Synthesis of poly(ethylene glycol)-metaxalone conjugates and study of its controlled release in vitro.

Metaxalone (Met), a drug for treatment of pain and stiffness due to muscular injuries, was covalently linked to poly(ethylene glycols) (PEG) via a chloroacetyl chloride spacer. The average weight molecular weights used for PEG are 4000, 6000 and 10,000, respectively, and the procedure of chemical modification for PEGs was conducted by a two-step protocol: (1) synthesis of N-chloroacetyl-metaxalone; (2) synthesis of PEG(4000)-Met, PEG(6000)-Met and PEG(10000)-Met. 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, in the same condition, the rate of hydrolysis for PEG(10000)-Met is the slowest among three prodrugs, and more amount of metaxalone can be detected releasing from prodrug matrices at the presence of alpha-chymotrypsin in a buffer solution with pH 8.0. It was also found that these novel prodrugs can effectively improve the metaxalone's pharmacokinetics, and furthermore can markedly increase its half-life period.