Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs

Twarog, Caroline; McCartney, Fiona; Harrison, Sabine M.; Illel, Brigitte; Fattal, Elias; Brayden, David J.

doi:10.1016/j.ejps.2020.105685

Cited by 23 publications

(18 citation statements)

References 58 publications

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“…However, a disadvantage with these models is that the level of detail is limited. A comparison in the general mechanisms of action between SNAC and sodium caprate is reported in Twarog et al, in which the authors suggest common mechanisms of action with indirect changes in the tight junctions resulting from membrane perturbation, as well as direct membrane effects. However, the molecular-level details remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…The phosphatidylcholine 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) molecule is one of the most abundant phospholipids in eukaryotic cell membranes, and it is often used in model systems to represent a bilayer. Oral drug absorption over lipid bilayers can be studied in in vitro models using transwell experiments with cell lines, as for example the human colon carcinoma cell line Caco-2, , or with the Everted sac model. , Absorption can also be studied in ex vivo models with different segments of mouse, rat, rabbit, or human intestinal region tissue mounted in, for example, an Ussing chamber model, , in a Franz cell model, or in an organ culture model of intestinal mucosal explants, as well as with cell-imaging tools combined with biophysical methods . The human colorectal adenocarcinoma cell line, Caco-2, , can be used as an in vitro transport model system to study permeability of the small intestinal epithelia .…”

Section: Introductionmentioning

confidence: 99%

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

2021

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2021

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“…The most advanced C10 formulation is the insulin/C10 formulation, which was tested up to phase 2 clinical trial showing an ∼2.2% bioefficacy compared to SC administration . Besides insulin, the effect of C10 on the oral absorption of macromolecules was mostly investigated using a model macromolecule (e.g., fluorescently labeled dextran 4000 Da (FD4)). − For example, the absorption of FD4 in rats increased with increasing C10 concentration, and both the intestinal C10 concentration and C10 amount are critical to driving FD4 absorption . However, the effect of C10 may be dependent on the physicochemical properties of peptides.…”

Section: Introductionmentioning

confidence: 99%

“…C10 facilitates the absorption of peptides via both paracellular and transcellular pathways by transiently opening tight junction and reversibly increasing membrane fluidity. ,− It is believed that the permeation-enhancing effect of C10 is driven by its monomeric form; however, most of these mechanisms were investigated using in vitro cell culture models and ex vivo isolated intestinal tissues where C10 was used at concentrations likely lower than in vivo . It has been proposed that C10’s effect is predominantly the perturbation of the intestinal epithelium at high concentrations in vivo ; however, this has not been thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide

et al. 2023

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Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

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“…C 10 has been the subject of numerous cell culture, preclinical, and clinical studies, making it one of the most widely studied permeation enhancers, and its safety in humans is well established. 12 , 13 , 14 , 15 , 16 However, C 10 is an anomaly, and the majority of permeation enhancers have not been examined for their effects following repeat dosing in animals or in humans.…”

Section: Introductionmentioning

confidence: 99%

Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Fein

Gleeson

Cochran

et al. 2022

Bioengineering & Transla Med

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Although protein drugs are powerful biologic therapeutics, they cannot be delivered orally because their large size and hydrophilicity limit their absorption across the intestinal epithelium. One potential solution is the incorporation of permeation enhancers into oral protein formulations; however, few have advanced clinically due to toxicity concerns surrounding chronic use. To better understand these concerns, we conducted a 30‐day longitudinal study of daily oral permeation enhancer use in mice and resultant effects on intestinal health. Specifically, we investigated three permeation enhancers: sodium caprate (C 10 ), an industry standard, as well as 1‐phenylpiperazine (PPZ) and sodium deoxycholate (SDC). Over 30 days of treatment, all mice gained weight, and none required removal from the study due to poor health. Furthermore, intestinal permeability did not increase following chronic use. We also quantified the gene expression of four tight junction proteins (claudin 2, claudin 3, ZO‐1, and JAM‐A). Significant differences in gene expression between untreated and permeation enhancer‐treated mice were found, but these varied between treatment groups, with most differences resolving after a 1‐week washout period. Immunofluorescence microscopy revealed no observable differences in protein localization or villus architecture between treated and untreated mice. Overall, PPZ and SDC performed comparably to C 10 , one of the most clinically advanced enhancers, and results suggest that the chronic use of some permeation enhancers may be therapeutically viable from a safety standpoint.

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Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs

Cited by 23 publications

References 58 publications

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

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

In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide

Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

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