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.
Highlights
Scientists have tried to enable oral administration of protein and peptide-based therapeutics ever since insulin[1] was discovered 100 years ago for the treatment of diabetes mellitus
We used AA molecular dynamics (MD) simulations to investigate the impact of six different permeation enhancers (PEs) on the structural and dynamical properties of the model cell membrane
The simulation results obtained in our study indicate that PEs can impact the membrane structural properties in a concentration-dependent manner, that is, an increased PE concentration can induce higher membrane leakiness
Summary
Scientists have tried to enable oral administration of protein and peptide-based therapeutics ever since insulin[1] was discovered 100 years ago for the treatment of diabetes mellitus. Peptide molecules are degraded by the acidic environment in the stomach and by the enzymes present in the stomach and in the lumen of the GI tract.[2,3] For this reason, the majority of therapeutic peptide drugs are administered parenterally.[1,4] technology has become much better over the last decades, the risk of discomfort and pain[5] from the injection remains, as the risk of a decrease in patient compliance.[6,7] In recent times, technologies have been developed to improve the peptide-based formulation and peptide structure against enzymatic degradation. Peroral peptides are in Received: September 3, 2021 Revised: November 12, 2021 Accepted: November 16, 2021
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