Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis
Adriana Bezerra-Souza,
Raquel Fernandez-Garcia,
Gabriela F. Rodrigues,
Francisco Bolas-Fernandez,
Marcia Dalastra Laurenti,
Luiz Felipe Passero,
Aikaterini Lalatsa,
Dolores R. Serrano
Affiliations
Adriana Bezerra-Souza
Laboratory of Pathology of Infectious Diseases (LIM-50), Medical School, University of São Paulo, Avenida Dr. Arnaldo 455, 01246903 Cerqueira César, SP, Brazil
Raquel Fernandez-Garcia
Departament of Pharmaceutics and Food Technology and Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense, Avenida Complutense, 28040 Madrid, Spain
Gabriela F. Rodrigues
Laboratory of Pathology of Infectious Diseases (LIM-50), Medical School, University of São Paulo, Avenida Dr. Arnaldo 455, 01246903 Cerqueira César, SP, Brazil
Francisco Bolas-Fernandez
Departament of Microbiology and Parasitology, School of Pharmacy, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain
Marcia Dalastra Laurenti
Laboratory of Pathology of Infectious Diseases (LIM-50), Medical School, University of São Paulo, Avenida Dr. Arnaldo 455, 01246903 Cerqueira César, SP, Brazil
Luiz Felipe Passero
Laboratory of Pathology of Infectious Diseases (LIM-50), Medical School, University of São Paulo, Avenida Dr. Arnaldo 455, 01246903 Cerqueira César, SP, Brazil
Aikaterini Lalatsa
Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2 DT, UK
Dolores R. Serrano
Departament of Pharmaceutics and Food Technology and Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense, Avenida Complutense, 28040 Madrid, Spain
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.
