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In situ formation of high viscous inverse lyotropic non-lamellar liquid crystalline phases is a promising approach for sustained drug delivery in the joint. The in situ forming process on exposure of two diclofenac-loaded preformulations to aqueous media was characterized with respect to depot size and shape, initial release and structural transitions using UV–Vis imaging and spatially and time-resolved synchrotron small-angle X-ray scattering (SAXS). The preformulations consisted of 10 % (w/w) ethanol, 10 % (w/w) water and a binary lipid mixture of glycerol monooleate (GMO):1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG) or GMO:medium chain triglycerides (MCT). Upon injection of preformulations into an employed injection-cell containing excess of bio-relevant medium, rapid generation of liquid crystalline depots was observed. UV–Vis images and constructed 2D SAXS maps of the injection-cell showed depots with different shapes and sizes, and features with high nanostructural heterogeneity. More extensive swelling of the GMO:DOPG-based preformulation was observed compared to the GMO:MCT-based preformulation. The UV image analysis found that a higher amount of diclofenac was released in the image area after 20 h from the GMO:MCT depot compared to the GMO:DOPG depot. The injection-cell setup employing UV–Vis imaging and synchrotron SAXS constitutes an attractive approach for evaluating the in situ forming processes of liquid crystalline depots.

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are promising for management of joint pain. As candidates for this delivery approach, five diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse and human of 3.44 - 141 min, 2.51 - 14 min, 0.58 - 1.31 min, and 0.23 - 1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6 to 28-fold larger than in plasma. The results highlight the significance of species as well as tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.