DESIGN AND PHARMACODYNAMIC EVALUATION OF NOVEL DUAL RELEASE FORMULATIONS OF TRIAZOLAM

Triazolam is an effective hypnotic that can cause amnesia and psychomo tor performance decrements, particularly after a 0.5 mg dose. Previous pharmacodynamic studies suggested a relationship between these effect s and triazolam plasma concentration. A novel dual release bilayer tab let was designed to mimic the onset of action of a 0.25 mg dose and to maintain the duration of a 0.5 mg dose without the side effects assoc iated with the 0.5 mg dose. The immediate release component of the bil ayer tablet contained 0.25 mg triazolam while the sustained release co mponent contained 0.15 mg triazolam. Two prototype formulations of the bilayer tablet, differing in rate of release in the sustained release component, were tested against a conventional 0.5 mg triazolam compre ssed tablet and placebo in a single-dose, double-blind, four-way cross over study in healthy male subjects. Triazolam plasma concentration ti me profile was obtained over 12 hours following single. administration of each treatment. Effects of triazolam on central nervous system fun ction were evaluated using psychomotor performance tests, immediate an d delayed recall tests and rating of sedation. The triazolam plasma co ncentrations were not significantly different among the active drug tr eatments, although the dual release tablets did give the expected prof iles. There were significant differences in triazolam effects on memor y and psychomotor performance. The slowest releasing dual-release tabl et showed significantly less psychomotor impairment and memory deficit than the conventional tablet. There was no difference in sedation amo ng the active drug treatments. The results of this pilot study show th e feasibility of modifying the pharmacologic effects and minimizing si de effects, while maintaning efficacy of a non-accumulating drug like triazolam with a novel dosage formulation.