Preparation And Evaluation Of Fenofibrate Solid Dispersions

There are about 40%insoluble drugs at present,which seriously reduces its gastrointestinal absorption and ultimately limits its clinical application.Therefore,the enhancement of drug dissolution is essential to improve its bioavailability in vivo.The preparation of solid dispersions are one of the most commonly used methods for increasing the solubility and dissolution of insoluble drugs.The new preparation methods include hot-melt extrusion method,spray drying method,spray congealing method,fluid-bed coating method and so on.In this paper,we prepared the fenofibrate solid dispersions by hot-melt extrusion method and spray congealing method,to promote drug dissolution and improve its bioavailability in vivo.And the mechanisms of solubilization of two solid dispersions were discussed.Furthermore,the effects of nucleation,storage temperature and humidity on the stability of these two solid dispersions were also investigated.The equilibrium solubilities of fenofibrate in different media were investigated in the paper firstly,and the dissolution medium of 0.3%SDS was determined.UV spectrophotometric method for the determination of the fenofibrate concentration in solid dispersions and its dissolution in vitro was established.It could be found that the concentration of fenofibrate had a fit linear relationship with the absorbance at 290 nm.The recovery rates were between 98.08%and 100.84%,and the relative standard deviations were all less than 2.00%.Amorphous solid dispersions of fenofibrate were prepared by hot-melt extrusion method secondly.The effects of the types of carrier,drug-carrier mass ratio,extrusion temperature and rotation rate on the dissolution in vitro were investigated.The final preparation of fenofibrate solid dispersions was determined as follows:FNB/PVP K30=1/5?w/w?,extrusion temperature 140?and rotation rate 30 rpm.It could be observed that the stability of FNB-PVP K30 SDs were affected by the nucleation,storage temperature and humidity.The accelerated testing results also showed that phase separation occurred at 40?/75%RH.The drug had a poor stability and existed in microcrystalline state.The wettability,liquid phase inhibition and solubilization property of FNB-PVP K30 SDs were studied.It was found that PVP K30 could not effectively inhibit liquid phase crystallization,but high concentration of PVP K30 decreased the solubilization effect of SDS.It was concluded that the dissolution improvement of the solid dispersion was the result of both the high dispersion of the amorphous state of the drug and the improvement of the wettability.The microcrystalline solid dispersions were prepared by spray congealing method thirdly.The effects of carrier type,drug-carrier mass ratio,melting temperature and atomization pressure on the dissolution of the drug in vitro were investigated by single factor testing.The optimum formulation for the preparation of fenofibrate solid dispersions by spray congealing method was determined as follows:FNB/PEG 6000=1/1?w/w?,melting temperature 120?and atomization pressure 0.2 MPa.The obtained fenofibrate solid dispersions had a small particle size(D₅₀=32.14?m),and its diffraction peak intensities at 6.18,12.54,17.84°were smaller than that of the solid dispersions prepared by hot-melt extrusion method and physical mixtures.The results presented suggested that the differences of particle size and crystallinity were the main mechanism of increasing dissolution,apart from the wettability.The results of accelerated testing revealed that the appearance and properties of FNB-PEG 6000 SDs,the concentration and dissolution of FNB-PEG6000 SDs remained almost unchanged,which were indicative of high stability of fenofibrate solid dispersions.Finally,the pharmacokinetics study in rats of two kinds of prepared solid dispersions in rats was investigated,and its physical mixtures and fenofibrate market tablet were compared.The HPLC method was established to analyze fenofibrate in vivo with indomethacin as the internal standard.The recovery rate of biological sample was 100.36%.The RSD of intra-day and inter-day precision were both less than15.00%,indicating the results were accurate and reliable.Then the rats were randomly divided into five groups,and five kinds of fenofibrate preparations were given orally respectively.Took blood from the canthus of rats at each time point.The protein was treated by methanol precipitation method,and the plasma concentration was determined by HPLC at different time points.The values of T_max?C_max?AUC_0?t?t and AUC_0??were calculated.The results showed that the self-made solid dispersions had a good bioavailability,and FNB-PVP K30 SDs was 6⁷times of its physical mixture and 2³ times of that of fenofibrate market tablet.The FNB-PEG 6000 SDs was 16¹7 times of the physical mixture and 4⁵ times of that of fenofibrate market tablet.