Azacitidine freeze-dried preparation and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations and in particular relates to an azacitidine freeze-dried preparation with stable proprieties. The active ingredient of the azacitidine freeze-dried preparation is a treatment effective amount of azacitidine; a solution contains an organic solvent, a freeze-drying proppant and injection water before freeze-drying; the organic solvent is selected from ethanol, isopropanol, methanol or a mixed solution thereof in any ratio, and preferably is ethanol; and the usage amount of the organic solvent is 0.3-6.0% of the total volume of the solution before freeze-drying. The invention also provides a preparation method of the azacitidine freeze-dried preparation which is simple in process, is suitable for scale production and can be clinically used.

Description

Technical field [0001] The invention belongs to the technical field of pharmaceutical preparations. Specifically, it relates to a freeze-dried azacitidine preparation and a preparation method. Background technique [0002] Azacitidine is a DNA methyltransferase inhibitor, which can cause DNA hypomethylation and has a direct cytotoxic effect. In May 2004, the US FDA approved the drug’s freeze-dried preparation Vidaza to be marketed for treatment of bone marrow. Treatment of all subtypes of hyperplastic syndrome. [0003] The structural formula of azacitidine is as follows: [0004] [0005] Azacitidine (Compound 1) is a cytosine nucleoside analogue, which is easily hydrolyzed in water and mainly produces two hydrolysates, which is the main impurity of azacitidine for injection. As shown in the following reaction, the nitrogen-containing heterocyclic ring of azacitidine is first opened to obtain compound 2 (RGU-CHO). This step is a reversible reaction, and compound 2 is further hydr...

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Problems solved by technology

[0010] US2011 / 0042247 A1 discloses a preparation method of azacitidine freeze-dried preparation. During the sample preparation process according to Example 1, it is found that the dissolution rate of raw materials is slow, the batching time is long, and the hydrolyzed impurities are relatively high, resulting in the production of related substances in the product. Larger, not conducive to product quality assurance

[0011] CN 103251564 A discloses azacitidine for injection and its preparation method. The measure of adjusting the pH of the solution is used to slow down the hydrolysis rate of the raw material. However, since the hydrolysis rate of this product is less affected by the pH, it slows down the hydrolysis rate of the raw material by controlling the pH of the solution. Hydrolysis is not ideal

[0012] WO 2013 / 012135 A1 discloses a preparation method of azacitidine freeze-dried preparation. The batching process adopts the method of directly dissolving azacitidine in 40%-60% tert-butanol aqueous solution, because azacitidine is in tert-butanol Insoluble in butanol, the dissolution rate of raw materials in the mixed solution is slow, resulting in slow batching speed and long time; and the amount of organic solvent is large, so the dissolved raw materials are easy to recrystallize and precipitate; tert-butanol is an organic solvent with a high boiling point, which is not easy Removed by freeze-drying, the final residue in the preparation is relatively high, and tert-butanol is not a low-toxic organic solvent specified in the 2010 edition of the "Chinese Pharmacopoeia", and product safety cannot be guaranteed; a large number of organic solvents pollute the environment and equipment. Not conducive to scale-up production

[0013] At present, the common problems in the preparation process of azacitidine powder injection are: 1. The raw materials are easily hydrolyzed and are insoluble drugs. The raw materials dissolve slowly, and the batching time is long, resulting in hydrolyzed impurities, which is not conducive to product quality assurance; 2. 1. Add additional auxiliary materials to improve the stability of the feed liquid and improve product quality, but the effect is not ideal; 3. To improve the stability of the feed liquid, a large amount of high-boiling organic solvents are added to the feed liquid, which is not conducive to industrial scale-up production and environmental protection

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