Cannabinoid Oral Mucosal Delivery: Approaches to Formulation, Fabrication, and Permeation Enhancement.

Cannabinoids such as cannabidiol (CBD) and tetrahydrocannabinol (THC) have garnered significant interest for their broad-spectrum pharmacological activity in managing chronic pain, neurological disorders, and cancer-associated symptoms. Despite their therapeutic promise, clinical translation remains hindered by poor aqueous solubility, extensive first-pass metabolism, and inconsistent systemic exposure following oral administration. Oral mucosal drug delivery systems offer a viable alternative by enabling transmucosal absorption, bypassing hepatic metabolism, and facilitating both rapid and sustained drug release. This review examines the evolution and design of oral mucosal dosage forms, including fast-dissolving films, mucoadhesive matrices, in situ gels, and particulate systems and highlights the critical role of formulation strategies in enhancing cannabinoid bioavailability. Fabrication techniques such as solvent casting, hot melt extrusion, and emerging 3D printing methods are also discussed, with a focus on their potential to enable personalized dosage forms. Furthermore, the integration of permeation enhancers like terpenes, and novel systems such as inclusion complexes and lipid-based carriers, presents new opportunities for improving the solubility and stability of lipophilic cannabinoids. Together, these innovations provide a framework for the development of stable, effective, and patient-centric oral mucosal cannabinoid delivery platforms with improved pharmacokinetic and therapeutic profiles.