Synthesis, characterization, and in vitro drug release study of methacrylate diclofenac conjugate as macromolecular prodrug.

Diclofenac was covalently coupled to 2-hydroxyl ethyl methacrylate (HEMA) to get a monomeric drug derivative of diclofenac. This monomer was subjected to radicular polymerization to get poly(diclo-EMA) conjugate. The in vitro drug release study of the polymeric prodrug was carried out in buffers of pH 1.2 and 7.4 mimicking the upper and lower gastrointestinal tract (GIT). The hydrolytic stability of the prodrug to pepsin was assessed in an acid buffer of pH 1.2 (simulated gastric fluid) and to α-chymotrypsin in an alkaline buffer of pH 7.4 (simulated intestinal fluid). The synthesized prodrug was also analyzed for analgesic activity, anti-inflammatory activity, and ulcerogenic index. The results showed that the drug release from the polymeric backbone takes place in a sustained manner over a period of 12 h and that the amount of drug released was comparatively higher at pH 7.4, indicating that the drug release should take place predominantly in the alkaline environment of the lower GIT rather than in the acidic environment of the upper GIT. This drug release behavior could be an ideal behavior as it may avoid or minimize the direct damage to the upper GIT caused by diclofenac. Moreover, a marked reduction of the ulcerogenic index and comparable analgesic and anti-inflammatory activities were observed with the synthesized prodrug as compared to diclofenac.