Can amphotericin B and itraconazole be co-delivered orally? Tailoring oral fixed-dose combination coated granules for systemic mycoses

Fernández-García, Raquel; Walsh, D.; O’Connell, P.; Slowing, Karla; Raposo, Rafaela; Ballesteros, M.; Jiménez-Cebrián, Aurora; Chamorro-Sancho, Manuel  J.; Bolás‐Fernández, F.; Healy, Anne Marie; Serrano, Dolores R.

doi:10.1016/j.ejpb.2023.01.003

Cited by 1 publication

(3 citation statements)

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“…A DSC Q200 (TA Instruments ® , New Castle, DE, USA) was utilised with nitrogen as the purge gas. A temperature range of 0-200 • C was used to scan the formulation (2-3 mg) previously placed in aluminium pans with a modulation rate of 0.8 • C every 60 s at 5 • C/min [16]. Thermograms of AmB and ITR were also acquired for comparison purposes.…”

Section: Modulated Temperature Differential Scanning Calorimetry (Mt-...mentioning

confidence: 99%

“…However, there is an increasing trend in AmB-resistant isolates of A. fumigatus [11,12]; hence, the use of fixed-dose combination products can be a useful approach to overcome this challenge [13][14][15]. Based on this premise, the pulmonary codelivery of AmB with itraconazole (ITR) can be an interesting strategy when considering their complementary mechanisms of action [16]. ITR is an antimycotic drug that belongs to the azoles group.…”

Section: Introductionmentioning

confidence: 99%

“…ITR is an antimycotic drug that belongs to the azoles group. This molecule blocks the ergosterol synthesis through a different mechanism of action, in which the inhibition of the lanosterol 14α-demethylase takes place [16,17]. Currently, ITR formulations are only available on the market for intravenous and oral administration, although a few attempts to achieve a suitable pulmonary delivery of ITR have also been investigated [18].…”

Section: Introductionmentioning

confidence: 99%

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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

Celi,

Fernández-García,

Afonso-Urich

et al. 2023

Pharmaceutics

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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.

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Section: Modulated Temperature Differential Scanning Calorimetry (Mt-...mentioning

confidence: 99%