Temozolomide lyophilized powder preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations and specifically relates to a temozolomide lyophilized powder preparation. The temozolomide lyophilized powder preparation comprises an active ingredient of temozolomide or a pharmaceutically acceptable salt thereof, and a solution before lyophilization further contains an excipient, a wetting agent, a buffer agent, an osmotic pressure regulating agent, a pH regulating agent, water for injection and an organic solvent, wherein the organic solvent is selected from one or any combination of ethanol, acetone, isopropanol, n-propanol, butanone, sec-butyl alcohol and methanol, and is preferably ethanol. The temozolomide lyophilized powder preparation provided by the invention has the advantages of stable quality, high re-dissolution speed and a small residual amount of the organic solvent. The invention further provides a method for preparing the preparation. The process provided by the invention is simple and convenient in preparation process and easy to control production links, the organic solvent accounts for a relatively small part of total volume of material liquid, the pollution to production equipment and environment caused by the organic solvent is reduced, and thus the method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations. Specifically relates to a temozolomide freeze-dried powder preparation with stable quality and fast reconstitution speed and a preparation method thereof. Background technique [0002] Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxoimidazo[5,l-d]-l,2,3,5-tetrazine-8-amide, which is imidazotetra Azines have the alkylating agent of antitumor activity, and the chemical structural formula is as follows: [0003] [0004] This product is a drug produced by Schering-Plough for the treatment of glioma and malignant melanoma. Domestic Temozolomide marketed preparations are hard capsules, oral preparations are easy to use, can be completely absorbed after oral administration, and the bioavailability is as high as 98%. The main side effects are nausea, vomiting, fatigue, constipation and mild bone marrow suppression, among which severe nausea and vomiting Sid...

AI Technical Summary

Problems solved by technology

[0006] Due to the poor solubility of temozolomide in water, about 3.1mg / ml, and the dissolution rate is slow, the batching time is too long, and the related substances in the product are high

The speed of using ordinary prescriptions and process ingredients is slow, which is not conducive to ensuring product quality. The final prepared freeze-dried powder has poor resolubility, which brings inconvenience and risks to clinical use. At the same time, it makes doctors and patients suspicious of product quality, which is not conducive to clinical application.

[0007] Chinese patent CN100588399 discloses a temozolomide freeze-dried powder injection. The preparation dissolves temozolomide by adjusting the pH and heating ultrasonically. The batching time is long, and a large amount of hydrolyzate is produced by heating, which is not conducive to the stability of the solution.

The batching speed is slow, and the raw materials can only be dissolved after stirring for at least 2 hours. The longer batching time is not conducive to product quality assurance

[0010] Chinese patent CN 102949351 discloses a preparation method of a temozolomide freeze-dried preparation, wherein a mixed solvent system of tert-butanol / water is used, the process batching speed is slow, which is not conducive to scale-up production, and the organic solvent used is tert-butanol It does not belong to the low-toxic organic solvents specified in the 2010 edition of the "Chinese Pharmacopoeia". It is generally used in large amounts in prescriptions, which is not conducive to safety and environmental protection.

Tert-butanol has a high freezing point and is not easy to remove during the freeze-drying process, resulting in a high residual concentration in the preparation, which is not conducive to drug safety

[0011] At present, the common problems in the preparation process of temozolomide powder injection are as follows: 1. It takes a long time to mix and produce hydrolyzed impurities, which is not conducive to the guarantee of product quality; 2. The product has poor resolubility, which is not conducive to clinical preparation and use, and there are risks in clinical use

3. In order to improve the resolubility of the product, additional substances are added as solubilizers, and these solubilizers have some pharmacological effects, which is not conducive to the safety of clinical medication

4. The amount of organic solvent used is large, which is not conducive to safety and environmental protection. The residual organic solvent in the preparation is relatively high, which is not conducive to the safety of medication

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