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Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

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Abstract

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is seen with particular frequency in immunocompromised patients, and associated with high rates of mortality. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole have become accepted as first- and second-line therapy, respectively. However, triazoles are associated with issues of oral bioavailability, high liver metabolism, and/or drug–drug interactions, increasing the variability of systemic concentrations. As a way to overcome these issues, inhalation appears to be a promising route for delivery of triazoles for prophylactic or curative therapy in IPA. Indeed, pulmonary drug delivery drastically increases the drug in situ while decreasing the systemic exposure, thereby limiting drug metabolization, side effects, and drug–drug interactions. The development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but with significant different solubility. In this review, we describe the most advanced and promising pharmaceutical developments for voriconazole and itraconazole.

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Abbreviations

AI90H:

amorphous itraconazole with Phospholipon® 90H

AI:

amorphous itraconazole

AIN:

amorphous itraconazole nanoparticle-based aggregates

AIP1:

itraconazole nanoparticle-based aggregates with polysorbate 20

AIP2:

itraconazole nanoparticle-based aggregates with polysorbate 80 and Poloxamer 407

AmphB-deox:

amphotericin B deoxycholate

AUC:

area under the curve

Cmax :

maximum peak concentration

CI:

crystalline itraconazole

CIN:

crystalline itraconazole nanoparticles

CIP:

crystalline itraconazole nanoparticle-based aggregates

dae:

aerodynamic diameter

DPI:

dry powder inhaler

FPF:

fine particle fraction

HPβCD:

hydroxypropyl -β-cyclodextrin

ICD:

amorphous itraconazole-based inclusion complex with HPβCD

IPA:

invasive pulmonary aspergillosis

IPEC:

International Pharmaceutical Excipients Council

ITZ:

itraconazole

MIC:

minimum inhibitory concentration

MMAD:

median mass aerodynamic diameter

PEG:

polyethylene glycol

PLGA:

poly(lactide-co-glycolide)

Seq:

saturation solubility equilibrium

SeβCD:

sulfobutyl ether-β-cyclodextrin

t1/2 :

terminal half-life

VCZ:

voriconazole

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Acknowledgments

The authors would like to thank Dr. PO Gubbins of the University of Missouri–Kansas City for his review of the manuscript.

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Conflict of Interest

R. Merlos received a PhD grant from "Région Wallonne" for a subcontracting project with Galephar Pharmaceutical and Université Libre de Bruxelles.

K. Amighi and N. Wauthoz both declare no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles, Boulevard du Triomphe, CP207 Campus de la Plaine, 1050, Brussels, Belgium

    Romain Merlos, Karim Amighi & Nathalie Wauthoz

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  1. Romain Merlos
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Merlos, R., Amighi, K. & Wauthoz, N. Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis. Curr Fungal Infect Rep 8, 331–342 (2014). https://doi.org/10.1007/s12281-014-0199-5

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