Formulation and Nose-to-Brain Uptake Study of Intranasal Diazepam Nano Emulgel on Rabbits as a Potential Approach to Control Epileptic Emergencies
Keywords:
Nano emulgel, Intranasal, Diazepam, In Vivo Kinetics, CSF aspirationAbstract
Drug Delivery to the brain is challenge long has been tried to be tackled, mainly the bloodbrain barrier act as a formidable opposing force to drug access. Intranasal administration is one of the methods that aim to overcome this challenge. Diazepam is a CNS-acting positive allosteric modulators of the GABA that is used as anxiolytic, sedative and anticonvulsant. It is a mainstay treatment for epileptic emergencies like status epilepticus. The aim of the study is to formulate Diazepam as a nano emulgel for intranasal administration to provide an alternative route for Diazepam administration to a patient suffering from convulsions using a preliminary animal model based on rabbits. A nano emulgel of Diazepam was tested by preparing a nanoemulsion using Tween 80 as surfactant and ethanol as co-surfactant in 1: 2 ratio (this component is referred to as Smix) with oleic acid as the oil phase with the Ratio of Smix to oil to Water of 50: 10: 40 then converted to an emulgel by addition of 0.5% w/w hydroxy propyl methyl cellulose. Diazepam nano emulgel viscosity was measured and compared to its original nanoemulsion to confirm increase the expected viscosity that’s is necessary for long retention in the nasal cavity where mucocilliary clearance is a major issue limiting time available for drug release and its absorption from application site (olfactory region). For the In Vivo study; Six rabbits weighting 1.5-2.25kg were anesthetized and Diazepam nano emulgel was given to them via thin polyvinyl chloride tube into posterior region of their nasal cavities. Cerebrospinal fluid samples were drawn at six time points and analyzed using HPLC and the Cmax, Tmax and AUC calculated at a dose of Diazepam of 1.23mg/kg for each rabbit. HPLC results valued the Cmax, Tmax and AUC at 1.33mg/ml, 5.2minutes and 14.75 mg/ml.min respectively indicating rapid onset of appearance in CSF at near IV values.
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