Poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) and its drug conjugates are some of the most intensively investigated drug-delivery systems. Metaxalone (Met) was covalently linked to PHPMA via a spacer, and the procedure of the chemical modification for PHPMA was conducted by a two-step protocol: (1) synthesis of PHPMA with different molecular weights and (2) synthesis of PHPMAMet. The Met content in the conjugate could reach 18%. The controlled drug-release studies were performed in buffer solutions with pH values equal to 1.1, 7.4, and 10.0. The results demonstrate that the rate of hydrolysis for PHPMAMet was the slowest at pH 1.1, and a greater amount of Met was detected releasing from prodrug matrices in the presence of enzyme in a buffer solution at pH 8.0. It was also found that the novel prodrug effectively improved Met's pharmacokinetics and, furthermore, markedly increased its half-life period. (c) 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012