Blog Post 3: Overcoming the Hurdles of Oral Peptide Delivery


Overcoming Challenges for Oral Peptide Absorption

Why oral delivery of peptides?

 

 

Peptides consist of amino acids linked together through by amide bonds, like beads on a chain. Because of the chemical variety of amino acids, peptides can be designed to interact with practically any therapeutic target, with high specificity. Despite this, peptide drugs only account for 5% of the global pharmaceutical market. More than 90% of these peptide drugs are given to patients parenterally, often resulting in low patient compliance. Enabling the oral route for peptides would greatly increase patient compliance and vastly lower the manufacturing costs.

What are the absorption limitations for oral peptides?

 

The lack in orally-available peptide drugs can be explained through the interaction of peptides with the absorptive environment. The gastrointestinal tract has evolved to efficiently break down a wide variety of dietary proteins and peptides into absorbable amino acids. Therapeutic peptides possess no more protection against the digestive machinery than dietary proteins do, and thus the fate of most peptide drugs is complete degradation before absorption can take place. Moreover, peptides often contain many hydrogen bond donors and acceptors, which prevents rapid diffusion over the lipidic plasma membrane of enterocytes. The following sections will dive deeper into the specific challenges peptides are faced with during their gastrointestinal transit.

Stomach Challenges:

Low pH and Proteolytic Enzymes

 

Within the acidic milieu of the stomach, oral peptides face their first significant hurdle. The low pH environment (1.5- 3) not only compromises the structural integrity of proteins but also sets the stage for enzymatic degradation. Proteolytic enzymes, notably pepsin, catalyze the hydrolysis of peptide bonds, leading to fragmentation and loss of biological activity. A thick mucous membrane also lines the stomach, to protect the gastric tissue from the harsh acidic  environment. This layer severely limits passive diffusion of large molecules, including peptides and proteins. Overcoming these challenges necessitates innovative formulation strategies capable of safeguarding peptides from acid-induced degradation while preserving their therapeutic integrity.

Small Intestine Challenges:

Enzymatic Degradation, Mucus Barrier, and Tight Junctions

 

Upon gastric emptying, peptides continue to be exposed to harsh environments. As the pH increases up to 7 the stomach-originating pepsin enzymes are deactivated, however new enzymes are released by the pancreas and are active at this pH. These enzymes display endopeptidase activity such as trypsin and chymotrypsin, but also enzymes with exopeptidase activities like carboxypeptidases and aminopeptidases. The broad substrate specificity of this mixture, called pancreatin, make it an environment that almost no peptide is stable against, unless specifically designed to be. The mucous membrane lining the gut wall further limits absorption and failure to penetrate this increases time spent in the digestive environment. Once a peptide drug has passed the mucosa, it can either be absorbed through passive diffusion over the plasma membrane, or through passive diffusion through tight junctions. However, the polar nature of peptides limits its tendency to permeate lipid membranes, as the aqueous solvation shell of a peptide first needs to de-solve prior to membrane insertion. Moreover, the large size of therapeutic peptides preclude diffusion through tight junctions, passage through which is usually reserved for molecules less than 500 daltons in size. Navigating through these challenges therefore demands innovative formulation approaches capable of enhancing peptide stability, permeability, and overall bioavailability.

 

 

Our Approach:


At SeraNovo we tackle these obstacles developing innovative solutions to overcome the challenges of oral peptide formulation. If you're interested in learning more about our approach, learn more about our PeptiDES platform here:

 

PeptiDES

 

Contact us via email or the form to optimize your peptide formulations.

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