Intranasal Palonosetron for Chemotherapy-Induced Nausea and Vomiting: Physicochemical considerations, Formulation challenges and a Risk-Based Translational Framework

AbstractPalonosetron is a well-established second-generation 5-HT3 receptor antagonist withapproximately 97% oral bioavailability, a long elimination half-life and demonstrated efficacy inpreventing chemotherapy induced nausea and vomiting (CINV). Despite its high oralbioavailability, intranasal administration may offer an alternative for patients unable to swallowor retain oral medication due to nausea, vomiting, dysphagia, or treatment-related oralcomplications. The primary rational for intranasal palonosetron is the reliable non-oral routerather than bioavailability or bypassing first-pass metabolism. This review critically examinesthe therapeutic rationale, physicochemical properties, formulation challenges, drug-deviceconsiderations, evidence gaps and translational needs. Particular attention is given to drugsolubility, ionization, nasal permeability, formulation stability, mucosal tolerability, andreproducible dose delivery as important considerations for formulation development. The reviewdistinguishes direct evidence concerning palonosetron from indirect findings involving otherintranasal drugs and delivery systems. Although intranasal palonosetron has been described inpatent literature, clinical evidence supporting its intranasal administration remains insufficient. Arisk-based translational framework is proposed, prioritizing the evaluation of nasal permeability,systemic pharmacokinetics, local safety, and device performance using a simple aqueousformulation. More complex mucoadhesive, thermosensitive, or nanocarrier-based systems shouldbe considered only when experimentally demonstrated limitations justify their additionalcomplexity. Overall, intranasal palonosetron remains a scientifically plausible but clinically unproven strategy, and its further development should depend on demonstrating meaningful advantages over established oral and intravenous therapies.