Preparation method for freeze-dried powder injection of posaconazole

Abstract

The invention relates to a freeze-dried powder injection of posaconazole and a preparation method thereof. The powder injection comprises active treatment ingredients consisting of posaconazole, cyclodextrin, a metal ion chelating agent and a pH conditioning agent. The preparation method comprises the following steps: dissolving cyclodextrin and disodium edetate under stirring; adjusting the pH value of a solution obtained in the previous step to 1 to 2; adding posaconazole and dissolving posaconazole under stirring so as to obtain a clear solution; adjusting the pH value of the clear solution to 2.0 to 3.5; allowing the volume of the solution to reach a fixed value through addition of water; and successively carrying out aseptic filtering, separation and freeze drying. According to the invention, through effective control of the proportions of posaconazole, the metal ion chelating agent and the like in a recipe, insoluble particles before and after combination of medicinal liquid is reduced, and the prepared freeze-dried powder injection of posaconazole has the advantages of good stability of active ingredients and convenience in transport and storage.

Description

technical field [0001] The invention relates to an antifungal freeze-dried powder injection of posaconazole and a preparation method thereof, belonging to the field of pharmaceutical preparations. Background technique [0002] Posaconazole (Posaconzole) is a novel triazole oral broad-spectrum antifungal drug developed by Schering-Plough, and its chemical name is 4-[4-[4-[4-[[(3R,5R)-5-(2 ,4-Difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl]methoxy]phenyl]-1-piperazinyl ]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, chemical structure As shown below, the structural formula is: [0003] [0004] Posaconazole was approved for marketing by the U.S. FDA in September 2006. The dosage form on the market is oral suspension, the trade name is Noxafil, and the concentration is 40mg / L. The compound has good antibacterial activity against Candida species, especially in refractory or invasive fungal infections resistant to polyenes ...

AI Technical Summary

Problems solved by technology

[0005] Posaconazole (logP value 5.5, pKa value 14.83) is a poorly water-soluble, weakly alkaline drug. At present, there are various preparation forms including tablets, capsules and suspensions. For example, patent document CN102958528 discloses an oral suspension , by adding thickeners and non-ionic surfactants, the stability of posaconazole can be increased to avoid the formation of solid cakes that are difficult to disperse, and the bioavailability can be improved, but the liquid preparation can only be administered orally , the application on critically ill patients who are difficult to swallow is limited, and it is not suitable for infants, coma and other people with difficulty swallowing

[0006] Patent document CN102958528 discloses a saconazole intravenous infusion preparation, the solubility of posaconazole is improved by adding a solubilizer and a chelating agent, but the liquid preparation can only be stored at 2-8°C, and the stability of the preparation is poor , causing inconvenience to transportation and storage;

[0007] Patent document CN103284959 discloses a kind of posaconazole freeze-dried powder injection and preparation method thereof, but there are following problems: 1) adopting this patent prescription to carry out test finds that adopting claim 7 described 3-10% organic solvent and When the mixed reagent of water for injection is used to dissolve the raw and auxiliary materials, when the organic solvent is 3%, posaconazole begins to precipitate when the pH is adjusted to 2.4, and when the proportion of organic solvent is gradually increased to 10%, when the pH is adjusted to 3.4, posaconazole A large amount of precipitation, the raw and auxiliary materials cannot be dissolved when the pH described in claim 9 of the patent is 4-7

2) The main drug in this patent is dissolved by adding an organic solvent. The main drug will not be completely included in the cyclodextrin, which may cause the main drug to not be completely dissolved when the product is reconstituted, the content of the main drug will decrease, and the insoluble particles 3) The organic solvent added in this patent will be corrosive to the freeze-drying equipment, and has safety risks. At the same time, it has a certain impact on the environment and is not suitable for industrial production;

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