PHARMACOKINETIC CHARACTERISTICS OF A NEW LIQUID SUSTAINED-RELEASE FORMULATION OF THEOPHYLLINE - MICROCAPS AS SACHET

A new sustained release theophylline (CAS 58-55-9) formulation was esp ecially designed for the elderly and children. Microcapsules of theoph ylline, administered as a suspension in water: proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. P harmacokinetic characteristics of 2 batches at the lower (T1) and uppe r (T2) in vitro dissolution specification range of this new formulatio n and a pellet formulation (R) as a comparator were evaluated in an op en, randomised, 3-way, multiple dose, crossover study with an asymmetr ic dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe p lasma concentrations with a high and long-lasting plateau were achieve d with this new formulation. Plateau times which are independent of th e asymmetric dosage regimen ranged from 16.4 h (T1) to 13.8 h (T2) and could therefore cover sufficient time of the dosage interval. Maximum plasma levels of 9.6 mu g/ml and 10.0 mu g/ml were attained 6.6 and 6 .1 h after dosing of T1 and T2? coinciding perfectly with the time of the critical morning dip at 2-6 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2), this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chr onopharmacokinetics of theophylline sustained release preparations. Bi oequivalence of all 3 formulations compared with each other with regar d to rate (C-max ss) and extent (AUC(ss)) of absorption could be estab lished for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the ref erence. All in all, the safely and efficacy of this new liquid sustain ed release theophylline preparation could be established. Furthermore, in vitro specifications were justified according to current EC guidel ines.