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.
Wang
L F
LF
School of Chemistry, Kaohsiung Medical University, Kaohsiung City, Taiwan. lfwang@cc.kmu.edu.tw
Chiang
H N
HN
Wu
P C
PC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004355:Drug Stability; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007052:Ibuprofen / Q000008:administration & dosage; D007660:Ketoprofen / Q000008:administration & dosage; D007700:Kinetics; D008689:Methacrylates / Q000008:administration & dosage / Q000627:therapeutic use; D009288:Naproxen / Q000008:administration & dosage; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008689:Methacrylates; D011108:Polymers; D011355:Prodrugs; D009288:Naproxen; C005044:hydroxyethyl methacrylate; D007660:Ketoprofen; D007052:Ibuprofen