In-Situ Gel-Based Nasal Delivery Enhancing Brain Targeting Via Intranasal Pathway

Abstract

Intranasal in-situ gels have gained significant attention as drug delivery systems capable of undergoing sol–gel transition in response to physiological stimuli such as temperature, pH, or ionic strength. This transformation increases nasal residence time, enhances mucoadhesion, and allows sustained drug release, thereby improving the potential for direct brain delivery. Neurological disorders such as Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, migraine, multiple sclerosis, and depression are often difficult to treat effectively because the blood–brain barrier (BBB) restricts the entry of many therapeutic agents into the central nervous system (CNS). Intranasal delivery offers a non-invasive alternative route that can bypass the BBB through the olfactory and trigeminal pathways. The objective of this review is to summarize recent advances in the formulation strategies, mechanisms of transport, evaluation parameters, and therapeutic applications of in-situ nasal gels for nose-to-brain delivery. Special emphasis is placed on thermosensitive, pH-sensitive, and ion-activated gels prepared using polymers such as poloxamer, chitosan, Gellan gum, and Carbopol. The novelty of this review lies in its integration of disease-specific applications with critical discussion of current limitations and translational challenges. Intranasal in-situ gels represent a promising approach for enhancing brain bioavailability, reducing systemic side effects, and improving patient compliance. However, further clinical investigations are required to confirm long-term safety, dose reproducibility, and therapeutic effectiveness in humans.