Thesis (Ph.D)-Cairo University,2022.

Bibliography: p. 159-240 .

Tween 80-functionalized chitosan-lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability and considerable hepatic metabolism of metoclopramide hydrochloride (MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Quality by Design approach. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, CHARacterized and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC-loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further undergone in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC0-∞) of the dual-optimized MTC-ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw/pure MTC- ISG formulation, respectively. Interestingly, the brain-AUC0.∞ of the dual-optimized MTC-ISG formulation was 10 and 3 times more than brain-AUC0-∞ of the MTC-oral tablet and the pure MTC-ISG intranasal formulation, respectively. It was also revealed that the dual-optimized formulation significantly had the lowest liver-AUC0-∞ (862.19 ng.g1.h ̈1) versus the MTC-oral tablet (5732.17 ng.g1.h1) and the pure MTC-ISG intranasal formulation (1799.69 ng.g1.h1). The brain/blood ratio, drug targeting efficiency, nose-to-brain direct transport percentage, and drug targeting index of the dual-optimized formulation were significantly higher than those of the pure MTC-ISG intranasal formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.