title: Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement.
abstract: Amorphous solid dispersions (ASDs) represent a promising formulation approach for poorly soluble drugs. We explored the formulation-related impact of ASDs on permeation rate, apparent solubility and molecular solubility of the poorly soluble drug ABT-102. The influence of fasted state simulated intestinal fluid (FaSSIF) as dispersion medium was also studied. ASDs were prepared by hot-melt extrusion. Permeation rate was assessed by the Caco-2 transwell assay. Cell viability and barrier integrity were assured by AlamarBlue©, TEER and permeability of the hydrophilic marker carboxyfluorescein. Apparent solubility and molecular solubility were evaluated by using centrifugation and inverse dialysis, respectively. The in vitro permeation rate of ABT-102 from aqueous dispersions of the ASD was found 4 times faster than that from the dispersions of the crystals, while apparent solubility and molecular solubility of ABT-102 were increased. Yet, a further increase in apparent solubility due to micellar solubilization as observed when dispersing the ASD in FaSSIF, did not affect molecular solubility or permeation rate. Overall, a good correlation between permeation rate and molecular solubility but not apparent solubility was seen.
authors.affiliation: Institute of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Kerstin J
authors.initials: KJ
authors.lastname: Frank
authors.forename: Karin M
authors.initials: KM
authors.lastname: Rosenblatt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Westedt
authors.forename: Peter
authors.initials: P
authors.lastname: Hölig
authors.forename: Jörg
authors.initials: J
authors.lastname: Rosenberg
authors.forename: Markus
authors.initials: M
authors.lastname: Mägerlein
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.forename: Martin
authors.initials: M
authors.lastname: Brandl
mesh_terms: D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004304:Dosage Forms; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry*; D010539:Permeability; D012995:Solubility; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C528492:ABT 102; D004304:Dosage Forms; D007191:Indazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea