Advances in the Oral Delivery of Peptides

Lipid-based technology can significantly aid in the oral delivery of peptides — a goal sought by emerging and major pharmaceutical companies.

Real Market Potential

Companies have been investigating the oral delivery of insulin, calcitonin, cyclosporine, leucine encephalin, HIV protease and other peptides for several years.

Significant Challenges

Oral delivery of biologics, including peptides, remains a significant challenge.^1,2 The hydrophilicity of peptides is one issue. These molecules have poor solubility in water, which makes it difficult to achieve the levels of absorption necessary for any therapeutic effect.

Peptides are susceptible to denaturation and degradation by digestive enzymes in the gastrointestinal (GI) tract and tend to have short half-lives due to rapid clearance in the liver and other tissues by proteolytic enzymes. One way peptides enter the bloodstream requires peptides to pass through the thick mucosal layer protecting the GI tract and then traverse the tight junction gap in the epithelium. Most hydrophilic molecules cannot make the trip.

As a result, complex post-translational modifications are typically necessary to ensure the right bioactivity and resistance properties, leading to higher manufacturing costs.

Limited Successes to Date

The first oral peptides approved in the United States — Linzess^® (linaclotide) from Allergan and Trulance^® (plecanatide) from Synergy Pharmaceuticals — treat GI disorders and do not require systemic delivery. In September 2019, Novo Nordisk received FDA approval for an oral version of its diabetes drug semaglutide (Rybelsus), which does require systemic delivery.

Chiasma, Entrega, Emisphere and Enteris Biopharma are examples of companies developing proprietary oral peptide delivery technologies. Several other start-ups and many large pharma companies have oral peptide development programs targeting a wide array of indications, including cancer, hepatitis B, bacterial infections, diabetes, obesity and endometriosis.^1,2

Many Different Strategies

One of the most common strategies for overcoming the challenges of oral peptide delivery is the use of excipients designed to inhibit enzyme degradation and increase permeability. Encapsulation and the use of protective coatings are other typical approaches.

Significant attention is also being directed at the use of mucoadhesive polymeric systems and specially designed emulsions, polysaccharide and inorganic nanoparticles, microspheres and liposomes, as well as derivatization with polyethylene glycol, hybridization with cell-penetrating peptides and the conversion of peptides into prodrugs.^1,2

Lipid-based solutions are attractive because lipids exhibit excellent biocompatibility and enable passage through the intestinal mucosal layer. In addition to liposomes, solid lipid particles (SLPs), self-emulsifying drug delivery systems (SEDDS), self-nanoemulsifying drug delivery systems (SNEDDS) and multi-emulsions are under investigation.²

ABITEC’s Lipid Solutions

ABITEC has been providing unique lipid solutions to the pharmaceutical industry for many years. We are currently developing next-generation lipids designed specifically to aid in the oral delivery of biologics. Early evidence suggests that incorporation into these new lipid emulsions leads to a significant reduction of degradation and increased oral absorption.

We are also exploring absorbing lipid emulsions of biologics onto a new carrier to produce tablets with desirable properties. The ability to formulate biologics as enteric-coated tablets offers an ideal delivery system for circumventing hydrophilicity, degradation and permeation issues.

ABITEC is working with industry innovators to bring oral delivery of biologics to market and with academic research groups and institutes to gain greater insight into the chemistry and biology involved in oral delivery of peptides. This knowledge will be used to achieve further advances in lipid-based technologies designed to enhance the oral delivery of many types of biologics.

References

1. Jahangir, Asadullah et al. “A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives.” Saudi Pharmaceutical Journal. 24: 413–428 (2016).
2. Chen, Liqubg et al. “Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins.” Acta Pharmaceutica Sinica B. 9: 902–922 (2019).