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Blood glucose changes and plasma insulin levels versus time profiles of diabetic rats following the administration of different exendin-4 formulations. Reprinted with permission from Biomaterials. 88 NP, nanoparticle; SC, subcutaneous.
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Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases worldwide. Current treatments are often associated with off-target effects and do not significantly impact disease progression. New therapies are therefore urgently needed to overcome this social burden. Glucagon-like peptide-1 (GLP-1), an incretin hormone, has been used to contr...
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... after oral administration, no alterations were observed in plasma concentrations, which was similar to results of capsules filled with empty nanoparticles. On the other hand, when administered orally, the capsule containing exendin-4 nanoparticles produced a slower but prolonged reduction in blood glucose levels, showing a maximum plasma concentration 5 h after administration, and also increased the insulin levels in a slower but prolonged way (Figure 5). In this present case, the bioavailability of exenatide-4 encapsu- lated into nanoparticles was 14%, compared with exenatide-4 administrated subcutaneously, which is a significantly higher value compared with other examples in literature, 88 a promising result considering the oral peptide administration in general. ...
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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them shortacting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on...
Citations
... 3 Glucagon-like peptide-1 (GLP-1) receptor activation is a promising treatment for hyperglycemia due to its various therapeutic actions. 4 However, GLP-1 receptor agonists (GLP-1RA) are only effective in subcutaneous injections, and the only approved oral dosage form, Rybelsus, is expensive and requires a high daily dose. 5,6 To address these problems, ongoing efforts are dedicated to developing a weekly oral dosage form of a therapeutic gene. ...
Activating the glucagon-like peptide-1 (GLP-1) receptor by oral nucleic acid delivery would be a promising treatment strategy against hyperglycemia due to its various therapeutic actions. However, GLP-1 receptor agonists are effective only in subcutaneous injections because they face multiple barriers due to harsh gastrointestinal tract (GIT) conditions before reaching the site of action. The apical sodium bile acid transporter (ASBT) pathway at the intestinal site could be an attractive target to overcome the problem. Herein, we used our previously established multimodal carrier system utilizing bile salt, protamine sulfate, and calcium phosphate as excipients (PTCA) and the GLP-1 gene as an active ingredient (GENE) to test the effects of different formulation doses against diabetes and obesity. The carrier system demonstrated the ability to protect the GLP-1 model gene encoded within the plasmid at the GIT and transport it via ASBT at the target site. A single oral dose, regardless of quantity, showed the generation of GLP-1 and insulin from the body and maintained the normoglycemic condition by improving insulin sensitivity and blood sugar tolerance for a prolonged period. This oral gene therapy approach shows significantly higher therapeutic efficacy in preclinical studies than currently available US Food and Drug Administration-approved GLP-1 receptor agonists such as semaglutide and liraglutide. Also, a single oral dose of GENE/PTCA is more effective than 20 insulin injections. Our study suggests that oral GENE/PTCA formulation could be a promising alternative to injection-based therapeutics for diabetics, which is effective in long-term treatment and has been found to be highly safe in all aspects of toxicology.
... conditions, as noticed after nutrient intake (Alavi et al., 2019;Araújo et al., 2012;Gilbert & Pratley, 2020;Muskiet et al., 2017;Nauck et al., 2021). Afterwards, GLP-1 binds to the GLP-1 receptors (GLP-1R), mainly located in the pancreatic islets, where GLP-1 stimulates insulin secretion and suppresses glucagon release from pancreatic β and α cells, respectively, as well as stimulates the neogenesis and the proliferation of β cells (Alavi et al., 2019;Araújo et al., 2012;Cheang & Moyle, 2018;Drucker, 2022;Gilbert & Pratley, 2020;Hinnen, 2017;Meier, 2012;Muskiet et al., 2017). ...
... conditions, as noticed after nutrient intake (Alavi et al., 2019;Araújo et al., 2012;Gilbert & Pratley, 2020;Muskiet et al., 2017;Nauck et al., 2021). Afterwards, GLP-1 binds to the GLP-1 receptors (GLP-1R), mainly located in the pancreatic islets, where GLP-1 stimulates insulin secretion and suppresses glucagon release from pancreatic β and α cells, respectively, as well as stimulates the neogenesis and the proliferation of β cells (Alavi et al., 2019;Araújo et al., 2012;Cheang & Moyle, 2018;Drucker, 2022;Gilbert & Pratley, 2020;Hinnen, 2017;Meier, 2012;Muskiet et al., 2017). Additionally, GLP-1 acts in the GLP-1R expressed in brain, heart, GIT, lungs, liver, kidneys, adipose tissue, and muscle (Alavi et al., 2019;Araújo et al., 2012;Cheang & Moyle, 2018;Drucker, 2022;Hinnen, 2017;Meier, 2012). ...
... Afterwards, GLP-1 binds to the GLP-1 receptors (GLP-1R), mainly located in the pancreatic islets, where GLP-1 stimulates insulin secretion and suppresses glucagon release from pancreatic β and α cells, respectively, as well as stimulates the neogenesis and the proliferation of β cells (Alavi et al., 2019;Araújo et al., 2012;Cheang & Moyle, 2018;Drucker, 2022;Gilbert & Pratley, 2020;Hinnen, 2017;Meier, 2012;Muskiet et al., 2017). Additionally, GLP-1 acts in the GLP-1R expressed in brain, heart, GIT, lungs, liver, kidneys, adipose tissue, and muscle (Alavi et al., 2019;Araújo et al., 2012;Cheang & Moyle, 2018;Drucker, 2022;Hinnen, 2017;Meier, 2012). Figure 1 illustrates the biological functions of GLP-1 in each tissue. ...
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non‐pharmacological actions (e.g., diet and exercise) co‐associated with the administration of antidiabetic drugs. Metformin is the first‐line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon‐like peptide‐1 (GLP‐1) analogs have been explored for managing the disease. GLP‐1 analogs trigger insulin secretion and suppress glucagon release in a glucose‐dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP‐1 analogs have an extended plasma half‐life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase‐4. However, GLP‐1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP‐1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non‐invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP‐1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface‐conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP‐1 and GLP‐1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides.
This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
... Thus, they have to be used at high concentrations, which could lead to side effects such as the absorption of unwanted molecules or damages to the epithelium tract. It could also induce a disturbed digestion of nutritive compounds due to a deficiency of pancreatic enzymes [211], as well as the increase in enzyme secretion due to feedback regulation [212][213][214][215]. ...
Recombinant biological molecules are at the cutting-edge of biomedical research thanks to the significant progress made in biotechnology and a better understanding of subcellular processes implicated in several diseases. Given their ability to induce a potent response, these molecules are becoming the drugs of choice for multiple pathologies. However, unlike conventional drugs which are mostly ingested, the majority of biologics are currently administered parenterally. Therefore, to improve their limited bioavailability when delivered orally, the scientific community has devoted tremendous efforts to develop accurate cell- and tissue-based models that allow for the determination of their capacity to cross the intestinal mucosa. Furthermore, several promising approaches have been imagined to enhance the intestinal permeability and stability of recombinant biological molecules. This review summarizes the main physiological barriers to the oral delivery of biologics. Several preclinical in vitro and ex vivo models currently used to assess permeability are also presented. Finally, the multiple strategies explored to address the challenges of administering biotherapeutics orally are described.
... The first attempt to deliver insulin orally was described in 1923 and involved the use of dilute alcohol as a solvent [41]; since then, there have been multiple other attempts, including some using permeation enhancers [6]. Several barriers must be overcome when developing orally administered peptides with a molecular weight above 1,000 Da, including enzymatic degradation in the GI tract, pH-induced conformational changes, limited permeability of the intestinal membrane, and variable GI tract absorption rates [2,3,42,43]. To overcome these barriers, peptides ideally need to have a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate [3,43]. ...
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.
... Insulin, 51 amino acids, can control glucose homeostasis by stimulating glucose uptake in the insulin-responsive tissues such as skeletal muscles and myocardium, and suppressing glucagon secretion from pancreatic α-cells [25,26]. T1DM and advanced T2DM patients are dependent on multiple daily insulin injections to control the blood glucose level in clinical [27][28][29][30][31]. Glucagon-like peptide 1 (GLP-1) is one of the most effective drugs for the treatment of T2DM [32][33][34]. GLP-1 increases the insulin secretion from pancreatic β-cells and decreases the glucagon release from pancreatic α-cells [35,36]. In addition, GLP-1 can stimulate the proliferation of pancreatic β-cells and slow the progression of T2DM. ...
Peptide drugs play an important role in diabetes mellitus treatment. Oral administration of peptide drugs is a promising strategy for diabetes mellitus because of its convenience and high patient compliance compared to parenteral administration routes. However, there are a series of formidable unfavorable conditions present in the gastrointestinal (GI) tract after oral administration, which result in the low oral bioavailability of these peptide drugs. To overcome these challenges, various nanoparticles (NPs) have been developed to improve the oral absorption of peptide drugs due to their unique in vivo properties and high design flexibility. This review discusses the unfavorable conditions present in the GI tract and provides the corresponding strategies to overcome these challenges. The review provides a comprehensive overview on the NPs that have been constructed for oral peptide drug delivery in diabetes mellitus treatment. Finally, we will discuss the rational application and give some suggestions that can be utilized for the development of oral peptide drug NPs. Our aim is to provide a systemic and comprehensive review of oral peptide drug NPs that can overcome the challenges in GI tract for efficient treatment of diabetes mellitus.
... The human GLP-1 analogue semaglutide is now approved as both a subcutaneous injection (as Ozempic) [5] as well as an oral formulation (as Rybelsus) [8] in European countries, Japan and the USA, among others. To allow oral administration, oral semaglutide is co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), a small fatty acid derivative that protects semaglutide against enzymatic degradation through a localised increase in pH and transiently enhances its absorption across the gastric epithelium via the transcellular route [9][10][11]. During the development of oral semaglutide, SNAC was studied extensively in non-clinical and clinical studies (including the present study), to investigate potential drug-drug interactions, pharmacokinetics and general safety. ...
Introduction:
Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave.
Methods:
Part A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF).
Results:
All subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure-response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms.
Conclusion:
This QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval.
Trial registration:
Clinicaltrials.gov identifier: NCT02911870.
... Furthermore, the lack of association between fpGLP-1 and the aortic Sdc-1 expression may be due to the very small amount of fpGLP-1 reaching the GLP-1Rs at the site of the aneurysm and does not exclude the direct effects of incretin therapy on the aortic Sdc-1 expression. Specifically, GLP-1 has a half-life of only 1-2 min as it is rapidly degraded by DPP-4, resulting in approximately only 10% of active endogenous GLP-1 reaching systemic circulation [51,52]. ...
A reduced prevalence of a thoracic aortic aneurysm (thoracic AA) is observed in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1)/GLP-1-based anti-diabetic therapy has indicated protective effects in thoracic AA and regulates the processes controlling the vascular tissue expression of Syndecan-1 (Sdc-1). Sdc-1 expression on macrophages infiltrating the aortic tissue contributes to a counter-regulatory response to thoracic AA formation in animal models through the interplay with inflammation/proteolytic activity. We hypothesized that elevated fasting plasma GLP-1 (fpGLP-1) increases the aortic Sdc-1 expression in T2D, which may contribute to a reduced prevalence of thoracic AA. Consequently, we determined whether T2D/thoracic AA associates with an altered Sdc-1 expression in the aortic tissue and the possible associations with fpGLP-1 and inflammation/proteolytic activity. From a cohort of surgical patients with an aortic valve pathology, we compared different disease groups (T2D/thoracic AA) with the same sub-cohort group of controls (patients without T2D and thoracic AA). The MMP-2 activity and Sdc-1, GLP-1R and CD68 expression were analyzed in the aortic tissue. GLP-1, Sdc-1 and cytokines were analyzed in the plasma. The aortic Sdc-1 expression was increased in T2D patients but did not correlate with fpGLP-1. Thoracic AA was associated with an increased aortic expression of Sdc-1 and the macrophage marker CD68. CD68 was not detected in T2D. In conclusion, an increased aortic Sdc-1 expression may contribute to a reduced prevalence of thoracic AA in T2D.
... In response to food intake, intestinal L-cells secret GLP1, which has shown the reduction of appetite, slowing gastric emptying, inhibition of β-cell apoptosis, stimulation of insulin secretion, and suppression of glucagon secretion. 2 Although their therapeutic potential is higher than that of insulin in diabetes treatment, they are unable to replace insulin due to having a shorter plasma lifetime, emphasizing the need to develop a unique delivery strategy. Previous studies have shown that firstgeneration oral gene formulation containing 100 μg of GLP1 per dose reduced hyperglycemia in diet-induced obesity mice after 8 days of multiple administration. ...
... Polymeric vehicles can offer the opportunity to Glucagon-Like Peptide-1 and analog to be delivered orally without the need of modifying their chemical structures. Recently, Novo Nordisk and Oramed Pharmaceuticals developed oral GLP-1 analog (ORMD-0901) that use an excipient to protect the peptide together with protease inhibitor [95,96]. ...
Diabetes mellitus is one of the long known chronic diseases, today over 400 million people are diagnosed with diabetes. Yet curing diabetes is a challenge. Over the decades, the approaches of treating diabetes mellitus have evolved and polymeric materials have played an integral part in developing and manufacturing anti-diabetic medications. However, injection of insulin remains the conventional therapy for the treatment of diabetes. Oral administration is generally the most preferred route; yet, physiological barriers lead to a challenge for the formulation development for oral delivery of antidiabetic peptide and protein drugs. This present review focuses on the role of different types of biodegradable polymers (e.g., synthetic and natural) that have been used to develop micro and nano particles based formulations for antidiabetic drugs (Type 1 and Type 2) and how the various encapsulation strategies impact its therapeutic effect, including pharmacokinetics studies, drug release profiles and efficacy of the encapsulated drugs. This review also includes studies of different dosage forms such as oral, nasal, inhalation and sublingual for the treatment of diabetes that have been investigated using synthetic and natural biodegradable polymers in order to develop an alternative route to subcutaneous route for a better control of serum glucose levels.
... GLP1 has been known as a euglycemic peptide having the ability to reduce high blood glucose levels to the normal range without any hypoglycemic episodes compared to conventional insulin-based therapeutics in the treatment of type 2 diabetes. 4,34,35 However, its extremely short physiological half-life (<5 min) due to the rapid inactivation by a DPP-4 enzyme demanded either a source of sufficient GLP1 supply or blocking the DPP-4 activity. Our current approach focused on the development of a GLP1 gene-based oral delivery system to supply sufficient GLP1 to the pancreas through the bypass of the DPP-4 activity and anticipate more insulin production. ...
Type 2 diabetes mellitus (T2DM) is a chronic and progressive hyperglycemic condition. GLP1 is an incretin secreted from pancreatic β-cell and helps to produce insulin to balance the blood glucose level without the risk of hypoglycemia. However, the therapeutic application of GLP1 is limited by its intrinsic short half-life and rapid metabolic clearance in the body. To enhance the anti-diabetic effect of GLP1, we designed a human cysteine modified IgG1-Fc antibody-mediated oral gene delivery vehicle, which prolongs the half-life of GLP1, protect from acidic and enzymatic degradation in the gastrointestinal tract (GI), uptakes and transports through neonatal Fc receptor (FcRn), and helps to release the GLP1 gene in the intestine. Our formulation could reduce the blood glucose from about an average of 320 mg/dL (hyperglycemic) to 150 mg/dL (normal blood glucose concentration) in diabetic mice, which is about 50% reduction of the total blood glucose concentration. 500µg GLP1 complexed with IgG1-Fc carrier was proven to be the optimal dose for a complete reduction of hyperglycemic conditions in diabetic mice. A significant amount of insulin production and the presence of GLP1 peptide was observed in the pancreatic islet of oral GLP1 formulation treated diabetic mice in immunohistochemistry analysis compare to non-treated diabetic mice. The orally given formulation was completely nontoxic according to histopathology analysis of mice organ tissues and no mice death was observed. Our antibody-mediated oral gene delivery system is a promising tool for various oral therapeutic gene delivery applications to treat disease like diabetes.
