1 research outputs found
Dynamic, Nonsink Method for the Simultaneous Determination of Drug Permeability and Binding Coefficients in Liposomes
Drug release from liposomal formulations
is governed by a complex
interplay of kinetic (i.e., drug permeability) and thermodynamic factors
(i.e., drug partitioning to the bilayer surface). Release studies
under sink conditions that attempt to mimic physiological conditions
are insufficient to decipher these separate contributions. The present
study explores release studies performed under nonsink conditions
coupled with appropriate mathematical models to describe both the
release kinetics and the conditions in which equilibrium is established.
Liposomal release profiles for a model anticancer agent, topotecan,
under nonsink conditions provided values for both the first-order
rate constant for drug release and the bilayer/water partition coefficient.
These findings were validated by conducting release studies under
sink conditions via dynamic dialysis at the same temperature and buffer
pH. A nearly identical rate constant for drug release could be obtained
from dynamic dialysis data when appropriate volume corrections were
applied and a mechanism-based mathematical model was employed to account
for lipid bilayer binding and dialysis membrane transport. The usefulness
of the nonsink method combined with mathematical modeling was further
explored by demonstrating the effects of topotecan dimerization and
bilayer surface charge potential on the bilayer/water partition coefficient
at varying suspension concentrations of lipid and drug