The Scientific Hurdles Facing Oral Peptides
For decades, the assumption has been that peptides administered orally would not survive the journey through the gastrointestinal (GI) tract to have a systemic effect. This low oral bioavailability is primarily due to a series of formidable natural barriers that peptides encounter. Overcoming these challenges is at the heart of modern oral peptide drug development.
Gastrointestinal Barriers to Oral Delivery
- Enzymatic Degradation: The GI tract is a highly proteolytic environment, full of enzymes designed to break down proteins and peptides into their constituent amino acids. In the stomach, pepsin rapidly cleaves peptide bonds under acidic conditions. In the small intestine, pancreatic enzymes like trypsin and chymotrypsin continue the digestion process. Unprotected peptides are quickly dismantled before they can be absorbed intact.
- Variable pH Levels: Peptides are sensitive to pH changes, which can cause them to denature or unfold, making them even more vulnerable to enzyme attacks. The stomach's low pH (1.5–3.5) and the intestine's higher pH (5–8) create a challenging environment.
- Mucus Layer: A thick, gel-like mucus layer lines the intestines, creating a physical and interactive barrier that impedes the diffusion and transport of larger molecules like peptides. The negatively charged mucins in this layer can bind to peptides, preventing them from reaching the absorptive epithelial cells.
- Epithelial Barrier: The intestinal wall itself is a single, tightly packed layer of epithelial cells designed to prevent large or foreign molecules from entering the bloodstream. Peptides are often too large and hydrophilic to easily pass through these tight junctions or across the cell membranes.
Innovative Technologies for Oral Peptide Delivery
With a clear understanding of the barriers, pharmaceutical scientists have developed clever strategies to allow oral peptides to work. These strategies focus on protecting the peptide, enhancing its absorption, and ensuring targeted release.
Oral Delivery Strategies
- Chemical Modifications: Altering a peptide's structure can enhance its stability and permeability. A common technique is cyclization, which links the ends of a peptide to form a ring structure that is more resistant to enzymatic breakdown. Another is PEGylation, which involves attaching polyethylene glycol molecules to the peptide to create steric hindrance that shields it from enzymes and reduces kidney clearance.
- Colloidal Delivery Systems: Encapsulating peptides in protective carriers is a highly effective strategy. Examples include liposomes, which are spherical vesicles formed from lipid bilayers, and nanoparticles made from polymers or mesoporous silica. These systems shield the peptide from degradation and can be designed for targeted or pH-triggered release.
- Absorption Enhancers: These excipients are co-formulated with peptides to temporarily increase intestinal permeability. Sodium salcaprozate (SNAC) is a well-known example used in Rybelsus® that enhances transcellular absorption. Other enhancers can reversibly open the tight junctions between epithelial cells.
- Enteric Coatings: Tablets or capsules can be covered with a pH-sensitive coating that prevents the peptide from being released until it reaches the less acidic environment of the small intestine, thus protecting it from stomach acid.
- Ingestible Devices: For maximum precision, technologies like the self-orienting ingestible millimeter-scale applicator (SOMA) are being explored. These devices are swallowed and autonomously inject the peptide directly into the stomach lining, ensuring rapid and predictable absorption comparable to injections.
Successful Oral Peptide Medications and Supplements
The success of oral peptide delivery hinges on the sophistication of the delivery technology. This creates a critical distinction between FDA-approved therapeutic drugs and over-the-counter supplements.
Oral vs. Injectable Peptides
| Feature | Oral Peptides | Injectable Peptides |
|---|---|---|
| Absorption Rate | Lower—requires advanced technology for bioavailability | Higher—enters bloodstream directly |
| Enzyme Resistance | Requires modification or encapsulation for stability | Not a concern as it bypasses the GI tract |
| Convenience | Easy to take, no injections required | Requires medical supervision or self-injection |
| Effectiveness | May be reduced compared to injectables, but improving with new tech | Typically higher bioavailability and effectiveness |
| Targeting | Can be designed for local action in the GI tract or systemic delivery | Effective for systemic conditions |
FDA-Approved Oral Peptides
- Oral Semaglutide (Rybelsus®): This FDA-approved drug for type 2 diabetes is a modified peptide formulated with the absorption enhancer SNAC. It is a prime example of a successful oral peptide that uses chemical modification and an enhancer to achieve therapeutic efficacy.
- Octreotide Capsule (Mycapssa®): Approved for acromegaly, this is another success story, developed using Chiasma's TPE (Transient Permeation Enhancer) technology, which temporarily increases intestinal permeability for absorption.
Oral Peptide Supplements
While the pharmaceutical industry makes strides with therapeutic drugs, the claims surrounding over-the-counter oral peptide supplements (e.g., collagen peptides) must be viewed with caution. Most of these are hydrolyzed, meaning they have already been broken down into smaller amino acid chains. While potentially beneficial as a source of amino acids, there is little evidence to suggest that the specific, intact peptides survive digestion to provide the claimed benefits. Without the advanced delivery technology used in prescription drugs, their systemic bioavailability as functional peptides is highly questionable.
Conclusion
In summary, the answer to "Do oral peptides work?" is no longer a simple 'no' but a conditional 'yes.' For a long time, the low oral bioavailability of peptides made them unsuitable for oral administration, requiring injection. However, innovative pharmaceutical technologies, including chemical modifications, protective delivery systems, and absorption enhancers, have enabled the successful development of effective oral peptide medications for systemic diseases. The future of medicine includes an expanding landscape of oral peptide therapeutics, but consumers must distinguish between these medically-formulated drugs and potentially ineffective dietary supplements.
