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.