Prolonged naproxen joint residence time after intra-articular injection of lipophilic solutions comprising a naproxen glycolamide ester prodrug in the rat.

ABSTRACT

Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16 mg/ml) were injected into the rat knee joint by dosing 6 µl formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245 min, an increase in the MRT(j) from around 0.11 to 3.3h and a 30% reduction in the maximum serum concentration were observed compared to that of the parent naproxen. The similar serum profiles obtained using the two oils indicate that the release was not affected by the oil viscosity. A prolonged naproxen joint residence time in rats was shown by intra-articular injection of an oil prodrug solution.