Preparation process of enoxaparin sodium

Abstract

The invention discloses a preparation process of enoxaparin sodium, which comprises the steps of preparing heparin sodium solution, preparing heparin degradation solution, preparing reducing solution, preparing crude product, refining, freeze-drying and the like. The weight-average molecular weight of the obtained product is 5000-6000, the peak molecular weight is 3000-6000, the component with molecular weight less than 3000 is not more than 11%, the component with molecular weight greater than 8000 is not more than 13%, and the anti-Xa activity is ≥ 135IU / mg.

Description

technical field

[0001] The invention belongs to the field of biotechnology, and in particular relates to a production process of enoxaparin sodium. Background technique

[0002] Enoxaparin sodium is a low-molecular sodium salt, which is mainly used in the prevention of coagulation and deep vein thrombosis in hemodialysis, the treatment of unstable coronary artery disease and the prevention of thrombosis related to surgery. Heparin is a kind of glycosaminoglycan widely present in animal organs, small intestinal mucosa, lung and other tissues.

[0003] In addition to having all the pharmacological effects of unfractionated heparin, low-molecular-weight heparin is used as an anticoagulant, usually for short-term use, and has a high therapeutic index. The US FDA has approved enoxaparin sodium as a prophylactic drug after low limb replacement.

[0004] At present, the degradation methods of low molecular weight heparins produced in China mainly include sodium nitrite degradatio...

Examples

Embodiment 1

[0027] 1. Weigh 3Kg heparin sodium, 45g sodium nitrite and 30g sodium borohydride respectively for later use;

[0028] 2. After adding 3Kg of heparin sodium into a 15-24L purified water reaction tank, stir at room temperature for 4-5 hours and dissolve to obtain a heparin sodium solution;

[0029] 3. After adjusting the pH of the above sodium heparin solution to 2~3 with hydrochloric acid, add 45g of sodium nitrite in a stirring state, then keep warm at 20~30°C and react for 2~3h under stirring, then let it stand for 20 After ~24h, the heparin degradation solution was obtained;

[0030] 4. After adjusting the pH value of the above-mentioned heparin degradation solution to 9-10 with sodium hydroxide solution, add 30 g of sodium borohydride for reduction for 10-12 hours. After the reaction is completed, adjust the pH value to 6.8-7.2 with sodium hydroxide solution to obtain the reduction solution ;

[0031] 5. Add 2 to 3 times the volume of ethanol to the above reducing soluti...

Embodiment 2

[0035] Example 2: The difference between this example and Example 1 is that the heparin sodium is 10Kg, the sodium nitrite is 150g, and the sodium borohydride is 100g. After lyophilization, 9Kg of enoxaparin sodium is obtained.

Embodiment 3

[0036] Example 3: The difference between this example and Example 1 is that the heparin sodium is 30Kg, the sodium nitrite is 450g, and the sodium borohydride is 300g, and 27Kg of enoxaparin sodium is obtained after freeze-drying.

technical field

[0001] The invention belongs to the field of biotechnology, and in particular relates to a production process of enoxaparin sodium. Background technique

[0002] Enoxaparin sodium is a low-molecular sodium salt, which is mainly used in the prevention of coagulation and deep vein thrombosis in hemodialysis, the treatment of unstable coronary artery disease and the prevention of thrombosis related to surgery. Heparin is a kind of glycosaminoglycan widely present in animal organs, small intestinal mucosa, lung and other tissues.

[0003] In addition to having all the pharmacological effects of unfractionated heparin, low-molecular-weight heparin is used as an anticoagulant, usually for short-term use, and has a high therapeutic index. The US FDA has approved enoxaparin sodium as a prophylactic drug after low limb replacement.

[0004] At present, the degradation methods of low molecular weight heparins produced in China mainly include sodium nitrite degradatio...

Examples

Embodiment 1

[0027] 1. Weigh 3Kg heparin sodium, 45g sodium nitrite and 30g sodium borohydride respectively for later use;

[0028] 2. After adding 3Kg of heparin sodium into a 15-24L purified water reaction tank, stir at room temperature for 4-5 hours and dissolve to obtain a heparin sodium solution;

[0029] 3. After adjusting the pH of the above sodium heparin solution to 2~3 with hydrochloric acid, add 45g of sodium nitrite in a stirring state, then keep warm at 20~30°C and react for 2~3h under stirring, then let it stand for 20 After ~24h, the heparin degradation solution was obtained;

[0030] 4. After adjusting the pH value of the above-mentioned heparin degradation solution to 9-10 with sodium hydroxide solution, add 30 g of sodium borohydride for reduction for 10-12 hours. After the reaction is completed, adjust the pH value to 6.8-7.2 with sodium hydroxide solution to obtain the reduction solution ;

[0031] 5. Add 2 to 3 times the volume of ethanol to the above reducing soluti...

Embodiment 2

[0035] Example 2: The difference between this example and Example 1 is that the heparin sodium is 10Kg, the sodium nitrite is 150g, and the sodium borohydride is 100g. After lyophilization, 9Kg of enoxaparin sodium is obtained.

Embodiment 3

[0036] Example 3: The difference between this example and Example 1 is that the heparin sodium is 30Kg, the sodium nitrite is 450g, and the sodium borohydride is 300g, and 27Kg of enoxaparin sodium is obtained after freeze-drying.