Release date:2020/5/26 10:43:46
Diabetes is increasing at an alarming rate in the United States. According to the CDC’s (Centers for Disease Control) National Diabetes Statistics Report for 2020 cases of diabetes have risen to an estimated 34.2 million. Although there are many anti-diabetic therapies, there is still a high proportion of patients with type 2 diabetes who do not reach the target blood glucose level after oral anti-diabetic drugs, and a more effective treatment plan is urgently needed.
In September 2019, Novo Nordisk announced that the FDA approved the oral Semaglutide tablets (trade name Rybelsus) to be marketed, combined with diet and exercise to improve blood sugar levels in patients with type 2 diabetes.
Semaglutide tablets are the first and currently the only oral glucagon-like peptide 1 (GLP-1) receptor agonist. The approval is based on the efficacy and safety of oral semaglutide in 10 PIONEER clinical trials involving a total of 9543 adults with type 2 diabetes.
About GLP-1 Receptor Agonist

Semaglutide is an analogue of the natural hormone GLP-1. GLP-1, a peptide hormone secreted by intestinal cells, stimulates the secretion of insulin and inhibits the secretion of glucagon by binding to the GLP-1 receptor, thereby promoting glucose metabolism. At the same time, it can also delay gastric emptying and suppress appetite.
Natural GLP-1 is secreted by the stimulation of glucose after a meal. In patients with type 2 diabetes, the level of GLP-1 secretion is significantly reduced, which is also one of the important reasons for the uncontrolled blood glucose of patients. Therefore, the development of GLP-1 analogues has been an important research and development direction for the treatment of type 2 diabetes.

In 2017, the US FDA approved Semaglutide injection (Ozempic) (0.5 mg or 1 mg) as an aid to diet adjustment and exercise to improve blood glucose levels in type 2 diabetes. In January of this year, Semaglutide injection Ozempic was again approved by the FDA to reduce the risk of major adverse cardiovascular events in adult patients with pre-existing cardiovascular disease, including myocardial infarction, stroke or death.
Currently, the FDA has approved a total of 6 GLP-1 receptor agonist products for the market. Except for semaglutide tablets (Rybelsus), the rest are injections.

Generic Name Commercial Name FDA Aprroval Year
Exenatide  Byetta, Bydureon  2005/2012
Liraglutide  Victoza, Saxenda 2010
Lixisenatide  Lyxumia in Europe, Adlyxin in the United States 2016
Albiglutide  Tanzeum 2014
Dulaglutide  Trulicity 2014
Semaglutide  Ozempic, Rybelsus 2017/2019

The emergence of semaglutide tablets has broken the dilemma that patients with type 2 diabetes need to receive GLP-1RA injections daily or weekly, providing them with a less invasive and convenient treatment option for controlling blood sugar.
From Injections to Pills 

From a convenient point of view, oral medication is the preferred method of medication for patients. Oral drugs are usually small molecules and need to be hydrophobic.
In general, the absorption of small molecule drugs mainly takes place in the intestine. However, the absorption of peptide drugs in the intestinal tract will face great challenges, because many peptidases present in the intestinal tract will degrade the polypeptide before it is absorbed.
The uniqueness of oral semaglutide is that a small molecule absorption enhancer called SNAC is added to allow semaglutide to be absorbed directly in the stomach.
At the same time, SNAC dissolution in the stomach can locally increase the pH of the environment, increase the solubility of semaglutide, and prevent semaglutide from being degraded by peptidases in the stomach.

The mechanism of absorption of semaglutide and SNAC coformulation tablet.
Image Source: Dovepress, The mechanism of absorption of semaglutide and SNAC coformulation tablet.
 Although semaglutide tablets are oral, their performance in controlling blood sugar and reducing patients' weight is no worse than that of somalutide injection.
At present, semaglutide has been approved in the United States, Switzerland and the European Union as an auxiliary means to improve blood sugar levels in adults with type 2 diabetes.

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Rybelsus® (oral semaglutide) approved for the treatment of adults with type 2 diabetes in the EU 
Rybelsus® (semaglutide tablets), the first GLP-1 in a tablet approved in the US
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