Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies

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10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)347-350
Number of pages4
JournalEpilepsy and Behavior
StatePublished - Aug 1 2015

Bibliographical note

Funding Information:
This research was funded by grants from the Academic Health Center, University of Minnesota ; the American Epilepsy Society ; and the Epilepsy Foundation . We thank Drs. Lisa Coles, Ilo Leppik, Leah Hanson, and Edward Patterson and Ms. Patricia Maglalang for helpful discussions.

Publisher Copyright:
© 2015 Elsevier Inc.

Copyright 2015 Elsevier B.V., All rights reserved.


  • Avizafone
  • Benzodiazepine
  • Diazepam
  • Intranasal
  • Midazolam
  • Prodrug
  • Prodrug enzyme

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