Conversion of a soluble diazepam prodrug to supersaturated diazepam for rapid intranasal delivery: Kinetics and stability

Rautiola, Davin; Cloyd, James C.; Siegel, Ronald A.

doi:10.1016/j.jconrel.2018.09.013

Cited by 9 publications

(9 citation statements)

References 30 publications

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“…1S). The rate constant, k 2 6 S.D., for cyclization of ORI, previously measured in vitro under the same conditions (Rautiola et al, 2018), was assumed to remain constant at 0.470 6 0.012 minutes 21 in vivo. As listed in Table 1, the APB concentrations were scaled with the AVF concentration so that hydrolysis of AVF would be complete at t % 4 minutes, regardless of the dose level.…”

Section: Resultsmentioning

confidence: 99%

“…where i represents each tissue compartment that has an outflow to the venous pool and j represents each tissue compartment that has an inflow from the arterial pool. At pH 7.4, the half-life for cyclization of ORI is 1.47 minutes (Rautiola et al, 2018), so we assume most of the conversion to DZP occurs in the nasal cavity. Absorbed ORI would continue to transform into DZP in the mucosa and in the blood (Upshall et al, 1990).…”

Section: Coadministration Of Prodrug and Converting Enzyme To Ratsmentioning

confidence: 99%

“…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. 1).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Coadministration Of Prodrug and Converting Enzyme To Ratsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…We are currently investigating a two-part formulation strategy for the intranasal delivery of benzodiazepines to treat seizure emergencies [9,10]. These formulations contain reactive species that must be kept separate during storage, namely a prodrug and an enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…The availability of such a device would revolutionize intranasal delivery by enabling two-part formulation strategies and opening up the pharmacokinetic advantages of intranasal delivery to drugs that cannot be stored in solution. Born out of a desire to coadminister reactive prodrug/enzyme combinations for intranasal delivery of drugs with low solubility [9,10], we have designed a pneumatically driven, dual chamber nasal spray device for rapid mixing and atomization of pre-metered doses. A description of the device mechanism and results from preliminary testing of a proof of concept prototype follows.…”

Section: Introductionmentioning

confidence: 99%

Nasal Spray Device for Administration of Two-Part Drug Formulations

Rautiola

Siegel

2019

2019 Design of Medical Devices Conference

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Intranasal drug delivery is an attractive route to noninvasively achieve a rapid therapeutic effect, avoid first pass metabolism, and bypass the blood brain barrier. However, the types of drugs that can be administered by this route has been limited, in part, by device technology. Herein, we describe a pneumatic nasal spray device that is capable of mixing liquid and solid components of a drug formulation as part of the actuation process during dose administration. The ability to store a nasal spray drug formulation as two separate components can be leveraged to solve a variety of stability issues that would otherwise preclude intranasal administration. Examples of drugs that could be delivered intranasally by utilizing this two-part formulation strategy include biomolecules that are unstable in solution and low solubility drugs that can be rendered into metastable supersaturated solutions. A proof of concept nasal spray device prototype was constructed to demonstrate that a liquid and solid can be rapidly mixed and atomized into a spray in a single action. The primary breakup distance and angle of the spray cone were measured as a function of the function of the propellant gas pressure.

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α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition

Kim

Hwang

Khalmuratova

et al. 2020

Journal of Controlled Release

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Conversion of a soluble diazepam prodrug to supersaturated diazepam for rapid intranasal delivery: Kinetics and stability

Cited by 9 publications

References 30 publications

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

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

Nasal Spray Device for Administration of Two-Part Drug Formulations

α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition

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