ZINC-INDOMETHACIN COMPLEX - SYNTHESIS, PHYSICOCHEMICAL AND BIOLOGICAL EVALUATION IN THE RAT

In continuation of our work on zinc complexes of acidic NSAIDs in order to improve their therapeutic index, zinc complex of indomethacin was synthesised and characterised by IR, NMR, UV, DSC, atomic absorption spectroscopy and elemental analysis. The pH-solubility profile at 25 degrees C and in vitro release pattern at 37 degrees C by dissolution method were determined for the zinc complex and compared with that of indomethacin. Zinc-indomethacin complex showed almost double the solubility and rate of dissolution at pH 6.0 as compared to the parent drug. Anti-inflammatory studies (using carrageenan-induced hind paw edema method) showed that the zinc complex is 2.99-times more potent than indomethacin and 2.55-times more potent than the corresponding physical mixture of indomethacin and zinc sulphate. ANOVA followed by Duncan's new multiple range test indicated a statistically significant difference (p < 0.01) among them. Ulcerogenic effects of the zinc complex were observed at 1.5-times the ED(50) of indomethacin as well as at 1.5-times its own ED(50), in rats. The lesion indices obtained were compared with that of indomethacin (at 1.5-times its ED(50)) and control and were statistically evaluated using the Kruskal-Wallis rank test. They were found to be significantly different (p < 0.001). The zinc complex at 1.5-times its own ED(50) was found to be the safest with practically no ulcers at all. These studies indicate that the dose of indomethacin and hence its ulcerogenic effects may be reduced appreciably by complexing it with zinc, with no change in its therapeutic action.