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Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action that have been widely employed in antimycotic therapy. In this work, microparticles containing a high dose of AmB and ITR (20, 30, and 40% total antifungal drug loading) were engineered for use in dry powder inhalers (DPIs) with an aim to improve the pharmacological effect, thereby enhancing the existing off-label choices for pulmonary administration. A Design of Experiment (DoE) approach was employed to prepare DPI formulations consisting of AmB-ITR encapsulated within \u03b3-cyclodextrin (\u03b3-CD) alongside functional excipients, such as mannitol and leucine. In vitro deposition indicated a favourable lung deposition pattern characterised by an upper ITR distribution (mass median aerodynamic diameter (MMAD) ~ 6 \u00b5m) along with a lower AmB deposition (MMAD ~ 3 \u00b5m). This offers significant advantages for treating fungal infections, not only in the lung parenchyma but also in the upper respiratory tract, considering that Aspergillus spp. can cause upper and lower airway disorders. The in vitro deposition profile of ITR and larger MMAD was related to the higher unencapsulated crystalline fraction of the drug, which may be altered using a higher concentration of \u03b3-CD.<\/jats:p>","DOI":"10.3390\/pharmaceutics15112601","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T01:54:30Z","timestamp":1699408470000},"page":"2601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Co-Delivery of a High Dose of Amphotericin B and Itraconazole by Means of a Dry Powder Inhaler Formulation for the Treatment of Severe Fungal Pulmonary Infections"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4937-7003","authenticated-orcid":false,"given":"Salom\u00e9 S.","family":"Celi","sequence":"first","affiliation":[{"name":"Departamento de Farmacia Gal\u00e9nica y Tecnolog\u00eda Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Gal\u00e9nica y Tecnolog\u00eda Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreina I.","family":"Afonso-Urich","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Gal\u00e9nica y Tecnolog\u00eda Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Paloma","family":"Ballesteros","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Gal\u00e9nica y Tecnolog\u00eda Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"},{"name":"Facultad de Farmacia, Instituto Universitario de Farmacia Industrial, Universidad Complutense de Madrid, Plaza de Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5093-9786","authenticated-orcid":false,"given":"Anne Marie","family":"Healy","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, D02 PN40 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-8420","authenticated-orcid":false,"given":"Dolores R.","family":"Serrano","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Gal\u00e9nica y Tecnolog\u00eda Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"},{"name":"Facultad de Farmacia, Instituto Universitario de Farmacia Industrial, Universidad Complutense de Madrid, Plaza de Ram\u00f3n y Cajal s\/n, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122788","DOI":"10.1016\/j.ijpharm.2023.122788","article-title":"Targeting lung macrophages for fungal and parasitic pulmonary infections with innovative amphotericin B dry powder inhalers","volume":"635","author":"Marchand","year":"2023","journal-title":"Int. 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