title: Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies.
abstract: 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".
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Siegel
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Mamta
authors.initials: M
authors.lastname: Kapoor
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA; Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Narsihmulu
authors.initials: N
authors.lastname: Cheryala
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA; Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA; Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: cloyd001@umn.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001236:Aspergillus oryzae / Q000201:enzymology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D003975:Diazepam / Q000008:administration & dosage / Q000627:therapeutic use; D004285:Dogs; D057487:Enzyme Therapy; D004798:Enzymes / Q000008:administration & dosage; D061985:Madin Darby Canine Kidney Cells; D008874:Midazolam / Q000008:administration & dosage / Q000627:therapeutic use; D010447:Peptide Hydrolases / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D012995:Solubility; D013226:Status Epilepticus / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D004798:Enzymes; D011355:Prodrugs; D001569:Benzodiazepines; D010447:Peptide Hydrolases; D003975:Diazepam; D008874:Midazolam
keywords: Avizafone; Benzodiazepine; Diazepam; Intranasal; Midazolam; Prodrug; Prodrug enzyme