Christophe Duret

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.

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

Purpose Itraconazole (ITZ) dry powders for inhalation (DPI) composed of nanoparticles (NP) embedded in carrier microparticles were prepared and characterized. Methods DPIs were initially produced by reducing the ITZ particle size to the nanometer range using high-pressure homogenization with tocopherol polyethylene 1000 succinate (TPGS, 10% w/w ITZ) as a stabilizer. The optimized nanosuspension and the initial microsuspension were then spray-dried with different proportions of or in the absence of mannitol and/or sodium taurocholate. DPI characterization was performed using scanning electron microscopy for morphology, laser diffraction to evaluate the size-reduction process, and the size of the dried NP when reconstituted in aqueous media, impaction studies using a multistage liquid impactor to determine the aerodynamic performance and fine-particle fraction that is theoretically able to reach the lung, and dissolution studies to determine the solubility of ITZ. Results Scanning electron microscopy micrographs showed that the DPI particles were composed of mannitol microparticles with embedded nano- or micro-ITZ crystals. The formulations prepared from the nanosuspension exhibited good flow properties and better fine-particle fractions, ranging from 46.2% ± 0.5% to 63.2% ± 1.7% compared to the 23.1% ± 0.3% that was observed with the formulation produced from the initial microsuspension. Spray-drying affected the NP size by inducing irreversible aggregation, which was able to be minimized by the addition of mannitol and sodium taurocholate before the drying procedure. The ITZ NP-based DPI considerably increased the ITZ solubility (58 ± 2 increased to 96 ± 1 ng/mL) compared with that of raw ITZ or an ITZ microparticle-based DPI (<10 ng/mL). Conclusion Embedding ITZ NP in inhalable microparticles is a very effective method to produce DPI formulations with optimal aerodynamic properties and enhanced ITZ solubility. These formulations could be applied to other poorly water-soluble drugs and could be a very effective alternative for treating invasive pulmonary aspergillosis.

In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice

The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1 mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation.

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

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

Temozolomide-Based Dry Powder Formulations for Lung Tumor-Related Inhalation Treatment

ABSTRACTPurposeTemozolomide dry powder formulations for inhalation, performed with no excipient or with a lipid or lactose coating, have been evaluated.MethodsThe particle size of raw temozolomide in suspension was reduced by a high-pressure homogenizing technique, and the solvent was evaporated by spray-drying to obtain a dry powder. The physicochemical properties of this powder were evaluated and included its crystalline state, thermal properties, morphology, particle size and moisture and drug content, and these properties were determined by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, laser light scattering, thermogravimetric analysis and high-performance liquid chromatography, respectively. The aerodynamic properties and release profiles were also evaluated using a multistage liquid impinger and a modified USP type 2 dissolution apparatus adapted for inhaler products, respectively.ResultsThe dry powder inhalation formulations had a high temozolomide content that ranged from 70% to 100% in the crystalline state and low moisture content. Aerodynamic evaluations showed high fine-particle fractions of up to 51% related to the metered dose. The dissolution profile revealed a similarly fast temozolomide release from the formulations.ConclusionsDry temozolomide powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion properties, represent an attractive alternative for use in local lung cancer therapy.

Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention

Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3). These powders were endotracheally insufflated in vivo at a single dose of 0.5mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice. ITZ was crystalline in F1 and assumed to be amorphous in the F2 and F3 formulations. F2 and F3 formulations allowed the in vitro formation of an ITZ supersaturated solution with a maximum solubility of 450±124ng/ml (F2) and 498±44ng/ml (F3), in contrast to formulation F1 (<10ng/ml). As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter tmax) and in larger quantities compared to the F1 formulation (plasmatic AUC0-24h of 182ngh/ml, 491.5ngh/ml and 376.8ngh/ml, and tmax of 60min, 30min and 5min for F1, F2 and F3, respectively). PL increased the systemic bioavailability of ITZ (determined by the AUCplasma to AUClung ratio) as a consequence of their wetting and absorption enhancement effect. ITZ lung concentrations after pulmonary administration remained higher than the targeted dose, based on the minimal inhibitory concentrations for Aspergillus fumigatus (2μg/glung), 24h post-administration for both F1 and F2 formulations. However, this was not the case for formulation F3, which exhibited a faster elimination rate from the lung, with an elimination half-life of 4.1h vs. 6.5h and 14.7h for F1 and F2, respectively.