Synthesis and properties of a naproxen polymeric prodrug

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Abstract
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 times 10−5 equiv. mol L−1 min−1 and 5.11 times 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.

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