Peptides are short chains of amino acids linked by peptide bonds. Compared with traditional small molecule drugs, peptide drugs are featured with strong drugability, high activity, high specificity, low toxicity, and no drug-drug interactions; compared with protein drugs, peptide drugs have the advantages of lower production cost, simpler R&D, and no immunogenicity. Therefore, since the discovery of insulin in 1920, peptide drugs have received increasing attention. Currently, more than 100 peptide drugs have been approved for marketing, with clinical applications covering metabolic diseases, cancer, neurological diseases, immune diseases, etc.
Although peptide drugs have a promising therapeutic future, they also have certain drawbacks. The presence of peptidases results in peptide drugs usually having a short half-life, and this instability affects drug development and efficacy. Problems such as low oral efficiency and poor cellular uptake can also affect late-stage drug formation.
Oral administration is gradually becoming a research focus as a safe and compliant route of drug delivery. In recent years, research on enhancing the oral absorption of peptides has made great progress in both preclinical and clinical trials. In 2019, the approval of oral semaglutide, developed by Novo Nordisk and Emisphere Technologies, became a major milestone in the field of oral peptides.
Strategies for oral delivery of proteins peptides
Since the discovery of insulin in 1920, oral peptide research has never stopped, and more than 20 strategies for delivering peptides orally have been reported. As shown in Figure 1, they include enteric coating, pH modulators, enzyme inhibitors; PEGylation, cyclization, prodrugs; mucosal adsorption, microneedling; absorption enhancers, nanotechnology and so on. Among them, the main delivery strategies to get industrial translation are chemical modifications, pH modulators/enzyme inhibitors, permeation enhancers, and SNEDDS.
Figure 1. Strategic approaches for oral delivery of peptides, source: reference 
Chemical modifications, which are mainly aimed at improving the half-life of peptides, include PEGylation (polyethylene glycol), glycosylation, lipidation, and using adjuvant molecules to enhance delivery. Among these, the combination of PEG with peptides improves thermal stability, resists protease degradation, reduces antigenicity, and prolongs half-life in vivo. In addition to PEG, lipidation and glycosylation of peptide drugs can also improve the enzyme stability of peptides and so on. For example, by fatty acid acylation of the lysine in position 26, semaglutide improves efficacy, enhances resistance to enzymatic degradation, improves plasma stability, and significantly prolongs half-life.
Note: Huateng Pharma provides high quality PEG derivatives for your PEGylation of peptide.
Figure 2. semaglutide structure
In addition, cyclic peptides are also one of the key areas of oral peptide research. Peptide cyclization is used to make peptides insensitive to hydrolases by removing the exposed C- and N-terminals from the peptide molecule. In addition, cyclization reduces the exposure of polar atoms to the surrounding environment by folding the peptide into a biologically active conformation, thereby improving the stability and bioavailability of the peptide for oral administration.
Although chemical modification of peptides has been extensively studied, it remains a challenge in terms of its industrial feasibility and high cost.
pH modulation/Enteric Coating
The pH environment of the GI tract leads to the hydrolysis and conformational changes of peptides, as well as their enzymatic degradation at that pH. It has been shown that peptides are relatively stable only in a narrow pH range similar to their isoelectric point.
The activity of GI enzymes is closely related to their pH environment. For example, pepsin can only degrade peptides in an acidic environment, , however, pepsin starts to lose their effect when the pH is over 3.
In the development strategy for oral semaglutide (Rybelsus®), one of the roles of the excipient SNAC is to raise the local intragastric pH to protect semaglutide from degradation by pepsin. For octreotide (Mycapssa®), enteric coating was used directly to avoid octreotide release in the stomach. In addition, Tarsa Therapeutics (Philadelphia, USA) has successfully completed a phase III trial for oral delivery of sCT (ORACAL) which comprises of an enteric coated capsule to bypass the stomach and citric acid to modulate the pH microenvironment in intestine.
Figure 3. SNAC Technology, source: Novo Nordisk official website
The addition of absorption enhancers to drug prescriptions is one of the commonly used means of oral formulation. Since a study in 1961 found that EDTA improved the oral absorption of heparin in dogs, absorption enhancers have received a lot of attention in pharmaceutical and biomaterials science. With the rapid development of these disciplines, excipients with better safety and better absorption-promoting effects are emerging. Absorption enhancers can be categorized according to their role as paracellular enhancers, transcellular enhancers, and both paracellular and transcellular enhancers.
There are tight junctions, adhesion junctions and desmosome junctions between cells, and these complexes maintain the morphology and integrity of the intestinal wall structure, preventing the passage of bacteria, and undigested proteins through the cellular interstitial space. Chelating agents can reduce Ca2+ concentration by chelating with extracellular Ca2+, which in turn leads to an increase in cellular paracellular permeability through a series of signaling pathways; the effect is reversible, and cellular permeability recovers after an increase in Ca2+ concentration. Commonly used chelating agents include EDTA, citric acid, etc. Oramed Pharma uses EDTA as absorption enhancers, and clinical studies have shown that the oral relative bioavailability of insulin in the group employing EDTA was 20% higher when compared to chitosan nanoparticles of insulin.
Most surfactants, including sodium caprylate and their derivatives, and bile salts, are commonly used transcellular absorption enhancers, which make drugs more accessible to cells by increasing the permeability of cell membranes or increasing the lipophilicity of the drug. For example, one of the reasons why SNAC, an excipient in oral semaglutide prescription, enhances absorption is that it promotes the monomerization of semaglutide and its interaction with the plasma membrane, thus increasing its permeability. Oral bioavailability has also been enhanced by the use of 5-CNAC in a clinical-stage sCT (SMC021), which is in phase III clinical trials.
In addition, such as sodium decanoate, sodium octanoate also has the effect of enhancing both paracellular and transcellular absorption. Sodium decanoate can increase intracellular Ca2+ concentration, phosphorylate myosin light chain after signaling to open cellular paracellular pathway, and also has the effect of disturbing the plasma membrane to enhance intestinal permeability.
Self-nanoemulsifying drug delivery systems (SNEDDS) were regarded as an important strategy for improving oral absorption of drug molecules.
Among the marketed products, cyclosporin A (Neoral® and Sandimmune®), as well as Voclosporin (wupkynis®) employ SNEDDS technology. SNEDDS is a lipid-based drug delivery system in which the formulation consists mainly of an oil phase, a surfactant and a co-surfactant. After oral administration, the self-microemulsions spontaneously and rapidly form O/W type drug-carrying microemulsions in the gastrointestinal fluid under gastrointestinal peristalsis, with droplet sizes <100 nm. The droplets formed in the gastrointestinal tract are small in size and widely distributed, which improves the concentration of difficult-to-solve drugs in the gastrointestinal tract and promotes osmotic transmembrane absorption. During the process of emulsion breaking and digestion, the fatty acids digested from the core oil, the bile acid salts secreted in the body and the phospholipids in the food can form mixed micelles, which wraps the raw materials into the micelles, thus promoting the absorption of the raw materials by the osmotic, transporter, cytosolic and lymphatic pathways. Some lipid excipients such as C8 octanoic acid oil, C10 decanoic acid derivatives also have a certain degree of pro-absorption effect.
However, it should be noted that Voclosporin is essentially a structural analog of cyclosporin A, and both are water-insoluble and lipophilic drugs. SNEDDS is not suitable for drugs with strong water solubility, and at the same time, for drugs with poor hydrophilic and lipophilic properties, there is a possibility that the drug may be heavily enriched in the interfacial layer after the formation of the microemulsion, leading to precipitation or degradation.
Overview of The Current Clinical Studies
Cyclosporin A (Sandimmune®), a cyclic peptide with a molecular weight of 1202, was the first FDA-approved oral peptide. 5 years later, Novartis developed and approved Neoral®, a modified version of cyclosporin A. In 2019, an oral formulation of semaglutide, developed by Novo Nordisk, was approved by the FDA for the treatment of type II diabetes mellitus. Octreotide extended-release capsules (Mycapssa®) were approved for marketing by the FDA in 2020. These last two oral peptide products are revolutionizing the field of oral peptides.
There are currently 17 oral peptide drugs successfully marketed worldwide, of which 8 are absorbed into the bloodstream after oral administration.
Table. Marketed oral peptide
We provide an overview of the current landscape of oral peptides in marketing and clinical studies, a review of the forms of delivery used, and a summary and analysis of the common strategies used for oral peptides that have been successfully translated into industry. In fact, each successfully marketed oral peptide may include a combination of different absorption enhancing strategies, such as octreotide (Mycapssa®), which uses both absorption enhancers and enteric coating technology, somatostatin (Rybelsus®), which has an optimized chemical structure, and excipient SNAC, which acts as both a pH modulator and an absorption enhancer.
With the emergence of more oral peptides and the availability of new functional excipients, oral peptide delivery technologies capable of overcoming human physiological barriers will continue to emerge, facilitating the wider clinical application of peptides.
Huateng Pharma is known worldwide for a variety of pharmaceutical intermediates used in research and development. We can provide antidiabetic drug intermediates such as semaglutide intermediates, liraglutide intermediates, canagliflozin intermediates, dapagliflozin intermediates and empagliflozin intermediates for your research. We have our own factory and make scale-up production with capacities varying from gram to kilograms and multi tons.
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