Cargando…

Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the orop...

Descripción completa

Detalles Bibliográficos
Autores principales: Serrano, Dolores R., Fernandez-Garcia, Raquel, Mele, Marta, Healy, Anne Marie, Lalatsa, Aikaterini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723921/
https://www.ncbi.nlm.nih.gov/pubmed/31374879
http://dx.doi.org/10.3390/pharmaceutics11080369
_version_ 1783448883116900352
author Serrano, Dolores R.
Fernandez-Garcia, Raquel
Mele, Marta
Healy, Anne Marie
Lalatsa, Aikaterini
author_facet Serrano, Dolores R.
Fernandez-Garcia, Raquel
Mele, Marta
Healy, Anne Marie
Lalatsa, Aikaterini
author_sort Serrano, Dolores R.
collection PubMed
description Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.
format Online
Article
Text
id pubmed-6723921
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-67239212019-09-10 Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis Serrano, Dolores R. Fernandez-Garcia, Raquel Mele, Marta Healy, Anne Marie Lalatsa, Aikaterini Pharmaceutics Article Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis. MDPI 2019-08-01 /pmc/articles/PMC6723921/ /pubmed/31374879 http://dx.doi.org/10.3390/pharmaceutics11080369 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Serrano, Dolores R.
Fernandez-Garcia, Raquel
Mele, Marta
Healy, Anne Marie
Lalatsa, Aikaterini
Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title_full Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title_fullStr Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title_full_unstemmed Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title_short Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis
title_sort designing fast-dissolving orodispersible films of amphotericin b for oropharyngeal candidiasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723921/
https://www.ncbi.nlm.nih.gov/pubmed/31374879
http://dx.doi.org/10.3390/pharmaceutics11080369
work_keys_str_mv AT serranodoloresr designingfastdissolvingorodispersiblefilmsofamphotericinbfororopharyngealcandidiasis
AT fernandezgarciaraquel designingfastdissolvingorodispersiblefilmsofamphotericinbfororopharyngealcandidiasis
AT melemarta designingfastdissolvingorodispersiblefilmsofamphotericinbfororopharyngealcandidiasis
AT healyannemarie designingfastdissolvingorodispersiblefilmsofamphotericinbfororopharyngealcandidiasis
AT lalatsaaikaterini designingfastdissolvingorodispersiblefilmsofamphotericinbfororopharyngealcandidiasis