Chemical conjugation of dexamethasone to a polyaspartamide and in vitro evaluation studies

Two macromolecular conjugates of dexamethasone containing different drug amounts were synthesized using PHEA as the polymeric carrier and a succinic group as spacer. The content of linked drug was equal to 25.3% w/w (conjugate A) and 12.7% w/w (conjugate B). Both polymeric conjugates, unlike the free drug, were water-soluble and the amount of unlinked drug was evaluated to be approximately about 0.01% w/w. Both conjugates were relatively stable in vitro at pH 7.4 whereas in the presence of esterase only the conjugate B was able to release drug under the used experimental conditions. This dissimilar behavior has been attributed to the distinct macromolecular conformations assumed in aqueous medium by the two conjugates with different drug contents. In plasma, both conjugates were able to release drug in the intact form but the release was greater with A than with B. This unusual behavior has been attributed to a different conformational organization of the conjugates in plasma, in contrast to that in the simpler esterase hydrolysis medium used in the study. In fact, the presence in the plasma of proteins and other enzymes, beside esterase, can influence the spatial structure and the hydrolysis rate of polymeric conjugates. Finally, drug penetration experiments through a conjunctival epithelial cell multilayer showed no significant transepithelial transport of dexamethasone linked to the polymer after 120 min of incubation.