For this month’s Journal Club you get two for the price of one! But more peptides is never a bad thing. I fell in love with peptides back in the early 90’s when I joined Amylin Pharmaceuticals and that love affair has continued through my association with the Boulder Peptide Foundation over recent years. Now with the renewed interest in oral delivery of peptides spurred on by the GLP-1 agonists, I can have my new life in oral drug delivery cross over with my secret identity as a peptide nerd.
One area that my scientific advisory team has been talking about more frequently is the concept of in situ hydrophobic ion-pairing (HIP) as a way to impart a more lipophilic character to hydrophilic drugs. And as we know, peptides usually fall into that bucket. I know leveraging lipid-based formulation approaches including self-emulsifying systems (SEDDS) with softgel encapsulation is a validated method of peptide delivery (e.g. cyclosporine A’s Neoral®). We often consider the stability imparted by the emulsion/lipid environment and the ability of excipients in the class to modulate tight junctions for better permeation. But adding in the concept of designing ion-pairing into our formulation as well takes it to another level. As the study outlined in the Truszkowska paper, HIP can be used to both improve the incorporation in the lipid carriers and also enhance membrane permeation. Just what you want for oral drug delivery.
But in my deep dive into the topic, I then came across the Sandmeier paper that not only looked at HIP1 but also reverse micelles2 (RM). Side note – I admit I had to google to make sure I understood the sequence of steps to incorporate a RM into SEDDS because that is getting fancy. Their findings were that RM may prove to be an even better strategy to increase peptide loading than HIP using semaglutide as their model compound. But since we know every peptide is a snowflake, it would need to be seen how this finding would reproduce in a broader peptide library. Maybe I can entice some of our readers to consider looking into this? Just a thought!
Of course, we have to work to see if these formulation techniques can be translated into actual medicines. That’s the fun and most rewarding part of my job when our products actually reach patients. But now I have two additional techniques to consider in my arsenal for rationally designed oral delivery of peptides. And as I said in the beginning, when it comes to peptides, I think we would all agree that more is better. Enjoy!
Open Access articles:
1Truszkowska, M., Ebert, M.L., Afzal, K.B., Györgyi, V., Bernkop-Schnürch, A.. Peptide drug delivery: Permeation behavior and intracellular fate of hydrophobic ion pairs in self-emulsifying drug delivery systems, Eur J Pharm Sci. 2025 Sep 1:212:107207. https://doi.org/10.1016/j.ejps.2025.107207
2Sandmeier, M., Ricci, F., To, D., Lindner, S., Stengel, D., Schifferle, Koz, S. & Bernkop-Schnürch, A.. Design of self-emulsifying oral delivery systems for semaglutide: reverse micelles versus hydrophobic ion pairs. Drug Deliv. and Transl. Res. 15, 2146–2161 (2025). https://doi.org/10.1007/s13346-024-01729-0
Lisa Caralli
Member, Scientific Advisory Board, Boulder Peptide Society
Sr. Director of Scientific Advisory at Catalent, Inc
https://www.linkedin.com/in/lisa-caralli-50b16318/