Use of stable isotopes for evaluation of drug delivery systems: comparison of ibuprofen release in vivo and in vitro from two 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 these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r > or = 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [2H0]ibuprofen, [2H4]ibuprofen, and [2H7]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [2H4]ibuprofen and a sustained release layer with a drug load of 300 mg [2H0]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the 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 (320 +/- 51), and Cmax was nearly four times greater (145 +/- 62.1 nmole/ml for HPMC versus 37.9 +/- 14.4 for EUDRAGIT).(ABSTRACT TRUNCATED AT 250 WORDS)