From microneedles to nanocarriers, researchers are reconsidering how to make GLP-1 drugs longer lasting, better tolerated and more patient-friendly, while warning that many next-generation systems are still years away from routine clinical use.
Review: Advances in GLP-1 receptor agonist delivery systems for obesity and diabetes
A new review article has been published in the journal Acta Pharmaceutica Sinica B summarizes the advances in three major glucagon-like peptide 1 receptor agonist (GLP-1RA) drug delivery systems. They are recommended for selected patients with obesity or type 2 diabetes, depending on indication, comorbidities, and treatment goals.
background
Obesity is a chronic metabolic disease characterized by excessive accumulation of body fat. More than 1 billion people around the world currently live with this health condition. Obesity has a significant negative impact on nearly every body system, increasing the risk of several other chronic diseases, including diabetes, heart disease, kidney disease, and cancer.
Lifestyle modifications and medications are the two main treatment options for both obesity and diabetes. However, the lack of long-term compliance with lifestyle modifications, adverse side effects, poor bioavailability, rapid clearance, and instability of many approved drugs have made obesity and diabetes management difficult.
Glucagon-like peptide-1 receptor agonists (GLP-1RA), such as exenatide, liraglutide, and semaglutide, have shown promise in reducing weight, improving glycemic control, and slowing the progression of cardiovascular and kidney disease.
Although these drugs are generally well tolerated, gastrointestinal side effects are common during treatment initiation or dose titration. Most GLP-1RAs are administered by subcutaneous injection, but oral semaglutide is also available. However, these methods have limitations such as low bioavailability, poor solubility, need for high-dose administration, gastrointestinal side effects, and frequent dosing.
To overcome these limitations, novel drug delivery systems have been recently developed, including nano- and microcarrier-based delivery systems, hydrogels, microneedle-based transdermal delivery systems, and enhanced long-acting or composite formulations.
This review focused on three major GLP-1RAs, including exenatide, liraglutide, and semaglutide, and provided a detailed overview of the potential utility and remaining challenges associated with these drug delivery systems.
Nanocarrier drug delivery system (NDDS)
Nanocarrier drug delivery systems (NDDS) have been developed to improve targeted drug delivery, enhance drug efficacy, increase bioavailability, and reduce side effects. In these systems, drugs are encapsulated or attached to nanoparticles that can cross biological barriers, facilitating direct delivery to specific tissues or cells.
The main challenges of NDDS include biocompatibility, biodegradability, immune evasion effects, solubility and stability in biological environments, and potential off-target effects.
Exenatide-loaded nanoparticles have been shown in cellular and animal studies to improve glycemic control, reduce insulin resistance, improve lipid profiles, reduce organ damage, and support weight management.
Liraglutide-loaded nanoparticles have been found in preclinical or early-stage studies to improve patient adherence, increase bioavailability, sustain hypoglycemic effects, reduce food intake and body weight, and prevent cardiomyopathy and lipotoxicity.
Semaglutide-loaded nanoparticles have been found in experimental models to improve glucose homeostasis and insulin sensitivity, reduce liver inflammation and oxidative stress, and manage diabetic cardiomyopathy and other metabolic disorders.
Microspheres and particulate systems
Microspheres are organic and inorganic spherical, free-flowing particles that can maintain their shape and structural integrity even when loaded with drugs. The high surface area to volume ratio facilitates controlled and sustained drug release.
Microparticles are composed of a variety of materials including polymers, ceramics, glasses, metals, and composites. These solid, porous, or hollow particles are widely used due to their versatility and biocompatibility.
The main challenges of microsphere and particulate systems include complex and costly manufacturing processes, product variability, and environmental degradation of certain components.
A new extended-release microsphere formulation of exenatide, known as DA-3091, has shown promise in the management of obesity, diabetes, and non-alcoholic fatty liver disease, providing effective metabolic control with less frequent dosing and potentially improving patient compliance.
Liraglutide-loaded microspheres have shown promise for sustained drug release for more than a month. These microspheres demonstrate therapeutic efficacy comparable to daily liraglutide injections, improving pancreatic and liver function while achieving high drug loading and encapsulation efficiency.
Hydrogel-based delivery system
Hydrogel-based delivery systems are composed of highly hydrated physically or covalently cross-linked polymer networks, which allow hydrogels to efficiently encapsulate and protect a wide range of bioactive substances.
Although hydrogels can mimic the extracellular matrix of the brain and may support central nervous system delivery strategies, penetration of the blood-brain barrier remains a major technical challenge.
The main challenges of hydrogel-based delivery systems include difficulty in large-scale production, difficulty in precisely controlling gelation, risk of immunogenicity, and potential for uneven drug distribution and retention within brain tissue.
Long-acting injectable exenatide-loaded hydrogels have shown promise in preclinical studies to minimize initial burst release, achieve stable and sustained drug delivery over a week, and improve glucose tolerance and weight management.
Semaglutide-loaded hydrogels have shown promise in experimental studies by maintaining therapeutic drug levels for more than six weeks with a single injection, effectively controlling blood sugar levels and body weight.
Transdermal drug delivery system (TDDS)
Transdermal drug delivery systems (TDDS) are non-invasive methods of delivering drugs through the skin. These systems are particularly suited to avoid gastrointestinal side effects, avoid first-pass metabolism, and maintain constant drug levels in the blood.
Distinct advantages of TDDS compared to other drug delivery systems include self-administration, sustained drug release, and reduced dosing frequency. These systems also enhance patient adherence by overcoming barriers associated with injectable and oral medications.
The main challenges of TDDS include limited drug loading capacity and insufficient skin penetration due to the low mechanical strength of polymeric microneedles and differences in skin properties between individuals.
TDDS formulated with exenatide has been shown in experimental studies to improve skin permeability, improve long-term storage stability, maintain blood concentrations for up to 48 hours, increase bioavailability, rapidly lower blood sugar levels, and reduce food intake.
In mouse models of diabetes and obesity, liraglutide-loaded TDDS has shown promise in increasing drug absorption, improving bioavailability, and effectively controlling glucose homeostasis and weight management.
long-acting or combined preparations
Long-acting formulations have been developed to stably release drugs over long periods of time, ranging from weeks to years. These formulations are particularly effective in improving compliance and treatment efficacy in patients with chronic diseases.
The main challenges associated with long-acting formulations include high material costs, limited availability of biomaterials, and system complexity.
Combined drug delivery systems are new ways to combine two or more therapeutically active agents, such as biologics or small molecules, into a single formulation. This method is useful for targeting multiple disease pathways simultaneously.
The main challenges of this method include maintaining stability and compatibility of multiple drugs, avoiding unwanted interactions, and optimizing pharmacokinetics and pharmacodynamics.
Once-weekly long-acting exenatide formulations are expected to significantly improve glycemic control and promote weight loss in patients with poorly controlled type 2 diabetes.
A combination formulation containing a liraglutide nanoformulation and an SGLT-2 inhibitor has been shown to significantly improve blood lipid profiles in patients with type 2 diabetes. Fixed ratio insulin and GLP-1RA co-formulations have stronger clinical trial support than many new nanocarrier, hydrogel, and microneedle systems.
take home message
This review highlights the potential clinical benefits and tolerability of new GLP-1RA delivery systems. However, many of these technologies are still in preclinical or early stages of development and require large-scale, long-term studies to more definitively assess long-term efficacy, safety, and cost-effectiveness before routine clinical use.
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