USE OF STABLE ISOTOPES FOR EVALUATION OF DRUG-DELIVERY SYSTEMS - COMPARISON OF IBUPROFEN RELEASE IN-VIVO AND IN-VITRO FROM 2 BIPHASIC RELEASE FORMULATIONS UTILIZING DIFFERENT RATE-CONTROLLING POLYMERS

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For the se formulations, such as a bilayer tablet, it is desirable to distingu ish and measure the release of drug from the different phases simultan eously. Mass spectrometric methods were developed to measure three ibu profen isotopomers in serum and two in dissolution fluid. The analytic al methods were linear (r greater than or equal to 0.992) over the con centration range of interest and recovery was greater than 99.2% for a ll isotopomers. Coadministration of [H-2(0)]ibuprofen, [H-2(4)]ibuprof en, and [H-2(7)]ibuprofen to male beagles demonstrated that the isotop omers were bioequivalent and verified the absence of any kinetic isoto pe effect due to deuterium incorporation (p = 0.286). These methods we re then used to evaluate a bilayer tablet formulation composed of an i mmediate release layer of 100 mg [H-2(4)]ibuprofen and a sustained rel ease layer with a drug load of 300 mg [H-2(0)]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro diss olution profiles were compared in the sustained release phase, while t he immediate release formulation remained the same. In male beagles, t he HPMC matrix delivered a significantly greater amount of ibuprofen ( p < 0.05). The AUC was threefold greater for HPMC (1067 +/- 437 nmole h/ml) versus EUDRAGIT(R) (320 +/- 51), and C-max was nearly four tim es greater(145 +/- 62.1 nmole/ml for HPMC versus 37.9 +/- 14.4 for EUD RAGIT(R). Although T-max for HPMC (3.4 +/- 1.9 h) lagged behind EUDRAG IT(R) (2.0 +/- 0.82 h), the difference was not significant (p < 0.05). The immediate release layer was absorbed to the same extent as an ora l solution (containing [H-2(7)]ibuprofen) that was administered concom itantly with the bilayer tablet. Using the stable isotope markers also demonstrated that the release rates of the two layers were independen t of each other, both in vivo and in vitro. Stable isotope techniques are a useful tool in the development of biphasic release formulations since they can be used to determine proper drug load of each phase as well as the appropriate rate of release.