Intranasal and inhaled delivery systems for targeting circadian dysfunction in neurodegenerative disorders, perspective and future outlook

Synchronisation of the suprachiasmatic nucleus (SCN) driven endogenous clock, located within the central nervous system (CNS), and exogenous time cues, is essential for maintaining circadian rhythmicity, homeostasis and overall wellbeing. Disordered circadian rhythms have been associated with various conditions, inclusive of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Traditional pharmacological approaches to circadian dysfunction in neurodegenerative disorders have primarily focused on oral drug delivery. Oral medications often face challenges in achieving the necessary systemic circulation to effectively bypass the blood brain barrier (BBB) and reach the CNS, primarily due to low or variable bioavailability. Advancements in non-invasive delivery methods, such as orally inhaled and intranasal formulations, present promising alternatives for targeting the CNS. Orally inhaled and intranasal drug delivery allows for medications to rapidly achieve high systemic circulation through increased bioavailability and fast onset of action. Additionally, intranasal delivery allows for therapies to bypass the BBB through the olfactory or trigeminal nerve pathways to directly enter the CNS. This review assesses the potential for orally inhaled and intranasal therapies to treat circadian disorders in neurodegenerative conditions. In addition, this review will explore melatonin as an example of enhancing therapeutic outcomes by adopting inhaled or intranasal drug delivery formulations to improve drug absorption and target circadian disorder more effectively.