In Vitro and In Vivo Evaluation of a Once‐Daily Controlled‐Release Pseudoephedrine Product

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Abstract
The functionality of a once‐daily, osmotic dosage form—gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)—was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)—240 and 120 mg—were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed‐release 12‐hour pseudoephedrine capsule given every 12 hours in a randomized 4‐way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14–17%). A one‐to‐one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high‐fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent. The validity of the in vitro/in vivo correlation was confirmed in a bioequivalence study in which GITS with similar in vitro release rate profiles, but manufactured under different conditions (batch size, quantitative core composition, manufacturing equipment, and manufacturing site), were shown to be bioequivalent.