Sustained-release ketamine-loaded lipid-particulate system: in vivo assessment in mice

Ketamine is used as an analgesic adjuvant in patients with chronic cancer-related pain. However, ketamine's short half-life requires frequent dose administration. Our aim was to develop a sustained release formulation of ketamine with high loading and to evaluate the in vivo pharmacokinetics and biodistribution in mice. Here, ketamine hydrochloride sustained-release lipid particles (KSL) were developed using the thin-film hydration method. The mean (± SD) encapsulation efficiency (EE) and drug loading (DL) of KSL were 65.6 (± 1.7)% and 72.4 (± 0.5)% respectively, and the mean (± SD) size of the lipid particles and the polydispersity index were 738 (± 137) nm and 0.44 (± 0.02) respectively. The release period of KSL in pH 7.4 medium was 100% complete within 8 h in vitro but a sustained-release profile was observed for more than 5 days after intravenous injection in mice. Importantly, the KSL formulation resulted in a 27-fold increase in terminal half-life, a threefold increase in systemic exposure (AUC_0-∞), and a threefold decrease in clearance compared with the corresponding pharmacokinetics for intravenous ketamine itself. Our findings demonstrate high encapsulation efficiency of ketamine in the sustained-release KSL formulation with prolonged release in mice after systemic dose administration despite 100% in vitro release within 8 h that requires future investigation.