Critical updates on oral insulin drug delivery systems for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by insulin resistance, leading to elevated blood sugar levels. Exogenous insulin can counteract the diminished response to insulin and effectively controlling blood glucose levels, thereby minimizing diabetes-related complications. However, given the injectable nature of exogenous insulin, apprehensions regarding its safety and the difficulties associated with its administration have hindered its widespread and prompt utilization. In this context, advanced oral insulin formulations can improve medication adherence in patients with diabetes and enhance their quality of life. Over the last 20 years, sophisticated pharmaceutical technologies have been utilized to provide insulin through oral formulations. Despite the limited absorption of oral insulin, these studies have demonstrated encouraging outcomes in translating clinical discoveries into commercialization. This review examines the advancements of several oral insulin formulations in preclinical and clinical trials, their effectiveness and safety characteristics, and potential implications for future treatment options.

Introduction

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia caused by insufficient insulin production, the inability of the body to effectively utilize insulin, or a combination of both. These variables can lead to many health repercussions, including cardiovascular diseases, neuropathy, renal failure, and vision loss [1]. Type 2 diabetes mellitus (T2DM) accounts for > 90% of all instances of diabetes mellitus [2]. The primary factors contributing to the development of T2DM are impaired secretion of insulin by pancreatic beta cells and diminished sensitivity of peripheral tissues to insulin, leading to a gradual decline in the production of natural insulin [3]. Exogenous insulin delivery is a potent treatment for severe hyperglycemia or when satisfactory regulation of blood sugar levels cannot be achieved despite the use of different oral hypoglycemic drugs.

However, the traditional subcutaneous (SC) mode of insulin delivery has several limitations, including the intricacy of insulin regimens, potential for hypoglycemia, adverse consequences of weight gain, and requirement for needle puncture. The oral delivery route has, thus, been suggested as an alternative method of administration. This method allows insulin to reach the liver by passing through portal circulation, which creates a gradient of insulin between the liver and the rest of the body, mimicking the natural insulin pathway (Fig. 1) [4]. This enables the inhibition of hepatic gluconeogenesis without any hindrance, while avoiding excessive insulin levels in the peripheral tissues. Elevated peripheral insulin levels are linked to weight gain and low blood sugar levels [5]. In addition, oral administration of insulin is anticipated to enhance patient compliance because of its ease of use, convenience, and non-invasive nature [6].

Attaining effective oral administration of insulin faces notable challenges because of its limited ability to be absorbed by the body, due to physical and chemical hindrances (Fig. 2). The gastrointestinal (GI) tract is lined with an epithelial layer of tightly interconnected cells. This layer acts as a physical barrier preventing the absorption of most peptides [7]. Owing to its high molecular weight (~ 5700 kDa) and hydrophilic properties, insulin has a slow diffusion rate across the epithelial layer [8]. The presence of a mucus barrier within the intestinal epithelium can also hinder the uptake of most medications. In addition, insulin undergoes chemical destruction in the stomach (due to its acidic pH) and enzymatic breakdown in the GI tract, leading to reduced bioavailability. Moreover, alterations in the conformation of the insulin polypeptide chain structure may lead to protein inactivation and a consequent reduction in its biological activity [7]. While the oral formulation of semaglutide, a peptide drug and GLP-1 receptor agonist for diabetes management, has successfully entered the market, its low bioavailability can result in significant variability in plasma concentrations. However, this challenge is effectively managed through once-daily dosing and a long half-life, which help stabilize steady-state levels and ensure consistent therapeutic effects for patients [9]. In contrast, insulin dosing is highly personalized, requiring precise and dynamic adjustments to maintain optimal blood glucose control and prevent hypoglycemic events. This complexity necessitates additional strategies to achieve effective management, underscoring the differences in treatment approaches between semaglutide and insulin. Various pharmacological approaches have been investigated to address these challenges and enhance the administration and absorption of orally delivered insulin.

This review comprehensively analyzes the recent data from relevant preclinical studies and clinical trials of therapeutic approaches that utilize oral insulin, including their effectiveness and safety profile.

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Table 2. Preclinical studies on single-stage polymeric nanoparticle formulations of oral insulin

Excipients mentioned in study: Eudragit RS 100, chitosan

Low, C.Y., Gan, W.L., Lai, S.J. et al. Critical updates on oral insulin drug delivery systems for type 2 diabetes mellitus. J Nanobiotechnol 23, 16 (2025). https://doi.org/10.1186/s12951-024-03062-7

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