Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis

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.

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

“…Although not approved in the U.S. or Canada, amorolfine is approved and commonly used topically to treat dermatophyte infections (tinea capitis, tinea pedis, and onchomycosis) in Australia and the United Kingdom [84,85]. The benzylamine antifungal, butenafine, is approved by the FDA for topical treatment of tinea pedis and has also been found to be effective against Leishmania and a variety of ocular pathogenic fungal infections [86][87][88]. The activity of trifluoroacetic acid-a strong carboxylic acid that is commonly utilized as a solvent and an ion pairing agent in organic reactions-presumably stems from the decrease in pH to a level that is toxic to the amoebae [89].…”

Nanoemulsified Butenafine for Enhanced Performance against Experimental Cutaneous Leishmaniasis

“…Although butenafine is active on Leishmania sp. parasites [ 41 ], there are not available clinical formulations to support its topical use for the treatment of cutaneous leishmaniasis. Thus, this study demonstrated for the first time that applying butenafine in the infected skin of BALB/c mice decreased the size of the skin lesion as well as parasitism.…”

Design of Non-Haemolytic Nanoemulsions for Intravenous Administration of Hydrophobic APIs

“…Many types of nanoparticles administered by various administration routes were brought into commercial products [2,3], for instance aprepitant (Emend ® ) by oral administration, amphotericin B (Ambisome ® ) by intravenous (IV) route, or leuprolide acetate (Eligard ® ) by the subcutaneous one [4][5][6]. The interest of nanomedicines is clearly established to permit the therapeutic valorisation of drugs [7,8], new or in a repurposing approach [9,10]. It can be also considered in the drug-discovery step to permit preclinical studies of leads [1].…”