Phenytoin Sodium Loaded Nanomicelle IV for Seizure Emergencies

Abstract

An acute seizure can be fatal if left untreated, causing brain damage and even death. Phenytoin sodium (PS) was used as a second-line drug, to treat seizures in emergency situations. Due to the administration and pharmacokinetic issues, it is now being replaced with newer anticonvulsant drugs having short half-life and sedative effects. In this study, our aim was to make a nanomicelle of PS that reduces administration challenges, improves brain availability, and lowers the dose, which could be helpful in the treatment of seizure emergencies. Phenytoin sodium-loaded nanomicelles (PSNM) were prepared by the thin film hydration method. With pluronic F127, we prepared a novel nanomicelle of less than 20 nm size and loaded with PS. The drug loaded nanomicelles showed an immediate release profile with a decreased plasma protein binding and improved lipid permeation compared to the marketed PS injection. Results of the in vivo acute toxicity study indicate that the optimized formulation is safe for administration. The biodistribution and pharmacokinetic studies of intravenously administered PSNM was evaluated (25 mg/kg) and compared with intravenously administered marketed phenytoin sodium of same dose. In biodistribution studies, PSNM showed a maximum brain drug concentration of 865 ± 1.0 µg at the 15th minute of administration whereas the marketed PS iv and PS solution exhibited a maximum concentration of 707.2 ± 65.6 and 168.4 ± 10.4 µg respectively at the end of 30 minutes. Over a period of 60 minutes, optimized formulation produced a higher plasma drug concentration than marketed formulation and PS solution indicating the reduced plasma protein binding. Also the optimized nanomicelle showed reduced drug deposition in peripheral organs compared to the marketed PS iv, thereby reducing chances of peripheral toxicity. Pharmacodynamic studies using the Maximal Electro Shock model (MES) confirmed that PSNM provide rapid anticonvulsant action at a reduced dose of 10 mg/kg. The results of the above studies indicate that..