STRUCTURAL MODIFICATION AND EVALUATION OF IBUPROFEN TO OVERCOME GI SIDE EFFECTS.

Ibuprofen-Chlorzoxazone (IBU-CZX) ester linked mutual prodrug was synthesized with the aim of improving the therapeutic index through prevention of gastrointestinal irritation and bleeding. The structure of the synthesized IBU-CZX hybrid ester was confirmed by IR and 1H NMR spectroscopy and their purity was established by elemental analysis, HPLC and TLC. The release of ibuprofen (IBU) as well as chlorzoxazone (CZX), from the ester prodrug was studied. A validated analytical HPLC method for the estimation of the IBU, CZX and the prodrug was developed using fenofibrate (FEN) as internal standard. The kinetics of ester hydrolysis was studied in four different non-enzymatic buffer solutions, at pH 3, 4, 5 and 7.4 as well as in experimental plasma. Study of skeletal muscle relaxant and anti-inflammatory properties in comparison with the parent drugs has shown that both skeletal muscle relaxant and anti-inflammatory activities were present at the same doses of the synthesized ester prodrug. The ester was found to be less irritating to gastric mucosal membrane than the parent drugs. These results suggest that the synthesized prodrug was characterized by better therapeutic index than the parent drugs.