title: New amphotericin B-gamma cyclodextrin formulation for topical use with synergistic activity against diverse fungal species and Leishmania spp.
abstract: Amphotericin B (AmB) has a broad antifungal and leishmanicidal activity with low incidence of clinical resistance. Its parenteral administration has high risk of nephrotoxicity that limits its use. In order to treat cutaneous infections, AmB topical administration is a safer therapy because of the low systemic absorption of the drug across mucous membranes. Moreover, in some developing countries both fungal topical infections and cutaneous leishmaniasis are an important health problem. The aim of this work is to formulate a topical amphotericin preparation and test its in vitro antifungal (against 11 different fungal species) and antileishmanial activity. γ-Cyclodextrin (γ-CD) was chosen to solubilise AmB. Furthermore, γ-CD has shown a synergistic effect on membrane destabilization with AmB. Topical novel formulations based on AmB-CD complex have exhibited greater antifungal activity (48%, 28% and 60% higher) when compared to AmB Neo-Sensitabs(®) disks, AmB dissolved in dimethyl sulfoxide (DMSO) and Clotrimazole(®) cream, respectively. Furthermore, AmB-CD methyl cellulose gel has shown significantly higher inhibition activity on biofilm formation, larger penetration through yeast biofilms and higher fungicidal activity on biofilm cells compared to AmB dissolved in DMSO. In addition, AmB-CD gel exhibited both high in vitro leishmanicidal efficacy with wider therapeutic index (between 2 and 8-fold higher than AmB deoxycholate depending on Leishmania spp.) and also in vivo activity in an experimental model of cutaneous leishmaniasis. These results illustrate the feasibility of a topical AmB formulation easy to prepare, physicochemically stable over 6 months, safe and effective against diverse fungal and parasitic cutaneous infections.
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain.
authors.forename: Helga K
authors.initials: HK
authors.lastname: Ruiz
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain.
authors.forename: Dolores R
authors.initials: DR
authors.lastname: Serrano
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, Moncada, Valencia 46113, Spain.
authors.forename: María Auxiliadora
authors.initials: MA
authors.lastname: Dea-Ayuela
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Bilbao-Ramos
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bolás-Fernández
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Torrado
authors.affiliation: Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal S/N, Madrid 28040, Spain. Electronic address: gloros@ucm.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: Molero
mesh_terms: D000287:Administration, Topical; D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D005782:Gels; D007891:Leishmania / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D010316:Particle Size; D063465:Skin Cream; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D047408:gamma-Cyclodextrins / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D005079:Excipients; D005782:Gels; D047408:gamma-Cyclodextrins; D000666:Amphotericin B; C023792:gamma-cyclodextrin
keywords: Amphotericin B; Antifungal activity; Antileishmanial efficacy; Biofilms; Cyclodextrin; Topical formulations