ABSTRACT:
Nose to brain drug delivery has emerged as a effective non-invasive method to overcome the limitations posed by the blood-brain barrier, especially in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, and depression. The nose cavity provides a direct physiological and anatomical avenue for the quick and precise delivery of drugs to the brain through the trigeminal and olfactory pathways, bypassing systemic circulation and first-pass metabolism. However, successful drug delivery through this route is influenced by numerous factors including the drug's physicochemical characteristics (e.g., pH, lipophilicity, molecular weight, and polymorphism), formulation variables (e.g., viscosity, osmolarity), and nasal anatomy. Various advanced drug carriers—such as nanoparticles, lipid-based carriers, liposomes, and nanoemulsions—have demonstrated enhanced permeation, bioavailability, and CNS targeting capabilities. Furthermore, formulation strategies like the utilization of prodrugs, enzymatic inhibitors, co-solvents, and absorption enhancers have significantly improved stability of drug and permeation through the nasal mucosa. This review provides a detailed overview of the physiological basis, transport mechanisms, influencing factors, and formulation approaches associated with nose to brain delivery. Emphasis is placed on nanocarrier systems and their capacity to transform CNS therapeutics through controlled, sustained, and site-specific delivery, while addressing the current limitations and future directions necessary for clinical translation.