Poor Membrane Permeability
A dissolved, intact molecule still has to cross the intestinal epithelium, and many do not. Size, polarity and hydrogen bonding determine whether a compound passes through cells or between them, and large polar molecules such as peptides are the hardest case in delivery.
How molecules cross
Most oral drugs cross by passive transcellular diffusion, which favors small, moderately lipophilic molecules. The paracellular route through tight junctions admits only small hydrophilic molecules, with an effective size cutoff of a few hundred daltons. Carrier-mediated uptake helps nutrients such as amino acids and some nucleosides. Molecules breaking Lipinski's rule of five, including most peptides, polar glycosides and many biologics, show low and variable absorption. For these compounds, permeability rather than solubility sets the ceiling.
Permeation enhancers
Intestinal permeation enhancers such as SNAC, sodium caprate and medium-chain fatty acid formulations transiently perturb membranes or loosen tight junctions. They are the basis of approved oral semaglutide and oral octreotide. Effects are local, short-lived and dose-dependent, bioavailability remains low and variable, and co-administration with food or water volume matters. Enhancer safety over chronic use is a regulatory focus. Formulators therefore aim to keep enhancer exposure local, brief and well characterized.
Measuring permeability
Caco-2 monolayers, PAMPA and Ussing chamber tissue give apparent permeability values that correlate with human absorption for passively absorbed drugs. BCS high permeability is defined as 85% or more of the dose absorbed. For peptides, in vitro data overpredict success, so animal pharmacokinetics is needed before any claim. Efflux transporters and metabolism in Caco-2 cells can also distort results, so bidirectional transport and recovery should be reported with every permeability value.
Key facts
- Poor absorption or permeation is more likely when a compound has more than 5 H-bond donors, more than 10 H-bond acceptors, MW over 500 or logP over 5 (Lipinski et al. 1997, Adv Drug Deliv Rev 23:3)
- Caco-2 permeability correlates with fraction absorbed in humans for passively transported drugs (Artursson and Karlsson 1991, Biochem Biophys Res Commun)
- Permeation enhancers underpin the clinical oral peptide products but yield modest, variable bioavailability (Maher et al. 2016, Adv Drug Deliv Rev)
- Oral semaglutide bioavailability is about 0.4 to 1% (FDA label, Rybelsus 2019)
How our delivery technology applies
Encapsulation helps permeability indirectly. Mucoadhesive outer layers hold particles against the epithelium, and inner layers can release an enhancer and the active together at the same spot, raising local concentration of both. That co-localization is the principle SNAC relies on. Layers do not make a large polar molecule lipophilic, so we expect incremental gains and test them in Caco-2 and animal models before any claim.
Send a permeability-limited active for a Caco-2 feasibility screen.
Related reading
Last updated: