title: Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules.
abstract: Intestinal permeation enhancers (PEs) offer an attractive strategy to enable oral peptide administration. However, optimal presentation of peptide and PE from solid-dosage forms is offset by slow dissolution rates in the small intestine, which reduces the likelihood that the PE can reach the threshold concentration for sufficient permeability enhancement. The purpose of this study was to design a PE-based liquid dispersion that can improve intestinal permeation of macromolecules across Caco-2 monolayers and isolated rat/human intestinal mucosae mounted in Ussing chambers. An enhancer screen in monolayers based on permeability (TEER, Papp[14C]-mannitol) and cytotoxicity (MTT assay) initially identified methyl 10-hydroxydecanoate (10-OHC10CH3) as a candidate. 10-OHC10CH3(20 mM) increased the Pappof fluorescent dextran of 4 kDa (FD4) (167-fold), 10 kDa (FD10) (429-fold), and 40 kDa (FD40) (520-fold) across monolayers. Blends of 10-OHC10CH3with low molecular weight PEGs (0.2-1 kDa) formed liquid dispersions in which enhancement capacity across monolayers of 10-OHC10CH3was increased over 10-OHC10CH3alone in the order PEG200< PEG400< PEG600< PEG1000. Finally, a 1:5 ratio of 10-OHC10CH3(10-20 mM)/PEG600(50-100 mM) increased the Pappof [14C]-mannitol across rat and human intestinal mucosae. This study highlights the potential future role for non-aqueous, PE-based liquid dispersions in oral delivery of macromolecules.
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. sammaher@rcsi.ie.
authors.forename: Sam
authors.identifier: 0000-0002-0856-1035
authors.initials: S
authors.lastname: Maher
authors.affiliation: Department of Surgery, St. Vincent's University Hospital, Elm Park, Merrion Road, Dublin 4, Ireland.
authors.forename: Mekki
authors.initials: M
authors.lastname: Medani
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, 00931-3346, Puerto Rico.
authors.forename: Nestor N
authors.initials: NN
authors.lastname: Carballeira
authors.affiliation: Department of Surgery, St. Vincent's University Hospital, Elm Park, Merrion Road, Dublin 4, Ireland.
authors.forename: Desmond C
authors.initials: DC
authors.lastname: Winter
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Baird
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D046911:Macromolecular Substances / Q000493:pharmacokinetics*; D008297:Male; D015394:Molecular Structure; D010539:Permeability; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D003652:Decanoic Acids; D046911:Macromolecular Substances; D013501:Surface-Active Agents; C000624981:methyl 10-hydroxydecanoate
keywords: Caco-2 monolayers; Ussing chambers; intestinal permeation enhancer; non-aqueous dispersion; oral peptide; sodium caprate