Solid lipid nanoparticles or polymeric nanoparticles: how to menage oral permeation of a molecule active in multidrug-resistant tuberculosis.

INTRODUCTION Recently a new compound, SS13, has been synthesized as a potential efflux inhibitor [1]. However, SS13 is insoluble in different simulated gastrointestinal media; thus, its oral permeation is limited. In this work, solid lipid nanoparticles (SLNs) and polymeric nanoparticles (NPs) have been prepared to increase the oral bioavailability of SS13. MATERIALS AND METHODS SS-13 anti-mycobacterial activity, chemical-physical properties, and pharmacokinetic on Sprague-Dawley rats after an intravenous infusion of 0.6 mL of compound solution were studied. SLNs, consisting of Witepsol E85 and Gelucire 44/14, and NPs composed of poly (lactic-co-glycolic acid) were prepared with a solvent emulsification evaporation method [2]. The chemical-physical characteristics of both nanoparticles were evaluated. SLNs ex vivo permeation, using 12-well cell culture plates suitably modified (project INCREASE SARDINIA 2016-17, protocol number 31351, University of Sassari) on the intestinal mucosa and the cytotoxicity were studied. NPs permeation and pharmacokinetic studies are ongoing. RESULTS SS13 increases the antitubercular activity of several drugs. Pharmacokinetic parameters (concentration at the end of infusion: 30µg/ml; AUC: 1134 ± 65 gml-1min; half-life: 28.7±0.9 min; clearance: 0.71±0.04 mlmin-1kg-1) indicate a poor aptitude of the compound to migrate to peripheral tissues. About 90% of SS13 was found in the SLNs. They can increase the ex vivo permeation of SS13 through the intestinal mucosa (70%) if compared to pure compound (3%) and affect the Caco-2 viability in a dose-dependent manner. NPs (particle size 281.2±17.57 nm; PI 0.114±0.043) are stable if stored at 4°C and are able to load SS13. Based on FTIR studies we may suppose the compound entrapment in NPs. Results of nanoparticle permeation and pharmacokinetics will be described. CONCLUSION These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.