Abstract
This study was designed to develop and optimize a thermosensitive intranasal gel incorporating temozolomide (TMZ) and N-acetylcysteine (NAC) as a promising platform for direct nose-to-brain drug delivery. Formulations were fabricated via cold technique utilizing Carbopol 934P and poloxamer 407 to improve gelation and mucoadhesion. After evaluating the formulations for clarity, pH, gelation temperature, gelling time, mucoadhesion, and drug loading, the formula A13 was elected as the optimized formulation based on a factorial design optimization approach. The optimized formula was further evaluated for stability, ex-vivo permeability, histopathology and in-vivo pharmacokinetic in rats. Compared with the corresponding in-situ gels containing the pure drugs, formulation A13 enhanced the ex-vivo nasal mucosal permeation of TMZ and NAC by 1.42-fold and 1.64-fold, respectively, indicating the superior permeability-enhancing effect of A13. Furthermore, histopathological examination revealed no evidence of structural damage following administration of formulation A13, confirming its safety for intranasal application. The in-vivo studies performed on rats showed significantly higher Cmax and AUC 0-24 results in brain of the optimized A13 by 1.4, 1.4, 2.6 and 1.87 folds in TMZ and NAC, respectively compared to in-situ gel of pure TMZ and in-situ gel of pure NAC, with a delayed (Tmax). The brain-to-blood concentration ratios of the TMZ-NAC-loaded in-situ gel were consistently higher than those of the pure-drug in-situ gels at most sampling time points, indicating more efficient nose-to-brain transport. Overall, these findings demonstrate that the optimized A13 is a promising and safe intranasal delivery system for enhancing the nose-to-brain delivery and bioavailability of TMZ and NAC.