A self-complementary, self-assembling microsphere system: Application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate

Felbamate (FBM) is a novel antiepileptic drug (AED) and neuroprotectant (NP ) compound that interacts with strychnine-insensitive (SI) glycine receptor s in brain (IC50 = 374 mu M) FBM concentrations required to interact with S I glycine receptors are consistent with brain levels following oral and int raperitoneal administration of AED and NP doses. Because of the solubility limits of FBM, an intravenous (iv) form has not been developed. Nevertheles s, an iv form could be important for the treatment of disorders such as sta tus epilepticus and neuronal damage due to hypoxic/ischemic events. Substit uted diketopiperazines precipitate in acid to form microspherical particles of uniform size (similar to 2 mu m). The microsphere system entraps drugs on precipitation and dissolves near physiological pH to release the drug ca rgo. Therefore, microspheres were used to produce an iv formulation of FBM. Mice were administered the FBM/microsphere (20-60 mg/kg FBM) and tested fo r protection against tonic extension seizures using maximal electroshock. T he FBM/microsphere was effective in a time- and dose-dependent manner follo wing iv administration. The median effective dose (ED50) for protection aga inst MES seizures at 30 min was 27.2 mg/kg [95% confidence interval (CI) = 20.8-33.4, slope = 6.5]. The ED50 for minimal motor impairment at 30 min wa s 167 mg/kg (95% CI = 155-177, slope = 28.1). Thus, the feasibility of enca psulating FBM or similar aqueous insoluble compounds in a microsphere syste m with delivery by the iv route for treatment of epilepsy and various centr al nervous system disorders has been clearly demonstrated. Studies were per formed in accordance with the Guide for the Care and Use of Laboratory Anim als. (C) Wiley-Liss Inc. and the American Pharmaceutical Association.