SNAC promotes the oral absorption of semaglutide tablets

Abstract: Semaglutide is a polypeptide compound with large molecular weight, hydrophilicity, and low permeability for the treatment of type 2 diabetes and obesity. Semaglutide injection has poor compliance that restricts its use,so semaglutide tablets appear. Semaglutide tablets mainly contain glucagon-like peptide-1 (GLP-1) analogues, semaglutide with the absorption enhancer N-(8-[2-hydroxybenzamido]) sodium caprylate (SNAC), but the oral bioavailability of its tablets is low. In order to improve oral  absorption, excipients are added to the tablets SNAC. Many scholars have studied SNAC to promote the oral absorption of semaglutide tablets. This article mainly provides a brief review.

Keywords: Semaglutide tablets; SNAC; Type 2 diabetes

With the improvement of social living standards, more and more people suffer from diabetes in the world, and about 1 in 11 people will have diabetes. Not only insulin can treat diabetes, but also glucagon-like peptide-1 (GLP-1) analogs are also important drugs. Previously, Novo Nordisk's GLP-1 analogue semaglutide injection formulation has been approved by the FDA for marketing,

but the problem of poor compliance with injectable antidiabetic drugs has always restricted the use of such drugs, so Novo Nordisk The company is also developing semaglutide for oral administration, and Novo Nordisk has submitted a marketing application for semaglutide tablets to the FDA [1]. The stomach contains more gastric acid and pepsin, so Semaglutide is easily degraded in the stomach and loses its pharmacological activity. It has been observed in experiments that the absorption of semaglutide alone orally in the human body is difficult to reach an effective concentration, and the absorption has great variability in different individuals and different medications of the same individual. Novo Nordisk tried to use the synthetic N-(8-[2-hydroxybenzamido]) sodium caprylate (SNAC) as a penetration enhancer to make tablets together with semaglutide, and developed a tablet for oral administration. Medicinal Semaglutide tablets [2]. This article gives a brief review of the research on SNAC to promote the oral absorption of semaglutide.

1SNAC

SNAC is the absorption enhancer of semaglutide tablets. It is an N-acetylated amino acid derivative synthesized from salicylic acid, which is weakly acidic and amphiphilic. SNAC is the only penetration enhancer approved to improve oral absorption.

 In other preclinical studies, SNAC has the effect of improving the penetration of peptides (such as insulin) in the intestine [3]. 

Semaglutide tablets containing SNAC are placed in different volumes of simulated gastric juice, and the pH value gradually changes from acidic to neutral. The smaller the volume, the more obvious the buffering effect; on the contrary, the SNAC-free Semaglutide tablets have no significant effect on the pH value of simulated gastric juice [4]. In view of the significant buffering effect of SNAC, the effect of pH on the stability of semaglutide was investigated in the presence of pepsin. Under the conditions of pH 2.6, 5.0 and 7.4, semaglutide was incubated with pepsin (3.5 U/ml), and the half-life was calculated, assuming that semaglutide had first-order degradation kinetics. Consistent with the pH-dependent activity of pepsin, the effect of pepsin on the stability of
semaglutide is most significant at low pH, and semaglutide is the most unstable to pepsin at pH 2.6, and the half-life is 16 minutes; on the contrary; When the pH value is increased to 5.0, the half-life is extended to 34 min. At neutral pH, semaglutide is almost completely stable, and the half-life is greater than 100 min .This can be inferred that SNAC can play a
buffering role in the stomach and increase the pH of the local gastric epithelial surface. The buffering effect of SNAC reduces the enzyme activity and prolongs the degradation time of Semaglutide in gastric juice, which is beneficial to the body's absorption.

The pH value during 30 minutes incubation in different volumes of simulated human gastric juice (SGF; n=3/group) 

Intact semaglutide and half-life under different pH values after incubation with pepsin (3.5 U/ml; N=4/group)

2 Semaglutide and SNAC

The effect of SNAC on increasing the apparent permeability of Semaglutide in the gastric epithelial model (NCI-N87) varies with time. When SNAC was added to the gastric epithelial model containing Semaglutide, the apparent permeability of Semaglutide increased significantly (10 min, P=0.008) in a short period of time compared with the absence of SNAC. As time passed, SNAC was the effect of improving the apparent permeability of Marutide was weakened (30 min, P=0.142; 60 min, P=0.568). SNAC was added to the gastric epithelial model containing semaglutide at different time intervals, and the degree of SNAC enhanced penetration was also different. When the interval is 10 min, the apparent permeability of semaglutide is 2.06±0.53, and when the interval is 30 min, the apparent permeability of semaglutide is 1.30±0.27. The longer the interval, the weaker the enhancement effect of SNAC on the apparent permeability of semaglutide [5] (see Figure 4)Apparent permeability of semaglutide after adding SNAC at different time intervals. SNAC has a penetration enhancing effect on semaglutide and has a concentration-dependent characteristic. When the gastric epithelial model was exposed to 20-60 mmol/L SNAC, the apparent permeability of semaglutide in this group was lower than that of the control group without SNAC. When the SNAC concentration in the model reached 70 mmol/L, the apparent permeability of semaglutide was almost doubled compared to the control group of the gastric epithelial model without SNAC, and even reached 7 times. when the concentration reached 80 mmol/L. The average Pap of semaglutide on a monolayer of cells cultured in NCI-N87 cells in the absence and presence of different amounts of SNAC.

3 Mechanism research

Semaglutide molecules are amphiphilic, and they can combine with each other through hydrophobic interactions to form oligomers. After semaglutide tablets are dissolved, SNAC can cause a change in the polarity of the solution and weaken the hydrophobic interaction between molecules. SNAC is lipophilic and can be effectively inserted into the upper cortical membrane of the stomach, thereby changing the inherent packaging integrity of cholesterol,phospholipids and proteins, thereby affecting the fluidity of the membrane [6]. For decades, SNAC has been thought to be based on the increased lipophilicity of non-covalent macromolecular complexes, increasing the passive transcellular penetration of the small intestinal epithelium. By ligating the dog model, it can be inferred that SNAC forms a complex around semaglutide in the stomach and causes a temporary increase in the local pH around the molecule; semaglutide can protect pepsin through SNAC and its solubility increases, thereby the concentration-dependent increase of semaglutide in gastric juice converts semaglutide into a more permeable monomeric form. This is due to the transcellular mechanism when the tablet is in close contact with epithelial cells [7]. After semaglutide tablets are digested, they corrode rapidly in the stomach, resulting in the release of a large amount of high-concentration SNAC, which

neutralizes the pH of the gastric juice near the tablet and inactivates pepsin; SNAC is believed to be induced Produce peptide monomers, increase the fluidity of gastric epithelial cell membrane, but do not affect tight junctions, thereby allowing semaglutide
to cross cells into the systemic circulation. In the gastric epithelial model (NCI-N87), EDTA and SNAC were added to observe the enhancement effect on the penetration of semaglutide. At the same time, a gastric epithelial model without adding any penetration enhancer was set up as a control group; the detection of semaglutide was Compared with the control group, EDTA has no significant difference in the accumulation of cells (P=0.057), while SNAC is significantly different from the control group (P<0.001) [5] (see Figure 7). In summary, it can be inferred that SNAC enhances the penetration of semaglutide mainly through transcellular pathways rather than extracellular pathways. The mechanism of SNAC inducing the transcellular flow of semaglutide through the gastric epithelium.Gastric epithelial model (NCI-N87) added EDTA and SNAC, the accumulation of semaglutide in the cell.

4 Summary

Compared with the injection form, the oral administration of semaglutide tablets can improve the compliance of diabetic patients. The penetration enhancer SNAC increases the apparent permeability of semaglutide in the transepithelial cell pathway, which

increases the plasma exposure and bioavailability of semaglutide; SNAC is based on the increased lipophilicity of non-covalent macromolecular complexes, Increase the passive transcellular penetration of the small intestinal epithelium. In fact, it is still unclear whether the high concentration of SNAC required to improve the penetration of the small intestinal epithelium is related to membrane disturbance, membrane fluidization, changes in payload solubility, or tight junction openings. Future research is needed. But what we can confirm is that SNAC is effective in improving the oral bioavailability of semaglutide tablets, and can provide a new option for type 2 diabetes patients in controlling blood sugar and reducing weight.

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