Diazepam nanocapsules as an alternative for sleep induction: Development study and toxicity assessment

Diazepam (DZP) is a sedative medication prescribed to treat anxiety and as a sleep inducer, although its residual effects are unfavorable to patients. Nanotechnology represents a tool to improve the pharmacological characteristics of drugs, reducing their side effects. This study aimed to develop and characterize DZP nanocapsules and to evaluate their toxicity in alternative models and the hypnotic-sedative effect in mice. Nanocapsules were prepared by the nanoprecipitation method and properly characterized. Long-term and accelerated stability studies were performed. The in vitro release profile was determined by diffusion in Franz cells. The safety of the formulation was evaluated in the Caenorhabditis elegans (C. elegans) and the oral acute toxicity in mice. Pharmacological evaluation was performed using thiopental-induced sleeping time. DZP was successfully incorporated into Poly-(ɛ-caprolactone) (PCL) nanocapsules, with high entrapment efficiency. The nanocapsule did not affect the development or survival of C. elegans, different from the free drug, which affected the nematode development at the higher tested dose. No signs of toxicity, nor body mass or feed consumption changes were observed during the 14 days evaluated. Finally, this innovative formulation carrying DZP can produce a hypnotic-effect at a reduced dose compared to the free drug, with no toxicity in alternative models.