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Preparation method of nadroparin calcium

A technology of nadroparin calcium and heparin sodium, which is applied in the field of pharmaceutical synthesis, can solve the problems of cumbersome process operation, high weight loss on drying ratio, low anti-Xa/anti-IIa ratio, etc., so as to improve preparation efficiency, reduce process steps, and reduce drying The effect of weight loss ratio

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

[0010] In the existing nadroparin calcium preparation method (CN103408676A), the anti-Xa / anti-IIa ratio is low, and the drying weight ratio and the percentage of nadroparin calcium less than 2000 fractions are slightly higher, which affects product quality, and the process operation is relatively Complicated problem, the present invention provides following solution:

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  • Preparation method of nadroparin calcium
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  • Preparation method of nadroparin calcium

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preparation example Construction

[0029] The invention discloses a preparation method of nadroparin calcium, and those skilled in the art can learn from 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.

[0030] A preparation method of nadroparin calcium provided by the present invention will be further described below.

Embodiment 1

[0031] Embodiment 1: preparation nadroparin calcium

[0032] Take 4 kg of refined heparin sodium, add 100-200 L of water to dissolve, adjust the pH of the solution to 4 with glacial acetic acid, then add 114 g of sodium nitrite to the solution, and stir for 5 hours at a temperature of 25 ° C to obtain a heparin sodium degradation solution. The prepared heparin sodium degradation solution was adjusted to pH 8 with sodium hydroxide, added 100 g of sodium borohydride (2.5% heparin sodium mass) for reduction for 10 h, and adjusted to pH 7 with glacial acetic acid to obtain a reduced solution.

[0033] Filter the reducing solution with a 0.22 μm filter membrane, add 0.5mol / L calcium chloride solution to the filtrate, stir evenly, and perform ultrafiltration with a 1000D ultrafiltration membrane to complete sodium-calcium replacement. Then add water for injection for ultrafiltration, repeat 2-6 times.

[0034] Add 95% ethanol to the ultrafiltration filtrate for precipitation, colle...

Embodiment 2

[0037] Embodiment 2: preparation nadroparin calcium

[0038] Take 4 kg of refined heparin sodium, add 100-200 L of water to dissolve, adjust the pH of the solution to 6 with glacial acetic acid, then add 132 g of sodium nitrite to the solution, and stir for 6 hours at a temperature of 20 ° C to obtain heparin sodium degradation solution. The prepared heparin sodium degradation solution was adjusted to pH 12 with sodium hydroxide, added 20 g of sodium borohydride (0.5% heparin sodium mass) for reduction for 16 hours, and then adjusted to pH 5 with glacial acetic acid to obtain a reduced solution.

[0039] Filter the reducing solution with a 0.22 μm filter membrane, add 0.1mol / L calcium chloride solution to the filtrate, stir evenly, and perform ultrafiltration with a 5000D ultrafiltration membrane to complete sodium-calcium replacement. Then add water for injection for ultrafiltration, repeat 2-6 times.

[0040] Add 95% ethanol to the ultrafiltration filtrate for precipitation...

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Abstract

The invention relates to the field of pharmaceutical synthesis, and discloses a preparation method of nadroparin calcium. The preparation method is characterized by comprising the following steps: firstly preparing a low-molecular heparin sodium degradation liquid by utilizing a sodium nitrite method, and reducing the low-molecular heparin sodium degradation liquid to obtain reduction liquid; filtering the reduction liquid, adding calcium chloride solution into the filter liquid to be uniformly stirred and hyper-filtered to obtain hyper-filtration liquid, adding ethanol into the hyper-filtration liquid, precipitating the mixed liquid to obtain precipitates, re-dissolving the precipitates in the water, filtering the solution to obtain filter liquid, and sterilizing and freeze-drying the filter liquid to obtain the nadroparin calcium finished product. According to the preparation process, a brand new preparation concept is provided, the oxidation of hydrogen peroxide and calcium-sodium replacement of cation exchange resin in the traditional method are omitted, the hyper-filtration method is integrated with the calcium chloride stirring to be matched with other optimization steps, so that the Xa-resisting / IIa-resisting ratio of the nadroparin calcium can be increased, the drying weight loss ratio of the nadroparin calcium and the ratio of components which are less than 2000 molecular scale are reduced, the process steps are greatly reduced, and the preparation efficiency is improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of nadroparin calcium. Background technique [0002] Heparin is a glycosaminoglycan, a mixture of polysaccharide chains with different chain lengths formed from uronic acid, with a molecular weight between 3000-30000D, and has anticoagulant effect. Heparin has been in use for more than 70 years and is still widely used today. However, there are disadvantages such as low bioavailability, short half-life, large individual differences in dosage, spontaneous bleeding tendency, and thrombocytopenia. [0003] Low-molecular-weight heparin is a fragment with a smaller molecular weight formed by heparin fractionation or degradation, most of which have a molecular weight below 8000D. According to the degradation method and molecular weight, it is currently divided into nadroparin calcium, enoxaparin sodium, and dalteparin sodium. [0004] Nadroparin calcium is...

Claims

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Application Information

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IPC IPC(8): C08B37/10
Inventor 杨中强卢颖虎耿纪唐建国杨兵李小羿
Owner ZHAOKE PHARMA HEFEI
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