Targeted Oral Fixed-Dose Combination of Amphotericin B-Miltefosine for Visceral Leishmaniasis

The incidence of visceral leishmaniasis (VL) remains a significant health threat in endemic countries. Fixed-dose combination (FDC) of amphotericin B (AmB) and miltefosine (MLT) is a promising strategy for treating VL, but the parenteral administration of AmB leads to severe side effects, limiting i...

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Detalhes bibliográficos
Autores: Fernández-García, Raquel, Walsh, David, O’Connell, Peter, Passero, Luiz Felipe D. [UNESP], de Jesus, Jéssica A. [UNESP], Laurenti, Marcia Dalastra, Dea-Ayuela, María Auxiliadora, Ballesteros, M. Paloma, Lalatsa, Aikaterini, Bolás-Fernández, Francisco, Healy, Anne Marie, Serrano, Dolores R.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:Brasil
Recursos:Universidade Estadual Paulista (UNESP)
Repositorio:Repositório Institucional da UNESP
Idioma:inglés
OAI Identifier:oai:repositorio.unesp.br:11449/297001
Acesso em linha:http://dx.doi.org/10.1021/acs.molpharmaceut.4c01133
https://hdl.handle.net/11449/297001
Access Level:acceso abierto
Palavra-chave:amphotericin B
coating
fixed-dose combination
miltefosine
oral delivery
visceral leishmaniasis
Descrição
Resumo:The incidence of visceral leishmaniasis (VL) remains a significant health threat in endemic countries. Fixed-dose combination (FDC) of amphotericin B (AmB) and miltefosine (MLT) is a promising strategy for treating VL, but the parenteral administration of AmB leads to severe side effects, limiting its use in clinical practice. Here, we developed novel FDC granules combining AmB in the core with a MLT coating using wet granulation followed by the fluidized bed technology. The granules maintained the crystalline structure of AmB throughout manufacturing, achieving an AmB loading of ∼20%. The MLT coating layer effectively sustained AmB release from 3 to 24 h following Korsmeyer-Peppas kinetics. The formulation demonstrated remarkable stability, maintaining >90% drug content for over a year at both 4 °C and room temperature under desiccated conditions. In vivo efficacy studies in Leishmania infantum-infected hamsters showed 65-80% reduction in parasite burden in spleen and liver, respectively, suggesting potential as an oral alternative to current VL treatments. Uncoated and coated granules demonstrated comparable performance in key aspects, including in vivo efficacy and long-term stability.

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