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

Author:

Celi Salomé S.1ORCID,Fernández-García Raquel1,Afonso-Urich Andreina I.1,Ballesteros M. Paloma12,Healy Anne Marie3ORCID,Serrano Dolores R.12ORCID

Affiliation:

1. Departamento de Farmacia Galénica y Tecnología Alimentaria, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain

2. Facultad de Farmacia, Instituto Universitario de Farmacia Industrial, Universidad Complutense de Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain

3. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, D02 PN40 Dublin, Ireland

Abstract

Over the past few decades, there has been a considerable rise in the incidence and prevalence of pulmonary fungal infections, creating a global health problem due to a lack of antifungal therapies specifically designed for pulmonary administration. 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 γ-cyclodextrin (γ-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 µm) along with a lower AmB deposition (MMAD ~ 3 µm). 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 γ-CD.

Funder

Universidad Complutense de Madrid

Ministry of Science and Innovation

Science Foundation Ireland

Publisher

MDPI AG

Subject

Pharmaceutical Science

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