A New Transmucosal Therapeutic System: Overview of Formulation Development and in Vitro/in Vivo Clinical Performance

Abstract

A new transmucosal therapeutic system (TmTs) was developed for controlled systemic delivery of drugs, which are labile to hepatic “first-pass” metabolism, through oral mucosa. It consists of a fast-release layer, which provides a rapid release of drug for prompt rise in blood drug concentration to reach the therapeutic level, and a sustained-release layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-release layer also contains mucoadhesive composition, so TmTs can be applied on gingival mucosa for continuous transmucosal controlled administration of drugs. Using isosorbide dinitrate (ISDN), a well-known antianginal drug which is known to be subjected to extensive presystemic elimination when taken orally, the systemic bioavailability has been improved by 37 fold in beagle dogs and by almost 5 fold in humans compared to that of marketed oral sustained-release tablet and the plasma concentration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle dogs 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 frequency of anginal attacks and prolongation in the duration of exercise time.