New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis.
OBJECTIVE
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.


CONCLUSIONS
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.
Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Boulevard du Triomphe - CP207 Campus de la Plaine, 1050, Brussels, Belgium. cduret@ulb.ac.be
Christophe
C
Duret
Nathalie
N
Wauthoz
Thami
T
Sebti
Francis
F
Vanderbist
Karim
K
Amighi
D000280:Administration, Inhalation; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D017964:Itraconazole / Q000008:administration & dosage* / Q000737:chemistry*; D008353:Mannitol / Q000737:chemistry; D008855:Microscopy, Electron, Scanning / Q000379:methods; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry; D011208:Powders / Q000737:chemistry; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
D010743:Phospholipids; D011208:Powders; D012996:Solutions; D017964:Itraconazole; D008353:Mannitol