Preparation Of Anti-tumor Drug Ixabepilone For Injection

Ixabepilone is a lactam derivative of epothilone B.It is a cytotoxic microtubule stabilizer.Tubulin is very important for cell division,similar to the mechanism of action of paclitaxel.Once ixabepilone binds to the ??-tubulin dimer subunit,??-tubulin is difficult to depolymerize,thereby stabilizing tubulin to exert antitumor effects.Ixabepilone has a novel chemical structure and is the first epothilone antitumor drug approved to date worldwide.It was first developed by BRISTOL MYERS SQUIBB under the trade name IXEMPRA KIT and was approved by the US FDA on October 16,2007.At present,there is no product listed in China.The goal of this research to develop ixabepilone for injection is to fill the gap in the domestic market.This paper first refers to the reference listed drug(IXEMPRA KIT),the dosage form and strength of ixabepilone for injection are as follows:?freeze-dried powder preparation 15 mg,solvent is 8 mL;?freeze-dried powder preparation 45 mg,the solvent is 23.5 mL.The quality standards for ixabepilone 15 mg and 45 mg lyophilized powder for injection and the quality standards for ixabepilone 8 mL and 23.5 mL for injection were developed.In order to optimize the product composition and process parameters,a prescription screening experiment was carried out to determine the optimal solvent as a tert-butanol-water mixed solution,and the volume ratio of tert-butanol to water for injection was optimized to be 50:50;and the concentration of the lyophilized stock solution was determined to be 4.6 mg/mL;and the pH value of solution was optimized to be 7.0-8.0,so that the freeze-dried stock solution and the lyophilized powder are more stable.Subsequently,the development of key process parameters was carried out,focusing on the preparation method of freeze-dried stock solution,freeze-drying process and freeze-drying procedure.By investigating the effects of temperature,light and oxygen on the stability of the lyophilized stock solution,it is proved that the lyophilized stock solution should not be placed at 2-8? for more than 10 h.At the same time,light and oxygen have a certain effect on the lycopene freeze-dried solution.Therefore,temperature control,light protection,and oxygen removal are required during the batching process.The compatibility between the production component system and the freeze-dried stock solution was investigated,and a reasonable production liquid distribution material was screened out.This determines a reasonable dosing process.Through the screening of the freeze-drying process,the problems of high residual t-butanol,freeze-dried spray bottle and the like were successfully solved,and the stability of the finished product was improved.Under the stability conditions(25?±2? RH60%±5%)and high temperature conditions(40?±2?)ixabepilone lyophilized powder and diluent stability were studied,which proved the rationality of the prescription process design.Finally,it entered the stage of production enlargement,established the production process parameters of ixabepilone freeze-dried powder and solvent,and laid the foundation for the production and marketing of the product.