Oral administration of buparvaquone nanostructured lipid carrier enables in vivo activity against Leishmania infantum

Leishmaniasis, a neglected tropical disease, is prevalent in 98 countries with the occurrence of 1.3 million new cases annually. The conventional therapy for visceral leishmaniasis requires hospitalization due to the severe adverse effects of the drugs, which are administered parenterally. Buparvaquone (BPQ) showed in vitro activity against leishmania parasites; nevertheless, it has failed in in vivo tests due to its low aqueous solubility. Though, lipid nanoparticles can overcome this holdback.

Highlights

Miltefosine is the only drug approved for leishmaniasis oral treatment.

We developed buparvaquone-NLC aiming to contribute it as a therapeutic option.

Buparvaquone dissolution was improved in simulated intestinal fluids.

Parasite burden reduction was higher than 80% in the liver.

Our work brings a new perspective for leishmaniasis oral treatment.

In this study we tested the hypothesis whether BPQ-NLC shows in vivo activity against L. infantum. Two optimized formulations were prepared (V1: 173.9 ± 1.6 nm, 0.5 mg of BPQ/mL; V2: 232.4 ± 1.6 nm, 1.3 mg of BPQ/mL), both showed increased solubility up to 73.00-fold, and dissolution up to 83.29%, while for the free drug it was only 2.89%. Cytotoxicity test showed their biocompatibility (CC50 >554.4 µM). Besides, the V1 dose of 0.3 mg/kg/day for 10 days reduced the parasite burden in 83.4% ±18.2% (p <0.05) in the liver. BPQ-NLC showed similar leishmanicidal activity compared to miltefosine. Therefore, BPQ-NLC is a promising addition to the limited therapeutic arsenal suitable for leishmaniasis oral administration treatment.

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Materials: Softisan® 154 was kindly donated by CREMER Oleo Division (Germany), glyceryl monocaprylate, medium-chain triglycerides (MCT) were kindly donated by Abitec (USA). Kolliphor® P188 was acquired from BASF (Germany) and Tween 80 from Millipore Sigma (Germany). Buparvaquone (purity 99.5%) was donated by Shaanxi King Stone (Xian, China). Buparvaquone analytical standard Vetranal Supelco was purchased from Merck Sigma (Germany). Culture media M199 and RPMI 1640, and MTT reagent (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) were purchased from Merck Sigma (Germany). Pancreatin (4X USP activity) was purchased from Merck Sigma (Germany). Purified water was obtained by a Milli-Q system from Merck Millipore (Germany). Organic solvents were HPLC grade, and all other chemicals used were of the at least analytical grade.

Article information: Lis Marie Monteiro, Raimar Löbenberg, Eduardo José Barbosa, Gabriel Lima Barros de Araujo, Paula Keiko Sato, Edite Kanashiro, Raissa H. de Araújo Eliodoro, Mussya Rocha, Vera Lúcia Teixeira de Freitas, Nikoletta Fotaki, Nádia Araci Bou-Chacra, Oral administration of buparvaquone nanostructured lipid carrier enables in vivo activity against Leishmania infantum, European Journal of Pharmaceutical Sciences, 2021. https://doi.org/10.1016/j.ejps.2021.106097.