title: Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug.
abstract: ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional 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. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.
authors.affiliation: Pharmaceutical Development, Schering AG, D-13342 Berlin, Germany. Heiko.Kranz@schering.de
authors.forename: H
authors.initials: H
authors.lastname: Kranz
authors.forename: C
authors.initials: C
authors.lastname: Guthmann
authors.forename: T
authors.initials: T
authors.lastname: Wagner
authors.forename: R
authors.initials: R
authors.lastname: Lipp
authors.forename: J
authors.initials: J
authors.lastname: Reinhard
mesh_terms: D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D003998:Dicarboxylic Acids / Q000737:chemistry; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D066298:In Vitro Techniques; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D010592:Pharmaceutic Aids / Q000737:chemistry*; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011205:Povidone / Q000737:chemistry; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D012995:Solubility; D013607:Tablets; D013997:Time Factors
chemical_list: D003692:Delayed-Action Preparations; D003998:Dicarboxylic Acids; D005079:Excipients; D010592:Pharmaceutic Aids; D010671:Phenylurea Compounds; D010880:Piperidines; D019707:Receptors, Chemokine; D013607:Tablets; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D011205:Povidone; C411885:BX 471