Bioavailability and in vivo release behavior of controlled-release multiple-unit theophylline dosage forms in beagle dogs, cynomolgus monkeys, and göttingen minipigs

J Pharm Sci. 2006 Sep;95(9):1888-95. doi: 10.1002/jps.20537.


To determine the usefulness of monkey as an animal model, bioavailability and in vivo release behaviors of theophylline (TP) after oral administration of controlled-release beads in dogs, monkeys, and minipigs were evaluated. Controlled-release beads were prepared using a centrifugal-fluid type granulator, that is, CF-granulator, and Ethylcellulose (EC) was used as controlled-release coating agent. Aqueous solution and EC-coated beads, which contained TP were orally administered to animals after at least 1-week intervals. In dogs and minipigs, their relative bioavailabilities of EC-coated beads were 33.1% and 47.0%, respectively, and in vivo TP release from EC-coated beads in the gastrointestinal tract of dogs and minipigs were not reflected in vitro data. In monkeys, relative bioavailability of EC-coated beads was 80.0% and the highest among the three species, and release amount of TP from EC-coated beads at 24 h after oral administration was 82.8% and 92.4%, which was almost correlated to in vitro data. Therefore, the discrepancy of the relative bioavailability in three species is considered to be due to the difference of in vivo release behavior of TP. The monkey may be useful animal model for bioavailability studies of controlled-release dosage forms of TP from the viewpoint of in vitro-in vivo release correlation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Availability
  • Chemistry, Pharmaceutical
  • Delayed-Action Preparations
  • Dogs
  • Macaca fascicularis
  • Male
  • Particle Size
  • Swine
  • Swine, Miniature
  • Theophylline / administration & dosage*
  • Theophylline / pharmacokinetics*
  • Vasodilator Agents / administration & dosage*
  • Vasodilator Agents / pharmacokinetics*


  • Delayed-Action Preparations
  • Vasodilator Agents
  • Theophylline