A strategy for the immediate-release of indomethacin from a sustained-release preparation using a chitosan hydrolysate

The dissolution and absorption rates of indomethacin from granules prepared using low molecular weight chitosan hydrolysate (MW 1400, C-1) were significantly faster than those of indomethacin powder alone. Indomethacin beads, prepared from a high molecular weight chitosan hydrolysate (MW 25000, C-2) exhibited a sustained-release profile in both in vitro and in vivo tests. The optimum formulation of indomethacin, which showed rapidly absorbed and sustained high plasma concentrations for a longer period, was obtained using a mixture of C-1 granules and C-2 beads. MRT and VRT values after dosing in Beagle dogs were prolonged by increasing the C-2 bead content, while AUC values fell when the bead content exceeded 80%. Percentage absorption, calculated using the deconvolution method, was 60-70% for mixtures containing ratios of between 5:5 and 2:8 of granules and beads up to 10 h after administration. Percentage absorption was increased by raising the granule content. The mixture containing 70% granules exhibited more than 90% absorption, although this content did not succeed in maintaining plasma levels. In order to obtain plasma concentrations with fewer inter-individual variations, a 3:7 mixture of granules and beads was selected as the optimum combination, since, in dogs, ratios of between 5:5 and 2:8 of granules and beads gave nearly the same plasma concentration profile, accompanied by rapid and gradual absorption. In volunteers, plasma levels after administration of a mixture (3:7 ratio) equivalent to 0.6 mg/kg of indomethacin, reached maximum concentrations at 0.5 h and were maintained for periods of up to 12 h at the therapeutic level.