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Current Fungal Infection Reports

, Volume 8, Issue 4, pp 331–342 | Cite as

Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

  • Romain Merlos
  • Karim Amighi
  • Nathalie WauthozEmail author
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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.

Keywords

Aerosol Antifungal Aspergillosis Fungal infection Pulmonary delivery Dry powder inhaler Dry powder for inhalation Nebulizer Nebulization Cyclodextrin Nanoparticle Solid dispersion Controlled-release drug delivery 

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

Notes

Acknowledgments

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

Compliance with Ethics Guidelines

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.

Human and Animal Rights and Informed Consent

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

Disclaimer

The findings and conclusions in this report are those of the author(s).

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of PharmacyUniversité Libre de BruxellesBrusselsBelgium

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