Brain-Targeted Intranasal Delivery of Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics

• Main Authors: Sravanthi Reddy Pailla (Author), Sunitha Sampathi (Author), Vijayabhaskarreddy Junnuthula (Author), Sravya Maddukuri (Author), Sujatha Dodoala (Author), Sathish Dyawanapelly (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics14050978; 1999-4923
• Keywords: brain targeting; catalepsy; zotepine; nose-to-brain delivery; pharmacokinetics; microemulsion; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 14, Iss 5, p 978 (2022)

The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% <i>w/w</i> of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% <i>w/w</i> of S_mix (Labrasol and Transcutol HP, and 40% <i>w/w</i> of water resulting in a globule size of 124.6 ± 3.52 nm with low polydispersity index (PDI) (0.212 ± 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug). In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC_0-t24 (18.63 ± 1.33 h × µg/g) in the brain by approximately 4.3-fold than oral ME (4.30 ± 0.92 h × µg/g) and 7.7-fold than intravenous drug solutions (2.40 ± 0.36 h × µg/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration.