Kinetics and hydrolysis mechanism of polymeric prodrugs containing ibuprofen, ketoprofen, and naproxen as pendent agents.

Polymeric prodrugs were prepared using methacrylic acid (MA) copolymerization with 2-hydroxyethyl methacrylate (HEMA), covalently linked with ibuprofen (HI), ketoprofen (HK), or naproxen (HN). It was previously shown that the acceptable composition of drug-linked monomer in polymeric prodrugs to prevent gastric mucosa irritation and maintain water solubility was in the range of 20-40 mol%. To investigate the applicability of these polymeric prodrugs, hydrolysis rates of HK-25, HN-29, and HI-30 (the number indicates the mole percent of the drug-linked monomers in the polymeric prodrugs), were studied in vitro with or without esterase. The polymeric prodrugs released a major fraction of the parent drugs and a fraction of the hydroxyethyl ester drug derivatives (drug-EtOH). The calculated hydrolysis rate constants and results correlated to the drug structural solubility and steric hindrance are discussed. The anti-inflammatory properties of these polymeric prodrugs were evaluated using carrageenan-induced edema test. The results indicate that HK-25 and HN-29 display greater potency to inhibit acute inflammatory processes than the free drugs over long periods. HI-30, however, retains a potency comparable to that of free ibuprofen.