title: Viability and permeability across Caco-2 cells of CBZ solubilized in fully dilutable microemulsions.
abstract: The purpose of this study was to evaluate the viability and permeability of carbamazepine (CBZ) solubilized in fully dilutable non-ionic microemulsions across Caco-2 cells used as a model for intestinal epithelium. Maximum solubilization capacity (SC) of CBZ was determined within water-in-oil (W/O), bicontinuous and oil-in-water (O/W) structures formed upon dilution. The effect of the nature of the oil phase, surfactant type, and the ratio between the oil phase and surfactant on the quantity of solubilized CBZ, droplets size, the viability of the cells and drug permeability was elucidated. We found that: (1) several fully dilutable microemulsions based on pharma-grade ingredients can be loaded with very significant amounts of CBZ, (2) W/O microemulsions (10wt% water) exhibit up to 3-fold higher solubilization capacity over the drug's solubility in oil (triacetin), (3) CBZ in the O/W microemulsions (80wt% water) exhibit up to 29-fold higher solubilization than in water, (4) the O/W droplets of the examined systems are 9-11nm in size, (5) the highest permeability was obtained in systems containing triacetin/alpha-tocopherol acetate/ethanol in 3/1/4wt% ratio as oil phase and Tween 60 as surfactant, (6) the replacement of alpha-tocopherol acetate by alpha-tocopherol inhibits CBZ release, (7) replacement of a saturated chain of Tween 60 by an unsaturated (Tween 80) or shorter chain (Tween 40) inhibited drug release, (8) the decrease in the oil phase to surfactant ratio leads to enhancement of drug release (dilution line 64>dilution line 73).
authors.affiliation: Casali Institute of Applied Chemistry, The Institute of Chemistry, Givat Ram, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Kogan
authors.forename: Ellina
authors.initials: E
authors.lastname: Kesselman
authors.forename: Dganit
authors.initials: D
authors.lastname: Danino
authors.forename: Abraham
authors.initials: A
authors.lastname: Aserin
authors.forename: Nissim
authors.initials: N
authors.lastname: Garti
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002220:Carbamazepine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008823:Micelles; D010539:Permeability; D012995:Solubility; D014867:Water
chemical_list: D000927:Anticonvulsants; D008823:Micelles; D014867:Water; D002220:Carbamazepine; D007770:L-Lactate Dehydrogenase