Drugs released from polymers: diffusion and elimination in brain tissue

Abstract

By providing a long-term and localized source of active drug molecules, controlled release polymer implants may reduce the systematic side effects and dose-to-dose variability associated with conventional drug administration. Implants may be particularly relevant for delivery of drugs to the brain, where therapy is frequently limited by the blood brain barrier. To aid in the design and application of new delivery systems, we developed methods for modeling drug transport in tissue in the vicinity of a continuous source. Transport was assumed to occur by diffusion with elimination due to irreversible metabolism reversible binding to fixed tissue components, or partitioning into capillaries. For polymer implants where diffusion in the polymer determines the rate of drug release, the rate of drug release from the polymer, drug concentration in the tissue, and drug penetration depend on rates of elimination and diffusion. Qualitatively similar results were obtained for degradable polymers. Model predictions were also used to interpret previously published data on the delivery of the steroid dexamethasone from an ethylene—vinyl acetate copolymer implant in rat brain. In general, molecules that are water-soluble, slowly eliminated, and diffusible are the best candidates for polymeric delivery to brain tissues. In contrast to conventional modes of administration, rapid permeation of active molecules through brain capillaries is the most significant barrier to effective drug distribution in the brain.