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Targeted High Lung Concentrations of Itraconazole Using Nebulized Dispersions in a Murine Model

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Purpose

The purpose of this study was to investigate the delivery of itraconazole (ITZ) particles to a murine lung model by nebulization.

Methods

Three ITZ formulations were prepared and characterized in the dry state using contact angle, dissolution, X-ray powder diffraction, scanning electron microscopy, and Brunauer–Emmett–Teller surface area analysis. Aerodynamic particle size distributions and lung deposition studies in 14 outbred male ICR mice were performed using aqueous dispersions of all the formulations. A separate dosing uniformity study was also performed to qualify use of the chamber.

Results

All formulations had an aggregated particle size of approximately 30 μm in diameter. Two formulations showed that 80% of the drug dissolved in less than 5 min. The remaining ITZ formulation had a slower dissolution and the lowest total emitted dose from the nebulizer used. High concentrations of ITZ were shown to be present in the mouse lung during the lung deposition study, up to 16.8 ± 0.13 μg/g (± SE) were achieved. Concentrations of up to 0.76 ± 0.03 μg/g (± SE) could be maintained from the single nebulized dose for at least 24 h.

Conclusion

An effective method of targeted delivery of ITZ to the deep lung is presented that may be useful for the treatment and prevention of acute fungal infections.

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Abbreviations

AIP:

amorphous itraconazole powder

AIP-D:

amorphous itraconazole powder dispersion

API:

active pharmaceutical ingredient

AUC:

area under the curve

BCS:

Biopharmaceutical Classification System

BET:

Brunauer– Emmett–Teller

BMT:

bone marrow transplant

CIP:

crystalline itraconazole powder

CIP-D:

crystalline itraconazole powder dispersion

C max :

maximum concentration of drug

EPAS:

evaporative precipitation into aqueous solution

GSD:

geometric standard deviation

ITZ:

itraconazole

λ :

elimination rate constant of a noncompartmental analysis

MMAD:

mass median aerodynamic diameter

%FPF:

percent fine particle fraction

SEM:

scanning electron microscopy

SFL:

spray freezing into liquid

T 1/2 :

half-life of drug

T max :

time of maximum drug concentration

XRPD:

X-ray powder diffraction

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Acknowledgments

Acknowledgement for assistance in the in vivo study is given to Laura Najvar and John R. Graybill at The Division of Infectious Diseases at The University of Texas Health Science Center in San Antonio, Texas. The authors also acknowledge partial financial support from The Dow Chemical Company.

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Authors and Affiliations

  1. College of Pharmacy, The University of Texas at Austin, Pharmaceutics PHR 4.214, 2409 W. University Avenue, Austin, Texas, 78712-1074, USA

    Jason T. McConville, Kirk A. Overhoff, Prapasri Sinswat, Jason M. Vaughn, Bradi L. Frei, David S. Burgess, Robert L. Talbert & Robert O. Williams III

  2. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA

    Bradi L. Frei, David S. Burgess & Robert L. Talbert

  3. Department of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA

    David S. Burgess, Robert L. Talbert & Jay I. Peters

  4. Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, 78712, USA

    Keith P. Johnston

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  1. Jason T. McConville
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  2. Kirk A. Overhoff
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  3. Prapasri Sinswat
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  9. Keith P. Johnston
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Correspondence to Jason T. McConville.

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McConville, J.T., Overhoff, K.A., Sinswat, P. et al. Targeted High Lung Concentrations of Itraconazole Using Nebulized Dispersions in a Murine Model. Pharm Res 23, 901–911 (2006). https://doi.org/10.1007/s11095-006-9904-6

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  • DOI: https://doi.org/10.1007/s11095-006-9904-6

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