Zolpidem Mucoadhesive Formulations for Intranasal Delivery: Characterization, In Vitro Permeability, Pharmacokinetics, and Nasal Ciliotoxicity in Rats

Yanfeng Wang, Mi Li, Shuai Qian, Qizhi Zhang, Limin ZHOU, Zhong Zuo, Benjamin Lee, Melvin Toh, Tony Ho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Zolpidem is a non-benzodiazepine hypnotic for the treatment of insomnia characterized by difficulties with sleep initiation. Our study aimed at developing a zolpidem mucoadhesive formulation with minimal local toxicity, prolonged nasal residence time, and enhanced absorption after intranasal delivery. In vitro permeability studies using artificial membrane and Calu-3 cell culture model indicated efficient permeability of zolpidem. Aqueous solubility of zolpidem was found to be significantly improved by hydroxypropyl-β-cyclodextrin. Various mucoadhesive formulations were then prepared comprising zolpidem, hydroxypropyl-β-cyclodextrin, and mucoadhesive polymers such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and sodium alginate. Pharmacokinetic studies in rats demonstrated that intranasally administered zolpidem could achieve significantly faster absorption rate and higher plasma concentration than that from oral route. In comparison with solution formulation (ZLP-S03), the optimized mucoadhesive formulation (ZLP-B01) containing 0.25% hydroxypropyl methylcellulose was found to improve Cmax from 352.6 ± 86.0 to 555.7 ± 175.8 ng/mL, and AUC0-inf from 32,890 ± 7547 to 65,447 ± 36,996 ng·min/mL with mild nasal ciliotoxicity in rats.

Original languageEnglish
Pages (from-to)2840-2847
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume105
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Scopus Subject Areas

  • Pharmaceutical Science

User-Defined Keywords

  • bioavailability
  • excipients
  • formulation
  • nasal absorption
  • nasal drug delivery
  • permeability
  • pharmacokinetics
  • physicochemical properties
  • solubility

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