Technical Articles
01 Feb 2018
Learn about Drug Eutectic Screening
01 Feb 2018
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On August 8, 2023, Novo Nordisk announced the results of a five-year, 17,000-person Phase III trial of semaglutide injection (SELECT study). The results showed that compared to placebo, a once-weekly subcutaneous injection of 2.4 mg semaglutide reduced the risk of major adverse cardiovascular events in overweight or obese adults with no history of diabetes by 20%, demonstrating the broader market potential of GLP-1 beyond weight loss and glycemic control. The announcement of these results led to a 17% increase in Novo Nordisk's stock price, pushing its market value above $420 billion.
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. It was previously approved in September 2017 and June 2021 for the treatment of blood sugar control in type 2 diabetes patients and weight loss in obese patients, respectively. Novo Nordisk expects to apply for regulatory approvals for semaglutide's expanded indications in the United States and the European Union this year. Semaglutide is set to become the first drug to prevent cardiovascular disease through weight loss.
Development of GLP-1 Receptor Agonists
Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by L cells in the intestine, encoded by the human glucagon gene. It belongs to the incretin family of gut hormones and has two active forms in the human body: GLP-1 (7-36) and GLP-1 (7-37), with the 30-amino acid GLP-1 (7-36) being the primary form. GLP-1 plays a crucial role in promoting insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and more. Due to its unique mechanism of action, it has become an important target for the treatment of type 2 diabetes. However, natural GLP-1 has a short half-life (1.5 minutes when given intravenously and 1.5 hours when given subcutaneously) because it is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) after release, rendering it ineffective for treatment. To make GLP-1 more suitable for clinical use, modifications are made to its structure to extend its half-life by preventing rapid degradation by DPP-4 while retaining its ability to bind to GLP-1 receptors and exert biological effects. These drugs are known as GLP-1 receptor agonists.
The development of GLP-1 receptor agonist drugs began with the approval of exenatide (Byetta) in 2005. Since then, several GLP-1-based medications have been approved and are listed in the table. Exenatide, a synthetic GLP-1 analog initially discovered in the venom of the Gila monster, has a short half-life of 2.4 hours, requiring twice-daily injections. To reduce the dosing frequency, AstraZeneca developed exenatide extended-release suspension for weekly injections. Liraglutide, developed by Novo Nordisk, is a GLP-1 analog with 97% homology to natural GLP-1. It uses modification of the GLP-1 main peptide chain with a fatty acid chain to increase the drug's affinity for albumin, extending its half-life to 13 hours and allowing for once-daily dosing. Semaglutide, also developed by Novo Nordisk, is considered the "second generation" of liraglutide. It has undergone further structural modifications to increase its affinity for albumin and resistance to DPP-4 degradation, extending its half-life to one week, enabling once-weekly dosing.
The development and challenges of semaglutide tablets
Despite the progress in extending half-lives and transitioning from twice-daily short-acting injections to once-weekly long-acting injections, there remains a significant unmet need for more convenient oral therapies for diabetes patients who require long-term medication. The challenges in developing oral formulations for GLP-1 receptor agonist drugs stem from issues related to the oral administration of peptides. These issues include susceptibility to digestion by enzymes, degradation in stomach acid, poor mucosal penetration in the gastrointestinal tract, and extremely low oral bioavailability.
To address these challenges, ideal peptides need to have a substantial therapeutic index, stability in the gastrointestinal tract, a longer half-life, and a lower clearance rate. Various approaches have been explored in the literature to enhance the oral delivery of peptides, including permeation enhancers, nanoparticles, intestinal devices, lipid-based drug delivery systems, or hydrophobic ion pairing, among others. Among these approaches, permeation enhancers are easier to incorporate into formulations and have been widely studied.
N-(8-(2-Hydroxybenzoyl)amino)octanoic acid sodium salt, abbreviated as SNAC, is a highly efficient carrier molecule developed by Emisphere Corporation in the 1990s. It was selected from numerous permeation enhancers as a promising candidate. SNAC is a synthetic derivative of bispicoline salicylate and acts as a carrier and permeation enhancer. In 2014, the approval of oral vitamin B12 (cyanocobalamin/SNAC) demonstrated the feasibility and safety of SNAC. Subsequently, SNAC has been extensively studied as a permeation enhancer for poorly permeable drugs.
In 2017, semaglutide injection was approved in the United States for the treatment of type 2 diabetes, and later, additional indications for weight loss were added. Semaglutide stands out as an ideal candidate for oral administration with SNAC due to its extended half-life (approximately 7 days after subcutaneous administration) and enhanced efficiency. The structure of semaglutide includes a peptide backbone produced by yeast fermentation, with modifications such as hydrophilic spacers and C18 fatty acid to increase affinity with albumin, avoiding rapid renal clearance, and prolonging the half-life. Alanine at position 8 is replaced by alpha-amino isobutyric acid to resist DPP-4 degradation. Arginine replaces lysine at position 34 to ensure the attachment of only one fatty acid side chain, improving side-chain stability.
Figure 1: Structural Diagram of Semaglutide
The oral semaglutide tablet developed by Novo Nordisk uses SNAC as a penetration enhancer. The potential mechanism of SNAC in oral semaglutide is illustrated in Figure 1. When the tablet disintegrates in the stomach, SNAC causes a local increase in stomach pH through a buffering effect. The elevation in stomach pH reduces the degradation of semaglutide by gastric proteases. On the other hand, SNAC promotes the monomerization of semaglutide by altering the polarity of the tablet's dissolution solution, thereby weakening hydrophobic interactions. The enhanced absorption of semaglutide primarily results from the indirect action of SNAC. SNAC binds to the lipid membrane of gastric cells, fluidizing the gastric epithelial cell membranes (a transition from solid to fluidic structure), allowing semaglutide to pass through the cells. Studies have shown that the absorption of semaglutide mainly occurs in the stomach.
Figure 2: Absorption and Protective Mechanism of Semaglutide
Product Introduction of Rybelsus®
Rybelsus®, developed by Novo Nordisk, is the first and currently the only oral GLP-1 receptor agonist medication on the market. It is intended for patients with type 2 diabetes, offering them a convenient and patient-friendly alternative to injections. Patients can switch between taking a daily Rybelsus® tablet and receiving a weekly injection of semaglutide.
Rybelsus® comes in three different dosages: 3 mg, 7 mg, and 14 mg. It was first approved in the United States in September 2019 and has since gained approval for sale in several countries, including Europe, Japan, and Canada. An application for Rybelsus® to be marketed in China was submitted in May 2022.
While Rybelsus® is currently approved for the treatment of type 2 diabetes, Novo Nordisk is also developing a 50 mg tablet version of semaglutide. They plan to submit marketing applications for this formulation in the United States and the European Union. Results from the Phase 3a OASIS trial in May 2023 demonstrated that the 50 mg tablet version of semaglutide led to a remarkable weight reduction of 17.4% for patients who continued treatment for 68 weeks, compared to a weight reduction of 1.8% in the placebo group, indicating excellent weight loss efficacy.
As a part of Crystal Pharmatech's CDMO business unit, Crystal Pharmatech is focused on providing research and production services for the development of oral formulations of both small molecule drugs and peptide medications. Their core technical team has extensive experience in oral formulation development, including dealing with poorly soluble compounds and challenging-to-deliver peptide drugs. They believe that with the strong crystal engineering and formulation development technology platform at Crystal Pharmatech, they can offer robust technical support for your oral tablet development of semaglutide or other GLP-1 receptor agonist medications.
Summary and prospects
In summary, GLP-1 receptor agonist medications have gained significant attention due to their excellent glucose-lowering effects, cardiovascular protection, and potential for weight loss. They are expanding beyond the treatment of metabolic diseases like diabetes into areas such as cardiovascular conditions, chronic kidney disease, non-alcoholic fatty liver disease, Alzheimer's disease, and more. The launch of Rybelsus® as an oral tablet marks a significant milestone in the development of oral formulations for peptide medications and offers a convenient treatment option for patients.
