Abstract
There has been a continuous interest in the development of controlled drug release systems to acornplish therapeutical optimization of drugs. In addition, recent advances in chronopharmacology indicate that the pharmacokinetics of some drugs show circadian rhythm. Both pharmacological and toxicological effects of such drugs are dependent on the time of day when the drug is administered.
Under these considerations, we have developed a novel controlled-release system called Time-Controlled Explosion System (TES) that can provide any desired release profile. TES has a four-layered spherical structure, which consists of core, drug layer, swelling agent (low-substituted hydroxypropylcellulose, L-HPC) layer and water insoluble polymer (ethylcellulose, EC) membrane. TES is characterized by a rapid drug release with a precisely programmed lag time ; i.e. expansion of the swelling agent by water penetrating through the outer membrane, destruction of the membrane by stress due to swelling force and subsequent rapid drug release. Lag time was controlled by the thickness of the outer EC membrane ; thus, a combination of TES particles possessing different lag times could offer any desired release profile of the drug.
After TES with different in vitro lag times were orally administrated to dogs and healthy volunteers, plasma drug concentration was monitored. There existed a good correlation between in vitro and in vivo lag time. And the in vivo release profile corresponded with the in vitro one. In these results, the drug absorption profile of TES can be mirrored by in vitro drug release behavior because TES can release the drug after the membrane destruction in the in vivo conditions in the same way as in vitro.
