Yihong Qiu

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.

Sustained-release hydrophilic matrix tablets of zileuton: formulation and in vitro/in vivo studies

Abstract Zileuton is a new active 5-lipoxygenase inhibitor which has been shown to be clinically effective in the treatment of asthma. It is a racemic mixture of S - and R -enantiomers. In the present study, hydrophilic polymer matrix tablets were used for oral controlled delivery of zileuton. The prototype formulations with drug loading of 50–60% were prepared and tested in vitro using USP apparatus I, II and III. In vivo absorption of three formulations with differing release rates was evaluated using crossover designs in beagle dogs. Plasma concentrations of the two enantiomers of zileuton were analyzed by a chiral HPLC method. The results indicated that the release of zileuton from the matrix tablets followed apparent zero-order kinetics when tested using USP apparatus I and II. Prolonged absorption of zileuton was achieved using the hydrophilic matrix system. In vivo drug release estimated by deconvolution based on the data of both S - and R -enantiomers was correlated with in vitro release. Linear relationships between in vitro and in vivo release were obtained with more rapid in vivo release than in vitro.

Formulation development of sustained-release hydrophilic matrix tablets of zileuton.

The purpose of this paper was to develop a hydrophilic matrix system for extended oral delivery of zileuton, and study the effects of certain formulation, processing, and dissolution variables on in vitro drug release. Tablet formulations with 60-70% drug and varying release rates were prepared by wet granulation using low and medium viscosity grades of hydroxypropylmethocellulose. In vitro drug release was evaluated using USP apparatus 1. The in vitro drug release from all formulations followed zero-order kinetics and was independent of compression force. In general, the release rate decreased with increasing drug load and higher polymer concentration or viscosity. High-shear granulation also resulted in lower release rate. Accelerated release was observed with increased agitation as well as in the dissolution media with higher surfactant concentration and/or ionic strength. No stereoselective release from the matrix system was observed. The hydrophilic matrix system effectively controlled the in vitro release of zileuton. Matrix tablets with desired release rates can be prepared by adjusting various formulation and processing parameters. The matrix system also has the advantage of simple processing and relatively low cost.