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Preparation method of high-quality low-molecular weight dalteparin sodium

A low-molecular, high-quality technology, applied in the field of biomedicine, can solve the problems of difficult product quality, unconcentrated molecular weight distribution, excessive residual impurities, etc., and achieve good antithrombotic activity and good stability

Active Publication Date: 2013-08-07
山东辰龙药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In its preparation process, high-quality heparin sodium is used as raw material, it is difficult to control the quality of the final product from the source of raw materials, and in the preparation process, organic solvents containing methyl groups are added and there is a lack of systematic and precise control of degradation conditions. As a result, the prepared low-molecular-weight heparin samples have shortcomings such as insufficient purity, non-concentrated molecular weight distribution, and excessive residual impurities. These are problems that cannot be solved by the current technology.
It is prone to risks in the process of finally making injectable drugs

Method used

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  • Preparation method of high-quality low-molecular weight dalteparin sodium
  • Preparation method of high-quality low-molecular weight dalteparin sodium

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Experimental program
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Effect test

preparation Embodiment 1

[0026] Specific steps:

[0027] 1) Enzymolysis: Weigh 100 g of crude heparin sodium, add 1200 g of water to it, and dissolve to obtain a raw material solution; adjust the temperature of the raw material solution to 37° C., add 1 g of papain, 0.5 g of ribonuclease II and 0.5 g of deoxyribonuclease I respectively. 5g, stirred and reacted for 12 hours, removed the precipitate, filtered the supernatant, and collected the filtrate;

[0028] 2) Oxidation: control the temperature of the filtrate obtained in step 1) to 45° C., adjust the pH value of the filtrate to 9.5 to 10 with 20% (w / v) sodium hydroxide solution, add 12 ml of hydrogen peroxide, and stir for 7 hours to obtain a purified solution ;

[0029] 3) Ultrafiltration for impurity removal: use an ultrafiltration membrane with a molecular weight cut-off of 4,000 Da to perform tangential flow circulating ultrafiltration on the purified solution obtained in step 2), and circulate the ultrafiltration for 7 hours to collect 316 m...

preparation Embodiment 2

[0037] Specific steps:

[0038] 1) Enzymolysis: Weigh 200g of crude heparin sodium, add 2000g of water to it, and dissolve it to obtain a raw material solution; adjust the temperature of the raw material solution to 37°C, add 4g of papain, 1g of ribonuclease II and 1g of deoxyribonuclease I, respectively, and stir to react After 12 hours, the precipitate was removed, the supernatant was filtered, and the filtrate was collected;

[0039] 2) Oxidation: control the temperature of the filtrate obtained in step 1) to 45° C., adjust the pH value of the filtrate to 9.5 to 10 with 20% (w / v) sodium hydroxide solution, add 25 ml of hydrogen peroxide, and stir for 7 hours to obtain a purified solution ;

[0040] 3) Ultrafiltration for impurity removal: the purified liquid obtained in step 2) was subjected to tangential flow circulating ultrafiltration using an ultrafiltration membrane with a molecular weight cut-off of 4000 Da, and the circulating ultrafiltration was performed for 7 hou...

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Abstract

The invention discloses a preparation method of high-quality low-molecular weight dalteparin sodium, belonging to the field of biomedicines. According to the method, a crude product, namely heparin sodium is taken as a raw material, compound enzymatic hydrolysis and improved nitrite degradation methods are taken as the basis, and then a low-molecular weight dalteparin sodium fine product with specific average molecular weight (5600-6400) is prepared through enzyme hydrolysis, oxidation, impurity removal by ultrafiltration, impurity removal by alcohol precipitation, degradation, reduction, alkali oxygen purification, ultrafiltration refining, freeze drying and other steps; and the preparation method has the characteristics of simple preparation process, good product stability, good anti-thrombotic activity and the like.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a method for preparing high-quality low-molecular-weight Dart Anrel. Background technique [0002] Heparin (unfractionated heparin) is a highly sulfated glycosaminoglycan that has anticoagulant effects both in vivo and in vitro. However, unfractionated heparin has defects such as low bioavailability, large side effects, and excessive frequency of administration, and its replacement product low molecular weight heparin, such as Darte Anrel, not only has better antithrombotic effect than unfractionated heparin, but also has high bioavailability and long half-life in vivo , less bleeding tendency and so on. The anticoagulant activity of heparin is divided into two categories: antithrombotic activity (FXa) and anticoagulant (FIIa) activity. In the process of antithrombosis, both anti-FXa activity and anti-FIIa activity are necessary. The measuring standard of FXa / FIIa is expressed by the...

Claims

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Application Information

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IPC IPC(8): C08B37/10A61P7/02
Inventor 周霞雷晓刚郭维
Owner 山东辰龙药业有限公司
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