Formulation strategies to improve the efficacy of intestinal permeation enhancers,

Maher, Sam; Brayden, David J.

doi:10.1016/j.addr.2021.113925

Cited by 55 publications

(28 citation statements)

References 349 publications

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“…This gives support to the hypothesis that for optimal permeation enhancement, C10 needs to be presented to the intestinal epithelium in a sufficiently high initial concentration and that intestinal dilution is detrimental to the permeation-enhancing effect. 20 , 23 , 38 The two more concentrated administrations (100 and 300 mM C10) achieved similar bioavailability and C max . This is in contrast to the pH study, where bioavailability increased with the increasing C10 concentration ( Table 2 ), the difference being that the dose increased along with the concentration in the pH study.…”

Section: Discussionmentioning

confidence: 83%

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: 83%

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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“…A disrupted mucosal barrier is thus identified as a potential therapeutic target [ 10 ]. In this study, we used the pharmaceutical surfactant SDS to induce partial intestinal barrier dysfunction, which has been reported to increase the GI absorption of low permeability drugs [ 17 , 39 ] in a concentration- and time-dependent manner [ 40 , 41 ]. It acts by incorporating into the lipid bilayer of the epithelial cells, which leads to destabilization of the cell membrane and the tight junction complex [ 39 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Sodium dodecyl sulfate (SDS) is an anionic surfactant commonly used as a pharmaceutical excipient in many oral dosage forms [ 17 ]. At the high concentration of 5 mg/mL in the intestinal lumen, SDS has the potential to alter epithelial barrier integrity and it has been shown to increase the permeability of different compounds in both the absorptive and secretory directions [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats

Peters

Dahlgren

Egerszegi

et al. 2022

IJMS

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Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of 51Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier.

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“…However, there remained an unmet need for an oral agent as an alternative option to subcutaneously administered GLP-1RAs. Semaglutide was an ideal candidate for oral delivery with SNAC due to its low molecular weight (4,113.6 Da), long half-life (~ 7 days after subcutaneous administration), and high potency relative to other peptides [14,40,46,56]. SNAC was therefore co-formulated with semaglutide to produce the first GLP-1RA suitable for oral administration.…”

Section: A Brief History Of Snacmentioning

confidence: 99%

“…A number of technologies for the oral delivery of peptides – typically insulin – have been described in the literature, including nanoparticles, microneedle devices, self-emulsifying drug delivery systems, peptide conjugation, and permeation enhancers (reviewed in detail by Durán-Lobato et al [ 44 ] and Zizzari et al [ 45 ]). Of these, permeation enhancers are the most widely tested approach to improve oral absorption of peptides, due to the relative ease with which they can be incorporated into formulations compared with nanotechnology or device-based systems [ 43 , 46 ].…”

Section: Challenges Of Developing An Oral Peptide Therapymentioning

confidence: 99%

A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes

Aroda

Blonde

Pratley

2022

Rev Endocr Metab Disord

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Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

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Formulation strategies to improve the efficacy of intestinal permeation enhancers,

Cited by 55 publications

References 349 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

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats

A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes

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