Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges

ABSTRACT

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), approved by the US FDA for obesity treatment, are typically administered subcutaneously, an invasive method leading to suboptimal patient adherence and peripheral side effects. Additionally, this route requires the drug to cross the restrictive blood-brain barrier (BBB), limiting its safety and effectiveness in weight management and cognitive addiction disorders. Delivering the drug intranasally could overcome these drawbacks.

Areas covered

This review summarizes GLP-1 RAs used as anti-obesity agents, focusing on the intranasal route as a potential pathway to deliver these biomolecules to the brain. It also discusses strategies to overcome challenges associated with nasal delivery.

Expert opinion

Nose-to-brain (N2B) pathways can address limitations of the subcutaneous route for GLP-1 RAs. However, peptide delivery to the brain is challenging due to nasal physiological barriers and the drug’s physicochemical properties. Innovative approaches, such as cell permeation enhancers, mucoadhesive systems, and nanocarriers in nasal formulations, along with efficient drug delivery devices, show promising preclinical results. Despite this, successful preclinical data does not guarantee clinical effectiveness, highlighting the need for comprehensive clinical investigations to optimize formulations and fully utilize the nose-to-brain interface for peptide delivery.

KEYWORDS:

• GLP-1 RAs
• nanoparticles
• nose-to-brain
• obesity
• olfactory region

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Article highlights

• Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promising outcomes for chronic weight management in obese individuals.

• Administration of GLP-1 RAs via the subcutaneous route poses several drawbacks including invasiveness, patient discomfort, systemic side effects, and the need to penetrate the restrictive blood-brain barrier (BBB).

• The nasal route offers a direct pathway to the brain through the olfactory and trigeminal nerve pathways, bypassing the BBB and facilitating drug delivery to the central nervous system (CNS) while minimizing side effects.

• Despite the potential benefits of nose-to-brain (N2B) drug delivery for enhancing obesity treatment, several challenges remain that need to be addressed.

• Various formulation strategies hold great potential in addressing the limitations associated with N2B peptide delivery, as demonstrated in numerous preclinical and clinical trials.

• Different intranasal devices are being evaluated for their effectiveness in N2B peptide delivery.

Declarations of Interest

F. Oveissi, S. Maleknia, A. Fathi, and T. Abrams are employed by Tetratherix Pty. Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This paper was funded by the International Macquarie University Research Excellence Scholarship (iMQRES) supported by New South Wales Ministry of Health and Medical Research (TSS Khan) and by a Fellowship grant from the National health and Medical Research Council (NHMRC) of Australia (APP173363) (D Traini).