Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties.

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.

Duret C ，Wauthoz N ，Sebti T ，Vanderbist F ，Amighi K ... -  《-》

New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis.

Duret C ，Wauthoz N ，Sebti T ，Vanderbist F ，Amighi K ... -  《International Journal of Nanomedicine》

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

Duret C ，Wauthoz N ，Sebti T ，Vanderbist F ，Amighi K ... -  《-》

Enhanced pulmonary absorption of poorly soluble itraconazole by micronized cocrystal dry powder formulations.

Micronized cocrystal powders and amorphous spray-dried formulations were prepared and evaluated in vivo and in vitro as pulmonary absorption enhancement formulations of poorly soluble itraconazole (ITZ). ITZ cocrystals with succinic acid (SA) or l-tartaric acid (TA) with a particle size diameter of <2μm were successfully micronized using the jet-milling system. The cocrystal crystalline morphologies observed using scanning electron microscopy (SEM) suggested particle shapes that differed from those of the crystalline or spray-dried amorphous ITZ. The micronized ITZ cocrystal powders showed better intrinsic dissolution rate (IDR) and pulmonary absorption profile in rats than that of the amorphous spray-dried formulation and crystalline ITZ with comparable particle sizes. Specifically, in rat pharmacokinetic studies following pulmonary administration, micronized ITZ-SA and ITZ-TA cocrystals showed area under the curve from 0 to 8h (AUC0-8h) values approximately 24- and 19-fold higher than those of the crystalline ITZ and 2.0- and 1.6-fold higher than the spray-dried ITZ amorphous values, respectively. The amorphous formulation appeared physically instable during the studies due to rapid crystallization of ITZ, which was its disadvantage compared to the crystalline formulations. Therefore, this study demonstrated that micronized cocrystals are promising formulations for enhancing the pulmonary absorption of poorly soluble compounds.

Karashima M ，Sano N ，Yamamoto S ，Arai Y ，Yamamoto K ，Amano N ，Ikeda Y ... -  《-》

Design of spray dried ternary solid dispersions comprising itraconazole, soluplus and HPMCP: Effect of constituent compositions.

A range of 17 ternary formulations of itraconazole (ITZ), HPMCP and Soluplus have been manufactured using spray drying. These amorphous solid dispersions (ASDs) were very stable against crystallisation and ITZ was found to be amorphous in all formulations after one year at 40°C/75% RH. A number of solid state analytical techniques including PXRD, DSC, small angle X-ray scattering, FTIR and solid state NMR were used to characterise the physicochemical properties of the ASDs following processing and storage and to assess any interactions between components. Microtrac laser scattering analysis revealed a relationship between polymer levels and particle size distribution (PSD). Dissolution studies indicated that higher Soluplus content in the formulation resulted in higher concentrations of ITZ in acidic media.

Davis MT ，Potter CB ，Mohammadpour M ，Albadarin AB ，Walker GM ... -  《-》