SNAC (Salcaprozate Sodium) CAS NO 203787-91-1 Inquire about SNAC (Salcaprozate Sodium)

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Basic information of SNAC

【Common name】 8-(2-Hydroxybenzamido) octanoic acid sodium SNAC

【CDE registration number】 F20190000006

【English name】sodium 8-(2-hydroxybenzamino)octanoate

【CAS NO.】 203787-91-1

【Molecular Weight】 301.32

【Molecular formula】 C15H20NNaO4

【Quality standard】 Import standard

【Application】 Amino acid derivative absorption enhancer

Semaglutide is a peptide drug developed by Novo Nordisk with extremely low oral bioavailability. Novo Nordisk has used the Eligen technology of Emisphere Technologies (using SNAC in Eligen technology as an accelerator, and SNAC is an excipient called 8-(2-hydroxybenzamido) sodium octanoate) and Merrion Pharmaceuticals The oral GIPET (Gastro-intestinal permeation enhancement technology) technology of the company realizes the oral administration of semaglutide preparations.

Semaglutide has more than 30 amino acids, and its main structural features include the replacement of the amino acid at the catalytic site of DPP-4 hydrolase (Aib8), and the grafting of octadecane on amino acid Lys26 through a spacer Diacids to bind albumin and delay renal clearance. From a structural point of view, this octadecanic acid should be related to oral absorption, but the articles quickly found on the Internet have not mentioned it yet.

From the 1990s to the beginning of this century, two American companies, Emisphere and Nobex, were active in the field of small molecular weight protein and peptide drug oral preparations, respectively adopting two representative technologies. The former developed a class of fat-soluble molecules with carboxyl groups called “delivery molecules”, which are actually an absorption enhancer that acts on the small intestine wall and is mixed with protein and polypeptide drugs; this technology is precisely the oral semaglutide The method used. The latter is to graft fat-soluble long-chain covalent bonds to the delivered protein or polypeptide drug to promote absorption.

Nobex’s technology was favored by Glaxo at the beginning of this century, investing 233 million US dollars to develop oral insulin; more than a year later, the experiment failed, Nobex dropped sharply, was acquired by an Indian company, and gradually disappeared. Emisphere has also cooperated with some large pharmaceutical companies such as Novo Nordisk and Novartis to develop oral insulin, oral calcitonin and other products, all of which ended in failure. Phase III clinical trials have no statistically significant oral efficacy. However, the operation team of Emisphere can always raise funds, and the company has been repeatedly defeated for more than 20 years. Until today, oral semaglutide finally saw the light.

The reason why Emisphere’s delivery molecules have repeatedly failed is due to two related technical challenges: 1) Absorption enhancers generally indiscriminately improve the permeability of the small intestine wall, which has considerable safety hazards; 2) Emisphere is used for oral insulin , The complex stability constant of delivery molecule and insulin is on the order of 10-3, which is too low and does not have selective permeation for drugs. In response to the drug regulatory department’s doubts about absorption enhancers, although Emisphere’s technical team has to admit that its delivery molecules are already known absorption enhancers, it emphasizes that the absorption enhancement effect of such molecules is short-lived and transient, and the small intestine wall is opened. The permeability of the drug will be closed quickly, as long as you don’t eat other things during the time of taking the medicine, it is still safe. It is for this reason that fasting is required for 6 hours and half an hour before and after taking oral semaglutide.

From the molecular formula, the main difference between Emisphere’s delivery molecules technology for semaglutide and insulin and calcitonin is that the semaglutide molecule itself has a similar structure of Nobex’s covalently grafted side chain, while This structure is similar to Emisphere’s delivery molecules. This not only improves the fat solubility of semaglutide itself, but also has better complexation stability with the delivery molecule, which may improve the specificity of the delivery molecule to promote the oral absorption of semaglutide. Although the oral absorption rate (bioavailability) of semaglutide is only 0.5-1%, the oral dose is still very low, which is 100-200 times that of the same drug injection; The highest in the preparation.

For oral semaglutide, people’s optimistic expectations are also due to seeing this as a beginning, thinking that since the first one is on the market, improved products will follow. In fact, according to Emisphere’s strategy, the room for further improvement is extremely limited. For example, a friend proposed to develop more effective absorption enhancers with better time resolution to improve the bioavailability and safety of oral peptide drugs. The misunderstanding of this idea is that the time window of drug administration is determined by the time of food digestion and absorption before taking the drug and the empty stomach time of the drug, and the absorption enhancer cannot be changed. At the same time, the efficiency of absorption enhancers is restricted by the safety limit of indifferent permeability of the small intestine wall, and too strong absorption enhancers should not be used. Even if we jump out of Emisphere’s mixed preparation strategy and develop absorption enhancers with larger complexation stability constants with peptide drugs to improve the specific absorption of peptides, the modification of peptides has more restrictions.

Although oral semaglutide is technically not as optimistic as many recent articles, its therapeutic and commercial impact as the first oral peptide drug cannot be ignored. Its indications – type 2 diabetes is a major disease that requires life-long medication. There are not a few patients who hate injections and can bear the economic burden of a hundred-fold increase in dosage. As for the requirement of fasting for 6 hours and 0.5 hours before and after, it should not be a big obstacle for the daily dose of medicine. Taking the medicine every morning can naturally satisfy the 6-hour fast without extra efforts; and the half-hour fast after taking the medicine (to ensure that the medicine is empty and not mixed with food) is not too long.

From a commercial point of view, the impact of oral semaglutide on the injection of GLP-1 receptor agonists should not be as great as described in the like article. First of all, Novo Nordisk launched a weekly injection of semaglutide at the same time, indicating that the market for injections will not be subverted. Weekly injection and daily oral administration, as a pair of products launched by Novo Nordisk, will have an impact on the existing GLP-1 receptor agonists on the market, even Novo Nordisk’s own daily injection Liraglutide may also be hit. In my estimation, oral semaglutide will not restrict better GLP-1 receptor agonists, such as products with a longer duration of action, more stable blood drug concentration, and less side effects. One of the advantages of GLP-1 receptor agonists lies in their pharmacological intelligence – they only exert their drug effect when the blood sugar is too high, and have no hypoglycemic effect when the blood sugar is not high, so as to ensure that they do not cause hypoglycemia. One of its main disadvantages is side effects such as nausea, diarrhea, and vomiting, which are related to blood levels (this is illustrated by the lower side effects of exenatide once a week than its twice-a-day formulation). Injections with longer efficacy (such as one injection per month) and stable blood drug concentration can most effectively play the advantages of GLP-1 receptor agonists and avoid disadvantages, and complement the two new products of Novo Nordisk .

It should also be pointed out that when prolonging the action time of polypeptide drugs in vivo, the strategy of modifying and prolonging the half-life can only be achieved once a week, and it is difficult to make it longer. This is because the in vivo concentration of drugs that prolong the half-life decreases exponentially, and the side chain branch that blocks the hydrolysis catalyzed by the DPP-4 enzyme should not be too large to avoid hindering the binding of the drug to the therapeutic target. At present, it seems that longer in vivo action time can only be achieved with long-acting controlled release.

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