Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder. For an 800 mg dose, 956 mg of drug substance (salt) was needed and the final weight of tablet was approximately 1074 mg. By carefully selecting polymers based on their physicochemical properties, the release rate could be modified between desired times of 4 to >10 h for the total drug release. Mixtures of API and polymer were melt granulated at 185 °C, which is below the melting point of API (212 °C) but above the glass transition temperatures of polymers used. The confocal Raman microscopic imaging revealed that the API remained as unmelted, crystalline particles, and polymers were finely distributed on the surface and in between API particles. The formulations were found to be robust as no change in tableting and drug release properties was observed when manufacturing parameters were altered to challenge the process. The in vivo modified-release properties of formulations were demonstrated in human pharmacokinetic studies.
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