Now showing 1 - 3 of 3
  • Publication
    Intestinal permeation enhancers for oral peptide delivery
    Intestinal permeation enhancers (PEs) are one of the most widely tested strategies to improve oral delivery of therapeutic peptides. This article assesses the intestinal permeation enhancement action of over 250 PEs that have been tested in intestinal delivery models. In depth analysis of pre-clinical data is presented for PEs as components of proprietary delivery systems that have progressed to clinical trials. Given the importance of co-presentation of sufficiently high concentrations of PE and peptide at the small intestinal epithelium, there is an emphasis on studies where PEs have been formulated with poorly permeable molecules in solid dosage forms and lipoidal dispersions.
    Scopus© Citations 264  2978
  • Publication
    Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol
    Epithelial damage caused by intestinal permeation enhancers is a source of debate over their safety. The medium chain fatty acid, sodium caprate (C10), causes reversible membrane perturbation at high dose levels required for efficacy in vivo, so the aim was to model it in vitro. Exposure of Caco-2 monolayers to 8.5mM C10 for 60min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [(14)C]-mannitol), (ii) recovery of cell viability parameters (monolayer morphology, plasma membrane potential, mitochondrial membrane potential, and intracellular calcium) and (iii) reduction in mRNA expression associated with inflammation (IL-8). Pre-incubation of monolayers with a mucosal prostaglandin cytoprotectant was attempted in order to further decipher the mechanism of C10. Misoprostol (100nM), inhibited C10-induced changes in monolayer parameters, an effect that was partially attenuated by the EP1 receptor antagonist, SC51322. In rat isolated intestinal tissue mucosae and in situ loop instillations, C10-induced respective increases in the [(14)C]-mannitol Papp and the AUC of FITC-dextran 4000 (FD-4) were similarly inhibited by misoprostol, with accompanying morphological damage spared. These data support a temporary membrane perturbation effect of C10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol.
    Scopus© Citations 37  724
  • Publication
    Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae
    Surfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based-PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to establish assess if increases in permeability (i) intestinal permeability (the apparent permeability coefficient (Papp) of [14C]-mannitol), (ii) epithelial histology, and (iii) short-circuit current (ΔIsc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for Papp values followed the order: C10 > C9 = C11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol® >C12E8 > C12 > Cremophor® A25 > C7 > sucrose stearate > Kolliphor® HS15 > Kolliphor® TPGS. Exposures that increased the Papp by ≥2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased ΔIsc response to CCh of 83%. A degree of separation between the increased Papp of [14C]-mannitol, histological damage, and diminution of the ΔIsc response to CCh was observed at selected PE concentrations (e.g. Labrasol® at 2 mg/mL). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability.
    Scopus© Citations 34  809