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.

A novel chemical delivery system for brain targeting.

Two different chemical approaches for brain drug delivery and targeting are proposed in the present review. One is a chemical drug delivery using a ring-closure reaction to the hydrophilic quaternary thiazolium compound in the brain. The other is a chemical drug targeting utilizing the nutrient receptor (transporter) system on the blood-brain barrier. The brain delivery system has been optimized and it was demonstrated that the brain delivery of three drugs, a drug for Parkinson's disease, an excitatory amino acid antagonist and a free radical scavenger, were improved by the conjugation with cis-2-formylaminoethenylthio derivatives in vivo. As for the brain targeting system, it was demonstrated that the conjugation with L-Glu improved the drug's brain distribution via the L-Glu excitatory and/or transport receptors in vitro and in vivo. These findings suggest that the concepts of two chemical approaches will contribute to the development of new central nervous system drugs.