Anti-convulsant efficacy of long-acting injectable cannabidiol formulation (IVL5005) in the pentylenetetrazol-induced convulsions, with pharmacokinetic characterization.

Introduction: Cannabidiol (CBD) has demonstrated therapeutic potential in neurological disorders, particularly epilepsy. Epidiolex®, an FDA-approved oral CBD solution, is indicated for rare epileptic disorders such as Lennox-Gastaut syndrome and Dravet syndrome. However, its clinical utility is limited by rapid metabolism, short duration of action, and low oral bioavailability. Methods: To address these limitations, we developed a long-acting injectable (LAI) formulation of CBD (IVL5005) using IVL-DrugFluidic® technology to achieve sustained and controlled drug release. CBD-loaded microspheres were manufactured and characterized by physicochemical analyses and in vitro release profiling. An in vivo pharmacokinetic study was conducted to evaluate systemic exposure following a single subcutaneous injection. The optimized formulation was selected for efficacy evaluation in a pentylenetetrazole (PTZ)-induced convulsion model. Results: All candidate formulations provided sustained systemic exposure for up to 4 weeks. The optimized IVL5005 formulation exhibited prolonged release with minimal initial burst. In the PTZ-induced convulsion model, IVL5005 demonstrated significant and durable anticonvulsant efficacy from a single dose, whereas the oral CBD solution produced only a transient effect. IVL5005 achieved a lower maximum plasma concentration compared with oral CBD solution, potentially reducing peak concentration-related adverse effects. No hepatic toxicity was observed with IVL5005, while liver changes were detected in the oral CBD group, likely due to extensive first-pass metabolism. Discussion: These results indicate that IVL5005 may overcome key limitations of oral CBD and support its further development as a long-acting therapeutic option for epilepsy.