Application of combinational supercritical CO2 techniques to the preparation of inhalable particles

•A scCO2 system with RESAS and SAS system effectively prepared drug NP.•Drug NP was obtained via spraying the ethanolic drug solution into scCO2.•We verified optimal scCO2 pressure, temperature, and organic solvent.•ScCO2 samples showed 24-fold greater inhalation properties than raw ONO-2921.

This study describes a supercritical CO2 (scCO2) system, which combines supercritical antisolvent (SAS) and rapid expansion from supercritical to aqueous solution (RESAS) processes, enabling the preparation of a poorly water-soluble drug (ONO-2921) as a dry powder for inhalable formulations. The SAS unit disperses the drug solution in scCO2 and the RESAS unit sprays the drug dispersion into water. Dispersing the ethanolic drug solution into a vessel purged with scCO2 practically eliminated crystallization of ONO-2921 when the CO2 pressure was more than 15 MPa at 40 °C. In contrast, a suspension containing submicron-sized particles was obtained when the scCO2-drug mixture was sprayed into water using a RESAS device. Suspensions were freeze-dried to create powdered samples for determining in vitro inhalation properties. Freeze-dried particles processed with 25 MPa of CO2 at 40 °C showed 24-fold greater deposition in the stage 2 fraction of the twin impinger than raw ONO-2921. The fine particle fraction value (aerodynamic diameter <4.7 μm) of its processed sample was 48.7% ± 0.6%. As this scCO2 approach does not require additives or excipients to prepare the particles, the pulmonary delivery of large amounts of ONO-2921 as an inhalable dry powder represents an attractive drug delivery system.

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