Oral Presentation: Engineering Oral Nanomedicines for the Treatment of Parasitic Diseases

Purpose - Visceral Leishmaniasis (VL) is the second deadliest parasitic disease after malaria managed mainly by parenteral chemotherapeutics. Buparvaquone (BPQ), an antiprotozoal hydroxylnaphtoquinone with known anti-leishmaniasis activity (ED50:0.05-0.1μM), has not been translated into an effective therapy due to its low aqueous solubility (< 30 ng mL-1, BCS Class II). The current project is aimed at enhancing the solubilisation capacity and oral bioavailability of BPQ in the gut by encapsulation in self-nanoemulsifying drug delivery systems (SNEDDS) prepared from GRAS excipients towards the development of an oral, thermally stable and ideally solid nanomedicine for the treatment of VL.

Methods - Pseudo-ternary phase diagrams were constructed to optimize BPQ-SNEDDS (BS) (Capryol:Labrafil M1944:Labrasol:BPQ 3:1:5.99:0.01 w/w/w/w). BPQ loading was quantified after centrifugation of BS containing excess BPQ (RP–HPLC). BS were characterised for particle size and zeta potential. Stability studies of BS were performed at 40±2oC and 75±5% relative humidity. BPQ solid SNEDDS (BSS) were prepared by adsorption of BS on acid-degraded glycol chitosan (14 kDa) and mixing with lactose and croscarmellose sodium prior to lyophilisation and characterisation (PXRD, DSC, FT-IR, TEM, SEM). BS filled capsules and BSS compressed tablets (1 bar, 10 seconds) underwent dissolution testing. The in vitro anti-leishmanial activity against L. infantum promastigotes was assessed. RP-HPLC was used to analyse plasma levels achieved after oral administration of BS and BPQ aqueous suspensions.

Results - The maximum loading of BPQ in SNEDDS was 16.92±1.59 mg g-1. BS aqueous dispersions elicited quasispherical nanoparticles (241±49.6 nm) (Figure 1A) that remained stable in terms of BPQ content, size and ζ-potential over 10 weeks. The porous BSS elicited nanoparticles of similar size upon reconstitution. Near complete release was observed with BS capsules and BSS tablets (Figure 1C,D). BS and BSS possess potent in vitro efficacy (nanomolar range) with negligible cytotoxicity. Hydrogen bonding between the hydroxyl groups of glycol chitosan and the quinine carbonyl group of BPQ was indicated (Figure 1G,F). BS significantly enhanced the bioavailability of BPQ after oral administration (55% increase in plasma AUC0-24).

Conclusions - The present study demonstrates for the first time enhancement of the oral bioavailbility of buparvaquone in mice with SNEDDS. Developed SNEDDS or solid-SNEDDS prepared from GRAS excipients are cost-effective, stable oral alternatives for the delivery of poorly soluble antiparasitic drugs.