A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms

Tuvia, Shmuel; Pelled, Dori; Marom, Karen; Salama, Paul; Levin-Arama, Maya; Karmeli, I.; Idelson, Gregory H.; Landau, I. Theodore; Mamluk, Roni

doi:10.1007/s11095-014-1303-9

Cited by 113 publications

(104 citation statements)

References 34 publications

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“…As with other MCFAs, C 8 in the OS temporarily rearranged zonula occludens-1 (ZO-1) in the tight junction. 20 Furthermore, to establish safety of long term use, daily doses of oral OS were administered in high doses to Cynomolgus monkeys for 9 months. 20 There were no significant changes in bodyweight, electrocardiogram, ophthalmic parameters, haematological scoring or clinical pathology.…”

Section: Fatty Acidsmentioning

confidence: 99%

“…20 Furthermore, to establish safety of long term use, daily doses of oral OS were administered in high doses to Cynomolgus monkeys for 9 months. 20 There were no significant changes in bodyweight, electrocardiogram, ophthalmic parameters, haematological scoring or clinical pathology. Adverse effects such as nausea were noted in the Phase III trial, most of which occurred in the first 3 months, but these were comparable to the injectable peptide counterpart, suggesting these were not due to sodium caprylate.…”

Section: Fatty Acidsmentioning

confidence: 99%

“…17 Chiasma also tested their Transient Permeability Enhancer (TPEÒ) formulation in rats using a similar study design. 20 FD4 was administered into the jejunum via a cannula 0, 30 and 60 min after their formulation and it was found that the area under the curve (AUC) was reduced when the FD4 was administered 60 min (8 § 1 AU) after the C 8 -containing formulation compared to 10min (64 § 15 AU). These results suggest that, as with C 10 , the effects on intestinal permeability are temporary and reversible for TPEÒ.…”

Section: Pe-induced Intestinal Epithelial Damagementioning

confidence: 99%

“…20 As the MW of enterobacterial toxins range from 70-900 kDa and LPS is >100 kDa, it would suggest that PEs are unlikely to open TJs sufficiently to allow 'by-stander' LPS or xenobiotics to permeate. 20 Furthermore, E. coli (pHTK3) was not able to translocate across Caco-2 monolayers in the presence of C 10 , but it was translocated in the presence of the strong detergent, TritonÒ-X-100 (16mM), 10 easily accounted for by the irreversible monolayer damage and compromised barrier. S. typhimurium was not able to translocate across isolated rat ileal mucosa upon co-exposure to C 10 (1-30mM).…”

Section: Pe-induced Intestinal Permeability Of Lps and Xenobioticsmentioning

confidence: 99%

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Safety concerns over the use of intestinal permeation enhancers: A mini-review

2016

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Intestinal permeation enhancers (PEs) are key components in »12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo-and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

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Section: Fatty Acidsmentioning

confidence: 99%

Section: Fatty Acidsmentioning

confidence: 99%

Section: Pe-induced Intestinal Epithelial Damagementioning

confidence: 99%

Section: Pe-induced Intestinal Permeability Of Lps and Xenobioticsmentioning

confidence: 99%

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Safety concerns over the use of intestinal permeation enhancers: A mini-review

2016

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“…Peptides, including insulin, are unstable and poorly permeate the small intestinal epithelium, hence their low oral bioavailability [38]. PEs are present in several solid-dose oral formulations for peptides, of which two technologies are advanced clinically [39,40]. Examples of advanced PEs include medium-chain fatty acids (MCFAs), acyl carnitines, bile salts, and alkyl maltosides [41].…”

Section: Hca: Cytotoxicity Of Polymers and Permeation Enhancersmentioning

confidence: 99%

High-content analysis for drug delivery and nanoparticle applications

Brayden

Cryan

Dawson

et al. 2015

Drug Discovery Today

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Publication information Drug Discovery Today, 20 (8): 942-957Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6636 Publisher's statementThis is the author's version of a work that was accepted for publication in Drug Discovery Today. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Drug Discovery Today, 20 (8), (2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 26A c c e p t e d M a n u s c r i p t Sally-Ann CryanSally-Ann Cryan has a pharmacy degree and a PhD in pharmaceutics ( Jeremy SimpsonJeremy Simpson carried out his PhD at the University of Warwick, followed postdoctoral work at the Scripps Research Institute in San Diego, and the Imperial Cancer Research Fund in London. After 9 years as a staff member at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), he was appointed as professor of cell biology at UCD, in 2008. He currently applies high-throughput imaging technologies to study subcellular transport pathways and the internalization routes taken by nanoparticles in cells. He runs the UCD Cell Screening Laboratory and is the author of more than 80 publications.High-content analysis (HCA) provides quantitative multiparametric cellular fluorescence data. From its origins in discovery toxicology, it is now addressing fundamental questions in drug delivery. Nanoparticles (NPs), polymers, and intestinal permeation enhancers are being harnessed in drug delivery systems to modulate plasma membrane properties and the intracellular environment. Identifying comparative mechanistic cytotoxicity on sublethal events is crucial to expedite the development of such systems. NP uptake and intracellular routing pathways are also being dissected using chemical and genetic perturbations, with the potential to assess the intracellular fate of targeted and untargeted particles in vitro. As we discuss here, HCA is set to make a major impact in preclinical delivery research by elucidating the intracellular pathways of NPs and the in vitro mechanistic-based toxicology of formulation constituents. A brief recap of cytotoxicity assaysIn vitro cell-based assays have long been used to assess the cytotoxic effects of drug exposure [1]. Cells undergoing acute necrosis swell and lose metabolic capacity, thereby losing the capacity to maintain a barrier to the extracellular space and the ability ...

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Oral Delivery of Therapeutic Peptides: Strategies for Product Development

Liu

2023

Oral Bioavailability and Drug Delivery

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A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms

Cited by 113 publications

References 34 publications

Safety concerns over the use of intestinal permeation enhancers: A mini-review

Safety concerns over the use of intestinal permeation enhancers: A mini-review

High-content analysis for drug delivery and nanoparticle applications

Oral Delivery of Therapeutic Peptides: Strategies for Product Development

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