New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders

TL;DR

This paper explores the nose-to-brain drug delivery pathway for treating brain disorders, using dodecyl creatine ester as a case study to highlight its potential and challenges.

Contribution

The paper provides a critical assessment of the nose-to-brain pathway from a drug development and industrial implementation perspective.

Findings

The nose-to-brain pathway allows direct drug delivery to neurons, bypassing the blood-brain barrier.

Dodecyl creatine ester demonstrates the pathway's potential for treating neuronal energy deficiencies.

Industrial and regulatory considerations are crucial for successful clinical translation of nasal drug delivery.

Abstract

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood–brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations—critical for successful clinical implementation and commercial development—remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical–clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway—or, more precisely, the “Nose-to-Neurons” pathway—offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.

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