(37g) Supercritical Fluid Assisted Preparation of Nano-in-Microparticles with Potential for Efficient Pulmonary Drug Delivery

Lung cancer is one of the most frequent and deadliest diseases among all types of cancers. Pulmonary drug delivery using nano-in-microparticles with aerodynamic diameter (d_ae) of 1-5 μm in the formulation of dry powder inhalers (DPI) has been proved to be an efficient therapy method due to targeted drug delivery to the lesion, lowering the subsequently side effects.

In this work, nano-in-microparticles composed of drug-free chitosan-based nanoparticles and mannitol as excipient were prepared using an improved supercritical assisted atomization technique (SAA-HCM). Well-defined spherical nano-in-microparticles with tapped density below 0.51 g/cm³ and theoretical mass median aerodynamic diameter about 1.30 μm were prepared successfully. From TEM photos, nanoparticles tended to gather at the outer of nano-in-microparticles to form an annulus due to high Péclet number of nanoparticles. Influences of process parameters including gas/liquid mass flow ratio, mass concentration and nanoparticles/mannitol ratio on sizes and morphologies of particles were investigated in detail. The redispersibility fraction of nanoparticles in vitro increased to about 40% when the nanoparticles/mannitol ratio decreased to 10:90 since lower value of ratio led to strong bridge effect of mannitol as well as weak interaction between nanoparticles. Quick disintegration of nano-in-microparticles back into initial nanoparticles was observed under conditions similar to the lung due to high hygroscopicity of mannitol in a moist environment. In summary, the disintegration behaviors of nano-in-microparticles and nanoparticles redispersibility were closely related with their structures determined by the particle formation mechanism.

Nano-in-microparticles can achieve high tumor cells uptake efficiency, which possess both advantages of high respirable fraction and long lung residence time. The SAA-HCM method provides an alternative for preparing particles with elaborate structures using a green technique.