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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
amorphous itraconazole with Phospholipon® 90H
amorphous itraconazole nanoparticle-based aggregates
itraconazole nanoparticle-based aggregates with polysorbate 20
itraconazole nanoparticle-based aggregates with polysorbate 80 and Poloxamer 407
amphotericin B deoxycholate
area under the curve
- Cmax :
maximum peak concentration
crystalline itraconazole nanoparticles
crystalline itraconazole nanoparticle-based aggregates
dry powder inhaler
fine particle fraction
amorphous itraconazole-based inclusion complex with HPβCD
invasive pulmonary aspergillosis
International Pharmaceutical Excipients Council
minimum inhibitory concentration
median mass aerodynamic diameter
saturation solubility equilibrium
- t1/2 :
Papers of particular interest, published recently, have been highlighted as: • Of importance
Maschmeyer G, Jaas A, Cornely OA. Invasive Aspergillosis—epidemiology, diagnosis and management in immunocompromised patients. Drugs. 2007;67(11):1567–601.
Thompson GR, Patterson T. Pulmonary aspergillosis. Semin Respir Crit Care Med. 2008;29:103–10.
Lass-Flörl C. Triazole antifungal agents in invasive fungal infections, a comparative review. Drugs. 2011;71(18):2405–19.
Díaz Sánchez C, López VA. Pulmonary Aspergillosis. Arch Bronconeumol. 2004;40(3):114–22.
Morris G, Kokki MH, Anderson K, Richardson MD. Sampling of Aspergillus spores in air. J Hosp Infect. 2000;44:81–92.
Latgé JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12(2):310–50.
Dagenais TRT, Keller NP. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin Microbiol Rev. 2009;22:447–65.
McConville JT, Wiederhold NP. Invasive pulmonary aspergillosis: therapeutic and prophylactic strategies. In: Williams III RO, Taft DR, McConville JT, editors. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, Informa Healthcare, vol. 172. 2008. p. 53–80.
Hasenberg M et al. Phagocyte responses towards Aspergillus fumigatus. Int J Med Microbiol. 2011;301:436–44.
Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest J. 2002;121(6):1988–99.
Amchentsev A, Kurugundla N, Saleh AG. Aspergillus-related lung disease. Respir Med CME. 2008;1:205–15.
Stevens DA et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis. 2000;30:696–709.
Sheppard DC. Molecular mechanism of Aspergillus fumigatus adherence to ghost constituents. Curr Opin Microbiol. 2011;14:375–9.
Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis: State of the art. Am J Respir Crit Care Med. 2006;173:707–17.
Traunmüller F et al. Efficacy and safety of current drug therapies for invasive aspergillosis. Pharmacology. 2011;88:213–24.
Walsh TJ et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–60.
Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408–15.
Yang W, Wiederhold NP, Williams RO. Drug delivery strategies for improved azole antifungal action. Expert Opin Drug Deliv. 2008;5(11):199–1216.
Perfect JR, Dodds Ashley E, Drew R. Design of aerosolized amphotericin B formulation for prophylaxis trials among lung transplant recipients. Clin Infect Dis. 2004;39:207–10.
Onoue S, Misaka S, Kawabata Y, Yamada S. New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy. Expert Opin Drug Deliv. 2009;6:793–811.
Ibrahim BM, Tsifansky MD, Yang Y, Yeo Y. Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease. Expert Opin Drug Deliv. 2011;8:451–66.
Sears MR, Lotvall J. Past, present and future beta-2-adrenoreceptor agonist in asthma management. Respir Med. 2005;99:152–70.
Smyth HDC, Saleem I, Donovan M, Verschraegen CF. Pulmonary delivery of anti-cancer agents. In: Williams III RO, Taft DR, McConville JT, editors. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, Informa Healthcare, vol. 172. 2008. p. 81–112.
Depreter F, Pilcer G, Amighi K. Inhaled proteins: challenges and perspectives. Int J Pharm. 2013;447:251–80.
Carvalho TC, Peters JI, Williams III RO. Influence of particle size on regional lung deposition—What evidence is there? Int J Pharm. 2011;406:1–10.
Hofmann W. Modelling inhaled particle deposition in the human lung—a review. J Aerosol Sci. 2011;42:693–724.
El-Sherbiny IM, Villanueva DG, Herrera D, Smyth HDC. Overcoming lung clearance mechanisms for controlled release drug delivery. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 101–126.
Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. J Clin Pharmacol. 2003;56:588–99.
O’Donnel P, Smyth HDC. Macro- and microstructure of the airways fro drug delivery. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 1–19.
Evans M. C, Koo JS. Airway mucus: the good, the bad, the sticky. Pharmacol Ther. 2009;121:332–48.
Harmsen AG, Muggenburg BA, Snipes MB, Bice DE. The role of macrophages in particle translocation from lungs to lymph nodes. Science. 1985;230:1277–80.
Wang YB, Watts AB, Peters JI, Williams III RO. The impact of pulmonary disease on the fate of inhaled medicines—a review. Int J Pharm. 2014;461:112–28.
Chono S, Tanino T, Seki T, Morimoto K. Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated to liposomes. J Drug Target. 2006;14:557–66.
Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97:382–7.
Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale and clinical applications, existing and potential. Int J Nanomedicine. 2006;1(3):297–315.
Olsson B, Bondesson E, Borgström L, et al. Pulmonary drug metabolism, clearance and absorption. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 36–50.
Wiedmann TS, Bhatia R, Wattenberg LW. Drug solubilisation in lung surfactant. J Control Release. 2000;65:43–7.
Patton JS. Mechanism of macromolecule absorption by the lungs. Adv Drug Deliv Rev. 1996;19:3–36.
Patton JS, Brain JD, Davies LA, et al. The particle has landed—characterizing the fate of inhaled pharmaceuticals. J Aerosol Med Pulm Drug Deliv. 2010;23(2):71–87.
Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392:1–19.
Williams HD et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499. Performed an overview of different strategies for poorly water-soluble drug.
Tolman JA, Williams III RO. Advances in the pulmonary delivery of poorly water-soluble drugs: influence of solubilisation on pharmacokinetic properties. Drug Dev Ind Pharm. 2010;36(1):1–30.
Ruge CA, Kirch J, Lehr CM. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges. Lancet Respir Med. 2013;1:402–13.
US Food and Drug Administration. 2014. http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=scogsListing&displayAll=true. Accessed June 2014.
Buggins TR, Dickinson PA, Taylor G. The effects of pharmaceutical excipients on drug deposition. Adv Drug Deliv Rev. 2007;59:1482–503.
US Food and Drug Administration. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073395.pdf. Accessed June 2014.
Baldrick P. Pharmaceutical excipient development: the need for preclinical guidance. Regul Toxicol Pharmacol. 2000;32:210–8.
Baldrick P. Pharmaceutical excipient development: a preclinical challenge. In: Katdare A, Chaubal MV. Excipient Development for Pharmaceutical Biotechnology and Drug Delivery System. Informa Healthcare; 2006. pp. 15–36.
Baldrick P. The safety of chitosan as a pharmaceutical excipient. Regul Toxicol Pharmacol. 2010;56:290–9.
Islam N, Gladki E. Dry powder inhalers (DPIs)—a review of device reliability and innovation. Int J Pharm. 2008;360:1–11.
Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence based guidelines. Chest. 2005;127:335–71.
Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377:1032–45.
Tolman JA et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm. 2009;72:199–205.
Beinborn NA, Du J, Wiederhold NP, Smyth HDC, Williams III RO. Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice. Eur J Pharm Biopharm. 2012;81(3):600–8.
Sinha B, Mukherjee B, Pattnaik G. Poly-lactide-co-glycolide nanoparticles containing voriconazole for pulmonary delivery: in vitro and in vivo study. Nanomedicine. 2013;9:94–104.
McConville JT et al. Targeted high lung concentration of itraconazole using nebulized dispersions in a murine model. Pharm Res. 2006;23(5):901–11.
Vaughn JM et al. Murine airway histology and intracellular uptake of inhaled amorphous itraconazole. Int J Pharm. 2007;38:219–24.
Yang W et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm. 2007;361:177–88.
Yang W et al. In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution. Eur J Pharm Sci. 2010;39:336–47.
Yang W, Johnston KP, Williams III RO. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats. Eur J Pharm Biopharm. 2010;75:33–41.
Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. Solid dispersion of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. Int J Pharm. 2012;428:103–13.
Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis. Pharm Res. 2012;29:2845–59.
Duret C et al. Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention. Eur J Pharm Biopharm. 2014;86:46–54. Study demonstrating the various steps of the characterization of a formulation intended to be administered by the pulmonary route from in vitro point of view to pharmacokinetic study on mice.
Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New inhalation-optimized itraconazole nanoparticle-based dry powders fro the treatment of invasive pulmonary aspergillosis. Int J Nanomedicine. 2012;7:5475–89.
Rundfeldt C, Steckel H, Scherliess H, Wyska E, Wlaz P. Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis. Eur J Pharm Biopharm. 2013;83:44–53.
Pardeike J et al. Development of an itraconazole-loaded nanostructured lipid carrier (NLC) formulation for pulmonary application. Int J Pharm. 2011;419:329–38.
Moazeni E et al. Preparation and evaluation of inhalable itraconazole chitosan based polymeric micelles. Daru. 2012;20:85.
Jafarinejad S et al. Development of chitosan-based nanoparticles for pulmonary delivery of itraconazole as dry powder formulation. Powder Technol. 2012;222:65–70.
Tolman JA et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2009;53(6):2613–5.
Vaughn JM et al. Single dose and multiple dose studies of itraconazole nanoparticles. Eur J Pharm Biopharm. 2006;63:95–102.
Alvarez CA et al. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis. J Infect. 2007;55:68–74.
Hoeben BJ et al. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50(4):1552–4.
Duret C, Wauthoz N, Rosière R, Sebti T, Vanderbist F, Amighi K. Prophylactic efficacy of inhaled itraconazole-mannitol dried solid dispersion against invasive pulmonary aspergillosis. Europe: Respiratory drug delivery; 2013.
US Food and Drug Administration. 2014. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128219.htm. Accessed June 2014.
Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother. 2008;61:17–25.
Pascual A et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46:201–11.
Vfend® characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000387/WC500049756.pdf. Accessed June 2014.
US Food and Drug Administration. 2014. http://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm. Accessed June 2014.
O’Neil MJ. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th ed. New Jersey: Merck; 2006.
Sporanox® characteristics. bijsluiters.fagg-afmps.be/DownloadLeafletServlet?id=123908. Accessed June 2014.
Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother. 2005;56:17–22.
De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61:27–37.
Wauthoz N, Amighi K. Phospholipids in pulmonary drug delivery. Eur J Lipid Sci Technol. 2014. doi:10.1002/ejlt.201300368.
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.
The findings and conclusions in this report are those of the author(s).
About this article
Cite this article
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
- Fungal infection
- Pulmonary delivery
- Dry powder inhaler
- Dry powder for inhalation
- Solid dispersion
- Controlled-release drug delivery