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

Siegel, Ronald A.; Kapoor, Mamta; Cheryala, Narsihmulu; Georg, Gunda I.; Cloyd, James C.

doi:10.1016/j.yebeh.2015.05.004

Cited by 11 publications

(11 citation statements)

References 11 publications

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“…When compared with rectal diazepam, intranasal midazolam was more effective in seizure cessation (OR 1.78; 95% CI 1.11-2.85) without differences in serious adverse effects (OR 0.70; 95% CI 0.27-1.86). Recently, water-soluble peptide prodrugs of midazolam and diazepam have been synthesized and coadministered with a converting enzyme in an aqueous vehicle that may enable transport across the nasal mucosa leading to higher absorption rate [72]. Buccal administration of midazolam seems an effective and safe alternative that might even be more effective than rectal diazepam in seizure control in children (OR: 1.78; 95% CIs: 1.11-2.85) [54 & ], possibly because transmucosal and sublingual absorption is faster and more complete than after rectal administration [73].…”

Section: Intranasal Rectal Buccal and Intramuscular Routes Of Adminmentioning

confidence: 99%

Recent advances in status epilepticus

Trinka

Brigo

Shorvon

2016

Current Opinion in Neurology

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Section: Intranasal Rectal Buccal and Intramuscular Routes Of Adminmentioning

confidence: 99%

Recent advances in status epilepticus

Trinka

Brigo

Shorvon

2016

Current Opinion in Neurology

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“…An approach to circumventing the problems with drug solubility and permeability without the need for special solvents is to use aqueous solutions of water-soluble prodrugs co-administered with converting enzymes. Siegel et al explored IN delivery of diazepam and midazolam prodrugs, both of which are converted to their respective drugs by Aspergillus oryzae protease [ 62 ]. However, since this enzyme comes from a fungus, it could be allergenic.…”

Section: Experimental Approaches To In Deliverymentioning

confidence: 99%

“…They found that this combination can create supersaturated solutions of diazepam and midazolam, and that this supersaturated solution exhibited a several-fold increase in permeation through Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers compared to saturated aqueous diazepam. They also created a chirally pure prodrug of midazolam, which, when converted into a supersaturated solution of midazolam, permeated the monolayers 25 times faster than saturated aqueous midazolam [ 62 ].…”

Section: Experimental Approaches To In Deliverymentioning

confidence: 99%

Intranasal Therapy to Stop Status Epilepticus in Prehospital Settings

Benfield

Musto

2017

Drugs R D

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Status epilepticus (SE) is a medical emergency characterized by uncontrolled, prolonged seizures with rapid and widespread neuronal damage. Patients that suffer from longer episodes of SE are more likely to have poorer clinical outcomes and a higher cost of healthcare. Understanding novel molecular mechanisms that regulate inhibitory and excitatory neurotransmission that initiate SE and the necessary medical infrastructure to stop SE could help identify targets for early intervention. Intranasal administration of benzodiazepines may shorten the time between initiation and cessation of seizures when compared to other routes of administration. Current pharmaceutical administration guidelines are appropriate for sporadic incidences of SE, but exploring other approaches is necessary to prepare for situations involving multiple patients outside of a hospital, such as a massive chemical weapons attack. Intranasal drug delivery helps to circumvent the blood–brain barrier and offers a noninvasive way to quickly administer drugs in settings that require an immediate response, such as nerve agent exposure. In addition, examining the intranasal delivery of new drugs, such as nanotherapeutics, may lead to more effective, noninvasive, scalable, and portable methods of treating SE.

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“…Although prodrug formulations typically rely on endogenous enzymes for in vivo biotransformation to the active drug (Jornada et al, 2015), unpublished results from a pilot canine study performed by our group suggested that exogenous enzyme would need to be included in the formulation to achieve the desired prodrug conversion rate and bioavailability. A series of in vitro experiments combining water soluble benzodiazepine prodrugs with the fungal converting enzyme Aspergillus oryzae protease (AOP) demonstrated that the formulations were capable of producing supersaturated solutions of the active drug, leading to an enhanced permeation rate of drug across cultured cell monolayers (Kapoor and Siegel, 2013;Kapoor et al, 2014Kapoor et al, , 2016Siegel et al, 2015). Further in vitro studies characterized the conversion kinetics of AVF to DZP (Rautiola et al, 2018), which first involves enzymatically catalyzed release of the lysine and formation of an open-ring intermediate (ORI), followed by spontaneous closure of ORI to form DZP ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats

Rautiola

Maglalang

Cheryala

et al. 2019

J Pharmacol Exp Ther

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Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B. Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% 6 6.0%, 112% 6 10%, and 114% 6 7% bioavailability; maximum plasma concentrations 71.5 6 9.3, 388 6 31, and 355 6 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 6 0.0080 minutes 21 for diazepam and 0.122 6 0.022 minutes 21 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.

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

Cited by 11 publications

References 11 publications

Recent advances in status epilepticus

Recent advances in status epilepticus

Intranasal Therapy to Stop Status Epilepticus in Prehospital Settings

Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats

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