Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam.

Author(s): Mahaguna V, Talbert RL, Peters JI, Adams S, Reynolds TD, Lam FY, Williams RO 3rd

Affiliation(s): College of Pharmacy, Austin, TX, USA.

Publication date & source: 2003-11, Eur J Pharm Biopharm., 56(3):461-8.

Publication type: Clinical Trial; Randomized Controlled Trial

The purpose of this study was to investigate the influence of hydroxypropyl methylcellulose (HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of controlled release formulations containing alprazolam. Tablet formulations contained alprazolam, excipients, and either HPMC K4MP or HPMC K100LVP. A ten patient in vivo clinical trial using a randomized, open-label, four-way crossover design was conducted in the fed and fasted states. Plasma alprazolam concentrations were determined for 72 h. The pharmacodynamic effects of alprazolam were monitored using subject rated sedation on visual analogue scale for wakefulness, observer rated sedation, and symbol digit modalities test (SDMT). Results indicated that the tablet formulations containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles, and the dissolution profiles did not change through 6 months at 40 degrees C/75% RH or 12 months at 25 degrees C/65% Relative Humidity (RH). The area under the plasma concentration-time curve, time to peak concentration, and peak plasma concentration were not significantly different between the two tablet formulations investigated in either the fed or fasted states. Pharmacodynamically, no significant differences in SDMT scores between the two formulations were found. In vitro dissolution results predicted in vivo pharmacokinetic and pharmacodynamic results irrespective of formulation or diet used in the controlled release tablet. The controlled release tablets were bioequivalent and pharmacodynamically equivalent irrespective of the tablet formulation.