What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion?
Our aim was to explore the influence of micelles and microparticles emerging in aqueous dispersions of amorphous solid dispersions (ASDs) on molecular/apparent solubility and Caco-2 permeation. The ASD, prepared by hot-melt extrusion, contained the poorly soluble model drug ABT-102, a hydrophilic polymer, and three surfactants. Aqueous dispersions of the ASD were investigated at two concentrations, one above and one close to the critical micelle concentration of the surfactants blend in the extrudate. Micelles were detected at the higher concentration and no micelles at the lower concentration. Apparent solubility of ABT-102 was 20-fold higher in concentrated than in diluted dispersions, because of micelles. In contrast, Caco-2 permeation of ABT-102 was independent of the ASD concentration, but three times faster than that of crystalline suspensions. Molecular solubility of ABT-102 (equilibrium dialysis) was also independent of the ASD concentration, but by a factor 2 higher than crystalline ABT-102. The total amount of ABT-102 accumulated in the acceptor during Caco-2 experiments exceeded the initial amount of molecularly dissolved drug in the donor. This may indicate that dissolution of amorphous microparticles present in aqueous dispersions induces lasting supersaturation maintaining enhanced permeation. The hypothesis is supported by a slower drug permeation when the microparticles were removed.
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, DK-5230, Denmark; Department of Pharmaceutical Technology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, D-69120, Germany.
Kerstin J
KJ
Frank
Ulrich
U
Westedt
Karin M
KM
Rosenblatt
Peter
P
Hölig
Jörg
J
Rosenberg
Markus
M
Mägerlein
Gert
G
Fricker
Martin
M
Brandl
D018938:Caco-2 Cells; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics*; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014867:Water / Q000737:chemistry*
C528492:ABT 102; D007191:Indazoles; D014867:Water; D014508:Urea
amorphous; microparticles; permeability; solid dispersion; solubility; supersaturation