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

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Abstract

The low aqueous solubility of diazepam (DZP) presents a challenge in formulating nasal sprays without the use of organic solvents. One approach to overcome this challenge involves co-administration of a soluble prodrug, avizafone (AVF), with a converting enzyme to produce supersaturated DZP at the site of administration. In addition to overcoming solubility issues, the supersaturated state of DZP provides an increased driving force for enhanced permeation across nasal mucosa. However, supersaturated solutions are metastable, and there is a limit to the degree of supersaturation (S) that can be reached without causing spontaneous phase separation of the solute. The aim of this article was to determine how formulation parameters affect the rate of DZP supersaturation, maximum degree of supersaturation, and phase separation kinetics. A model enzyme, Aspergillus oryzae protease (AOP), was used to convert AVF to DZP, via an open ring intermediate (ORI). A second derivative UV spectroscopic method was developed to simultaneously monitor DZP solution concentration and the time course of DZP phase separation. Fitting a kinetic model, with prior knowledge of the enzyme kinetic parameters, the rate constant for conversion of ORI to DZP was found to be 0.470 ± 0.012 min−1. Kinetics and supersaturated solution stability were studied as a function of formulation parameters, including temperature, pH, buffering agent, AVF concentration, and enzyme concentration. The maximum aqueous solution concentration for DZP at 32 °C was determined to be 1.22 ± 0.03 mM DZP (S = 9.38) and was insensitive to changes in formulation parameters, excepting temperature. Supersaturated solutions of DZP could be maintained at the maximum concentration for >24 h, even in the presence of phase separated DZP. Polarized light microscopy, PXRD, and DSC analysis indicated that the phase separated DZP was amorphous upon formation and remained so for >24 h. Our findings suggest that co-administration of AVF with a suitable human converting enzyme will provide a viable mechanism for IN delivery of DZP and result in very rapid and complete absorption to quickly terminate seizure emergencies.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Controlled Release
Volume289
DOIs
StatePublished - Nov 10 2018

Bibliographical note

Funding Information:
We thank Dr. Narsihmulu Cheryala and Prof. Gunda I. Georg from the Institute for Therapeutics Discovery and Development (ITDD) for their helpful advice and for providing avizafone. We also thank Dr. Seema Thakral from the Characterization Facility at the University of Minnesota for conducting PXRD measurements and Ms. Usha Mishra from the Center for Orphan Drug Research (CODR) for assisting with HPLC training. Financial support for this work was provided by the Epilepsy Foundation (PI: Dr. James C. Cloyd), a 3M Science and Technology Fellowship in Drug Delivery, a Rowell Graduate Fellowship, and the American Foundation for Pharmaceutical Education. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC Program.

Funding Information:
We thank Dr. Narsihmulu Cheryala and Prof. Gunda I. Georg from the Institute for Therapeutics Discovery and Development (ITDD) for their helpful advice and for providing avizafone. We also thank Dr. Seema Thakral from the Characterization Facility at the University of Minnesota for conducting PXRD measurements and Ms. Usha Mishra from the Center for Orphan Drug Research (CODR) for assisting with HPLC training. Financial support for this work was provided by the Epilepsy Foundation (PI: Dr. James C. Cloyd), a 3M Science and Technology Fellowship in Drug Delivery , a Rowell Graduate Fellowship , and the American Foundation for Pharmaceutical Education . Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC Program .

Publisher Copyright:
© 2018 Elsevier B.V.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Avizafone
  • Diazepam
  • Enzyme kinetics
  • Intranasal
  • Metastable
  • Precipitation
  • Prodrug
  • Prodrug/enzyme
  • Second derivative spectroscopy
  • Seizure emergencies
  • Spinodal
  • Supersaturated drug

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