weight distribution by traditional solvent fractional precipitation separation and purification technology. For narrow fragments, traditional anion exchange chromatography can only transform calcium, but fails to separate fragments that conform to the molecular weight distribution of nadroparin calcium

Method used

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  • Preparation and purification process for nadroparin calcium

Examples

Experimental program
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Effect test

Embodiment 1）

[0026] Weigh 1 kg of undegraded heparin sodium, and the specific steps include:

[0027] a. Prepare 1 kg of undegraded heparin sodium with 5% acetic acid solution into a 5% (w / v) aqueous solution, add 40 g of sodium nitrite solution dropwise for depolymerization reaction, and adjust the pH value to 2.8 in the presence of acetic acid. The temperature was controlled at 20°C, the depolymerization reaction was carried out for 150 minutes, and then the pH value of the reaction solution was adjusted to 6.5 with sodium hydroxide solution to terminate the reaction;

[0028] b. Add 100 g of sodium borohydride to the feed solution whose depolymerization reaction has been terminated in the previous step. The amount of sodium borohydride added is 10% of the weight of undepolymerized heparin sodium. When the temperature of the feed liquid is lowered to 15°C, slowly add hydrochloric acid dropwise, adjust the pH of the reaction feed liquid to 2.0, and stir for 10 minutes; then continue to dr...

Embodiment 2）

[0035] Weigh 1 kg of undegraded heparin sodium, and the specific steps include:

[0036] a. Prepare 1 kg of undegraded heparin sodium with 6% acetic acid solution into a 5% (w / v) aqueous solution, add 36 g of sodium nitrite solution dropwise for depolymerization reaction, and adjust the pH value to 3.0 in the presence of acetic acid, and react The temperature was controlled at 22°C, the depolymerization reaction was carried out for 180 minutes, and then the pH value of the reaction solution was adjusted to 7.0 with sodium hydroxide solution to terminate the reaction;

[0037] b. Add 80 g of sodium borohydride to the feed solution whose depolymerization reaction has been terminated in the previous step. The amount of sodium borohydride added is 8% of the weight of undepolymerized heparin sodium. When the temperature of the feed liquid is lowered to 10°C, slowly add hydrochloric acid dropwise, adjust the pH of the reaction feed liquid to 2.2, and stir for 12 minutes; then contin...

Embodiment 3）

[0044] Weigh 1 kg of undegraded heparin sodium, and the specific steps include:

[0045] a. Prepare 1 kg of undegraded heparin sodium with 8% acetic acid solution into a 5% (w / v) aqueous solution, add 30 g of sodium nitrite solution dropwise for depolymerization reaction, and adjust the pH value to 3.4 in the presence of acetic acid. The temperature was controlled at 25°C, the depolymerization reaction was carried out for 210 minutes, and then the pH value of the reaction solution was adjusted to 7.5 with sodium hydroxide solution to terminate the reaction;

[0046] b. Add 60 g of sodium borohydride to the feed solution whose depolymerization reaction has been terminated in the previous step. The amount of sodium borohydride added is 6% of the weight of undepolymerized heparin sodium. When the temperature of the feed liquid is lowered to 12°C, slowly add hydrochloric acid dropwise, adjust the pH of the reaction feed liquid to 2.5, and stir for 15 minutes; then continue to drop...

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Abstract

The invention relates to a preparation and purification process for nadroparin calcium. The process comprises the following steps: depolymerization; reduction; recrystallization; chromatography; and filtration. According to the invention, the process can effectively extract a fragment with a narrow molecular weight distribution range; nadroparin calcium is obtained through improvement of a preparation process for low-molecular-weight heparin calcium, an out-dated solvent fractional precipitation method is changed, conditions for anion exchange chromatography are optimized, and the fragment both meeting requirements for molecular weight of LMWH in China and according with molecular weight distribution of nadroparin calcium are obtained through gradient?elution.

Description

technical field [0001] The invention relates to a preparation and purification process of nadroparin calcium. Background technique [0002] Low-molecular-weight heparin (LMWH) is a kind of oligosaccharide mixture with lower molecular weight obtained by fractionating or degrading unfractionated heparin as the starting material. It has anti-Xa activity and can inhibit the formation of thrombus and arteriovenous thrombosis in vivo and in vitro, but it does not affect platelet aggregation and the combination of fibrinogen and platelets. Nadroparin calcium belongs to a kind of low-molecular-weight heparin, and it has been widely used clinically at home and abroad as a first-line anticoagulant drug. The coagulation and fibrinolytic systems have little effect. When antithrombotic effect occurs, bleeding is less likely. At present, it is mainly used for the prevention and treatment of deep venous thrombosis and pulmonary embolism, hemodialysis anticoagulation, unstable coronary a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10A61P7/02
Inventor 丁建文张华
Owner CHANGSHAN BIOCHEM PHARM JIANGSU CO LTD
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