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Orally Bioavailable and Effective Buparvaquone Lipid Based Nanomedicines for Visceral Leishmaniasis Lindsay A Smith, Dolores Remedios Serrano, Marion Mauger, Francisco Bolás-Fernández, Maria Auxiliadora Dea-Ayuela, and Aikaterini Lalatsa Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00097 • Publication Date (Web): 15 May 2018 Downloaded from http://pubs.acs.org on May 16, 2018
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Molecular Pharmaceutics
Orally Bioavailable and Effective Buparvaquone Lipid Based Nanomedicines for Visceral Leishmaniasis Lindsay Smitha, Dolores R. Serranob, Marion Maugera, Francisco Bolás-Fernándezc, Maria Auxiliadora Dea-Ayuelad, Aikaterini. Lalatsaa* a
Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth, PO1 2DT, UK. b
Departament of Pharmaceutics and Food Technology and Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense, Avenida Complutense, 28040 Madrid, Spain. c
Departament of Microbiology and Parasitology, School of Pharmacy, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040-Madrid, Spain. d
Departamento de Farmacia, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Edificio Seminario s/n, 46113-Moncada, Valencia, Spain.
*Author for correspondence Dr. Aikaterini Lalatsa, Senior Lecturer in Pharmaceutics, Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth, PO1 2DT, UK, Email:
[email protected], Tel: +44 2392 84 3929
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Graphical Abstract
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Molecular Pharmaceutics
Abstract Nano-enabled 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 able to enhance the solubilisation capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailbility compared to aqueous BPQ dispersions (probe – sonicated) resulting in an increased plasma AUC0-24 by 55% that is four 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 (
