Thanks to the huge success of Semaglutide, a drug in the GLP-1 receptor agonist class, it became a household name almost overnight.
Originally developed by Novo Nordisk as a glucose-lowering drug for the treatment of type 2 diabetes, in June 2021, the FDA approved Semaglutide to be marketed as a weight-loss drug (under the trade name Wegovy). The drug is a glucagon-like peptide 1 (GLP-1) receptor agonist that mimics its effects by reducing hunger, eating less, and calorie intake, making it effective in weight loss. In addition, several recent clinical trials have shown that GLP-1 receptor agonists, such as simethicone, also reduce the risk of cardiovascular disease.
The GLP-1 receptor agonist class of drugs requires long-term use for therapeutic benefit, and these drugs require patients to be administered by injection on a daily (liraglutide) or weekly (simelglutide) basis. Oral versions, currently under development, similarly require frequent administration. Therefore, maintaining sustained plasma GLP-1 receptor agonist levels through improved dosing techniques is important for better treatment of diabetes, weight loss, and the prevention of cardiovascular disease.
Recently, researchers at Stanford University published a paper in Cell Reports Medicine titled "Use of a biomimetic hydrogel depot technology for sustained delivery of GLP-1 receptor agonists reduces burden of diabetes management".
The study developed a polymer nanoparticle hydrogel delivery system, which the team tested to deliver the GLP-1 receptor agonists liraglutide or simethicone, which sustained sustained-release therapeutic drug levels in rats for up to 42 days (6 weeks) after a single injection, which is equivalent to 4 months in humans.
The corresponding author of the paper, researcher Eric Appel, said, "Using the hydrogel delivery system developed in this study, only three injections of injectable selegiline are needed per year, which will make it easier for patients with diabetes or obesity to adhere to their treatment regimen and improve adherence."
To stabilize GLP-1 receptor agonists and prolong their therapeutic effects, the researchers used a variety of strategies, developing medications that ranged from twice-daily to once-weekly. The pharmacokinetic profile of liraglutide supports its once-daily administration, whereas simethicone can be administered weekly. While moving from daily to weekly dosing has improved patient compliance, this still leaves room for improvement.
In this study, the research team hopes to develop long-acting liraglutide and simelglutide formulations that improve from daily or weekly dosing to a single dose of continuous treatment for more than 4 months.
The research team drew inspiration from other long-acting drug products, such as Lupron Depot, a potent microsphere-based formulation of the peptide Leuprorelin for the treatment of endometriosis that can be administered every 3 months. However, this microsphere-based drug release technology requires substantial optimization for compatibility and release of other drugs and achieves extended release for up to several months only for relatively hydrophobic peptides.
Therefore, the research team attempted to design an injectable hydrogel delivery technology to achieve months-long sustained release of GLP-1 receptor agonists. Hydrogels can address some of the drawbacks of microsphere technology because they maintain the natural aqueous environment surrounding the encapsulated drug and are therefore compatible with drug molecules developed in existing approved water-soluble formulations.
The research team sought to utilize an injectable hydrogel platform that was generated by self-assembly via dynamic, endocytosis-driven supramolecular interactions between biodegradable nanoparticles and hydrophobically modified hydroxypropylmethylcellulose (HPMC) derivatives for the development of a long-acting GLP-1 receptor agonist formulation. The team has previously demonstrated that these polymeric nanoparticle (PNP) hydrogels are capable of delivering a wide range of biologic releases (including proteins, vaccines, and cells), with release times ranging from a few days to more than 6 months.
Unlike conventional covalently cross-linked hydrogels, PNP hydrogels are formed through strong and dynamic physical interactions. Thus, these materials address the shortcomings of other hydrogel-based drug storage technologies with the following advantages:
1)Mild formulation requirements that facilitate drug stability during manufacturing and storage
2)Remarkable shear-thinning properties, which can be injected with a needle
3)Its structure and rapid self-healing properties mitigate the sudden release of drugs stored therein
4)Having a sufficiently high yield stress to form a robust reservoir that persists under normal stresses in the subcutaneous space after drug administration
5)Prolong the release of therapeutic drugs
In addition, these PNP hydrogels are designed to be biodegradable, have been shown to be non-immunogenic in mice, rats, pigs, and sheep, and do not promote the body's immune response to the drugs they are loaded with. These PNP hydrogels can be prepared and stored in pre-filled syringes and remain stable under standard storage conditions.
Next, the team tested the optimization of the pharmacokinetics of GLP-1 receptor agonists through the drug encapsulation and release properties of these PNP hydrogels. Using a type 2 diabetic rat model, the team demonstrated that a single injection of PNP hydrogels loaded with a GLP-1 receptor agonist drug could be maintained for more than 42 days (6 weeks). Moreover, PNP hydrogel-delivered GLP-1 receptor agonist treatment maintained blood glucose and weight management in type 2 diabetic rats comparable to the effects of once-daily direct GLP-1 receptor agonist medication. The half-life of simethicone in rat blood (0.29 days) was much lower than that in human blood (7 days), and the sustained effect of 6 weeks in rats was calculated to be equivalent to only one treatment every 4 months in humans.
These results suggest that long-acting GLP-1 receptor agonists delivered using PNP hydrogels are a promising therapeutic approach to manage type 2 diabetes and obesity more effectively and reduce the burden of medication for patients. In addition to its use in the treatment of type 2 diabetes and obesity, this work could help advance the development of long-acting formulations of therapeutic peptides and proteins more broadly.