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), a hydroxylnaphtoquinone with known antileishmaniasis activity (ED50:0.05μM), has not been translated into an effective therapy due to its low aqueous solubility (<30ngmL-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: Pseudoternary phase diagrams were constructed to optimize BPQ-SNEDDS (BS) (Capryol:Labrafil M1944:Labrasol:BPQ 3:1:5.99:0.01w/w/w/w). BPQ loading was quantified after centrifugation of BS containing excess BPQ (RP–HPLC). Stability studies of BS were performed at 40 ± 2 oC 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 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 or BPQ.Results: The maximum loading of BPQ in SNEDDS was 16.92±1.59mgg-1. BS aqueous dispersions elicited quasispherical nanoparticles (241±49.6nm) that remained stable over 10 weeks (content, size and ζ-potential). The porous BSS elicited similar size nanoparticles upon reconstitution. Near complete release was observed with BS capsules and BSS tablets. BS and BSS possess potent in vitro efficacy (nanomolar range) with negligible cytotoxicity. BS significantly enhanced the bioavailability of BPQ after oral administration (55% increase in plasma AUC0-24).Conclusions: Developed SNEDDS or solid-SNEDDS prepared from GRAS excipients are cost-effective, stable oral alternatives for the delivery of poorly soluble antiparasitic drugs

Engineering synergistically active and bioavailable cost-effective medicines for neglected tropical diseases; the role of excipients

Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses. Excipients are necessary for ensuring the stability and bioavailability of currently available antileishmaniasis drugs which in their majority are poorly soluble or have severe side-effects. Thus, selection of excipients that can ensure bioavailability and safety as well as elicit a synergistic effect against the Leishmania parasites without compromising safety will result in a more efficacious, safe and fast to market medicine. We have evaluated the in vitro activity of 30 commercially available generally regarded as safe (GRAS) excipients against different Leishmania spp., their cytotoxicity and potential use for inclusion in novel formulations. Amongst the tested excipients, the compounds with higher selectivity index were Eudragit E100 (cationic triblock copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate), CTAB (cetyltrimethylammonium bromide, cationic), lauric acid, Labrasol (non-ionic, caprylocaproyl polyoxyl-8 glycerides) and sodium deoxycholate. An ideal excipient needs to possess amphiphilic nature with ionic/polar groups and possess a short or medium fatty acid chain such as lauric (C12), capric (C10) or caprylicacid (C8). Inclusion of these excipients and identification of the optimal combination of drug and excipients would lead to a more effective and safer antileishmanial therapies