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Preparation method for low-molecular-weight heparin calcium

A low-molecular-weight heparin and weight-average molecular weight technology, applied in the field of preparation of low-molecular-weight heparin calcium, can solve problems affecting product quality, cumbersome process operations, low potency of anti-Xa factor and low ratio of anti-Xa/anti-IIa, etc., to achieve guaranteed Stabilize, improve production efficiency, reduce the effect of decomposition

Active Publication Date: 2014-10-01
ZHAOKE PHARMA HEFEI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In view of the existing low molecular weight heparin calcium preparation method (CN1554671A), the anti-Xa factor potency and the anti-Xa / anti-IIa ratio are low, which affects the product quality, and the process operation is complicated. The present invention provides the following solutions:

Method used

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[0026] The invention discloses a preparation method of low-molecular-weight heparin calcium, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The preparation method of the present invention has been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.

[0027] The preparation method of a low molecular weight heparin calcium provided by the present invention will be further described below.

Embodiment 1

[0028] Embodiment 1: Preparation of low molecular weight heparin calcium

[0029] Degradation: Dissolve 2.5kg of refined heparin sodium in an aqueous solution, add acetic acid to adjust the pH to 2-4, add 80.00g of sodium nitrite to react for 4-6h.

[0030] Oxidation: Add 660 mL of 30% (mass percentage, the same below) hydrogen peroxide solution to the degradation solution prepared in the previous step to oxidize for 15 minutes.

[0031] Neutralization: Add 25% sodium hydroxide solution to neutralize the pH value to 6.5-7.0.

[0032] Alcohol precipitation: Add 95% ethanol to the neutralizing solution for alcohol precipitation, and dissolve the alcohol precipitation with water for injection to form a low molecular weight heparin sodium solution.

[0033] Calcified resin: 0.5mol / L calcium chloride solution on JZD001X7-II type macroporous strongly acidic styrene-based cation exchange resin, replace until the pH value of the lower column liquid is neutral, and then rinse the ion ...

Embodiment 2

[0037] Embodiment 2: Preparation of low molecular weight heparin calcium

[0038] Degradation: Dissolve 2.5kg of refined heparin sodium in an aqueous solution, add acetic acid to adjust the pH to 2-4, add 81.25g of sodium nitrite to react for 4-6h.

[0039] Oxidation: Add 660 mL of 30% hydrogen peroxide solution to the degradation solution prepared in the previous step to oxidize for 15 minutes.

[0040] Neutralization: Add 25% sodium hydroxide solution to neutralize the pH value to 6.5-7.0.

[0041] Alcohol precipitation: Add 95% ethanol to the neutralizing solution for alcohol precipitation, and dissolve the alcohol precipitation with water for injection to form a low molecular weight heparin sodium solution.

[0042] Calcified resin: 0.5mol / L calcium chloride solution on JZD001X7-II type macroporous strongly acidic styrene-based cation exchange resin, replace until the pH value of the lower column liquid is neutral, and then rinse the ion exchange resin with water for inje...

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Abstract

The invention relates to the field of medical synthesis, and discloses a preparation method for low-molecular-weight heparin calcium. The method disclosed by the invention comprises the following steps: preparing a low-molecular-weight heparin sodium solution by virtue of a sodium nitrite method at first, and then carrying out resin calcification on cation exchange resin by use of a calcium chloride solution, then carrying out calcium-sodium ion substitution on the calcified cation resin columns on the low-molecular-weight heparin sodium solution, and finally filtering, freeze-drying and crushing the substitution solution after the calcium-sodium ion substitution to obtain the low-molecular-weight heparin calcium. According to the preparation method disclosed by the invention, a step of preparing low-molecular-weight heparin with the extremely low pH value is avoided; the low-molecular-weight heparin calcium is obtained by resin one-time moderate substitution for the low-molecular-weight heparin sodium, so that the loss of anti-Xa factor titer in severe environments is avoided, the anti-Xa / anti-IIa ratio is increased, and the production steps are simplified.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of low molecular weight heparin calcium. Background technique [0002] Heparin is a mixture of oligosaccharides such as uronic acid and glucosamine, which has anticoagulant activity. It has been more than 80 years since its discovery, and there is still no product that can completely replace it. It is still an important biochemical drugs. Heparin is the drug of choice for the prevention of postoperative thrombosis and the treatment of venous thrombosis. However, a large amount of use can cause side effects such as bleeding and induction of thrombocytopenia, which limits its large-scale use. [0003] Low-molecular-weight heparin is a sugar fragment with a smaller molecular weight obtained by fractionation or degradation of heparin. Its weight-average molecular weight is 3000-8000. Thrombosis has little effect on the blood coagulation system, less ble...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
Inventor 耿纪卢颖虎杨中强王成飞周慧仙李小羿
Owner ZHAOKE PHARMA HEFEI
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