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Date of publication:2020/6/17 17:03:37
oral-peptide
 
Proteins and peptides are the building blocks of life and have evolved to become a very promising basis for targeting a range of diseases. Currently, there are more than 200 approved therapeutic proteins and more than 100 peptides on the market.

Research has demonstrated that peptide therapeutics can offer several advantages that are distinct and desirable. Peptides serve a highly specific set of functions in the body that cannot be mimicked by simple chemical compounds. Thus, compared with small-molecule active pharmaceutical ingredients, peptides are able to exhibit increased potency and selectivity due to specific interactions with their targets.

As a result, peptides have the potential for decreased off-target side-effects and decreased systemic toxicity. Moreover, because the body naturally produces peptides, peptide-based therapeutics are often well-tolerated and are less likely to elicit immune responses.

Though peptide therapeutics offer numerous advantages, and the growth of such drugs is strong, there remain challenges with the route and method of delivery of peptide drugs.

Most peptide drugs are administered parenterally, with approximately 75% given via injectable routes such as subcutaneous, intravenous, and intramuscular administration. However, oral administration of macromolecular drugs such as peptides is the main direction in the field of formulation development, especially for patients with chronic diseases such as type 2 diabetes. Since the early stage of the disease has little effect on the patient's quality of life, the effects of different administration methods on the patient's life directly determine the drug compliance and sales.

Currently, the US Food and Drug Administration (FDA) has approved three oral peptide drugs.

Among them, Allergan's (acquired by AbbVie) Linzess® (linaclotide) and Synergy's (acquired by Salix) Trulance® (plecanatide) are taken orally for the treatment of gastrointestinal diseases and do not require absorption to exert a systemic effect.

In September 2019, Novo Nordisk's oral drug Rybelsus® (semaglutide) was approved by the FDA. The drug needs to exert a systemic effect, marking the development of oral peptide drugs into a new era.

 
Oral Peptide Drugs Approved by FDA
Name  Active Ingredient Dosage Form/Administration Route Classification Indication Approved Date Company
LINZESS Linaclotide Capsule/Oral Guanylate cyclase-C agonists Irritable Bowel Syndrome with Constipation (IBS-C); Chronic idiopathic constipation (CIC) Aug. 20, 2012 Allergan
TRULANCE Plecanatide Tablet/Oral Guanylate cyclase-C agonists Chronic idiopathic constipation (CIC) Jan. 19, 2017 Snlix
RYBELSUS Semaglutide Tablet/Oral GLP1 Receptor Agonist Type 2 diabetes Sep. 20, 2019 Novo Nordisk
 

Main Barriers for Oral Administration of Peptide Drugs

First of all, the hydrophilicity of peptides is a problem. The poor solubility of peptides in water makes it difficult to achieve the level of absorption required for therapeutic effects.

Second, peptides are easily denatured and degraded by digestive enzymes in the gastrointestinal tract (GI), and due to the rapid clearance of proteolytic enzymes in the liver and other tissues, peptides often have a shorter half-life. Peptides enter the bloodstream after oral administration, requiring them to pass through the mucosal layer that protects the gastrointestinal tract and then pass through the tight junction gap of the epithelium.

oral peptide drugs

Oral Peptide Drug Delivery System

The reason why oral semaglutide has achieved a breakthrough in oral macromolecular drugs is mainly because of the penetration enhancer sodium octoate (Salcaprozate Sodium, SNAC) and semaglutide fit perfectly. As a long-acting analogue of GLP-1, the semaglutide molecule is a traditional linear peptide, and the molecule itself does not possess any oral bioavailability at all. SNAC non-specifically increases the permeability of the intestinal mucosal barrier, allowing semaglutide to penetrate the intestinal mucosal epithelial cells in a short time, thereby being absorbed into the blood by the capillaries under the intestinal mucosa. Although mixed with SNAC, oral semaglutide preparations have only about 1% oral bioavailability, but for type 2 diabetes patients who are extremely hungry for reducing the number of injections, safe and effective oral preparations will greatly improve the quality of life.

1. Permeation Enhancer, PE

In many in vivo and in vitro experiments with oral macromolecules, surfactants, bile acid salts, bacterial toxins, chelating agents, medium-chain fatty acids, etc., have shown different degrees of penetration promotion. So far, the only penetration enhancers that have been used in human experiments are SNAC, Sodium Caprate, (C10), medium-chain fatty acids, bile acid salts, and eight-carbon derivatives.

2. C10

C10 is sodium caprate, which is a saturated medium-chain fatty acid. It has been approved by the United States and the European Union as a food additive and is one of the main excipients of ampicillin (Doktacillin). C10 is an anionic surfactant that is sensitive to the pH and ionic strength of the solution. It is insoluble and inactive in strongly acidic environments such as the stomach and can activate its detergent-like activity in alkaline environments such as the small intestine. A large number of in vitro experiments have confirmed that C10 at low concentrations (2.5 mM) mainly increases macromolecular permeability by reversibly interfering with intestinal mucosal epithelial cell bypass. At high concentrations (8-13 mM), it directly affects the intestinal mucosa structure and paracellular pathways. So far, except for ampicillin, there is no drug approved with C10 as a delivery system.

3. SNAC

SNAC is a chemically synthesized salicylic acid acetyl amino acid derivative. It was originally a high-efficiency molecule selected by Emisphere from many penetration enhancers. Oral vitamin B12 with SNAC as the main excipient has been approved as a medical food, and SNAC has also been recognized by the FDA as generally recognized as safe (GRAS). Like C10, it can be directly mixed with API to make uncoated oral tablets, which is easy to control the production cost and scale of the preparation.

After years of unremitting efforts by Novo Nordisk, the FDA officially approved oral semaglutide for the treatment of type 2 diabetes on September 20, 2019. Different from C10 and most traditional views, Novo Nordisk stated in relevant reports that after the oral preparation is graded in the stomach, SNAC can effectively increase the local pH around the semaglutide molecule and prevent the degradation of peptides by pepsin. In addition, SNAC allows semaglutide to be absorbed into the blood after penetrating the gastric mucosa on the cell membrane surface with a concentration gradient through contact with the brush border of intestinal mucosal epithelial cells. This verifies that SNAC enhances the bioavailability of macromolecules, not by destroying the intestinal mucosal barrier.

In addition to the above advantages, there are of course many problems with penetration enhancers such as SNAC. First of all, although oral semaglutide can effectively avoid perennial subcutaneous injections in patients with type 2 diabetes when comparing the difference between weekly subcutaneous injections and daily oral administration, the difference in feelings does not seem to be very obvious. Moreover, in order to achieve better bioavailability, oral semaglutide requires fasting and water for 6 hours before taking it, and no meals can be eaten for half an hour after taking this medicine, which also brings discomfort to patients. In addition, the bioavailability of only about 1% also makes the cost of APIs for oral semaglutide tablets significantly higher than long-acting injections, which will undoubtedly increase the terminal selling price of oral semaglutide tablets. Finally, it is necessary to discuss safety issues. Although penetration enhancers such as SNAC will not cause serious effects such as bacterial translocation, due to the huge changes in environmental conditions such as the pH value of digestive juice in the intestine, penetration enhancers have a significant impact on the bioavailability of the payload. There are also huge fluctuations in the increase. Therefore, only safe drugs, such as GLP-1 analogs, whose therapeutic dose differs greatly from dangerous doses are suitable for administration by penetration enhancers. The size of the therapeutic window of peptide drugs will be the key point for evaluating their suitability for oral administration.

Conclusion

Oral peptides have clearly become the future trend of peptide drug development. At present, there are many oral peptide drugs in the clinical stage.
Oral Peptide Drugs in Clinical Stage
Technology Drug Clinical Stage Company
Eligen Insulin Phase I Emisphere Technologies (USA)
Mycapssa Octreotide Phase III Chiasma (USA)
Peptelligence Leuprorelin Phase II Enteris BioPharma (USA)
Eligen GLP-1 Phase II The University Hospital of Basel (Switzerland)
Peptelligence Parathyroid Hormone Phase II Entera Bio Ltd (Israel)
Eligen Salmon calcitonin Phase III Nordic Bioscience (Denmark) / Novartis (Switzerland)
POD Insulin Phase II Oramed (Israel)
Oshadi Icp Insulin Phase I Oshadi Drug Administration (Israel)
Peptelligence Salmon calcitonin Phase II Tarsa Therapeutics  (USA)

Huateng Pharma, a professional semaglutide intermediates​ factory and manufacturer, focuses on Semaglutide Intermediates​ producing for many years. 

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[3] Liraglutide, Used For Treating Against Type 2 Diabetes And Obesity
[4] The things you need to know about diabetes