Oral peptide delivery with lipid-based excipients

Peptides are often perceived as incompatible with lipid‑based formulations because they are typically hydrophilic, large molecules with limited membrane permeability. While this is true for many peptides, it is far from the full picture.

A peptide does not need to be lipophilic to benefit from lipid‑based excipients. Two well‑known oral peptide medicines illustrate this clearly:

Despite their therapeutic potential, peptides face three major barriers when administered orally:

1. Degradation in the gastrointestinal environment: stomachacidic pH and proteolytic enzymes found in both stomach and duodenum can alter peptide structure.

2. Solubility: peptide solubility is strongly influenced by pH, ionic strength and molecular structure. A peptide may be soluble in gastric conditions but poorly soluble in the intestine—or vice versa—making absorption unpredictable.

3. Permeability: most peptides exhibit very low intestinal permeability because of their large size and hydrophilicity, which limit passive diffusion through the intestinal epithelium.

Overcoming these three hurdles is the key to successful oral peptide delivery.

For hydrophilic peptides, a lipidization or hydrophobization step by ion pairing is often required to increase logP and facilitate incorporation into lipid systems.

Lipid‑based formulations (LBF) offer versatile solutions depending on peptide properties:

• LBF type I/II: for lipophilic peptides, which will be solubilized in oils and co‑surfactants;

• LBF type III/IV (SEDDS, SMEDDS, SNEDDS): for hydrophilic peptides, which will be suspended or dispersed with surfactants.

• SLN and NLC: innovative nanocarriers offering protection and solubilization, but this technology still lacks industrial scale-up possibilities.

For peptides, absorption often relies on the paracellular pathway, which is tightly regulated by intestinal tight junctions. Medium‑chain fatty acid esters (C8–C10) are known to transiently open tight junctions, while preserving epithelial integrity.