Investigation Into Posaconazole Enteric Tablets

Invasive fungal infection was an increasingly serious global health problem,which greatly increased the morbidity and mortality of immunocompromised patients.Amongst the fungals,aspergillus fumigatus,cryptococcus neoformans and candida albicans were the three main pathogens for invasive fungal infections.Posaconazole was an antibacterial drug approved by FDA to prevent pathological changes caused by invasive aspergillus,and was also to be used for the treatment of fungal infections caused by oropharyngeal candida that was itraconazole and fluconazole resistant.The marketed posaconazole preparation was named as Noxafil^?,containing the dosage forms of suspensions,tablets,and injections.In this study,HPMCAS,an enteric polymer,was used as a polymeric carrier to prepare posaconazole solid dispersions,and with further excipients including disintegrating agents,binders,diluents and other excipients,posaconazole enteric tablets were prepared.It was expected that a generic posaconazole entric tablet that was consistent with the reference product Noxafil^?Enteric Tablets could be developed in this study.In this study,the basic physical and chemical properties of posaconazole and the enteric polymer HPMCAS were firstly determined.High performance liquid chromatography（HPLC）was used to establish an in vitro release and drug content determination method.This method showed strong specificity and high sensitivity,providing an accurate and reliable analysis method for the following research.Hot-melt extrusion was used to prepare posaconazole solid dispersion with HPMCAS.The extrusion temperature and rotation speed were screened according to the amount of impurities,the material yield,and the torque value during the extrusion process.It was found that when the temperature was 130℃ and 140℃,the detected drug impurtities was within the requirement.The drug impurtities increased with increasing extrusion temperature.The rotation speed was set at 50rpm due to the acceptable torque value and the yelid.The drug-polymer ratio was then evaluated using dissolution behavior.It was found that drug release rate increased when the drug to polymer ratio decreased from 1:1～1:3.When the drug to polymer ratio was 1:4 and 1:5,no further increase of drug released rate was observed.Based on the tablet weight and the drug release rate,drug to polymer ratio was fixed at 1 to 3.Such posaconazole solid dispersion showed good acid resistance where by less than 10%drug was released in acid media.After the dissolution media was changed to pH6.8,more than 90%drug was released in 15 minute.The particle size of the milled solid dispersion was investigated,and the in vitro dissolution results showed that milled solid dispersions that were controlled by 60-mesh screen showed the best dissolution behavior.The tablet preparation was further investigated,including the preparation of core tablets using direct compression and the coating process.Taking the disintegration time and hardness of the original formulation as the evaluation index,the percentage of the binder and the disintegrant in the formulation by determining the disintegration time and the tablet hardness.It was found that tablet with12.5%binder and 4.2%disintegrant showed similar hardness and disintegration time to those of the reference tablet.The coating process was optimized by studying the parameters including the air inlet temperature,the rotating speed,the concentration of coating solution,and feeding speed of the coating solution.The results showed that when the air inlet temperature was 80℃,the rotating speed was 10r/min,the coating concentration was20%,and the spraying speed was 5g/min,the tablets showed smooth and uniform surface,and the coating time was short.In vitro dissolution results showed that tablets prepared in this study had good acid resistance,and the drug release was more than 90%in pH6.8 medium in 15minutes,which was consistent with the reference tablets.The statibility of solid dispersions were carried out under the stressed conditions including high temperature（60℃/0%RH）and high humidity（25℃/90%RH）for up to 90 days.FT-IR,DSC,XRD,in vitro release,drug content were of the solid dispersions over aging were determined.The results showed that no significant change was observed in any results of FT-IR,DSC,XRD,in vitro release studies after 90 days,indicating the high stability of the melt extrudates.