Rapid intranasal delivery of diazepam utilizing prodrug/enzyme formulations: a promising drug delivery strategy for outpatient treatment of seizure emergencies

Background: Diazepam is effective in interrupting status epilepticus and halting acute repetitive seizures. It is imperative to achieve a therapeutic concentration of diazepam as quickly as possible, because 1) seizures become increasingly difficult to control when treatment is delayed, so a short window of opportunity exists when rescue therapy with benzodiazepines, such as diazepam, is maximally effective; and 2) the risk of life-threatening complications and permanent neuronal damage increases with prolonged seizure activity. Substantial effort and resources have been dedicated to developing a safe, rapid-acting diazepam nasal spray that can be administered in emergency situations or prophylactically by patients who experience auras. However, formulating an aqueous solution of diazepam for a nasal spray device has been challenging because the drug has very low solubility. This solubility issue can be circumvented by co-administering a hydrophilic prodrug of diazepam with a converting enzyme. Besides addressing solubility, this strategy leads to an increase in the chemical activity gradient that drives drug absorption.