In vivo release of bupivacaine from subcutaneously administered oily solution. Comparison with in vitro release

Abstract

A non-randomized cross-over study was performed with bupivacaine HCl (5 mg ml −1) aqueous solution and bupivacaine free base (4.44 mg ml −1) in Viscoleo/castor oil 2:1 (v/v) administered s.c. to male Wistar rats. Plasma levels were analyzed by LC–MS. Plasma profiles obtained after administration of oily solution showed a prolonged bupivacaine release with lower peak plasma levels as compared to administration of an aqueous formulation applied in the same compartment. t 1/2, t max, C max and AUC 0−∞ for the aqueous solution were 63±8 min, 19±16 min, 194±46 ng ml −1 and 25,000±3000 ng min ml −1, respectively, while the corresponding data for the oil solution were 368±89 min, 334±186 min, 36±25 ng ml −1 and 25,000±6000 ng min ml −1. The present data indicate the potential of designing an oil formulation of bupivacaine with a prolonged local analgetic effect exhibiting a minimum of systemic toxicity. In vivo release of bupivacaine from the oil solution was evaluated by a numerical deconvolution method. In vivo release kinetics was found to be first-order and corresponded well with in vitro release kinetics found using a rotating dialysis cell. This led to establishment of an in vitro/in vivo correlation for this particular formulation.