The Application Of Spacer Groups In Macromolecular Prodrug Synthesis And Study Of Its Controlled Release In Vitro

Prodrug is a new drug delivery system based on polymer compounds. It has four main parts that are polymer carrier, active drug, spacer and targeting moiety. And the releasing rate of active drug from macromolecular prodrug was mostly decided by what kind of polymer carrier and spacer are used.PEG-Met conjugates were prepared: Metaxalone is a muscle relaxant, used to treat the pain and stiffness of muscle injuries. Its half-life is 3.5 hours and low solubility in water which restricts high clinical applications. Met was first modified into N-chloroacetyl-Met by reaction with chloroacetyl chloride, the yields was 92.6%. Then the intermediate was linked to PEG (Mn=2000, 4000, 6000 and 10000), and PEG2000-Met, PEG4000-Met, PEG6000-Met and PEG10000-Met were prepared. The conjugates were characterized by IR, UV, ~1HNMR and DSC. The release studies were performed in pH 1.1, 7.4 and 10.0 buffer solutions, the hydrolysis rates of PEG10000-Met is the slowest of the three macromolecular prodrugs in the same condition.D-Met conjugates were prepared: metaxalone was attached to dextran (Mn=20000, 40000), D20000-Met and D40000-Met were prepared. The release studies were performed in pH 1.1, 7.4 and 10.0 buffer solutions, the hydrolysis rates of D20000 -Met is more slowly than D40000-Met in the same condition.The six novel Macromolecular prodrugs can improve the pharmacokinetics of metaxalone, particularly by increasing its half-life. In the present of a-chymotrypsin, the release studies were performed in pH 8.0 buffer solutions, more of the metaxalone were released in the presence of a-chymotrypsin than in its absence.