LIPOSOMES AS A LIPID-BASED FORMULATION TO INCREASE THE BIOAVAILABILITY OF POORLY WATER-SOLUBLE DRUG FENOFIBRATE

Abstract

This thesis investigates the biopharmaceutical knowledge of different liposomal formulations using two different phosphatidylcholines (EPC and S 90) in the presence and absence of gelatine. The study aimed to characterize the oral lipid-based formulations in terms of physiochemical features, X-ray diffraction, dissolution, in vitro lipolysis and in vivo pharmacokinetic studies. The prepared liposomes were used to investigate the physical features of vesicular phospholipid gels (VPGs) and the light-scattering assessed the size and polydispersity of the liposomes. Fenofibrate-loaded liposomes had remarkably high entrapment efficiency (95%–99%). The dissolution behaviour of the samples was evaluated in a paddle model and the results showed a negative correlation between the rate of liposome release and gelatine concentration. The prepared liposomes were used in a dynamic in vitro lipolysis model to study the digestion and solubilisation of the drug formulations in biorelevant media simulating the gastrointestinal environment. The release profile of fenofibrate for all liposomal formulations showed a general increasing trend (regardless of the type of phosphatidylcholine and amount of gelatine) towards the release of fenofibrate from the formulations in the aqueous phase. For the in vivo studies, EPC and S 90 liposomes were administered orally to fasted rats for pharmacokinetic characterization. The in vivo studies demonstrated that Soluthin S 90 formulations, regardless of the presence or absence of gelatine, showed significantly higher (p<0.01) pharmacokinetic parameters in terms of AUC and Cmax. All formulations showed a similar Tmax, and the presence or absence of gelatine had no significant effect on AUC, Cmax or Tmax for both EPC- and Soluthin S 90-type liposomal formulations. In this study, the absence and presence of gelatine in the in vitro rat lipolysis model correlated with the results of the in vivo pharmacokinetic studies, and the data from the NaOH titration, corresponding with the digestion and FA release, virtually correlated with the in vivo plasma concentration. However, in term of the drug solubilisation profile, no significant correlation was observed between the in vitro and in vivo studies, particularly in the case of the in vitro lipolysis model. In conclusion, the addition of gelatine did not have a significant effect on pharmacokinetic parameters. The new phosphatidylcholine mixture, Soluthin S 90, strongly improved the absorption and bioavailability of fenofibrate-loaded liposomes. Further studies should be performed to investigate the effect of fenofibrate-loaded liposomes prepared by Soluthin S 90 on the intestinal permeability of the API and solubilisation capacity of the formulations in an in vitro lipolysis model combined with an absorption step. It is also recommended to combine the formulation with different surfactants to choose the optimal formulation. In addition, it is necessary to examine the bioavailability of different poorly water-soluble drugs (PWSDs) formulated in Soluthin S 90 liposomes to elucidate the pharmacokinetic effect of such a formulation.