Precision Drug Delivery of LY-11h for Acute Myeloid Leukemia Treatment Using Machine Learning-Assisted Hot Melt Extrusion and 3D-Printed Technologies

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy, and LY-11h is a novel acylhydrazide-based histone deacetylase inhibitor with promising therapeutic potential for AML. However, its poor aqueous solubility, limited intestinal dissolution, and narrow therapeutic window hinder oral formulation development and motivate the development of dosage forms with flexible dose-design capabilities. Herein, an integrated hot-melt extrusion (HME)–fused deposition modeling (FDM) strategy was developed to convert LY-11h into printable amorphous solid dispersion (ASD) dosage forms. Methods: HPMC-AS was used as a pH-responsive carrier to enhance intestinal release while restricting premature gastric release, and HPC-EF was incorporated to improve filament processability. Single-factor and DoE studies identified critical formulation and process variables and established formulation–process–property relationships, while machine learning further modeled nonlinear interactions and guided optimization. In-line near-infrared spectroscopy combined with polarized light microscopy enabled real-time monitoring of LY-11h amorphization and melt homogenization during HME. Results: ExtraTrees and Bagging models showed promising predictive performance for key filament properties, and PAT-stage validation confirmed strong agreement with experimental values. The 15 DoE-designed ASD filaments were successfully fabricated into FDM-printed tablets with reproducible geometry. Equilibrium-solubility and in vitro dissolution studies demonstrated enhanced intestinal-pH solubility and reproducible pH-responsive release. Conclusions: Collectively, these findings establish a technological proof of concept for the manufacture of LY-11h dosage forms with adjustable formulation and geometric attributes. Further in vivo pharmacokinetic studies are required to determine whether these manufacturing capabilities translate into predictable dose–exposure relationships and individualized dose control.