In vitroevaluation of S-(+)-ibuprofen as drug candidate for intra-articular drug delivery system

Abstract

Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the efficacy of S-(+)-ibuprofen on cartilage degradation as drug candidate for DDS loading. Humeral cartilage and joint capsule explants were collected from healthy sheep shoulder joints and they were cultured in mono- or in co-culture for 13 days with LPS in combination with S-(+)-ibuprofen at 50 µM and 1 mM. S-(+)-ibuprofen (50 µM) blocked prostaglandins production in LPS-activated explants but did not reduce cartilage degradation. By contrast, 1 mM S-(+)-ibuprofen treatment of cartilage explants reduced nitric oxide synthesis by 51% (p = 0.0072), proteoglycans degradation by 35% (p = 0.0114) and expression of serum amyloid protein - the main protein induced upon LPS challenge - by 44% (p < 0.0001). On contrary, in presence of synovial membrane, the protective effects of S-(+)-ibuprofen on cartilage damages were significantly diminished. At 1mM, S-(+)-ibuprofen reduced the cell lysis during culture of cartilage and joint capsule either in mono- or in co-culture. This study performed on sheep explants shows that 1 mM S-(+)-ibuprofen inhibited cartilage degradation via a mechanism independent of cyclooxygenase inhibition. Reduction of prostaglandins synthesis at 50 µM in all treatment groups and reduction of cartilage degradation observed at 1 mM suggest that S-(+)-ibuprofen could be considered as a promising drug candidate for the loading of intra-articular DDS.

Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review

“…The effects of different NSAIDs are thus shown to vary 43,47 by formulation, model system, and concomitant drugs 48,49 and some have physiological effects on chondrocytes 39,50,51 . Our results demonstrate the potential effect of celecoxib on the microstructure of cartilaginous cells.…”

The Added Value of the “Co” in Co-Culture Systems in Research on Osteoarthritis Pathology and Treatment Development

“…However, most likely the strong stimulation with IL-1β would not have allowed for the detection of any differences. In combination with LPS stimulation, addition of sheep synovial capsule tissue to cartilage weakened the protective effect of S-(+)-ibuprofen on nitric oxide synthesis and aggrecan loss, possibly related to the higher levels of PGE 2 produced by the synovium ( Bédouet et al, 2015 ). In contrast, the combination with synovial tissue eliminated the requirement for continuous presence of IL-1 receptor antagonist in order to prevent GAG and collagen loss and improve chondrocyte viability in IL-1α-stimulated cartilage explants ( Mehta et al, 2019 ).…”

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

“…However, the long-term use of Ibp and related NSAIDs are associated with a variety of well-recognized side effects [45], in particular those involving the gastro-intestinal system (GIT) such as erosions and ulcerations, because of loss or diminished protection of the GIT mucosa. Therefore, in order to reduce such side effects during NSAIDs treatment of patients, a localized therapeutic approach that is based on the development of intra-articular drug delivery systems has been suggested [46][47][48][49][50]. In order to improve the permanence of drugs in the joint cavity, biodegradable polymers including PLGA have been proposed with the ability to provide long-term sustained release, and maintain a therapeutic concentration of drug in joint cavity [51].…”