Oral Insulin Breakthroughs In Development

INTRODUCTION

Diabetes is a chronic metabolic disorder primarily classified into two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM, an autoimmune disease often diagnosed in adolescence, is marked by the body’s inability to produce insulin. In contrast, T2DM, which constitutes the majority of diabetes cases, is associated with insulin resistance and is typically diagnosed in adulthood. By 2030, the global prevalence of T2DM is expected to rise, primarily due to unhealthy lifestyle choices such as poor diet and lack of physical activity, leading to obesity. Insulin, a protein hormone, is crucial for diabetes management. While subcutaneous injections are the most common delivery method, they have limitations, including poor patient compliance and rapid insulin clearance. Noninvasive delivery methods, particularly oral administration, have been explored extensively but remain hindered by challenges related to insulin bioavailability in the gastrointestinal tract. Despite promising developments, oral insulin has yet to reach clinical application.

 

A BACKGROUND OF ORAL INSULIN RESEARCH

Research into oral insulin delivery has faced numerous challenges since the first attempts in 1921, shortly after insulin’s discovery. Early attempts at getting a viable delivery system, like giving patients insulin enterally or changing formulations by adding alcohol, did not lead to a better metabolic state. [14,15]. Despite setbacks, companies like Emisphere, Diabetology, and Oramed continued to develop oral insulin formulations, with clinical trials from 2001 to 2019 showing mixed results. Often, trials failed to demonstrate superior glycemic control over placebo, largely due to small sample sizes and challenges with insulin bioavailability. Some companies abandoned the development, but others pressed on, underscoring the continued ambition to make oral insulin a reality [16,17].

A key obstacle to oral insulin delivery is the gastrointestinal (GI) environment, which presents fluctuating pH levels and digestive enzymes that degrade insulin. The stomach, with a pH as low as 2.5, poses a significant threat to insulin stability, making enteric coatings essential for protection [18]. Additionally, enzymes such as pepsin in the stomach and trypsin in the small intestine cleave insulin into inactive peptides, complicating oral administration. Some formulations, like Oramed’s ORMD-0801, use proteinase inhibitors to protect insulin, but long-term concerns about enzyme inhibition remain [21,22].

The mucus lining of the GI tract further complicates drug absorption. This viscoelastic layer, composed mainly of water, mucin, and electrolytes, traps insulin molecules, preventing them from reaching epithelial cells for absorption. Researchers have explored mucosal adhesion systems using materials like chitosan (CS), a positively charged polysaccharide that interacts with the negatively charged mucus. This interaction increases insulin’s residence time, enhancing absorption, with preclinical studies showing promising improvements in insulin bioavailability [26–28].

Finally, the epithelial barrier, consisting of various cell types and tight junctions (TJs), also limits insulin absorption. Strategies aimed at opening TJs or using cell-penetrating peptides (CPPs) have resulted in modest improvements in bioavailability. However, risks associated with TJ disruption, such as immune responses, make these approaches less viable for long-term use. Although CPPs have doubled insulin’s transcellular transport, oral bioavailability remains low at 2.48%, highlighting the persistent challenges in oral insulin delivery [29–36].

 

A NEW APPROACH TO ORAL INSULIN DELIVERY

Recently, experts have started investigating new oral insulin delivery systems, focusing on the encapsulation of insulin within different types of nanoparticles to enhance its stability and absorption in the gastrointestinal (GI) tract. These systems were tested in preclinical models using animals like rats to assess their effectiveness in improving insulin bioavailability. Different formulations were explored, including lipid-based nanoparticles (such as solid lipid nanoparticles and nanostructured lipid carriers), polymeric nanoparticles (like chitosan-based systems and hydrogels), and inorganic nanoparticles (such as mesoporous silica and quantum dots). 

The studies assessed the ability of these carriers to protect insulin from degradation by stomach acid and enzymes, as well as their efficiency in facilitating insulin transport across the intestinal barrier. Key parameters evaluated included insulin encapsulation efficiency, bioavailability rates, and the impact on blood glucose levels in diabetic animals. Additionally, safety assessments were conducted in some cases, examining the potential toxicity of these carriers over long-term use.

 

TYPES OF NANOCARRIER-BASED ORAL INSULIN FORMULATIONS

Many nanocarrier-based oral insulin systems are currently being explored. Nanocarriers are tiny particles, often under 1000 nm in size, designed to protect insulin from degradation in the gastrointestinal (GI) tract and improve its absorption. These carriers can be classified into lipid-based, polymeric, and inorganic nanoparticles. Lipid-based nanoparticles, like solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), are advantageous for cellular uptake due to their lipid composition. Still, they face challenges with encapsulating hydrophilic molecules like insulin. Despite these challenges, some SLN formulations have achieved bioavailability rates of around 5% in animal studies [48].

Polymeric nanoparticles, another important category, use natural or synthetic polymers such as chitosan and poly(lactic-co-glycolic acid) (PLGA). The FDA has approved these polymers for their biocompatibility. Chitosan-based formulations, for instance, have shown promise due to their ability to interact with the mucus layer in the intestines and improve insulin absorption, achieving bioavailability rates of up to 18% in animal models [63]. Insulin can also be encapsulated with hydrogels and micelles. It provides sustained release and enhanced stability in the GI tract [68,70].

Inorganic nanoparticles, such as mesoporous silica nanoparticles (MSNs) and quantum dots (QDs), are also gaining traction in oral insulin delivery. These carriers offer exceptional drug-loading capacities and protection for insulin in the harsh GI environment. For example, MSNs modified with polyethylene glycol (PEG) have been reported to stabilize insulin and improve its bioavailability [74]. However, concerns about the long-term toxicity of inorganic nanoparticles remain, particularly regarding their effects on the liver, kidneys, and nervous system [75].

 

SURFACE MODIFICATION OF INSULIN NANOPARTICLES

Surface modifications of nanoparticles (NPs) have been explored to enhance the stability and absorption of oral insulin. Various strategies include using coatings, such as hydrogels and gelatin, which protect insulin in acidic environments. Hydrogels, for instance, have demonstrated the ability to control insulin release in diabetic mice, while gelatin-coated NPs maintain stability in gastric conditions [50, 90]. Additionally, pollen encapsulation techniques have been shown to significantly improve oral insulin bioavailability, leveraging the protective structure of pollen particles [92].

Adjusting the surface charge of NPs has also been investigated. Negatively charged NPs enhance mucus permeability, while positively charged ones prolong their presence in the mucus layer. Interestingly, studies have shown that surface charge only has a limited impact on insulin bioavailability, as negatively and positively charged NPs exhibited similar absorption rates in diabetic rats [79, 66]. Lastly, zwitterionic and protein-based modifications further improve NP permeability and stability, highlighting the importance of surface characteristics in oral insulin delivery systems [80, 81].

 

CLINICAL TRIALS ON ORAL INSULIN AND THEIR SUCCESS RATES

Several clinical trials have assessed the efficacy of different oral insulin formulations. Nodlin™, developed by NOD Pharmaceuticals, was one of the early formulations tested in a Phase I clinical trial. In 2012, this trial involved 12 healthy volunteers over four days and showed promising glucose-lowering effects. Nodlin’s performance was comparable to subcutaneously injected neutral protamine Hagedorn insulin, with a biopotency of 37%. However, the trial also exhibited high variability, with a standard deviation of 90%, indicating inconsistencies in its efficacy [119].

Another oral insulin formulation, HDV-I, developed by Diasome Pharmaceuticals, was designed to target liver cells. In a small clinical trial involving six patients with type 2 diabetes (T2DM), HDV-I demonstrated superior hypoglycemic effects compared to a placebo, particularly after breakfast. However, its impact on glycemic control after other meals was less pronounced, and its efficacy compared to subcutaneous insulin still needs to be discovered. Although a larger Phase II/III study began in 2008 with 230 patients, the results and recruitment status have yet to be published [120].

One of the most notable oral insulin candidates is Oramed’s ORMD-0801. Despite promising results in Phase II trials, where it achieved a 0.6% reduction in baseline HbA1c levels in patients with T2DM, the formulation failed to demonstrate significant efficacy in a larger Phase III trial. In 2023, with 710 participants, the trial found no significant improvement in glycemic control after 26 weeks of treatment compared to a placebo, highlighting the ongoing challenges in developing effective oral insulin [121, 122].

Overall, while initial trials have shown potential, the success of oral insulin in clinical settings has been limited. These results underscore the need for further research and refinement of delivery systems to overcome the current challenges associated with oral insulin formulations.

 

CURRENT PROGRESS AND CHALLENGES IN THE DEVELOPMENT OF ORAL INSULIN

Although significant progress has been made in developing oral insulin, several challenges remain before it can become a viable treatment. Initial trials, such as those involving Nodlin™ and HDV-I, showed some promise in lowering blood glucose levels. Still, issues like variability in efficacy and incomplete data from large-scale studies hinder conclusive results [119,120]. Despite encouraging Phase II outcomes, Oramed’s ORMD-0801 failed to demonstrate significant improvement in glycemic control in a recent Phase III trial, highlighting the difficulties in achieving consistent efficacy [121,122]. While some formulations have advanced to later-stage trials, reliable and effective oral insulin treatments are still not ready for widespread use.

 

CONCLUSION

The study concludes that significant clinical success remains elusive despite extensive research and innovative approaches to develop oral insulin, such as nanocarrier systems, oral microneedles, and gene therapy. While certain strategies have shown potential in targeting specific cells and improving oral bioavailability, clinical trials have yet to produce effective results. The failure of promising candidates in advanced trials underscores the ongoing challenges in creating a viable oral insulin delivery system, making it clear that more research is needed before it can become a practical treatment option for diabetes.

 

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