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New Respirable and Fast Dissolving Itraconazole Dry Powder Composition for the Treatment of Invasive Pulmonary Aspergillosis

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ABSTRACT

Purpose

Novel itraconazole (ITZ)-based dry powders for inhalation (DPI) were optimized for aerodynamic and dissolution properties and contained excipients that are acceptable for inhalation.

Methods

The DPI were produced by spray drying solutions. The drug content, crystallinity state, and morphological evaluation of the dry powders were determined by high performance liquid chromatography, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, respectively. A particle size analysis was conducted using laser light scattering. The aerodynamic behaviors of the powders were characterized by impaction tests. ITZ dissolution rates were evaluated using a dissolution method adapted to inhaled products.

Results

The DPI presented very high fine particle fractions that ranged from 46.9% to 67.0% of the nominal dose. The formulations showed very fast dissolution rates compared to unformulated crystalline ITZ with the possibility of modulating the dissolution rate by varying the quantity of phospholipids (PL) incorporated. ITZ remained amorphous while the mannitol was crystalline. The α, β and δ-mannitol polymorph ratios varied depending on the formulation compositions.

Conclusion

This formulation strategy could be an attractive alternative for treating invasive pulmonary aspergillosis. The ITZ and PL content are key characteristics because of their influence on the dissolution rate and aerosol performance.

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Abbreviations

API:

active pharmaceutical ingredient

CI:

Carr’s index

dae :

aerodynamic diameter

DPI(s):

dry powder(s) for inhalation

ED:

emitted dose

FDA:

Food and Drug Administration

FPD:

fine particle dose

FPF:

fine particle fraction

IA:

invasive aspergillosis

IC:

immunocompromised

ICDD:

International Center for Diffraction Data

ITZ:

itraconazole

IV:

intravenous

MIC:

minimal inhibitory concentration

MsLI:

multi-stage liquid impactor

MTDSC:

modulated temperature differential scanning calorimetry

NGI:

next generation impactor

PL:

phospholipids

PSD:

particle size distribution

PXRD:

powder X-ray diffraction

RIR:

reference intensity ratio

RPM:

round per minute

SD:

spray dried

SEM:

scanning electron microscopy

TGA:

thermogravimetric analysis

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Authors and Affiliations

  1. Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Boulevard du Triomphe - CP207 Campus de la Plaine, 1050, Brussels, Belgium

    Christophe Duret, Nathalie Wauthoz & Karim Amighi

  2. Laboratoires SMB S.A., 26-28 Rue de la Pastorale, 1080, Brussels, Belgium

    Thami Sebti & Francis Vanderbist

Authors
  1. Christophe Duret
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  2. Nathalie Wauthoz
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  3. Thami Sebti
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  4. Francis Vanderbist
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  5. Karim Amighi
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Correspondence to Christophe Duret.

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Duret, C., Wauthoz, N., Sebti, T. et al. New Respirable and Fast Dissolving Itraconazole Dry Powder Composition for the Treatment of Invasive Pulmonary Aspergillosis. Pharm Res 29, 2845–2859 (2012). https://doi.org/10.1007/s11095-012-0779-4

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  • DOI: https://doi.org/10.1007/s11095-012-0779-4

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