Development of Controlled-Release SK&F 82526-J Buffer Bead Formulations with Tartaric Acid as the Buffer

Abstract

ABSTRACTThe purpose of this research was to design and develop a novel controlled-release bead formulation for oral administration with buffer crystals as a carrier for loading offenoldopam mesylate, an intravenous antihypertensive agent, which provides an in vitro release rate of 30–50 mg/hr for 6–8 hr. Buffer crystals were coated in a jluid-bed granulator with a blend of gastrointestinal (GI) insoluble/ enteric Eudragit® polymers (such as RSPM/S100 polymer blend), drug was layered on these polymer-subcoated buffer beads by a slurry coating process, and the drug-layered beads were subsequently overcoated using a blend of GI insoluble/enteric polymers. The release offenoldopam and tartaric acid was monitored by a two-stage dissolution procedure using USP Apparatus 2 (paddles at 50 rpm) and HPLC methodologies. The overcoating of drug-layered tartaric acid crystals with Eudragit polymers with different permeabilities significantly affected the release offenoldopam. However, even the least permeable polymer, Eudragit RS, could not sustain the release of tartaric acid beyond 2 hr, suggesting the need to subcoat freely water-soluble tartaric acid crystals prior to drug layering. By varying the typehatios of the GI insoluble/enteric polymers for subcoat and overcoat, capsule formulations were developed, which released fenoldopam and tartaric acid at different rates. The use of Eudragit polymer blends at the optimized ratios for both subcoat and overcoat resulted in a significant retardation in the release of tartaric acid; still, the tartaric acid release was faster than that of fenoldopam, suggesting the need to use a less water-soluble fumaric or succinic acid crystals as the buffer. However, the technology described using tartaric acid crystals as the buffer will be highly useful for weakly basic drug substances with less stringent pH-dependent solubility profiles.