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

Abstract

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.

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

“…In some cases, mixing surfactants can increase enhancement action still further [86]. Combinations of medium chain fatty acids with PEG-8 glycerides increased permeation of FD4 across isolated rat intestinal tissue by 10-fold over the respective individual agents [87].…”

Effects of Drugs and Excipients on Hydration Status

“…On the other hand, the existence of pharmaceutical excipients that modify gastrointestinal absorption, the so-called critical pharmaceutical excipients or absorption-modifying excipients, owing to their capacity to alter the integrity of the intestinal epithelial cell membrane, should be highlighted [188,189,190]. Specifically, recently published studies demonstrated that some of these excipients, i.e., chitosan and sodium lauryl sulphate, increase intestinal permeability and subsequent absorption and bioavailability [188,189].…”

“…Specifically, recently published studies demonstrated that some of these excipients, i.e., chitosan and sodium lauryl sulphate, increase intestinal permeability and subsequent absorption and bioavailability [188,189]. In this connection, Labrasol ® (a lipoidal excipient) and its salts, combined with medium-chain fatty acid at low concentrations, also raises intestinal permeability due to mild mucosal perturbation [190].…”

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy

“…Thus far, the syntheses of metformin docusate and metformin stearate have been reported in the literature. , However, their potential to improve the anticancer activity of metformin has not been explored. We decided to evaluate various bulky anionic permeation enhancers such as sodium caprate, sodium laurate, sodium oleate, sodium cholate, and sodium docusate which have a proven capability to improve the permeability of hydrophilic small molecules as well as macromolecules. − We also envisaged that the development of lipophilic metformin salts could further facilitate their incorporation into lipid-based drug delivery systems which could further improve the oral bioavailability and oral chemotherapeutic effect of metformin.…”