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Epileptic seizure emergencies are life-threatening conditions, which in their most severe form, status epilepticus, have a high mortality rate if not quickly terminated. Treatment requires rapid delivery of anti-epileptics such as benzodiazepines to the brain. The nasal route is attractive due to its non-invasiveness, potential for direct nose to brain delivery, high vascularity, relatively large absorptive surface area, and avoidance of intestinal/liver metabolism. However, the limited volume of the nasal cavity and poor water solubility of anti-epileptics restrict absorption, leading to insufficient therapeutic brain levels. This review covers various formulation approaches adopted to improve nasal delivery of drugs, especially benzodiazepines, used to treat seizure emergencies. Other general topics such as nasal anatomy, challenges to nasal delivery, and drug/formulation considerations for nose to brain delivery are also discussed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Water-soluble prodrugs can be rapidly converted by enzymes to hydrophobic drugs, whose aqueous thermodynamic solubilities are low, but are maintained in aqueous solution at supersaturated concentrations due to slow precipitation kinetics. Recently, we investigated avizafone (AVF) in combination with Aspergillus oryzae protease as a prodrug/enzyme system intended to produce supersaturated diazepam (DZP). Several fold enhancement of permeation of supersaturated DZP across Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers was observed, compared to saturated DZP solutions. However, prodrug conversion was incomplete, putatively due to partial racemization of AVF and stereoselectivity of A oryzae protease. Here we report synthesis of chirally pure AVF, and demonstrate complete conversion to supersaturated DZP followed by complete DZP permeation at enhanced rates across MDCKII-wt cell monolayers. We also synthesized, for the first time, a chirally pure prodrug of midazolam (MDZ-pro) and carried out the same sequence of studies. A oryzae protease was identified as a benign and efficient activating enzyme for MDZ-pro. The MDZ-pro/A oryzae protease system showed greater than 25-fold increase in absorption rate of MDZ across MDCKII-wt monolayers, compared to saturated MDZ. Such chirally pure prodrug/enzyme systems are promising candidates for efficient intranasal delivery of benzodiazepine drugs used in the treatment of seizure emergencies., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)