Supercritical CO2 assisted preparation of chitosan-based nano-in-microparticles with potential for efficient pulmonary drug delivery.

• Separated nano-in-microparticles were fabricated by supercritical CO 2 -based technique. • Theoretical mass median aerodynamic diameter of nano-in-microparticles was 1∼2 μm. • Disintegration of nano-in-microparticles and release of nanoparticles were achieved. • Mechanism of aggregation and redispersibility of nanoparticles was revealed. Nano-in-microparticles used for inhalation lung cancer therapy combine the advantages of microparticles with aerodynamic diameters of 1∼5 μm for deep lung deposition and nanoparticles for long residence time in lung, high mucus penetrating and cancer cells uptake efficiency. In this work, nano-in-microparticles composed of chitosan nanoparticles and mannitol were prepared using a modified supercritical CO 2 assisted atomization (SAA-HCM) technique. Influences of process parameters of CO 2 /liquid mass flow ratio, total mass concentration and nanoparticles/mannitol ratio on size and morphologies of nano-in-microparticles were investigated in detail. Well-defined spherical nano-in-microparticles with theoretical mass median aerodynamic diameter of 1∼2 μm were obtained under optimized conditions. Fraction of about 40 % of nanoparticles was redispersed in deionized water at nanoparticles/mannitol ratio of 10:90. Meanwhile, quick disintegration of nano-in-microparticles was observed under conditions simulating high humidity in lung. In summary, dissociation of nano-in-microparticles and redispersibility of nanoparticles were determined by the structure of nano-in-microparticles according to particles formation mechanism. This work will expand the applicability of SAA-HCM to the preparation of nano-in-microparticles from nanosuspension and provide more references for designing of particles with elaborate structures. [ABSTRACT FROM AUTHOR]