Synthesis and Properties of Sucrose- and Lactose-Based Aromatic Ester Surfactants as Potential Drugs Permeability Enhancers

Abstract

The delivery of therapeutics across biological membranes (e.g., mucosal barriers) by avoiding invasive routes (e.g., injection) remains a challenge in the pharmaceutical field. As such, there is the need to discover new compounds that act as drug permeability enhancers with a favorable toxicological profile. A valid alternative is represented by the class of sugar-based ester surfactants. In this study, sucrose and lactose alkyl aromatic and aromatic ester derivatives have been synthesized with the aim to characterize them in terms of their physicochemical properties, structure–property relationship, and cytotoxicity, and to test their ability as permeability enhancer agents across Calu-3 cells. All of the tested surfactants showed no remarkable cytotoxic effect on Calu-3 cells when applied both below and above their critical micelle concentration. Among the explored molecules, lactose p-biphenyl benzoate (URB1420) and sucrose p-phenyl benzoate (URB1481) cause a reversible ~30% decrease in transepithelial electrical resistance (TEER) with the respect to the basal value. The obtained result matches with the increased in vitro permeability coefficients (Papp) calculated for FTIC-dextran across Calu-3 cells in the presence of 4 mM solutions of these surfactants. Overall, this study proposes sucrose- and lactose-based alkyl aromatic and aromatic ester surfactants as novel potential and safe permeation enhancers for pharmaceutical applications.

Sugar-Based Monoester Surfactants: Synthetic Methodologies, Properties, and Biological Activities

“…SEs (7a-m) were synthesized using a modified Mitsunobu procedure [31] starting from sucrose (6) and various saturated or (poly)unsaturated fatty acids, or alkyl aromatic/aromatic acids (3) (Scheme 2). This optimized reaction gave preferentially the esterification at 6-OH of sucrose and proceeds with a sucrose/fatty acid 1:1.5 molar ratio using 2.5 equivalents of triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) in dry dimethylformamide (DMF) at room temperature for 24-30 h [32,33]. This The procedure gave the corresponding 6-O-sucrose esters in moderate yields.…”