Labrasol and Salts of Medium-Chain Fatty Acids Can Be Combined in Low Concentrations to Increase the Permeability of a Macromolecule Marker Across Isolated Rat Intestinal Mucosae.

Authors:
Joanne Heade
Joanne Heade
UCD School of Veterinary Medicine and UCD Conway Institute
Sam Maher
Sam Maher
University College Dublin
Ireland
Sinead B Bleiel
Sinead B Bleiel
AnaBio Technologies Ltd
David J Brayden
David J Brayden
University College Dublin
Ireland

J Pharm Sci 2018 Jun 17;107(6):1648-1655. Epub 2018 Feb 17.

UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address:

In addition to their solubilizing properties, excipients used in lipid-based formulations can improve intestinal permeability of macromolecules. We determined whether admixing of medium-chain fatty acid (MCFA) permeation enhancers with a lipoidal excipient (Labrasol) could potentiate transepithelial flux of a poorly permeable macromolecule (fluorescein isothiocyanate dextran 4 kDa [FD4]) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C), sodium undecylenate (C), or sodium laurate (C) combined with Labrasol increased the apparent permeability coefficient (P) of FD4 to values typically seen with higher concentrations of MCFAs or Labrasol alone. For example, combination of C (0.5 mg/mL) with Labrasol (1 mg/mL) increased the P of FD4 by 10- and 11-fold over the respective individual agents at the same concentrations where no enhancement was evident. The increased enhancement ratios seen with the combinations were associated with some perturbation in intestinal histology and with attenuation of an epithelial functional measure, carbachol-stimulated inward short-circuit current. In conclusion, combining three MCFAs separately with Labrasol increased the P of FD4 to values greater than those seen for MCFAs or Labrasol alone. Ultimately, this may permit lower concentrations of MCFA to be used in combination with other excipients in oral formulations of poorly permeable molecules.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2018.02.012DOI Listing
June 2018
33 Reads

Publication Analysis

Top Keywords

intestinal mucosae
8
mcfas labrasol
8
fd4 values
8
low concentrations
8
labrasol increased
8
increased fd4
8
rat intestinal
8
medium-chain fatty
8
labrasol
7
concentrations
5
values typically
4
concentrations mcfas
4
higher concentrations
4
typically higher
4
example combination
4
10- 11-fold
4
11-fold respective
4
respective individual
4
fd4 10-
4
mg/ml increased
4

Similar Publications

Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae.

Int J Pharm 2018 Mar 16;539(1-2):11-22. Epub 2018 Jan 16.

UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

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 assess the effects of PEs on (i) apparent permeability coefficient (P) of [C]-mannitol (ii) histology score and (iii) short-circuit current (ΔI) responses to a cholinomimetic (carbachol, CCh). Read More

View Article
March 2018

Efficacious intestinal permeation enhancement induced by the sodium salt of 10-undecylenic acid, a medium chain fatty acid derivative.

AAPS J 2014 Sep 25;16(5):1064-76. Epub 2014 Jun 25.

School of Veterinary Medicine, Veterinary Sciences Centre and Conway Institute, University College Dublin, Room 214 Belfield, Dublin 4, Ireland,

10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC11, would improve intestinal permeation similar to the established enhancer, sodium caprate (C10), but without the toxicity of the parent saturated MCFA, decylenic acid (C11). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C11 > C10 = uC11. Read More

View Article
September 2014

Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules.

AAPS J 2017 01 13;19(1):244-253. Epub 2016 Oct 13.

School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

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. Read More

View Article
January 2017

Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae.

Eur J Pharm Sci 2009 Nov 6;38(4):291-300. Epub 2009 Sep 6.

UCD School of Agriculture, Food Science and Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

The effects of two absorption promoters, (sodium caprate (C(10)) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C(10) (10 mM) and melittin (10-50 microM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [(14)C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C(10) on flux were greater than those of melittin at the concentrations selected. Read More

View Article
November 2009