Brain targeting of chitosan-based diazepam mucoadhesive microemulsions via nasal route: formulation optimization, characterization, pharmacokinetic and pharmacodynamic evaluation

Abstract

Objective: The aim of present investigation was to develop microemulsions (MEs) and mucoadhesive microemulsions (MME) of diazepam for brain uptake through nasal administration for the treatment of seizure emergency.

Significance: Status epilepticus (SE) is a medical emergency, requires intravenous administration of diazepam which requires hospitalization of patient. Initiation of therapy at home via nasal administration of diazepam could prevent the damage of brain due to delay of therapy initiation.

Methods: Diazepam MEs were prepared by phase titration method, optimized by using Box–Behnken design. The influence of independent variables oleic acid, surfactant mixture (tween 80:propylene glycol), and water on dependent variables size, flux, and zeta potential was investigated. Optimized MEs, MMEs, and Calmpose (i.v route) were evaluated for pharmacokinetic and pharmacodynamic studies on rats.

Results: MME2 composed of oleic acid (5), surfactant mixture (50), water (45), and chitosan (0.5) showed size of 96.45 nm, PDI 0.21 and zeta potential 13.52 mV. MME2 showed significantly high flux of 846.96 ± 34 µg/cm2/h and AUCbrain 1206.49 ± 145.8. The drug targeting efficiency (314%) and direct nose-to-brain transport (68.1%) of MME2 were significantly high compared to Calmpose (i.v) and ME. The latency periods of minimal clonal seizures and generalized tonic–clonic seizures of MME2 was significantly increased (p < 0.0001) compared to drug solution and Calmpose (i.v).

Conclusion: The brain uptake of diazepam from chitosan-based MMEs via nasal route is significantly high compared to i.v route.

Keywords:

• Box–Behnken design
• status epilepticus
• microemulsion
• diazepam
• chitosan
• brain targeting
• intranasal

Disclosure statement

No potential conflict of interest was reported by the authors.