Synthesis and properties of a naproxen polymeric prodrug.
A water-soluble polymeric prodrug containing a naproxen moiety was synthesized. The carboxylic groups of naproxen were condensed with the hydroxyl groups of 2-hydroxyethyl methacrylate (HEMA) to produce a drug-linked monomer, denoted HN. The polymeric prodrug was prepared by copolymerization of HN with methacrylic acid. The molar percentage of HN in the polymeric prodrug was 26 mol%, as determined by 1H NMR. To investigate the pertinence of this polymeric prodrug, the hydrolysis was studied in-vitro with or without esterase or lipase. The kinetics of enzymatic catalysis was calculated from a Lineweaver-Burk plot. The anti-inflammatory activity was evaluated using the carrageenan-induced oedema test. The polymeric prodrug released a major fraction of the free naproxen and a significant fraction of the hydroxyethyl ester derived-naproxen. The maximum hydrolysis rate Vmax, and the Michaelis constant Km were calculated to be 2.16 x 10(-5) equiv. mol L-1 min-1 and 5.11 x 10(-2) equiv. mol L-1. The maximum anti-inflammatory inhibition of free naproxen appeared at 2 h and quickly decreased thereafter. In contrast, the polymeric prodrug showed a maximum at around 2-3 h and then slowly decreased. This indicates that the polymeric prodrug displays greater potency than free naproxen in the inhibition of acute inflammatory processes over long periods.
Kaohsiung Medical University, School of Chemistry, 100 Shih-Chun 1st Rd, Kaohsiung City 80708, Taiwan. lfwang@cc.kmu.edu.tw
L F
LF
Wang
H N
HN
Chiang
W B
WB
Chen
D000818:Animals; D002351:Carrageenan / Q000008:administration & dosage / Q000494:pharmacology; D002384:Catalysis; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D004950:Esterases / Q000494:pharmacology; D005260:Female; D006868:Hydrolysis; D007700:Kinetics; D008049:Lipase / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009288:Naproxen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011108:Polymers; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D011108:Polymers; D011355:Prodrugs; D009288:Naproxen; D002351:Carrageenan; D004950:Esterases; D008049:Lipase