Next-Generation Oral Delivery Systems: Phytosomal Hinokitiol Tablets via REGEMAT 3D Bioprinter-Based 3D Printing for Enhanced Bioavailability

Abstract

The administration of hinokitiol, a natural bioactive compound with promising therapeutic potential, particularly against breast cancer, faces notable challenges related to its poor solubility and low bioavailability, limiting its clinical applications. The present study aimed to advance a previously developed liquid hinokitiol-loaded phytosomal formulation by incorporating it into 3D-printed oral tablets using a REGEMAT 3D Bioprinter, containing either pure drug or drug-loaded phytosomes to enhance the pharmacokinetic performance and therapeutic efficacy of this compound. The tablets were formulated using hydroxypropyl methylcellulose-based paste and subjected to comprehensive quality control tests, including weight variation, thickness, drug content, friability, and in vitro dissolution. Scanning electron microscopy revealed that the phytosome-loaded tablets had a denser, waxy-like appearance with fewer voids, which contributed to improved drug release profiles. Molecular docking and molecular dynamics simulations revealed strong and stable interactions between hinokitiol and target proteins, providing insight into the potential anticancer activity of this compound through hydrogen bonding with DNA guanine 19 and hydrophobic interactions with residues such as Trp-1510, Leu-1513, and Met-1533. In vitro dissolution experiments showed faster and more complete drug release from phytosome-loaded tablets compared with those containing pure hinokitiol. Pharmacokinetic evaluation in male Wistar rats revealed the superior performance of phytosome-loaded tablets, with a higher maximum plasma concentration and greater area under the curve. These results highlight the potential of 3D-printed tablets with hinokitiol-loaded phytosomes as a novel drug delivery system that significantly improves the bioavailability, drug release, and therapeutic efficacy of hinokitiol. The integration of nanotechnology and 3D printing in the present study offers a promising platform for enhancing the clinical utilization of bioactive compounds with poor solubility, such as hinokitiol.