Oral peptide therapeutics: Getting easier to swallow?


Bruce H. Morimoto
Alkahest, Inc., San Carlos, USA


Oral drug delivery is the preferred route of administration for small molecule therapeutics. High compliance and patient acceptance are some advantages of the oral route of administration. For peptide therapeutics, oral administration has not been a viable option. Recent advances in both design and delivery have changed the landscape. There are now several examples of oral peptide therapeutics in development for indications ranging from diabetes to Alzheimer disease. What was once unthinkable, that is an oral peptide therapeutic, is now in the realm of possible.


Peptide therapeutics have traditionally been administered by a parenteral route such as intramuscular, subcutaneous and intravenous. And although alternative routes have been attempted like intranasal and inhalation, the dream would be to develop an oral peptide therapeutic. Nature has thrown up multiple barriers to the oral delivery of peptides, including the acidic pH of the stomach and the proteolytic environment of the intestine. If those hurdles were not enough, the chemical nature of the polar peptide bond makes membrane permeability a formidable challenge. 

The gastrointestinal (GI) tract has evolved to effectively digest proteins and peptides; therefore, an oral peptide therapeutic must avoid degradation by acidic (low) pH and various endo- and exo-proteases. If successful, then absorption into the blood requires penetration of the epithelial layer. 

Examples of natural oral peptidic products exist such as cyclosporin A and the plant derived cyclotides. But these tend to be the exception rather than the rule. That said, a very active area of ...