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A heparin-derived polysaccharide mixture and its preparation method and pharmaceutical composition

A mixture and polysaccharide technology, applied in the field of medicine, can solve the problems of decreased antithrombotic ability, low activity of anticoagulation factor IIa, etc.

Active Publication Date: 2016-08-31
SHANGHAI SEANPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Clinical practice has proved that there is no need to monitor the coagulation time during the use of the currently marketed low molecular weight heparin, and the above-mentioned adverse reactions caused by long-term use of heparin have been reduced to a certain extent
Basic studies have shown that long-chain heparin with a large molecular weight will bind to plasma proteins, macrophages, endothelial cells, platelets, platelet factor 4, osteoblasts, etc., resulting in the above adverse reactions
When the molecular weight of the heparin fragment is low, not only the anticoagulant factor IIa activity is very low, but also the adverse reactions caused by the use of heparin and the existing low molecular weight heparin will be greatly reduced
However, when low-molecular-weight heparin is prepared by conventional methods, its antithrombotic ability gradually decreases as the molecular weight of heparin decreases.

Method used

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  • A heparin-derived polysaccharide mixture and its preparation method and pharmaceutical composition
  • A heparin-derived polysaccharide mixture and its preparation method and pharmaceutical composition

Examples

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preparation example Construction

[0044] In a preferred example of the present invention, the preparation method comprises the steps of:

[0045] 1. In an inert solvent (such as dichloromethane), use a quaternary ammonium base (such as benzyltrimethylammonium hydroxide) to degrade heparin quaternary ammonium salt (such as heparin benzethoxyammonium salt).

[0046] Wherein, the temperature and time of the degradation reaction are not particularly limited, and usually the reaction temperature can be 5-80° C.; the reaction time is usually 1-10 days.

[0047] 2. The obtained heparin-derived polysaccharides can be separated and purified by conventional methods, such as alcohol precipitation, gel filtration, ultrafiltration, etc., and impurities and decolorization can be removed by sodium borohydride or hydrogen peroxide.

[0048] The heparin-derived polysaccharide mixture of the present invention has higher antithrombotic activity and lower side effects than natural heparin or low-molecular-weight heparin already o...

Embodiment 1

[0067] Preparation of heparin benzylethoxylate ammonium salt (raw material)

[0068] To an aqueous solution (1250 ml) of benzethonium chloride (270 g) was added a solution of commercially available heparin sodium (100 g) in water (1000 ml) (Note: heparin derived from porcine). After stirring for 30 minutes, a precipitate of heparin benzethonium salt formed. Then, the reaction mixture was filtered at room temperature to obtain a filter cake, which was washed with water and dried in vacuum to obtain 305 g of heparin benzethonium salt (white).

Embodiment 2

[0070] Preparation of heparin-derived polysaccharide mixture

[0071] 1. Heparin-derived polysaccharide mixture

[0072] The heparin benzethonium salt (10 g) obtained in Example 1 was dissolved in dichloromethane (50 ml), heated to 25° C. and maintained at the reaction temperature. To this solution, 14 ml of benzyltrimethylammonium hydroxide (40%, w / v) methanol solution was added, and the addition method was divided into 7 additions, 2 ml each time, with a time interval of 24 hours, so that the heparin was gradually degraded. Wherein after the last addition, react for another 24 hours, so the total reaction time is 168 hours.

[0073] Then the reaction mixture is cooled to about 20°C, 60ml of 10% sodium acetate methanol solution is added to the reaction mixture, and stirred, the precipitate is precipitated, filtered to obtain a filter cake, washed with methanol, and dried in vacuo to obtain a heparin-derived polysaccharide mixture (shallow yellow, 2.0 g).

[0074] 2. Purifi...

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Abstract

The invention relates to a heparin-derived polysaccharide mixture, a preparation method and a pharmaceutical composition thereof. Specifically, the heparin-derived polysaccharide mixture of the present invention is a degradation product of heparin quaternary ammonium salt, and has the following characteristics: a weight-average molecular weight of 1500-4200 Daltons; high activity of anticoagulant factor Xa and anticoagulant factor IIa The activity of the compound is low, and the content of the polysaccharide with a molecular weight greater than 5000 Daltons in the mixture is less than 5%. The heparin-derived polysaccharide mixture of the invention has excellent antithrombotic performance, low side effects, and no residues of unfavorable components such as organic bases and dermatan sulfate.

Description

technical field [0001] The present invention relates to the field of medicine, and more specifically relates to a polysaccharide mixture derived from a heparin, a preparation method thereof, and a pharmaceutical composition containing the polysaccharide compound. Background technique [0002] Heparin is a mixture of sulfated polysaccharides of animal origin (pig or bovine), which has been widely used due to their good antithrombotic properties, such as the preparation of antithrombotic drugs, drugs for the treatment of cardiovascular diseases, and drugs for the treatment of cerebrovascular diseases drugs etc. [0003] However, heparin has a number of deficiencies that limit the application of heparin. A major drawback is that excessive use of heparin can cause spontaneous bleeding, so the clotting time should be measured before each injection. In addition, heparin can cause allergic reactions, thrombocytopenia, osteoporosis, and spontaneous fractures. [0004] Heparin has...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08L5/10A61K31/727A61P7/02A61P9/00A61P9/10
Inventor 徐学明王海青贾龙顾玉兰
Owner SHANGHAI SEANPHARM
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