Fabrication of timed-release indomethacin core-shell tablets for chronotherapeutic drug delivery using dual nozzle fused deposition modeling (FDM) 3D printing.

In the present study, timed-release indomethacin tablets, releasing drug after predetermined lag times, were developed for the effective treatment of early morning stiffness in rheumatoid arthritis using two-nozzle fused deposition modeling (FDM) 3D printing with a Bowden extruder. The developed core-shell tablets consisted of a drug-containing core and release-regulating shell with different designed thicknesses (i.e., 0.4 mm, 0.6 mm, 0.8 mm). The filaments to fabricate cores and shells were prepared using hot-melt extrusion (HME), and different filament compositions were formulated for core tablets and screened for rapid release and printability. Eventually, the HPMCAS-based formulation comprised a core tablet enclosed by a shell of Affinisol™ 15LV, a swellable polymer. During 3D printing, one nozzle was dedicated to printing core tablets loaded with indomethacin, and the other nozzle was dedicated to printing shells, making a whole structure produced at once without inconvenient filament change and nozzle cleanout. The mechanical properties of filaments were compared using a texture analyzer. The core-shell tablets were characterized for dissolution profiles and physical attributes (e.g., dimension, friability, hardness). SEM image indicated a smooth and complete surface of the core-shell tablets. The tablets showed 4-8 h of lag depending on the shell thicknesses and released most of the drugs in 3 h, regardless of the shell thicknesses. The core-shell tablets showed high reproducibility but exhibited low dimensional accuracy in the shell thickness. This study explored the suitability of using two-nozzle FDM 3D printing with Bowden extrusion for producing personalized chronotherapeutic core-shell tablets and discussed possible challenges that needed to be considered for a successful printing process using this technology.