A NEW TRANSMUCOSAL THERAPEUTIC SYSTEM - OVERVIEW OF FORMULATION DEVELOPMENT AND IN-VITRO IN-VIVO CLINICAL-PERFORMANCE

A new transmucosal therapeutic system (TmTs) was developed for control led systemic delivery of drugs, which are labile to hepatic ''first-pa ss'' metabolism, through oral mucosa. It consists of a fast-release la yer, which provides a rapid release of drug for prompt rise in blood d rug concentration to reach the therapeutic level, and a sustained-rele ase layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-rel ease layer also contains mucoadhesive composition, so TmTs can be appl ied on gingival mucosa for continuous transmucosal controlled administ ration of drugs. Using isosorbide dinitrate (ISDN), a well-known antia nginal drug which is known to be subjected to extensive presystemic el imination when taken orally, the systemic bioavailability has been imp roved by 37 fold in beagle dogs and by almost 5 fold in humans compare d to that of marketed oral sustained-release tablet and the plasma con centration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle do gs and in human volunteers. Multi-fractional absorption model has been successfully applied for pharmacokinetic analysis, which demonstrates that the rate-limiting step for the transmucosal systemic delivery is the release of ISDN from the TmTs. Clinical studies performed in the anginal patients for up to one year have demonstrated the therapeutic benefits of this TmTs in achieving a substantial reduction in the freq uency of anginal attacks and prolongation in the duration of exercise time.