The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.

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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.

Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.Aerosolized administration of antifungals is gaining favor for the prevention of invasive pulmonary mycoses (4). Aerosolized administration can achieve high, localized lung tissue concentrations while avoiding systemic toxicities. However, the formulations currently used clinically include intravenous preparations that are not specifically designed for aerosolized administration. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) are novel technologies utilized to improve the dissolution and bioavailability of poorly water-soluble drugs (8). Both technologies can produce nanostructured particles (Ͻ1 micron in diameter) capable of drug delivery to the alveolar space (5).We hypothesized that aerosolized administration of EPAS and SFL formulations of itraconazole (ITZ) would be an effective prophylaxis strategy against invasive pulmonary aspergillosis. An established murine model was used to simulate the pathogenesis of invasive pulmonary aspergillosis and assess survival following pulmonary inoculation. We also measured steady-state lung tissue and serum ITZ concentrations.Five-week-old male outbred ICR mice (Harlan SpragueDawley, Indianapolis, IN) were rendered immunosuppressed by cortisone acetate administered subcutaneously at a dose of 100 mg/kg of body weight on days Ϫ1, 0, ϩ1, and ϩ6 and were inoculated with Aspergillus flavus ATCC MYA-1004 (ITZ MIC, 0.125 g/ml per CLSI M38-A microdilution methodology) (14) via an inhalation chamber as previously described (13, 16). Animals were divided into four groups: ITZ oral solution (Sporanox oral liquid [SOL]) administered by oral gavage (30 mg/kg three times a day), aerosolized EPAS (30 mg/kg twice a day), aerosolized SFL (30 mg/kg twice a day), and control (aerosolized sterile distilled water). EPAS and SFL formulations were manufactured using pharmaceutical grade ITZ powder (Hawkins, Inc., Minneapolis, MN) (3,17,18,20,21). For the EPAS formulation, ITZ and poloxamer 407 were dissolved in dichloromethane and the solution was sprayed into a heated aqueous solution containing 4% polysorbate 80, causing rapid evaporation of the dichloromethane and subsequent precipitation of nanostructured crystalline ITZ. For SFL, an organic feed solution was prepared by dissolving ITZ (0.1% wt/vol), polysorbate 80 (0.75% wt/vol), and poloxamer 407 (0.75% wt/vol) into acetonitrile. The organic feed solution was atomized into liquid nitrogen to produce frozen amorphous particles. Lyophilization of the particles yielded stabilized nanostructured particle aggregates. EPAS, SFL, and control were administered via a 20...

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