Macromolecular prodrugs. XII. Kinetics of release of naproxen from various polysaccharide ester prodrugs in neutral and alkaline solution

Abstract

Naproxen was attached to dextran, soluble starch and hydroxyethyl starch through ester linkages. Drug fixation to dextran was further established by incorporation between the drug and the carrier of a glycolic acid spacer arm. The kinetics of hydrolysis of the naproxen polysaccharide conjugates was studied in aqueous solution over the pH range 6.72–10.53 at 37° C. The pH dependence of the various pseudo-first-order rate constants showed almost parallel straight-line portions with slopes close to unity, indicating that the hydrolysis reactions were subject to specific base catalysis. The rates of degradation of the conjugates in neutral and alkaline solution differed by a factor of approximately 500 with the naproxen glycolic acid ester derivative as the most sensitive conjugate to undergo base-catalyzed hydrolysis. At physiological pH and temperature, the latter compound degraded with a half-life of 3.6 h. Under the same conditions the half-lives of regeneration of naproxen from the dextran, the soluble starch and the hydroxyethyl starch derivative were 183, 800 and 1600 h, respectively. Although the soluble starch and the hydroxyethyl starch prodrugs possessed excellent sustained release properties in vitro, a major impediment for the applicability of these carrier agents might arise from the limited aqueous solubility of the conjugates even at relatively low drug load. The results obtained have been discussed in relation to design of parenteral depot formulations of NSAID compounds.