Synthesis, characterization and release of cromoglycate from dextran conjugates

Abstract

This paper describes the synthesis of a macromolecular derivative of the anti-asthmatic drug sodium cromoglycate. Cromoglycic acid (CGA) was covalently bound to dextran (Mol. Wt 10 000) by two methods. The first, involving chlorination of the free acid, followed by reaction with dextran in formamide, resulted in low yields (1.5%) of an ester complex (CGA-DEX) containing 2.5% w/w CGA. During hydrolysis experiments in phosphate buffer pH 7.4, this conjugate was found to release cromoglycate with a half-life of 10 h. In the second method, CGA was reacted with dextran via an imidazolide intermediate. This procedure gave higher yields (30–50%) of CGA-DEX, with the complexes containing between 0.8 and 40% w/w CGA, dependent upon reaction conditions. CGA-DEX containing 0.8% w/w CGA released cromoglycate with a half-life of 39 min, whilst another batch containing approx. 40% w/w CGA had a release half-life of 290 min, in buffer of pH 7.4 at 37°C. In contrast to previously reported conjugates of metronidazole and benzoic acid, the dextran conjugates of CGA studied released the drug more rapidly.