Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis

Adriana Bezerra-Souza,Dolores R Serrano,Luiz Felipe Passero,Francisco Bolas-Fernandez,Raquel Fernandez-Garcia,Aikaterini Lalatsa,Marcia Dalastra Laurenti,Gabriela F Rodrigues

doi:10.3390/pharmaceutics11070353

Abstract

Leishmaniasis is a neglected tropical disease affecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse effects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new effective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-effective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose <10°) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-effective and readily scalable repurposed medicine for VL.

Highlights

Leishmaniasis is an infectious disease caused by parasites belonging to the Leishmania genus
The solubility of butenafine was tested in four different excipients (Peceol, Capryol 90, Labrasol, and Labrafil M1944CS) that are commonly utilized in the development of lipid-based formulations and have been shown to possess efficacy against leishmaniasis [22] (Table 1)
Due to the low miscibility between Peceol and Labrafil, and the higher butenafine solubility in Peceol, Peceol was chosen as the oil phase to be combined with Capryol and Labrasol for the pseudo-ternary diagram and identification of the optimal composition (Table 2) able to yield microemulsions upon aqueous dilutions

Summary

Introduction

Leishmaniasis is an infectious disease caused by parasites belonging to the Leishmania genus. Leishmania parasites are transmitted by insect vectors from the genus Lutzomyia sp. In the New World and Phlebotomus sp. In the Old World [1,2]. Leishmaniasis presents in the cutaneous (CL) and visceral (VL) leishmaniasis forms, depending on the type of host immune response and infecting parasite species [3,4]. In the New World, parasites of the subgenus Vianna cause only CL and mucocutanoues leishmaniasis (MCL) while parasites of the subgenus Leishmania are responsible for CL and VL [5]. VL is a chronic disease caused by L. VL is a chronic disease caused by L. (L.) infantum and L. (L.) donovani species [6,7,8] residing in host macrophages, mainly from spleen, liver, bone marrow, and lymph nodes, and is characterized by prolonged fever, hepatosplenomegaly, lymphadenopathy, anemia with leukopenia, hypergammaglobulinemia and hypoalbuminemia, weight loss, edema, and a debilitating state leading to weakening and death if untreated [6]

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