Now showing 1 - 4 of 4
  • Publication
    Safety concerns over the use of intestinal permeation enhancers: A mini-review
    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.
      289Scopus© Citations 83
  • Publication
    Oral delivery strategies for nutraceuticals: Delivery vehicles and absorption enhancers
    Lifestyle issues contribute to the development of obesity, type 2 diabetes, and cardiovascular disease. Together with appropriate diet and exercise, nutraceuticals may contribute to managing prevention at an early stage prior to therapeutic intervention. However, many useful food-derived bioactive compounds will not sufficiently permeate the small intestine to yield efficacy without appropriate oral delivery technology. The pharmaceutical industry uses commercialised approaches for oral delivery including solubilizing technologies for small molecules, which could be applied to selected nutraceuticals with solubility issues. Systems currently being studied for labile and poorly permeable hydrophilic peptides and macromolecules include nanoparticles, intestinal permeation enhancers (PE) and mucolytics. These may also have potential for application to nutraceuticals with similar sub-optimal physicochemical characteristics. Scope and approach We introduce factors which effect oral delivery of four types of nutraceuticals, namely fatty acids, bioactive peptides, micronutrients, and phytochemicals. Factors preventing oral absorption can arise from molecule physicochemical characteristics, which influence solubility, stability, and epithelial permeability in the gastrointestinal tract (GIT). We highlight the potential of selected delivery strategies to improve oral bioavailability of different types of nutraceuticals. Key findings and conclusions There is an opportunity for the nutraceutical industry to leverage the pharmaceutical industry's progress in oral drug delivery. The use of delivery approaches using formulation with excipients or substances with a history of use in man has potential to improve solubility, stability, or permeability of nutraceuticals, leading to improved oral bioavailability. Leveraging oral delivery formulation approaches across nutraceutical and pharmaceutical molecules will lead to synergies for both fields.
      1409Scopus© Citations 85
  • Publication
    Evaluation of PepT1 transport of food-derived antihypertensive peptides, Ile-Pro-Pro and Leu-Lys-Pro using in vitro, ex vivo and in vivo transport models
    Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP) are food-derived antihypertensive peptides which inhibit angiotensin-converting enzyme (ACE) and may have potential to attenuate hypertension. There is debate over their mechanism of uptake across small intestinal epithelia, but paracellular and PepT1 carrier-mediated uptake are thought to be important routes. The aim of this study was to determine their routes of intestinal permeability using in vitro, ex vivo and in vivo intestinal models. The presence of an apical side pH of 6.5 (mimicking the intestinal acidic microclimate) and of Gly-Sar (a high affinity competitive inhibitor and substrate for PepT1) were tested on the transepithelial apical to basolateral (A to B) transport of [3H]-IPP and [3H]-LKP across filter-grown Caco-2 monolayers in vitro and rat jejunal mucosae ex vivo. A buffer pH of 6.5 on the apical side enabled Gly-Sar to reduce the apparent permeability (Papp) of [3H]-IPP and [3H]-LKP, but this inhibition was not evident at an apical buffer pH of 7.4. Gly-Sar reduced the Papp across isolated jejunal mucosae and the area under the curve (AUC) in intra-jejunal instillations when the apical/luminal buffer pH was either 7.4 or 6.5. However, the jejunal surface acidic pH was maintained in rat jejunal tissue even when the apical side buffer pH was 7.4 due to the presence of the microclimate which is not present in monolayers. PepT1 expression was confirmed by immunofluorescence on monolayers and brush border of rat jejunal tissue. This data suggest that IPP and LKP are highly permeable and cross small intestinal epithelia in part by the PepT1 transporter, with an additional contribution from the paracellular route.
      445Scopus© Citations 32
  • Publication
    Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro
    Two food-derived ACE inhibitory peptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), may have potential as alternative treatments for treatment of mild- or pre-hypertension. Lack of stability to secretory and intracellular peptidases and poor permeability across intestinal epithelia are typical limiting factors of oral delivery of peptides. The stability of IPP and LKP was confirmed in vitro in rat intestinal washes, and intestinal and liver homogenates over 60min. A positive protein control for peptidases, insulin, was significantly digested in each format over the same period. Neither tripeptide showed cytotoxic activity on Caco-2 and Hep G2 cells using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, even after chronic exposure. The basal Papp of fluorescein isothiocyanate (FITC)-labeled IPP and FITC-LKP across isolated rat jejunal and colonic mucosae were low, but were significantly increased in each tissue type by the medium chain fatty acids (MCFA) permeation enhancers, sodium caprate (C10) and the sodium salt of 10-undecylenic acid (uC11). IPP and LKP were therefore stable against intestinal and liver peptidases and were non-cytotoxic; their Papp values across rat intestinal mucosae were low, but could be increased by MCFA. There is potential to make on oral dosage form once in vivo pharmacology is confirmed. 
      459Scopus© Citations 35