Progress towards a prodrug/enzyme intranasal delivery system for rapid prevention/reversal of seizure emergency

Sporadic epileptic seizure emergencies (SEs) require rapid treatment to prevent the emergence of status epilepticus, a condition that can present morbidities and possible mortality. First-line treatment of SEs has involved IV administration of benzodiazepines (BZDs) to the patient in the emergency department of a hospital, outpatient buccal administration, or administration of an outpatient rectal gel. These therapies are suboptimal for a variety of reasons, and recently, BZD nasal sprays have been introduced. Such sprays must solve the problem of poor aqueous solubility of BZDs. The present sprays contain organic excipients, which can be irritating, and the BZDs show either moderate bioavailability or slow absorption. In this Perspective we review work on a purely aqueous formulation containing avizafone (AVF), a prodrug of the BZD diazepam (DZP), and the converting enzyme human amino peptidase B (APB). Mixing these two ingredients at the point of administration creates a supersaturated aqueous DZP solution, which is rapidly absorbed across the nasal mucosa without the irritation mentioned above. We review characterization of the enzyme reaction and in vivo studies in which Sprague-Dawley rats were administered the AVF/APB formulation intranasally. Tmax values of DZP in both plasma and brain were both about 8 min, and brain concentrations appear to have reached 70 ng/g, which is considered adequate for controlling seizures within 2 min. We also describe a method to ensure the long-term shelf stability of the ingredients. These results encourage further development of the AVF/APB formulation. Studies with APB and an alternative BZD, midazolam (MDZ), were not as promising due to a kinetic bottleneck following the enzyme reaction.