Mucopenetrating nanoparticles for enhancement of oral bioavailability of furosemide: In vitro and in vivo evaluation/sub-acute toxicity study.

The aim of this study was to formulate and evaluate chitosan (CS)/alginate (ALG) nanoparticles (NPs) loaded with furosemide (FSM) in an attempt to enhance its release, permeability and bioavailability. Non-everted gut sac method was used to evaluate the ex vivo permeation of FSM from its suspension and the selected CS/ALG NPs formulation. The pharmacokinetic parameters of FSM subsequent to oral administration of the selected formulation were assessed in rats. In vivo subacute toxicity study of the prepared blank and FSM loaded formulations was evaluated in rats. The selected optimized formulation (F3) showed optimum particle size (PS), polydispersity index (PDI), zeta potential (ZP) and acceptable percentage entrapment efficiency (%EE) of 253.8nm±4.6, 0.25±0.03, -35mV±1 and 96%±1, respectively. The release profile of FSM from the selected formulation was characterized by initial burst effect in 0.1N HCl. Scanning electron microscope (SEM) demonstrated a smooth surface and spherical shape for the lyophilized optimized NPs. Selected CS/ALG NPs (F3) presented a significant enhancement (p≤0.01) in permeation parameters of FSM as well as in T, C, AUC and AUC. Subacute toxicity study results revealed that the selected formulation was safe and nontoxic. The histopathological inspection of the stomach and small intestine tissues of the loaded NPs (F3) and blank groups reflected no obvious signs of cellular toxicity or inflammatory reaction. CS/ALG NPs loaded with FSM enhanced both drug release and mucus-penetrating ability leading to an overall increase in FSM bioavailability. In addition, the in vivo subacute toxicity study results indicated the safety of the prepared NPs for oral drug delivery.