In Silico-Based Experiments on Mechanistic Interactions between Several Intestinal Permeation Enhancers with a Lipid Bilayer Model

Abstract

Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNACall with a negative chargeand neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70−100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…Several clinical studies have demonstrated how modified release coatings can enable the delivery of antibodies for the treatment of IBD, these have recently been reviewed by Brayden [33]. Where systemic delivery of biologics is desired, formulations may need to incorporate permeation enhancers, such as medium chain fatty acids or salcaprozate sodium, to enable passage across the colonic epithelium [161,162]. At present there are 5 FDA-approved products that deliver peptides orally for systemic action, these include Rybelsus® (semaglutide) and Mycapssa® (octreotide) [33].…”

“…From a drug development perspective, MD has many potential applications for formulation design. MD could be used to definitively map the drug loading and release mechanisms of stimuli-responsive formulations and as such design targeted dosage forms with highly explainable in vivo behaviours [161,252]. MD has also been used to understand the formation of polymer coated nanoparticles produced by flow nanoprecipitation, exemplifying how atom-level insight could be used to optimise colontargeted nanoformulations [257,258].…”

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

“…Siani et al studied doxorubicin, a widely used cancer treatment drug, in sphingomyelin-based membranes in order to optimize the liposome-based drug delivery for doxorubicin . Kneiszl, Hossain, and Larsson studied how intestinal permeation enhancers interact with membranes to lay the basis for improving the efficacy of oral administration drugs . Sabin et al studied polyethylenimine and its interactions with membranes using simulations and showed that polyethylenimine induces pore-forming in the membrane, contributing to an understanding of the DNA cell transfection process .…”

“…275 Kneiszl, Hossain, and Larsson studied how intestinal permeation enhancers interact with membranes to lay the basis for improving the efficacy of oral administration drugs. 280 Sabin et al studied polyethylenimine and its interactions with membranes using simulations and showed that polyethylenimine induces pore-forming in the membrane, contributing to an understanding of the DNA cell transfection process. 15 Winslow and Robinson developed a new phase-sensitive membrane raft probe through QM/MM simulations of different probes in the membrane.…”

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes

“…The deprotonated FA charges can cause repulsive forces, increasing the distance between FAs and counteracting the "diluting" effect of FAs which was mentioned earlier in this section. Interestingly, a recent study by Larsson et al investigated the effect of C10-n on the APL of a POPC membrane using an allatom force field at 310.15 K. 41 The APL was also computed differently, dividing the simulation box by the number of phospholipid molecules without counting the number of C10n, so the trends in the APL cannot be compared directly with our results. They found a modest increase of about 3% in the area per POPC molecule caused by the incorporation of 10% C10-n.…”