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Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.Key words spray freeze-drying; liquid nitrogen; ciclosporin; porous particle; tert-butyl alcohol Inhalation is the most appropriate route to deliver drugs to treat respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.1-3) This route directly targets the site of action and reduces the occurrence of systemic adverse effects. In addition, there is increasing interest in the use of pulmonary delivery to administer systemically-acting macromolecules, such as inhaled insulin product.4) The aerodynamic size of drug particles should be 5-6 µm or less for optimal airway deposition.5-7) However, particles in this size range have potentially cohesive property and tend to disperse poorly.One approach to achieve excellent inhalation delivery by simultaneously improving the micromeritic properties and reducing the cohesive properties of agents is to design spherical particles with relative large geometric diameters and low particle mass densities. Inter-particulate cohesion could be reduced by enlarging and spheronizing the individual particle, and aerosol performance could be improved by decreasing the weight of the particles, ultimately like soap bubbles. In particular, particle design focused on particle density has been specifically resear...

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