NSAIDs bound to methacrylic carriers: microstructural characterization and in vitro release analysis

Abstract

Chemically controlled drug delivery systems or ‘polymeric drugs’ based on copolymers of 2-hydroxyethyl methacrylate, HEMA, and five methacrylic derivatives which incorporate ibuprofen or ketoprofen in their chemical structure by means of labile ester bonds, MAI, MAK, MAEK, MEI and MEK, have been prepared by free radical polymerization in solution at 50°C. Three different spacers have been incorporated to the monomer structure: an aromatic amide, an aliphatic ester and a combined aromatic amide/aliphatic ester. Copolymerization reactions of the methacrylamide derivatives with HEMA follow the terminal model with reactivity ratio values, determined by the Tidwell and Mortimer (J. Polym. Sci. A 1965;3:369–378) non-linear least-squares treatment, of r MAI=0.38, r HEMA=1.69; r MAK=0.30, r HEMA=0.48; and r MAEK=0.66, r HEMA=2.85. From these values and considering that the methacrylates MEI and MEK are structurally related to HEMA, the microstructural analysis give us a random distribution of the monomeric units. The HEMA-rich copolymers, used for the in vitro experiments, showed a very high population of sequences with the active residue isolated by HEMA units. The in vitro release experiments were carried out at pH 7.4 and 9, using six different compositions for each copolymer system (1, 2.5, 5, 10, 20 and 30 wt% of the active acrylic monomer). The results show a controlled release in terms of weeks with very different profiles which depend on the type of spacer (the aromatic ester is more susceptible to hydrolysis than the aliphatic one), drug (ketoprofen release rate is higher than the ibuprofen one), composition of the copolymer (as a general rule, the release rate increases with the content of the attached drug until some composition where this effect is reverted because of the global increase in hydrophobicity) and pH (the release rate is noticeably higher in a strong basic medium, pH 9).