Mechanisms of drug release from cyclodextrin complexes.
This review addresses the issue of the mechanisms of drug release from cyclodextrin complexes. More specifically, it attempts to answer the question whether drug release from aqueous formulations is slow or incomplete? A critique of the literature, our own work, and various simulations suggests that drug release from cyclodextrin complexes is rapid and quantitative in most cases. In aqueous solution, drug/cyclodextrin complexes are continually forming and dissociating with lifetimes in the range of milliseconds or less. Although the stronger the binding, the slower the relative kinetics of dissociation, the rates are still fast and essentially instantaneous. After parenteral administration, the major driving force for dissociation of weakly to moderately bound drugs appears to be simple dilution. For strongly bound drugs, binding constants of 10(-4)M(-)(1) or higher, or for those cases where dilution is minimal, contributions from competitive displacement by endogenous materials, drug binding to plasma and tissue components, drug uptake into tissues not available to the complex or the cyclodextrin, rapid elimination of the cyclodextrin and possibly pH and temperature effects, may also be important. After parenteral administration, it does appear that cyclodextrins might cause some alterations in the fraction of free drug eliminated in the urine during that time frame where the cyclodextrin is itself undergoing substantial renal clearance.
Stella
VJ
Department of Pharmaceutical Chemistry and the Center for Drug Delivery Research, The University of Kansas, Lawrence, USA
Rao
VM
Zannou
EA
Zia
V