Converting nanosuspension into inhalable and redispersible nanoparticles by combined in-situ thermal gelation and spray drying

While nanoparticulate drugs for deep lung delivery hold promise for particular disease treatments, their sizerelated physical instability and tendency of being exhaled during breathing remain major challenges to their inhaled formulation development. Here we report a viable method for converting drug nanosuspensions into inhalable, stable and redispersible nano-agglomerates through combined in-situ thermal gelation and spray drying. Itraconazole (ITZ) nanosuspensions were prepared by flash nanoprecipitation, and co-spray dried with two different grades of the gel-forming polymer, methylcellulose (MC M20 and MC M450) as protectants. MC M20 was found superior in protecting ITZ nanoparticles against thermal stress (through nanoparticle entrapment within its gel network structure) during spray drying. In terms of redispersibility, an S-f/S-i ratio (i.e., ratio of nanoparticle sizes after and before spray drying) of unity (1.02 +/- 0.03), reflecting full particle size preservation, was achieved by optimizing the suspending medium content and spray drying parameters. Formulation components, nanosuspension concentration and spray drying parameters all showed a significant impact on the aerosol performance of the resulting agglomerates, but an absence of defined trends or correlations. Overall, the MC-protected nano-agglomerates displayed excellent in-vitro aerosol performance with fine particle fractions higher than 50% and mass median aerodynamic diameters within the 2-3 mu m range, which are ideal for deep lung delivery.