Rheological blends for drug delivery. II. Prolongation of nerve blockade, biocompatibility, and in vitro-in vivo correlations

Abstract

Rheological polymer blends of hyaluronic acid (HA) and hydroxypropylmethyl cellulose (HPMC) were evaluated as prolonged duration delivery vehicles for local anesthetics using a rat sciatic nerve blockade model. HA-HPMC blends extended the duration of sensory block approximately threefold compared to that achieved using a bupivacaine solution. Blending HA and HPMC facilitated the injection of higher polymer concentration delivery vehicles and reduced the rate of polymer hydration compared to HA solutions, enabling prolonged drug release. The duration of effective nerve block was correlated with each of the zero shear viscosity, polymer concentration, yield stress, and gel point frequency of the blends, while a two-parameter model correlating duration of nerve block with zero shear viscosity and humectancy provided improved fits to the in vivo data compared to any single variable alone. The blends exhibited no cytotoxicity and induced only a mild short-term inflammatory reaction in vivo at the site of injection, with all blends largely resorbed 4 days postinjection.