Absorption Enhancers: Applications and Advances

Aungst, Bruce J.

doi:10.1208/s12248-011-9307-4

Cited by 249 publications

(123 citation statements)

References 35 publications

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“…The main candidates in oral peptide trials are the medium chain fatty acid (MCFA)-based sodium caprate (C 10 ), sodium caprylate (C 8 ), and the C 8 derivative (SNAC), as well as acyl carnitines, EDTA, and selected bile salts. 6,7 EDTA is different from the other PEs in that it acts by chelating calcium and thus affecting the TJs. In their seminal 1994 review on the toxicology of PEs, Curatolo and Ochoa remind us of the fact that many PEs are surfactants with a history of use in man in drug products and in the food processing industry, and that extensive safety testing was carried out on many of these PEs in the 1950s.…”

Section: Intestinal Pes In Clinical Trials For Oral Peptidesmentioning

confidence: 98%

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: Intestinal Pes In Clinical Trials For Oral Peptidesmentioning

confidence: 98%

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

2016

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“…In fact, the bactericidal effect that the MCFAs showed in bacterial growth experiments was not reflected in these results. Since quite a long time, MCFAs and their salts have been tested as permeability enhancers to improve drug absorption and delivery (Shima et al 1997;Aungst 2012). However, most studies have been performed using the human derived cell line Caco-2, and information on IPEC-J2 cells cannot be found to our best knowledge.…”

Section: Discussionmentioning

confidence: 99%

Effects of medium-chain fatty acids on the structure and immune response of IPEC-J2 cells

2016

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Medium-chain fatty acids (MCFAs) have been suggested as an alternative to the use of antibiotics in animal nutrition with promising results. First, we studied the sensitivity of Salmonella Enteritidis and an enteropathogenic Escherichia coli strain against caprylic (C8), capric (C10) and lauric (C12) acids. A porcine in vitro model using the porcine cell line IPEC-J2 was used to test the effects of MCFAs on structural and immunological traits without and with a concomitant challenge with E. coli or S. Enteritidis. The three MCFAs exerted an inhibitory effect on bacterial growth, stronger for C12 than C8 or C10, S. Enteritidis being more sensitive than the E. coli strain. Flow cytometry showed a numeric concentration dependent increase in the adhesion of E. coli or S. Enteritidis to IPEC-J2 cells. Measurement of transepithelial electrical resistance after bacterial challenge showed negative effects of all MCFAs on IPEC-J2 cells at the highest concentrations. Immune parameters were affected by C8, since a concentration dependent effect starting at 5 mM was observed for mRNA expression of IL-6 and TLR-4 (up-regulated) and IL-8 (down-regulated). TLR-4 was up-regulated with C10 at 2 and 5 mM. The three MCFAs affected also the epithelial morphology through downregulation of Occludin and up-regulation of Claudin-4 expression. In conclusion, the three MCFAs under study influenced bacterial growth rates and modified the gene expression to a different degree in the cell line IPEC-J2 but the effect on the morphological structure and response of the cells after bacterial challenge could not be assessed. Although these tests show a prior estimation of MCFAs effects in intestinal epithelium, in vivo confirmation is still needed.

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“…proteases) and inhibiting efflux pumps [23]. PEs have been studied for several years in efforts to develop non-parenteral formulations for peptides, proteins, and other pharmacologically active compounds that have less than optimal membrane permeability [24]. PEs can be useful in optimizing drug delivery for oral as well as transdermal/transmucosal (e.g.…”

Section: Permeation Enhancersmentioning

confidence: 99%

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Dave

Gupta

et al. 2016

Drug Development and Industrial Pharmacy

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The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds. AbstractThe Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability.Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/ hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.

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Absorption Enhancers: Applications and Advances

Cited by 249 publications

References 35 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

Effects of medium-chain fatty acids on the structure and immune response of IPEC-J2 cells

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

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