Addditive manufacturing of solid formulations tailoring oral administration for preclinical research

This doctoral thesis is the result of an industrial Ph.D. in collaboration with Chiesi Farmaceutici S.p.A. where the applications of advanced 3D printing technologies, specifically semi-solid extrusion (SSE) and direct powder extrusion (DPE), for the design, fabrication and characterization of oral solid dosage forms intended for preclinical in vivo studies are investigated. The research addresses the intrinsic limitations of early-stage drug research, such as restricted material availability, rodent administration dimensional constraints, and the need for precise modulation of drug release kinetics to support pharmacokinetic and pharmacodynamic investigations. Two model drugs, caffeine (BCS Class I) and naproxen (BCS Class II), were selected to be formulated targeting sustained and immediate release profiles, respectively. The 3D-printed dosage forms were engineered to match the dimensions of size 9 capsules, commonly used for oral administration in rodent models, with a target dose of 1.65 mg per unit and with all excipients chosen from the GRAS list, to support potential in vivo administration. A comprehensive workflow was established, encompassing formulation design, 3D modeling, printing process optimization, and characterization of the printlets. For caffeine, both matrix and reservoir-type hydrogels were investigated using SSE. DPE was employed to fabricate matrix-based formulations using thermoplastic polymers and powder blends. For naproxen, various strategies were explored: SSE formulations included cyclodextrin complexes, lipidic excipients, liposomal carriers, and liquisolid hydrogels. DPE technology was used to produce matrix-based formulations with suitable size and drug content. Both API’s printed formulations underwent complete characterization, including solid-state analyses (X-ray diffraction, differential scanning calorimetry), rheological evaluation, imaging (scanning electron microscopy and micro-computed tomography), drug content assay, and dissolution testing in simulated gastric fluid. Finally, the best promising caffeine 3D printed prototypes were further evaluated in vivo in rat models to assess pharmacokinetic profiles and systemic drug exposure. The caffeine SSE reservoir formulations achieved sustained release profiles in vitro, reaching between 40% and 76% of release in 120 minutes. In contrast, DPE matrix formulations matched the reference capsule in release kinetics, but demonstrated superior performance in in vivo studies, prolonging systemic drug exposure. In vivo administration studies in rats confirmed the feasibility of using 3D-printed formulations for preclinical pharmacokinetic investigations, highlighting the importance of physiological conditions in modulating drug release. Regarding naproxen, the SSE optimized liquisolid hydrogels enabled the fabrication of low infill density solid forms with rapid drug release in simulated gastric fluid. On the contrary, DPE technology produced matrix-based forms where further refinements are needed to achieve immediate release performance. This thesis establishes proof-of-concept for the use of SSE and DPE 3D printing technologies in the preparation of oral solid dosage forms for preclinical research. The study highlighted the critical role of formulation composition, printing parameters, and 3D model design in achieving the desired release kinetics. The minimal material requirements and rapid adaptability of 3D printing technologies present significant advantages for preclinical research, facilitating efficient screening and optimization of novel compounds. The ability to tailor drug loading and release kinetics in miniaturized dosage forms demonstrates the potential of additive manufacturing to advance the prototyping and customization of pharmaceutical formulations, thereby supporting their strategic research and enabling the integration of these technologies into future proprietary research projects.