Rehydrated sterically stabilized phospholipid nanomicelles of budesonide for nebulization: physicochemical characterization and in vitro, in vivo evaluations

BACKGROUND: Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization. METHODS: PEG(5000)-DSPE polymeric micelles containing budesonide (BUD-SSMs) were prepared by the coprecipitation and reconstitution method, and the physicochemical and pharmacodynamic characteristics of BUD-SSMs were investigated. RESULTS: The optimal concentration of solubilized budesonide at 5 mM PEG(5000)-DSPE was 605.71 ± 6.38 μg/mL, with a single-sized peak population determined by photon correlation spectroscopy and a particle size distribution of 21.51 ± 1.5 nm. The zeta potential of BUD-SSMs was −28.43 ± 1.98 mV. The percent entrapment efficiency, percent yield, and percent drug loading of the lyophilized formulations were 100.13% ± 1.09%, 97.98% ± 1.95%, and 2.01% ± 0.02%, respectively. Budesonide was found to be amorphous by differential scanning calorimetry, and had no chemical interaction with PEGylated polymer according to Fourier transform infrared spectroscopy. Transmission electron microscopic images of BUD-SSMs revealed spherical nanoparticles. BUD-SSMs exhibited prolonged dissolution behavior compared with Pulmicort Respules(®) (P < 0.05). Aerodynamic characteristics indicated significantly higher deposition in the lungs compared with Pulmicort Respules(®). The mass median aerodynamic, geometric standard deviation, percent emitted dose, and the fine particle fraction were 2.83 ± 0.08 μm, 2.33 ± 0.04 μm, 59.13% ± 0.19%, and 52.31% ± 0.25%, respectively. Intratracheal administration of BUD-SSMs 23 hours before challenge (1 mg/kg) in an asthmatic/chronic obstructive pulmonary disease rat model led to a significant reduction in inflammatory cell counts (76.94 ± 5.11) in bronchoalveolar lavage fluid compared with administration of Pulmicort Respules(®) (25.06 ± 6.91). CONCLUSION: The BUD-SSMs system might be advantageous for asthma or chronic obstructive pulmonary disease and other inflammatory airway diseases.