Enhancement the Bioavailability of Fenofibrate using Self emulsifying Microspheres and Dry emulsion

Abstract

Oral administration of fenofibrate (FF) is considered a practical route of administration for enhancing the bioavailability of the drug. However poor solubility of the drug as well as poor absorption is some of the major limitations which should be overcome when considering this route. Self emulsifying microspheres (SEM) by virtue of forming the drug in a molecular form as solid dispersion and small particle size can greatly enhance the drug absorption. Incorporation of the drug in lyophilized dry emulsion provides higher dissolution and better bioavailability. The objective of this study was to prepare FF loaded self emulsifying microspheres and lyophilized dry emulsion for the oral route to improve the drug bioavailability and provide high blood levels of fenofibric acid which is the active metabolite of fenofibrate. FF loaded self emulsifying microspheres were successfully prepared using quasi solvent diffusion method to form the drug in a molecular form and FF loaded lyophilized dry emulsion was successfully prepared by lypholization to enhance the dissolution and the bioavailability of the drug. A full factorial design was constructed for the self emulsifying microspheres to study the influence of four independent variables namely; the type of the polymer, the amount of Aerosil, the amount of talc and the type of the oil. The dependent variable was the entrapment efficiency percentage (EE %). Bioavailability and pharmacokinetic study of fenofibrate self-emulsifying microspheres and dry emulsion in human volunteers was performed for the selected FF self emulsifying microspheres and dry emulsion formulations. FF loaded dry emulsion showed smaller particle size and higher entrapment efficiency (EE %) compared to their alternative self emulsifying microspheres. Also they had higher dissolution pattern than alternative self emulsifying microspheres. Both self emulsifying microspheres and dry emulsion showed good stability up to six months. FF loaded self emulsifying microspheres and dry emulsion which showed reasonable entrapment efficiency (63% and 74%) were selected for further comparative studies. FF loaded self emulsifying microspheres (F6) were prepared by quasi solvent diffusion method using drug loaded in castor oil (0.8 gm containing 0.667 gm drug), Polymer: HPMC AS LF (0.1 gm), Aerosil 200:0.4 g, Talc:0.5 g, while dry emulsion (E6) was prepared by the same components using lypholization technique. Both self emulsifying microspheres and dry emulsion had high values of yield, high drug loading, small angle of repose, small particle size and high values of entrapment. It should be mentioned that dry emulsion has higher values of yield, higher drug loading, smaller angle of repose, smaller particle size and higher values of entrapment. Both self emulsifying microspheres and dry emulsion are capable of formation of microemulsion upon contact with the intestinal fluid. The microemulsion formed by the microspheres and dry emulsion was characterized for spontaneity of self-emulsification, droplet size and polydispersity index analysis, viscosity, zeta potential, Count rate, Conductivity and %Transmittance. DSC studies of the microspheres and dry emulsion showed low crystallinity indicating the presence of drug in amorphous form. The pharmacokinetics in human plasma showed that the relative bioavailability of self emulsifying microspheres and dry emulsion was enhanced compared to that of the market product (Lipanthyl ® ) with values of 265.52% and 243%, respectively. It is worthy to note that the method of preparation had a significant effect on the bioavailability of fenofibrate, as evidenced by the significantly shorter (Tmax) of lyophilized dry emulsion (E6) compared to self emulsifying microspheres (F6), with values of 2.00 and 2.50 hr, respectively.