Palonosetron-loaded binary ethosome-incorporated transdermal gel: Formulation optimization, in vitro/in vivo evaluation, and therapeutic efficacy in chemotherapy-induced nausea and vomiting

This study aimed to develop a transdermal gel formulation of palonosetron-loaded binary ethosomes (PAL-BE-G) and systematically evaluate its in vitro physicochemical properties, in vivo pharmacodynamics, and pharmacokinetics. PAL-BE was fabricated via the injection-ultrasonication method, and its formulation was optimized using Box-Behnken design. The optimized PAL-BE appeared as a clear, transparent dispersion with pale blue opalescence and exhibited excellent stability at 4 °C. Fourier-transform infrared (FT-IR) spectroscopy verified the formation of hydrogen bonds between palonosetron (PAL) and excipients, with no chemical interactions detected. Subsequently, PAL-BE-G was prepared with 0.5% carbomer 940 as the gel matrix, which maintained favorable storage stability at 4 °C for 120 days. In vitro release assays showed a 94% cumulative release rate of PAL within 36 h, confirming the sustained-release property of the gel. In vitro transdermal permeation studies demonstrated that PAL-BE-G possessed superior skin penetration efficiency. Safety evaluations confirmed the excellent biocompatibility of PAL-BE-G with no significant skin irritation. In vivo pharmacodynamic assays revealed that PAL-BE-G exerted comparable antiemetic efficacy against chemotherapy-induced nausea and vomiting (CINV) to commercial PAL injection. Pharmacokinetic studies indicated that the absolute bioavailability of PAL-BE-G was 18.74 ± 3.26%, with sustained drug release in vivo. In conclusion, the successfully developed PAL-BE-G integrates high transdermal permeability, ideal sustained-release behavior, and favorable safety profiles. It provides a novel therapeutic alternative for CINV patients, especially those unable to tolerate oral administration, and offers experimental and theoretical support for the transdermal delivery of poorly soluble drugs.