Epidural pre-formed long-acting implants as a novel and challenging approach for brain drug delivery

Antipsychotic drugs often fail to reach therapeutic levels in the brain because the blood-brain barrier limits penetration, making safe, effective treatment difficult. We engineered a solvent-free, pre-formed long-acting implant based on poly(lactic-co-glycolic acid) that delivers risperidone from the epidural space. In mice, we directly compared epidural, parenchymal, and head subcutaneous implantation. The implant showed an early burst within 8 h, followed by sustained release for 30 days. Cell viability assays with brain-relevant cells showed no cytotoxicity. Pharmacokinetic profiling demonstrated that epidural and parenchymal delivery achieved similar concentrations of risperidone in plasma and brain interstitial fluid, both substantially higher than head subcutaneous delivery. Animal safety testing revealed minimal immune response after epidural placement, comparable to untreated controls, whereas parenchymal placement produced localized immune activation near the implant site. These results identify epidural implantation of a pre-formed risperidone device as a minimally invasive strategy that can maintain brain exposure while reducing procedure-related risk and supporting long-term adherence.