Delivery of Phenytoin Sodium Directly to the Brain using Nano Lipid Carriers NLCs as a Treatment for Acute Epileptic Seizure

Abstract

An acute epileptic seizure is a seizure emergency fatal condition that needs immediate medical attention. Mortality and worse neurologic outcomes are directly associated with the duration of seizure activity. The IV phenytoin sodium remains the second-line therapeutic agent for the immediate treatment of status epilepticus. Nanocarrier-mediated intranasal delivery is a promising strategy to treat acute seizure or seizure emergencies. The direct nose-to-brain drug transport through olfactory epithelium has been extensively studied in recent years as an effective approach for treating neurodegenerative diseases, enabling faster and direct onset of action bypassing the BBB, thus reducing systemic exposure of the drug. Phenytoin sodium formulated as anano lipid carrier (NLC) seems to be promising as an intranasal delivery system for controlling acute seizures. The Phenytoin sodium loaded NLCs (PS-NLC) were prepared by melt emulsification followed by ultrasonication method and were further characterized. Three different sized PS-NLCs (lt50 nm, 50-100 nm, and lt100nm sized) were prepared by varying the probe sonication time inorder to study the effect of particle size on intranasal olfactory epithelial uptake. In vitro drug release study showed an immediate drug release from PS-NLC (lt50nm), which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation of drug from PS-NLC (lt50nm) through olfactory epithelium compared to the control drug solution and other formulations. The developed NLCs also showed good biocompatibility in both L929 and HBCEC cells. In vivo acute toxicity study on 50 Wistar rats revealed that intranasal PS-NLC formulation is non-toxic up to 250 mg/ kg dose and was shown liver toxicity at a dose of 500 mg/ kg dose. The in vivo pharmacokinetic study revealed higher drug concentration in CSF and brain within 5 minutes on intranasal administration of PS-NLC (lt50nm) than intranasal control drug solution and marketed IV phenytoin sodium indicating direct and rapid