RT Journal Article
T1 Can Amphotericin B and Itraconazole be co-delivered orally?Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
A1 Fernández García, Raquel
A1 Walsh, David
A1 O'Connell, Peter
A1 Slowing Barillas, Karla Verónica
A1 Raposo González, Rafaela
A1 Ballesteros Papantonakis, María De La Paloma
A1 JImenez-Cebrian, Aurora
A1 Chamorro Sancho, Manuel
A1 Bolas Fernández, Francisco
A1 Healy, Anne Marie
A1 Serrano López, Dolores Remedios
AB The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi designs of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19-30.48 mm), C. parapsilosis (26.38-27.84 mm) and C. krusei (11.48-17.92 mm. AmB release was prolonged from 3 to 24 hours when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of F2), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, including a decrease in blood urea nitrogen (~17 g/dl) and alanine aminotransferase (<30 U/l) and an increase in the levels of bilirubin (~0.2 mg/dl) and alkaline phosphatase (<80 U/l), which could be indicative of a liver failure. Once-daily regimen for 10 days can be a promising therapy.
PB Elsevier
SN 0939-6411
YR 2023
FD 2023
LK https://hdl.handle.net/20.500.14352/72850
UL https://hdl.handle.net/20.500.14352/72850
LA eng
NO Fernández García, R., Walsh, D., O´Conell, P. et al. «Can Amphotericin B and Itraconazole Be Co-Delivered Orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses». European Journal of Pharmaceutics and Biopharmaceutics, vol. 183, febrero de 2023, pp. 74-91. DOI.org (Crossref), https://doi.org/10.1016/j.ejpb.2023.01.003.
NO Banco Santander
NO Science Foundation Ireland
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Unión Iberoamericana de Universidades
DS Docta Complutense
RD 4 abr 2025