Enhanced permeation of diazepam through artificial membranes from supersaturated solutions

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Abstract

The present work consists of studies of saturated and supersaturated solutions of diazepam (DZP) in [glycofurol (GF)/water] cosolvent systems, which are a potential dosage form for intranasal administration of DZP in rapid response to epileptic seizure emergencies. Equilibrium solubility of DZP increased in a convex manner with GF content, and also increased with temperature. Rapidly mixed supersaturated 40 mg/mL solutions displayed temporal stability, with long periods before onset of crystallization. Permeation of supersaturated DZP across polydimethylsiloxane (PDMS) membranes, chosen as an in vitro model for nasal mucosa, was shown to be well described by Theeuwes's transference equation, when DZP was formulated up to three times its solubility in a particular cosolvent vehicle. Transference and time lag were independent of vehicle composition, indicating that permeation enhancement was due virtually exclusively to enhanced driving force due to supersaturation. Implications of these results on potential intranasal DZP delivery systems based on supersaturation are discussed.

Original languageEnglish (US)
Pages (from-to)896-905
Number of pages10
JournalJournal of Pharmaceutical Sciences
Volume95
Issue number4
DOIs
StatePublished - Apr 2006

Bibliographical note

Funding Information:
This work was supported by NIH grant EB003125. We thank James Cloyd and Jennifer Riss for providing DZP, Anna Grosberg and Clint Jones for initial explorations, and Dennis Weller for developing the HPLC assay.

Keywords

  • Diazepam
  • Glycofurol/water cosolvent systems
  • PDMS membrane
  • Permeation
  • Supersaturation
  • Time lag
  • Transference

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