Evaluation of Mucosal Damage and Recovery in the Gastrointestinal Tract of Rats by a Penetration Enhancer

Narkar, Yogeeta; Burnette, Ronald R.; Bleher, Reiner; Albrecht, Ralph M.; Kandela, Angki; Robinson, Joseph R.

doi:10.1007/s11095-007-9509-8

Cited by 28 publications

(25 citation statements)

References 61 publications

(75 reference statements)

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“…Pretreatment with C 10 for 15 min (followed by removal) did not increase FD4 absorption when the flux marker was administered 15 min later, in marked contrast to the significant absorption promotion seen when both agents were administered together or when FD4 was administered within 10 min (Wang X, PhD Thesis, NUI Dublin 2009). While another promoter, SDS, increased phenol red absorption in rat intestine, its effects took longer than C 10 to dissipate [118]. In another rat perfusion study, co-administration of either SDS, EDTA, or C 10 with cefoxitin increased absorption of the antibiotic [113]; upon removal of the promoter, cefoxitin plasma levels continued to increase with SDS and EDTA, but not in the case of C 10 .…”

Section: [12] Intestinal Absorption Promotersmentioning

confidence: 98%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

195

176

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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Section: [12] Intestinal Absorption Promotersmentioning

confidence: 98%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

195

176

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“…alcohol, food (spices and fatty meals) and drug molecules (e.g., non-steroidal anti-inflammatory drugs, laxatives and chenodeoxycholate, a bile salt used to dissolve gall stones). [42][43][44] Every 3 days the small intestinal epithelia is entirely renewed, and each day, 10 11 epithelial cells are shed. 45,46 There is a high rate of cellular turnover and the intestine has a high capacity to replace cells, due to migrating stem cells from the intestinal crypt (Fig 1).…”

Section: Normal Repair Mechanismmentioning

confidence: 99%

“…49 Stage 2 is restitution or migration, where adjacent healthy epithelia begin crawling using lamellipodia in order to patch exposed areas between cells. 43 A number of cofactors including polyamines and trefoil peptides are also involved. Stage 3 is restoration of the barrier involving repair and closure of paracellular spaces.…”

Section: Normal Repair Mechanismmentioning

confidence: 99%

“…The most relevant systems therefore to test intestinal damage are oral gavage and intact intra-intestinal loop instillations/perfusions as these use intact tissue with a mesenteric blood supply. 43 Instillations/perfusions reveal local damage to the intestinal segment, but repair occurs more readily than in in vitro. These studies cannot however, examine repeat-dosing regimens in which damage may be accumulated and not have sufficient time to fully recover before the next challenge.…”

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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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“…Although it is well known that the instilled rat intestinal mucosa is restituted within 45 min in response to exposure to surfactants, including SDS [47] and C10 [48], investigations of Caco-2 monolayer recovery have not gone much beyond noting the restoration of basal levels of transepithelial electrical resistance (TEER) in fresh medium, a process that can take up to 24 h (e.g., [49]). However, HCA revealed that, when Caco-2 cells were exposed to 8.5mM C10 for 60 min, nuclear intensity, intracellular calcium, nuclear area, plasma membrane potential, mitochondrial membrane potential, and cell number were all increased [33].…”

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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Evaluation of Mucosal Damage and Recovery in the Gastrointestinal Tract of Rats by a Penetration Enhancer

Abstract: Absorption barrier recovery could be measured using a poorly absorbed marker. Functional recovery showed a good correlation with morphological recovery. The local effects of SDS were found to be temporary and reversible.

Cited by 28 publications

References 61 publications

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

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

High-content analysis for drug delivery and nanoparticle applications

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