The megaloporous system:A novel principle for zero-order drug delivery I. In vitro and in vivo performance

In vitro dissolution tests (USP XX paddle apparatus at 100 rpm and USP XX dissolution apparatus 3) were used to evaluate the drug release from a commercial preparation (Theolin retard) and from two megaloporous systems, performed in both acidic (pH 1) and buffered medium (pH 6.8). Theolin retard demonstrated a biphasic drug release pattern, which appeared to be sensitive to the pH and the dissolution model. In acidic conditions, the theophylline extraction rates from the megaloporous systems, the one prepared with Eudragit RS polymer (preparation B) and the other partly with Eudragit L polymer (preparation C), were constant, similar and independent of the dissolution model applied. In buffered medium, the rate of drug delivery from preparation B was found to be lower in the paddle apparatus and from preparation C faster in the dissolution apparatus 3, when compared to the rates in the respective models at pH 1. The dosage forms have been evaluated and compared with a neutral solution (preparation D) in a single dose study (latin-square design) in 8 healthy volunteers. Both, maximum concentration of the drug in plasma from Theolin retard (Cmax = 5.8 ± 1.6 μg/ml), preparation B (C)max = 3.2 ± 1.1 μg/ml) and preparation C (Cmax = 4.4 ± 1.9 μg/ml) and peak times (9.0 ± 1.7, 8.4 ± 1.6 and 7.8 ± 1.7 h, respectively) were significantly different from the neutral solution (9.5 ± 1.8 μg/ml and 2.0 ± 0.5 h). No significant difference between complete absorption and the extent of drug released was found for either Theolin retard (96 ± 16%, 0.2 < P < 0.25) or preparation C (87 ± 20%, 0.05 < P < 0.10). Preparation B released its theophylline content incompletely during the 32 h of the plasma measurements, i.e. 75 ± 24% (P < 0.025). A value for the deviation of the ideal performance in vivo (DIP) is introduced to compare the in vivo release from oral controlled release dosage forms to the ideal performance in vivo, i.e. 8.33% of the drug content released each hour in the first 12-h period after administration. For Theolin retard and preparation C this value was found to be similar and considerably lower than the mean DIP value for preparation B. Comparison of the in vitro drug delivery from preparation C and Theolin retard with the release in vivo reveals, that the rate of theophylline release in the two dissolution models appears to be about 1.5 times higher than the rate for both preparations in viv

The megaloporous system:A novel principle for zero-order drug delivery. II. A model for the mechanism of drug delivery

The megaloporous system is composed of two phases with different liquid-penetration properties (the housing matrix phase and the restraining matrix phase) and delivers most of its drug content at a zero-order rate. The mechanism of drug release from the system is based on the concept of a decrease in the rate of surface area exposure in time of the restraining matrix phase (containing the drug) to the penetration liquid with simultaneously an increase in time of the total restraining matrix phase surface area, contributing to the delivery process. This model is mathematically represented by a convolution integral. It provides an explanation for the substantially constant release characteristics of drug from the megaloporous system. By using empirical equations in the convolution integral for the rate of restraining phase unit supply to the extraction liquids and for the drug release function of one restraining phase unit, it can be concluded that the model adequately describes the release principle of the megaloporous syste