Development of a multi particulate extended release formulation for ZK 811 752, a weakly basic drug


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Abstract

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional mini matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Mini matrix tablets were prepared by direct compression of drug, matrix former (polyvinylacetate/polyvinylpyrrolidone; Kollidon® SR) and excipients (lactose, calcium phosphate or maize starch). To solve the problem of pH-dependent solubility fumaric acid was added to the drug–polymer excipient system. The addition of fumaric acid was found to maintain low pH-values within the mini tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, micro environmental conditions for the dissolution of the weakly basic drug were kept constant and drug release was demonstrated to be pH-independent. Incorporation of water-soluble (lactose) or highly swellable (maize starch) excipients accelerated drug release in a more pronounced manner compared to the water-insoluble excipient calcium phosphate. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for mini matrix tablets stored at 25 °C/60% RH and 30 °C/70% RH for up to 6 months.

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