In vivo evaluation of two new sustained release formulations elaborated by one-step melt granulation: level A in vitro-in vivo correlation

Abstract

The objective of this study was to evaluate in vivo two sustained release formulations elaborated by a one-step melt granulation method using theophylline as model drug. Both formulations presented differences in the in vitro release profile due to the hydrophilic or lipophilic nature of the binder employed (PEG 6000 or glycerol monostearate). The formulations were administered to Beagle dogs, and plasma levels were compared. Both formulations provided a sustained plasma concentration profile after oral administration to dogs. Significant differences (p<0.05) in the plasma concentration-time curves between the two formulations were found, with higher C(max) (6.05+/-2.00 vs. 2.55+/-0.82 microg/mL), higher AUC(0-infinity) (70.24+/-16.10 vs. 33.00+/-8.96 h microg/mL) and delayed T(max) (6.00+/-2.12 vs. 3.17+/-0.98 h) for the formulation containing PEG 6000. Absolute bioavailability of theophylline was 96% and 46% for the formulations containing PEG 6000 and glycerol monostearate, respectively. These results are consistent with those obtained in vitro, with slower release rate of theophylline from tablets elaborated with glycerol monostearate than that obtained with tablets elaborated with PEG 6000. Moreover, the formulation containing PEG 6000 provided a plasma concentration-time profile similar to that obtained with the marketed formulation Theo-Dur. A very good Level A IVIVC was observed between dissolution and absorption profiles of the drug from both test formulations. Our results showed that one-step melt granulation in a high shear mixer allows for an easy modulation of the release profile and, consequently, of the plasma level profile of the drug by selecting the type of binder used.