Ex vivo and in vivo Assessment of Paliperidone Thermal in situ Gel as Nasal-to-Brain Delivery System in Rats

Muna Yehia Ismail; Fatima Jalal Al-Gawahri

doi:10.54133/ajms.v9i2.2460

Authors

Muna Yehia Ismail Department of Pharmaceutics, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq; Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq
Fatima Jalal Al-Gawahri Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq https://orcid.org/0000-0002-4906-6241

DOI:

https://doi.org/10.54133/ajms.v9i2.2460

Keywords:

Bioavailability., Ex vivo, Nasal-to-brain delivery, Paliperidone, Thermal gel

Abstract

Background: Paliperidone (PAL), an antipsychotic drug, has limited brain availability when administered orally due to poor blood–brain barrier penetration and systemic side effects. Intranasal delivery offers a promising strategy for direct brain targeting. Objective: To investigate the pharmacokinetics and brain-targeting efficiency of paliperidone-loaded nanosuspension thermo-responsive in situ gel for nose-to-brain delivery. Methods: The optimized NB-IG7 formulation was evaluated for ex vivo permeation using a Franz diffusion cell with sheep nasal mucosa, employing simulated nasal fluid. The cumulative drug permeation, steady-state flux (Jss), and permeability coefficient (P) were determined spectrophotometrically. In vivo pharmacokinetic and brain-targeting studies were done on male rats, where NB-IG7 gel was administered nasally vs. an IV dose. Over 48 hours, plasma and brain drug levels were measured for pharmacokinetic measurements. Results: The ex vivo tests showed that NB-IG7 had 3.3 times higher permeation across the nasal mucosa than PAL suspension, which confirmed that it had better mucosal penetration. Intranasal administration of NB-IG7 achieved significantly higher brain concentrations of PAL compared with IV administration. The brain C_max and AUC0–48_hr were 1.89µg/ml and 63.6 hr·µg/ml, respectively, representing 2.66- and 2.68-fold increases over IV administration (C_max 0.71µg/ml, AUC0–48_hr 23.7hr·µg/ml). Plasma exposure was lower after intranasal delivery (C_max 0.19µg/ml, AUC_0–48hr 4.66hr·µg/ml) compared with IV dosing (C_max 0.87µg/ml, AUC0–48_hr13.98hr·µg/ml). Brain-targeting assessments showed markedly enhanced values (DTE 807%, DTI 8%, and %DTP 91%), confirming efficient nose-to-brain transport via olfactory and/or trigeminal pathways. Conclusions: The new formula had superior enhanced brain targeting with reduced systemic exposure.

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