Salcaprozate sodium (SNAC) enhances permeability of octreotide across isolated rat and human intestinal epithelial mucosae in Ussing chambers

Fattah, Sarinj; Ismaiel, Mohamed; Murphy, Brenda; Rulikowska, Aleksandra; Frias, Jesus Maria; Winter, Desmond C.; Brayden, David J.

doi:10.1016/j.ejps.2020.105509

Cited by 31 publications

(12 citation statements)

References 49 publications

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“…In a study by Gradauer et al on alkyl-maltosides, the permeation-enhancing effect was abolished in the presence of simulated intestinal fluids . Another study using the permeation enhancer SNAC also showed lower octreotide apparent permeability in an ex vivo model when formulated in FaSSIF-V2 and rat simulated intestinal fluid, rSIF, compared to when delivered in Krebs–Henseleit buffer …”

Section: Discussionmentioning

confidence: 96%

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Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat

et al. 2021

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In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50–300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and C max of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60–120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

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Section: Discussionmentioning

confidence: 96%

“… 42 Another study using the permeation enhancer SNAC also showed lower octreotide apparent permeability in an ex vivo model when formulated in FaSSIF-V2 and rat simulated intestinal fluid, rSIF, compared to when delivered in Krebs–Henseleit buffer. 43 …”

Section: Discussionmentioning

confidence: 99%

Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat

et al. 2021

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“…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%

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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“…Labrasol , is a mixture of mono-, di-, and triglycerides (C8, C10) plus PEG 400 mono/diesters (C8, C10). Both internal and external data , suggested that this and related fatty acid/lipid-based excipients may act to transiently modulate intestinal paracellular permeability, increasing the intestinal absorption of low-permeability drugs. , A similar enabled formulation-based approach based on the permeation enhancing properties of SNAC (salcaprozate sodium) had proven viable for the GLP-1 agonist semaglutide, , which was recently approved by the FDA as an oral agent. After an extensive formulation screen, 35 was dosed ID to rats in a 30% Labrasol/70%PBS solution, and the data are shown in Table .…”

Section: Results and Discussionmentioning

confidence: 99%

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

Tucker¹,

Embrey²,

Alleyne

et al. 2021

J. Med. Chem.

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Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

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Salcaprozate sodium (SNAC) enhances permeability of octreotide across isolated rat and human intestinal epithelial mucosae in Ussing chambers

Cited by 31 publications

References 49 publications

Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat

Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat

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

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

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