POLYMERIC CONTROLLED RELEASE OF DEXAMETHASONE IN NORMAL RAT-BRAIN

[摘要] Controlled release polymeric implants may improve delivery of anti-edema agents to the central nervous system. Ethylene-vinyl acetate copolymer (EVAc) matrices containing dexamethasone (35% w/w) were implanted either intracranially or intraperitoneally in Fisher 344 rats. Selective extraction and high performance liquid chromatography were used to quantify tissue concentrations after implantation of the drug-loaded polymer or intraperitoneal injection of an equivalent dose. Dexamethasone was detected in brain for up to 21 days after intracranial polymer implantation, with peak levels of 4.0 +/- 0.7-mu-g/g tissue measured in the ipsilateral hemisphere. Concentrations in the contralateral hemisphere and peripheral circulation were measurable for the first 12 h only (peak level at 1 h of 0.5 +/- 0.2-mu-g/g in the contralateral hemisphere). By contrast, intraperitoneal bolus administration of dexamethasone in control animals resulted in minimal brain levels (peak at 1 h of 0.8 +/- 0.4-mu-g/g) and very high plasma levels (peak at 4 h of 23.6 +/- 6.0-mu-g/g). No drug was detected in the brains of animals with intraperitoneal dexamethasone-EVAc implants. Measured dexamethasone concentrations were compared to a one-compartment pharmacokinetic model. The experimental results are best described by assuming diffusion-limited release of dexamethasone from the polymer (characteristic release constant of 0.5-mu-g h-1/2) and first order drug elimination (half-life of 16 h).

[发布日期] 1991-08-01

[关键词] TARGETED DRUG DELIVERY;DEXAMETHASONE;CONTROLLED RELEASE;BRAIN EDEMA;POLYMER;PHARMACOKINETIC MODELING