Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses

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 th...

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Autores: Fernández García, Raquel, Walsh, David, O'Connell, Peter, Slowing Barillas, Karla Verónica, Raposo González, Rafaela, Ballesteros Papantonakis, María De La Paloma, JImenez-Cebrian, Aurora, Chamorro Sancho, Manuel, Bolas Fernández, Francisco, Healy, Anne Marie, Serrano López, Dolores Remedios
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/72850
Acceso en línea:https://hdl.handle.net/20.500.14352/72850
Access Level:acceso abierto
Palabra clave:663/665
Oral delivery
Amphotericin B
Fixed-dose combination
Granules
Spray-coating
Itraconazole
Quality by design
Antifungal therapy
Azoles
Candida spp
Tecnología de los alimentos
3309 Tecnología de Los Alimentos
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oai_identifier_str oai:docta.ucm.es:20.500.14352/72850
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spelling Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic MycosesFernández García, RaquelWalsh, DavidO'Connell, PeterSlowing Barillas, Karla VerónicaRaposo González, RafaelaBallesteros Papantonakis, María De La PalomaJImenez-Cebrian, AuroraChamorro Sancho, ManuelBolas Fernández, FranciscoHealy, Anne MarieSerrano López, Dolores Remedios663/665Oral deliveryAmphotericin BFixed-dose combinationGranulesSpray-coatingItraconazoleQuality by designAntifungal therapyAzolesCandida sppTecnología de los alimentos3309 Tecnología de Los AlimentosThe 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.ElsevierUniversidad Complutense de Madrid20232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/72850reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengPID2021-126310OA-I00 Not available Not availablePR26 16-20355 Not availableENF03 2017 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/728502026-06-02T12:44:21Z
dc.title.none.fl_str_mv Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
title Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
spellingShingle Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
Fernández García, Raquel
663/665
Oral delivery
Amphotericin B
Fixed-dose combination
Granules
Spray-coating
Itraconazole
Quality by design
Antifungal therapy
Azoles
Candida spp
Tecnología de los alimentos
3309 Tecnología de Los Alimentos
title_short Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
title_full Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
title_fullStr Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
title_full_unstemmed Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
title_sort Can Amphotericin B and Itraconazole be co-delivered orally? Tailoring Oral Fixed-Dose Combination Coated Granules for Systemic Mycoses
dc.creator.none.fl_str_mv Fernández García, Raquel
Walsh, David
O'Connell, Peter
Slowing Barillas, Karla Verónica
Raposo González, Rafaela
Ballesteros Papantonakis, María De La Paloma
JImenez-Cebrian, Aurora
Chamorro Sancho, Manuel
Bolas Fernández, Francisco
Healy, Anne Marie
Serrano López, Dolores Remedios
author Fernández García, Raquel
author_facet Fernández García, Raquel
Walsh, David
O'Connell, Peter
Slowing Barillas, Karla Verónica
Raposo González, Rafaela
Ballesteros Papantonakis, María De La Paloma
JImenez-Cebrian, Aurora
Chamorro Sancho, Manuel
Bolas Fernández, Francisco
Healy, Anne Marie
Serrano López, Dolores Remedios
author_role author
author2 Walsh, David
O'Connell, Peter
Slowing Barillas, Karla Verónica
Raposo González, Rafaela
Ballesteros Papantonakis, María De La Paloma
JImenez-Cebrian, Aurora
Chamorro Sancho, Manuel
Bolas Fernández, Francisco
Healy, Anne Marie
Serrano López, Dolores Remedios
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 663/665
Oral delivery
Amphotericin B
Fixed-dose combination
Granules
Spray-coating
Itraconazole
Quality by design
Antifungal therapy
Azoles
Candida spp
Tecnología de los alimentos
3309 Tecnología de Los Alimentos
topic 663/665
Oral delivery
Amphotericin B
Fixed-dose combination
Granules
Spray-coating
Itraconazole
Quality by design
Antifungal therapy
Azoles
Candida spp
Tecnología de los alimentos
3309 Tecnología de Los Alimentos
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/72850
url https://hdl.handle.net/20.500.14352/72850
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv PID2021-126310OA-I00 Not available Not available
PR26 16-20355 Not available
ENF03 2017 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-SinDerivadas 4.0 Internacional
https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-SinDerivadas 4.0 Internacional
https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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