Orally bioavailable and effective buparvaquone lipid-based nanomedicines for visceral leishmaniasis

Smith, Lindsay and Serrano, Dolores R. and Mauger, Marion and Bolás-Fernández, Francisco and Dea-Ayuela, Maria Auxiliadora and Lalatsa, Aikaterini (2018) Orally bioavailable and effective buparvaquone lipid-based nanomedicines for visceral leishmaniasis. Molecular Pharmaceutics, 15 (7). pp. 2570-2583. ISSN 1543-8384 (https://doi.org/10.1021/acs.molpharmaceut.8b00097)

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Abstract

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 AUC 0-24 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 (<37 nM) and were able to near completely inhibit parasite replication in the spleen while also demonstrating 48 ± 48 and 56 ± 23% inhibition of the parasite replication in the liver, respectively, compared to oral miltefosine after daily administration over 10 days. The proposed platform technology can be used to elicit a range of cost-effective and orally bioavailable noninvasive formulations for a range of antiparasitic and infectious disease drugs that are needed for closing the global health innovation gap.

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