Continuous Microfluidic Manufacture of Nano-in-Microparticles Combining 3D-Printed Micromixers and Spray Drying

Conventional nanoparticle manufacturing techniques remain costly, labor-intensive, and difficult to scale, while also being subject to batch-to-batch variability. These limitations hinder their clinical translation, particularly in first-in-human trials. Emerging transformative technologies such as microfluidics and three-dimensional (3D) printing offer opportunities to develop agile, continuous, and scalable manufacturing processes. This study aims to demonstrate the feasibility of continuous microfluidic production of nanoparticles using customizable 3D-printed chips, integrated with atomization technologies, to generate solid nano-enabled controlled release therapies. 3D-printed microfluidic chips were designed using computational fluid dynamics (CFD) to optimize flow characteristics. Nifedipine (NFD)–loaded nanoparticles were continuously manufactured with Eudragit L-100 and subsequently embedded into pullulan microparticles by spray-drying, yielding nano-in-microparticles (NIM). Particle size, encapsulation efficiency, solid-state properties, permeability, and release kinetics were assessed in ex vivo Franz cell studies across porcine intestinal membranes. Continuous microfluidic processing produced NFD-loaded nanoparticles with 95% encapsulation efficiency. Spray-drying yielded spherical pullulan-based NIMs of ~ 10 µm, which, upon rehydration, released NFD nanoparticles of ~ 100 nm. The nanoparticles retained their amorphous state and displayed a three-fold increase in intestinal permeability compared to free drug, accompanied by a three-fold reduction in lag time. Release studies demonstrated reduced burst release and a sustained zero-order release profile over 24 h, favorable for blood pressure maintenance therapy. The integration of 3D-printed microfluidic chip design with continuous manufacturing and spray-drying enables scalable production of solid nano-enabled therapies. The NFD-loaded NIMs demonstrated enhanced permeability and controlled release, supporting the potential of this platform for the clinical translation of nanomedicines.