Orally Bioavailable and Effective Buparvaquone Lipid-Based Nanomedicines for Visceral Leishmaniasis

• Published in: Molecular pharmaceutics 2018-07, Vol.15 (7), p.2570-2583
• Main Authors: Smith, Lindsay, Serrano, Dolores R, Mauger, Marion, Bolás-Fernández, Francisco, Dea-Ayuela, Maria Auxiliadora, Lalatsa, Aikaterini
• Format: Article
• Language: English
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00097

Nanoenabled lipid-based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxy­napthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug). Here we describe a self-nanoemulsifying system (SNEDDS) with high loading and thermal stability up to 6 months in tropical conditions and the ability to enhance the solubilization capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailability compared to aqueous BPQ dispersions (probe-sonicated), resulting in an increased plasma AUC0–24 by 55% that is 4-fold higher than any previous reported values for BPQ formulations. BPQ SNEDDS can be adsorbed on low molecular glycol chitosan polymers forming solid dispersions that when compressed into tablets allow the complete dissolution of BPQ in gastrointestinal media. BPQ SNEDDS and BPQ solid SNEDDS demonstrated potent in vitro efficacy in the nanomolar range (