This study presents a practical and tunable 3D printing-based approach for manufacturing oral controlled-release bilayer tablets by modulating drug release solely through layer ratio control within a single dosage form. Theophylline-loaded filaments were prepared via hot-melt extrusion (HME) using Kollicoat^® IR or hydroxypropyl cellulose as polymer matrices. The mechanical properties of the manufactured filaments were evaluated and compared with commercial filaments to confirm their suitability for fused deposition modeling (FDM) printing. Physicochemical characterization using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy indicated partial crystallinity and molecular dispersion of the drug within the polymer matrices. Using a dual-nozzle FDM 3D printer, five bilayer tablets composed of two drug-loaded filaments at different layer ratios were successfully fabricated without altering formulation composition or processing conditions. Drug release studies revealed distinct dissolution behaviors that were strongly dependent on the bilayer composition. Overall, this study demonstrates that controlled drug release can be effectively achieved through geometric modulation of bilayer structures using a combined HME–FDM 3D printing approach, providing a practical platform for personalized oral drug delivery without increasing formulation complexity.

Oral administration remains the most convenient and favored route for systemic delivery of small-molecule drugs, primarily due to patient compliance and the absence of invasive procedures. Yet, poor aqueous solubility, chemical/enzymatic instability, and limited permeability in the gastrointestinal (GI) tract often result in low bioavailability (BA) of many therapeutic agents. Polymeric micelles formed from the self-assembly of amphiphilic block copolymers have gained considerable attention as a nanotechnology-driven solution to overcome these challenges. Their hydrophobic core–hydrophilic shell structure enables efficient encapsulation of poorly soluble small molecule drugs, providing protection from acidic or enzymatic degradation while potentially enhancing drug transport across the intestinal epithelium. This review examines the design principles, formulation strategies, and in vivo performance of polymeric micelles for oral delivery of small molecule drugs. We discuss strategies to improve micelle stability in the GI environment, including optimization of core hydrophobicity, kinetic stabilization, and corona engineering, and compare polymeric micelles with established alternatives such as self-micro emulsifying drug delivery system (SMEDDS) and amorphous solid dispersions (ASDs) across critical performance parameters. Despite decades of preclinical progress, no oral polymeric micelle formulation has reached regulatory approval, underscoring the persistent challenge of maintaining micellar structural integrity under the dynamic conditions of the GI environment. This review therefore examines not only the promise but also the structural vulnerabilities of oral micelles, proposing a stability-centered framework for interpreting micelle function under GI conditions. Finally, we discuss current translational challenges and suggest directions for future research toward clinical application of oral polymeric micelle systems.

Background: Ritonavir (RTV), an HIV-1 (human immunodeficiency virus-1) protease inhibitor, has low aqueous solubility and poor oral bioavailability, requiring large amounts of excipients that result in bulky dosage forms and poor patient compliance. We aimed to develop an RTV-loaded polymeric micelle formulation with high drug loading capacity that improves aqueous solubility, reduces the excipient burden and associated excipient-related adverse effects, and remains stable after lyophilization without a cryoprotectant. Methods: RTV-loaded micelles were prepared from the amphiphilic block copolymer poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) by thin-film hydration. Particle size and the polydispersity index (PDI) were measured by dynamic light scattering and encapsulation efficiency and drug content by HPLC, before and after lyophilization. The drug-to-excipient ratio was compared with the commercial product (Norvir^®), and pharmacokinetics were evaluated in male Sprague-Dawley rats after single oral administration. Results: Micelles showed a mean particle size of 25.9 ± 0.09 nm, a PDI of 0.224 ± 0.008, and an encapsulation efficiency of 98.9 ± 1.54%, with particle size and drug content retained after lyophilization and reconstitution without any cryoprotectant. Drug content reached 27.3% (w/w) versus 12.5% for the commercial product, a 2.6-fold reduction in excipients per unit dose. In rats, the micelle formulation showed pharmacokinetic parameters comparable to those of the Norvir^® suspension (C_max, 2243.9 ± 1226.4 vs. 2106.1 ± 835.9 ng/mL; AUC_last, 6695.3 ± 2162.6 vs. 8178.2 ± 2892.1 h·ng/mL; T_max, 0.9 ± 0.6 vs. 1.5 ± 0.5 h), with no significant differences. Conclusions: The PEG-b-PCL micelle achieved high RTV loading, substantially reduced excipients, and provided oral exposure comparable to the commercial product, supporting its potential as an alternative oral delivery system.