Preparation Of Fenofibrate Solid Dispersion Pellets By Fluid-bed Coating Technique And Evaluation Of In Vitro-in Vivo Correlation

Fenofibrate(FNB),a poorly soluble drug,has low dissolution and bioavailability. There are a few marketed fenofibrate dosage forms such as micronised FNB powder in capsules,chewable tablets,dispersible tablets,sustained-release tablets and so on, whose oral bioavailability was nevertheless unsatisfactory.To achieve therapeutic plasma level,poorly water-soluble drugs should be administered orally in high doses.It is therefore of great importance to enhance the dissolution rate of poorly soluble drug and consequently improve its bioavailability. Solid dispersion technique is one of the methods to improve the dissolution of drugs. Solid dispersions can be manufactured by a variety of methods such as the melting method,the solvent evaporation method,the solvent-melting method and so on.In this study,we employed a one-step fluid-bed coating technique to prepare solid dispersion of fenofibrate by using PEG,PVP and PVP/SLS as carders.The physicochemical properties of FNB solid dispersion pellets were evaluated both in vitro and in vivo.In the first part,solid dispersion pellets of PEG/FNB,PVP/FNB and PVP/SLS/FNB were prepared.Factors including cartier type and cartier/drug ratio that might influence the formation of solid dispersion were studied using dissolution rate as a criterion.The physicochemical properties were investigated by differential scanning calorimetry and X-ray powder diffractometry.Results indicated that the formation and dissolution rate of solid dispersion were mainly influenced by cartier/drug ratio and cartier type.With regard to solid dispersion of the PEG/FNB, the differential scanning calorimetry showed that the melting peak of FNB disappeared,while X-ray diffraction still showed FNB crystal diffraction peaks.This phenomenon indicated that FNB,which was in a microcrystalline state,form eutectic mixture with PEG.The differential scanning calorimetry and X-ray diffraction showed that FNB was amorphous in PVP/FNB and PVP/SLS/FNB solid dispersions.After storage for several months,the dissolution of PVP/FNB and PVP/SLS/FNB solid dispersions changed little,whereas the dissolution rate of PEG/FNB solid dispersions decreased,especially at higher PEG/FNB ratios.In the second part,oral bioavailabilities of FNB solid dispersion pellets and Lipanthyl^?,a commercial fenofibrate product,were compared in six Beagle dogs(at a dose of 30mg calculated as fenofibrate).Fenofibric acid is the active metabolite of FNB in vivo.Single dose of FNB was given orally in a cross-over experimental design.The drug levels in plasma were assayed by a validated HPLC method. Pharmacokinetic analysis was performed by means of a model-independent method using 3p87 computer program.Results showed that there was a 3-5 fold increase in bioavailability for FNB solid dispersion pellets at high cartier/drug ratio as compared to Lipanthyl(?).It is indicated that the fluidized bed coating technique can possibly be used to deposit fenofibrate solid dispersions on non-pareils.Through analyzing oral bioavailability and the dissolution of solid dispersion pellets in biorelevant media which can provided a more accurate simulation of pharmacokinetic profiles,good in vitro-in vivo correlation was obtained.Therefore,it is possible to predict in vivo performance of FNB by simply studying the dissolution characteristics in vitro.