Preparation And Drug Release Behavior Regulation Of Dexamethasone Implant

Zero-order release,the ideal drug delivery,can maintain a stable drug concentration.However,the releae behavior of biodegradable implant mostly performs two or three phase.This study aimed to prepare the Dexamethasone intraocular implant by hot melt extrusion and to adjust the drug release behavior of the implant.The first part of this study was to develop and validated a HPLC method for the determination of Dexamethasone in implant.In addition,the compatibility between Dexamethasone and PLGA was investigated by DSC.The results showed that the method had good specificity,linearity,precision and accuracy,PLGA and Dexa were partially miscible,and dexamethasone had good thermal stability.Secondly,the dexamethasone implants were prepared by hot melt extrusion method.The effects of drug loading,process temperature and screw speed on the die swelling phenomena and in vitro release of implants were investigated.DSC,XPRD and SEM were used to characterize the implants.The data showed that the effect of temperature and screw speed on the drug release behavior of the implant was not significant,but they had a great influence on the die swelling phenomena.The die swelling ratio decreases with the increase of the temperature and the effect of screw speed was to the contrary.The die swelling ratio was about 1 at 115 ℃,30 r/min.The release curve of the implant had a lag phase followed a rapid release phase.The drug loading mainly affected the cumulative release of the first day,and had no effect on the release rate at the later stage.DSC,XPRD and SEM showed that the crystalline dexamethasone existed in implant.The effect of pH,temperature,SDS concentration of release medium on in vitro release was investigated in order to establish an accelerated in vitro release testing method.Finally,the definite in vitro release method was: saline containing 1%SDS,0.02%NaN3 as release medium,water bath temperature 45 ℃,shaking rate 90 r / min.The effects of water soluble additives on the drug release from dexamethasone implant were investigated through mass loss,weight average molecular weigh change,DSC,SEM.SEM revealed that the lag phase of the implants might be due to the dense skeletal structure of the implants.The in vitro release results showed that poloxamer F68,sorbitol and lactose couldn’t improve release behavior of dexamethasone implants,and the drug release curves were non-linear,while the drug release rate from dexamethasone implant containing mannitol was constant.DSC data indicated the physical state of mannitol in implant was still crystal.During drug release the more mannitol in implant,the faster mannitol release rate was.Mass loss and weight average molecular weigh change results showed that the degradation rate of the polymer decreased with increasing mannitol amount.The image of SEM suggested that the addition of mannitol could form pores during the release and preparation process.Besides,mannitol could alter the degradation mechanism of implants that was from heterogeneous to homogeneous.These phenomena could be explained by the autocatalytic effect which would accelerate degradation of PLGA.The porosities caused by mannitol leaded to increase mobility of drug as well as the PLGA degradation acid products.Therefore,the autocatalytic effect was decreased,and inside degradation rate of the implants became slower.Therefore,the regulation of drug release behaviors of biodegradable implants was achieved by adding manitol to the system.Adding mannitol could form a porous implant,which could weaken the autocatalytic of PLGA.