Investigation of diclofenac release and dynamic structural behavior of non-lamellar liquid crystal formulations during in situ formation by UV-Vis imaging and SAXS.

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).

Spatially and time-resolved SAXS for monitoring dynamic structural transitions during in situ generation of non-lamellar liquid crystalline phases in biologically relevant media.

Formation of high viscous inverse lyotropic liquid crystalline phases in situ upon exposure of low viscous drug-loaded lipid preformulations to synovial fluid provides a promising approach for design of depot formulations for intra-articular drug delivery. Rational formulation design relies on a fundamental understanding of the synovial fluid-mediated dynamic structural transitions occurring at the administration site. At conditions mimicking the in vivo situation, we investigated in real-time such transitions at multiple positions by synchrotron small-angle X-ray scattering (SAXS) combined with an injection-cell.

Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation.

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 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.

Transport characteristics in a novel in vitro release model for testing the performance of intra-articular injectables.

There is a need for bio-predictive and well-characterized in vitro release models in the development of intra-articular depot formulations. Here, the commercially-available Scissor system, a membrane-based two-compartment release testing instrument, was applied to characterize the transport and release of the drug diclofenac employing conditions intended to mimic transport in the synovial joint. The fate of hyaluronic acid and human serum albumin, the main bio-relevant components incorporated in the system, was investigated.

Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension.

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.

A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.