title: Zolpidem Mucoadhesive Formulations for Intranasal Delivery: Characterization, In Vitro Permeability, Pharmacokinetics, and Nasal Ciliotoxicity in Rats.
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.
authors.affiliation: Renascence Therapeutics Limited, 2 Dai Fu Street, Tai Po Industrial Estate, New Territories, Hong Kong.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Renascence Therapeutics Limited, 2 Dai Fu Street, Tai Po Industrial Estate, New Territories, Hong Kong.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Renascence Therapeutics Limited, 2 Dai Fu Street, Tai Po Industrial Estate, New Territories, Hong Kong.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lee
authors.affiliation: Renascence Therapeutics Limited, 2 Dai Fu Street, Tai Po Industrial Estate, New Territories, Hong Kong.
authors.forename: Melvin
authors.initials: M
authors.lastname: Toh
authors.affiliation: Renascence Therapeutics Limited, 2 Dai Fu Street, Tai Po Industrial Estate, New Territories, Hong Kong. Electronic address: tho@rns-therapeutics.com.
authors.forename: Tony
authors.initials: T
authors.lastname: Ho
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry; D000269:Adhesives; D000281:Administration, Intranasal; D000818:Animals; D019540:Area Under Curve; D002463:Cell Membrane Permeability; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008567:Membranes, Artificial; D009297:Nasal Mucosa / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D000077334:Zolpidem
chemical_list: D000269:Adhesives; D005079:Excipients; D006993:Hypnotics and Sedatives; D008567:Membranes, Artificial; D011725:Pyridines; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077334:Zolpidem
keywords: bioavailability; excipients; formulation; nasal absorption; nasal drug delivery; permeability; pharmacokinetics; physicochemical properties; solubility