FORMULATION DEVELOPMENT - Innovative Drug Delivery Approaches for GLP-1 Agonists: Enhancing Medication Adherence & Treatment Outcomes

INTRODUCTION

Obesity is a major global health issue, affecting more than 890 million adults. In 2022, 2.5 billion adults aged 18 years and older were overweight.¹ Glucagon-Like Peptide-1 (GLP-1) recep­tor agonists have emerged as a revolutionary treatment for obe­sity, showing significant effectiveness in reducing weight by regulating appetite and energy balance.² However, most of the current GLP-1 formulations have limitations that can affect patient adherence and treatment success, such as frequent injections, gastrointestinal side effects, inconsistent and low bioavailability, as well as high price.

Advancements in pharmaceutical technology are paving the way for improving GLP-1 agonist formulations, delivery methods, and cost. These innovations aim to overcome existing challenges while enhancing therapeutic effectiveness. Optimizing delivery systems is crucial for long-term obesity treatment and medication adherence.

This article highlights recent developments in GLP-1 agonist formulations and delivery methods, including advanced injectable formulations (eg, prolonged release), novel oral delivery systems (eg, buccal tablets), and topical formulations (eg, transdermal patches). These advancements are vital for healthcare providers and researchers striving to improve obesity treatment outcomes.

GLP-1 & GLP-1 ANALOGS

Glucagon-like peptide-1 (GLP-1) is a 37-amino acid hor­mone derived from the proglucagon gene, recognized for its wide-ranging pharmacological potential.3 It is primarily secreted in the intestine in an inactive form, which is then enzymatically converted into its active variants. GLP-1 exerts its effects by bind­ing to GLP-1 receptors (GLP-1R), which are predominantly found in the pancreas. This interaction promotes insulin secretion and inhibits glucagon release, contributing to reduction of glucose in blood.4 Beyond the pancreas, GLP-1 receptors are also expressed in various organs, including the brain, heart, gastrointestinal tract, lungs, liver, kidneys, adipose tissue, and skeletal muscle, contributing to its diverse physiological roles.³

However, the active forms of GLP-1 have a very short plasma half-life (less than 2 minutes) due to rapid degradation by the en­zyme dipeptidyl peptidase-4 (DPP-4).^3,4 This enzymatic cleavage not only inactivates GLP-1 but also generates metabolites that may act as antagonists at the GLP-1 receptor.³ Because enzyme DPP-4 is mainly located on the surface of the intestinal cells, a large portion of GLP-1 is degraded to inactive metabolites, and only 25% of GLP-1 reaches the blood circulation.

GLP-1 analogs are peptides that were developed to mitigate the limitations associated with endogenous GLP-1, including the short plasma half-life (t1/2) and the rapid enzymatic degradation by DPP-4.

GLP-1 DRUGS & AVAILABLE DOSAGE FORMS

The first drug in this class for treat­ment of type 2 diabetes, Exenatide (Byetta^®), received approval from the US FDA in 2005. More than a decade later, in 2017, long-acting and more potent GLP-1 analogs, such as Semaglutide, were de­veloped (Table 1).

Semaglutide, initially approved in 2017 under the brand name Ozempic^® for the treatment of type 2 diabetes, re­ceived FDA approval in 2021 as Wegovy^® for obesity management. By that same year, it had become one of the top 100 most-prescribed drugs in the US.

INJECTABLE DOSAGE FORMS

GLP-1 receptor agonists have emerged as effective pharmacological tools for managing obesity, with clinical tri­als demonstrating weight loss ranging from 5% to 15% of initial body weight over a 12-month period.¹ However, most of these agents require subcutaneous admin­istration, which can negatively impact pa­tient adherence due to the discomfort and inconvenience of regular injections.⁵

Currently, injectable GLP-1 analogs are divided into short- and long-acting drugs. Short-acting GLP-1 analogs (Table 2) reduce glucose response after eating food by increasing insulin secretion and delaying gastric emptying. Due to their short plasma half-life t1/2 (~2-4 h), they are administered once or twice daily.

Short-acting GLP-1 analogs often re­sult in fluctuating plasma concentrations, contributing to side effects and inconsistent therapeutic outcomes. These limitations have driven pharmaceutical research to­ward developing advanced delivery sys­tems that maintain efficacy while improving patient compliance.¹

One major advancement is the devel­opment of long-acting injectable formula­tions. These utilize technologies, such as microsphere encapsulation, depot sys­tems, and molecular modifications, to ex­tend drug release and reduce injection frequency.⁶ Polymer-based microsphere systems, in particular, use biodegradable materials to enable gradual drug release, potentially supporting once-monthly or even less-frequent dosing schedules.

Forming depots in situ represents an­other innovative approach. In the body, the liquid formulation converts to a gel sys­tem upon injection, allowing for sustained drug release through a matrix formation.¹ Molecular modification is used to reduce the susceptibility of the drug to enzyme degradation providing longer half-life.

ORAL FORMULATIONS

Oral tablets and capsules are consid­ered the most convenient dosage forms for pharmaceuticals. Oral Semaglutide was approved by the FDA in 2019 as the first oral GLP-1 receptor agonist for type 2 diabetes. Oral Semaglutide has a lower bioavailability (0.8%) compared to subcutaneous Semaglutide but achieves therapeutic levels with once-daily admin­istration. The half-life of oral Semaglutide is approximately 1 week, allowing for steady-state activity with daily dosing.

Formulating GLP-1 drugs for oral ad­ministration presents several challenges due to the inherent properties of peptides. Peptides are susceptible to degradation by stomach acid and digestive enzymes, which significantly reduces their bioavail­ability.⁷

Additionally, the large molecular size and hydrophilicity of peptides hinder their absorption across the gastro-intesti­nal epithelium.⁷ By innovative approaches, such as using protective barriers, perme­ation enhancers, and advanced delivery systems to improve bioavailability, re­searchers are developing new GLP-1 ana­log drugs to make oral formulations a promising alternative for improving patient experience and adherence.⁵

 KEY APPROACHES TO OVERCOME CHALLENGES IN PEPTIDE DELIVERY

• Protein engineering to resist enzymatic degradation
• Enzyme inhibitors and stabilizers for pro­tection and stability
• PEGylation and albumin binding for half-life extension
• Enteric coatings for pH protection
• Encapsulation systems (eg, nanoparti­cles, liposomes)
• Permeation enhancers like SNAC
• Mucoadhesive systems for prolonged mucosal contact

Several of these approaches are achieved by use of appropriate excipients.

ROLE OF EXCIPIENTS IN ORAL FORMULATIONS

Excipients play crucial roles in en­hancing the stability and bioavailability of oral GLP-1 formulations. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrroli­done (PVP), and microcrystalline cellulose (MCC), to name a few, are commonly used as matrix formers, binders, and fillers in tablet formulations. MCC for example is one the excipients used in oral formula­tion of Semaglutide.⁸ Another formulation aid that has been used in Semaglutide tablets is called SNAC (Sodium N-(8-[2-Hydroxylbenzoyl] Amino) Caprylate; Sal­caprozate sodium), which is an absorption enhancer used to improve the bioavail­ability of peptide and protein therapeutics when administered orally. SNAC enhances absorption by neutralizing the pH in the stomach, protecting the drug from degra­dation by gastric enzymes and increasing membrane permeability.⁸

Often a combination of approaches is investigated to study GLP-1 absorption and stabilities. The use of hydrophobic polymers such as poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) in oral tablets and enzyme inhibitors may show potential for improving the oral bioavailability of GLP-1 agonists.⁹

These technologies work together to protect the peptide from enzymatic break­down while ensuring close contact with the intestinal tissue, thereby enhancing ab­sorption. For example, encapsulation of Li­raglutide, a long-acting GLP-1, in PLGA NPs significantly protected the drug from degradation in simulated gastric and in­testinal fluids.^10,11 Another example is Oc­treotide (Mycapssa^®), a synthetic analog of the natural peptide hormone somatostatin, which is formulated using enteric coating in combination with Transient Permeability Enhancer (TPE^®) technology to facilitate oral delivery.¹⁷ Enteric coatings are used in oral peptide formulations under devel­opment, but for oral Semaglutide an alter­native strategy is used for gastric absorption rather than intestinal targeting.

Mucoadhesive hydrophilic polymers, such as POLYOX™ polyethylene oxide, are other polymeric excipients that are investi­gated in buccal delivery systems, such as tablets and oral films.^12-14 In an older study, researchers investigated the absorp­tion and effects of a mucoadhesive, biodegradable buccal GLP-1 tablets in 10 patients with type 2 diabetes.¹² Bilayer buccal tablets were prepared using POLYOX™ as an adhesive layer with a per­meation enhancer. Therapeutic GLP-1 lev­els were achieved via buccal delivery and significant glucose-lowering effects in both fasting and postprandial states were ob­served.¹²

Another study explored the develop­ment of a bilayer buccal film designed to deliver a GLP-1 receptor agonist (GLP-1 RA) as a noninvasive alternative to injec­tions for managing type 2 diabetes.¹³ The film consists of a mucoadhesive layer con­taining the peptide and a backing layer to direct drug release unidirectionally. Using biodegradable polymers and the perme­ation enhancer sodium glycodeoxycholate (GDC), the researchers aimed to improve peptide absorption through the buccal mucosa. Physicochemical characterization confirmed favorable properties, such as rapid disintegration, peptide stability, and good surface morphology. Ex vivo studies using porcine buccal tissue demonstrated that a 1:2 ratio of GLP-1 RA to GDC yielded the highest peptide flux, although higher GDC concentrations showed some tissue irritation. The findings support the potential of this bilayer film as a promising buccal delivery system for GLP-1 RAs, of­fering a patient-friendly alternative to in­jectable therapies. Such advancements in oral formulation technology represent a significant step toward making GLP-1 ag­onist therapy more accessible and accept­able to patients.

EVALUATION OF ORAL GLP-1 RECEPTOR AGONISTS: SAFETY & EFFICACY CONSIDERATIONS

Although oral GLP-1 medications offer a more convenient alternative to in­jections, their safety is still under investiga­tion. For instance, Pfizer stopped the development of danuglipron following a clinical trial incident involving liver-related complications.

To ensure the safe and effective use of oral GLP-1 therapies, continued research is essential. This includes evaluating their long-term safety, effectiveness, and drug-to-drug interactions.¹⁵

ALTERNATIVE DELIVERY ROUTES & NOVEL APPROACHES

Recent advancements in drug delivery have opened new avenues for administer­ing GLP-1 receptor agonists beyond tradi­tional methods. Among these, transdermal systems, including patches, are being ex­plored for their ability to provide sustained drug release while bypassing first-pass metabolism. These systems are not only noninvasive but also offer the convenience of easy removal. Intranasal delivery is an­other promising route, leveraging the nasal cavity’s rich blood supply and per­meability.

Although intranasal delivery of GLP-1 receptor agonists has not yet reached clin­ical application, extensive research on sim­ilar peptide drugs supports its potential. For instance, intranasal insulin has been widely studied for its ability to bypass the blood-brain barrier and achieve systemic effects, demonstrating the nasal route’s vi­ability for peptide absorption when com­bined with permeation enhancers and mucoadhesive agents.¹⁶ Similarly, calci­tonin, a peptide hormone used in osteo­porosis treatment, has been successfully delivered intranasally, offering a precedent for GLP-1 analogs.¹⁶ These examples highlight the nasal mucosa’s rich vascular­ization and permeability, making it a promising target for future GLP-1 delivery systems. With appropriate formulation strategies, including the use of absorption enhancers and protective carriers, in­tranasal GLP-1 therapies could offer a noninvasive, patient-friendly alternative to injections.

Microneedle technologies are gaining attention as a hybrid between injections and transdermal delivery. These tiny, min­imally invasive needles can deliver GLP-1 agonists directly into the dermis, re­ducing discomfort and eliminating the need for sharps disposal. Innovations in dissolvable microneedles further support controlled release and patient-friendly ad­ministration.

SUMMARY

Evaluation of drug delivery systems for GLP-1 receptor agonists from injectable to advanced oral, buccal, transdermal, and intranasal formulations has resulted in significant milestones in the treatment of obesity and type 2 diabetes. While in­jectable formulations remain effective, their limitations in patient adherence have driven innovation toward more convenient and patient-friendly delivery systems. Oral Semaglutide has paved the way for non-invasive alternatives, though challenges in peptide stability and absorption persist. Emerging technologies, such as mucoad­hesive buccal films, microneedles, and transdermal patches, demonstrate prom­ising potential to overcome these barriers, offering sustained release, improved bioavailability, and enhanced patient com­pliance.

REFERENCES

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13. Karki, S., Malhotra, S., Ijaz, M., O’Cearb­haill, E., Rollet, N., & Brayden, D. J. (2025). Design of a bilayer film for buccal delivery of GLP-1 peptide receptor agonist for the treat­ment of type 2 diabetes mellitus. University College Dublin.
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Dr. Nasrin Mahmoudi is a Senior Lead Application Scientist in the Application Development and Innovation team within the Health & Pharma Solutions business group of Roquette. She helps customers in the North American region to develop their products. She was a post-doctoral fellow at Rutgers University and earned both her PharmD and Ph.D. from the Medical Sciences University of Tehran.

Dr. Michael Baumann is a Global Product Manager for METHOCEL™ within the Health & Pharma Solutions business group at Roquette. With more than 2 decades of experience in the excipients industry, he leverages scientific knowledge to create and promote consumer-friendly solutions for affordable and health-conscious medicines and supplements. He earned his PhD from the Clausthal University of Technology.