Preparation method of azacitidine for injection

Patent metadata

Field	Value
Publication number	US-10617649-B2
Application number	US-201716086592-A
Country	US
Kind code	B2
Filing date	Mar 17, 2017
Priority date	Mar 24, 2016
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

Disclosed is a preparation method for an azacitidine for injection, wherein each injection vial of azacitidine for injection contains 100 mg of azacitidine and 100 mg of mannitol. The preparation method comprises the steps of measuring 80% of the total volume of water for injection at a temperature of 2-6° C.; adding mannitol, and stirring to completely dissolved at a temperature of 2-6° C.; adding azacitidine, stirring to completely dissolved at a temperature of 2-6° C. to obtain an azacitidine solution for injection; filling each injection vial with 23 ml azacitidine solution for injection after filtration; freeze-drying at a preset temperature; and stoppering, capping and packaging after nitrogen filling. The preparation method has the advantages of a simple process, low energy consumption, high production efficiency and stable product quality.

First claim

What is claimed is:

1. A preparation method of azacitidine for injection, wherein each injection vial of azacitidine for injection contains 100 mg of azacitidine and 100 mg of mannitol, the preparation method comprising the following steps:
a. adding water for injection at a temperature of 2-6° C.;
b. adding mannitol, and stirring to completely dissolve, at a temperature of 2-6° C.;
c. adding azacitidine, and stirring to completely dissolve, at a temperature of 2-6° C., to obtain an azacitidine solution for injection, wherein upon completion of steps a) thru c), 80% of the volume of the azacitidine solution is water for injection, with the balance of the volume of the azacitidine solution being mannitol and azacitidine;
d. filling each injection vial with 23 ml of the azacitidine solution for injection after filtration;
e. freeze-drying at a preset temperature; and
f. stoppering, capping and packaging after nitrogen filling.

2. The preparation method of azacitidine for injection according to claim 1 , wherein the preparation method does not comprise a step of adsorbing with an activated carbon.

3. The preparation method of azacitidine for injection according to claim 1 , wherein the azacitidine has a content of ≤0.6 Eu/mg of bacterial endotoxin.

4. The preparation method of azacitidine for injection according to claim 1 , wherein the mannitol has a content of ≤2.5 Eu/g of bacterial endotoxin.

5. The preparation method of azacitidine for injection according to claim 1 , wherein a prepared product of azacitidine for injection has a content of ≤1.2 Eu/mg of bacterial endotoxin.

6. The preparation method for azacitidine for injection according to claim 1 , wherein the temperature for preparing a solution is controlled at 4-6° C.

7. The preparation method for azacitidine for injection according to claim 1 , wherein the freeze-drying step comprises:
a. pre-freezing step: placing a sample into a shelf after a temperature of the shelf is reduced to −35±5° C. and maintaining the temperature for 2 hours;
b. first sublimation drying step: reducing vacuum degree to 50-150 μbar, raising the temperature of the shelf to −10° C. at a rate of 15° C./h, and maintaining the temperature for 15 hours; and
c. second sublimation drying step: maintaining vacuum degree to 50-150 μbar, raising the temperature of the shelf to 30° C. at a rate of 20° C./h, maintaining the temperature for 18 hours, stoppering after nitrogen filling, and taking out from a freeze-drier.

Assignees

• Zhejiang Huahai Pharm Co Ltd

Inventors

• Shi Xiangjie
• Liu Jiening
• Wang Xinshi
• Hu Libin
• Chen Hao
• Wang Zhiyun

Classifications

• A61K31/706 Primary

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K9/19 Primary

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• F26B5/06

  the process involving freezing · CPC title