A Prodrug Approach Involving In Situ Depot Formation to Achieve Localized and Sustained Action of Diclofenac After Joint Injection

• Published in: Journal of pharmaceutical sciences 2014-12, Vol.103 (12), p.4021-4029
• Main Authors: Thing, Mette, Ågårdh, Li, Larsen, Susan, Rasmussen, Rune, Pallesen, Jakob, Mertz, Nina, Kristensen, Jesper, Hansen, Martin, Østergaard, Jesper, Larsen, Claus Selch
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Chemistry, Pharmaceutical - methods; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - chemistry; Diclofenac - administration & dosage; Diclofenac - chemistry; drug delivery systems; Humans; Hydrogen-Ion Concentration; injectables; Injections, Intra-Articular - methods; joint injection; Knee Joint - drug effects; Male; non-steroidal anti-inflammatory drugs; physicochemical properties; precipitation; prodrugs; Prodrugs - administration & dosage; Prodrugs - chemistry; Rats; Rats, Sprague-Dawley; Solubility; Solutions - administration & dosage; Solutions - chemistry; suspensions; Synovial Fluid - drug effects
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24221

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 7.52), has relatively high solubility at low pH (6.5mg mL−1 at pH 4) and much lower solubility at physiological pH (4.5μg mL−1 at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43h after an initial lag period of 8h. Detectable amounts of prodrug were found in the rat joint up to 8days after knee injection of the acidic prodrug solution. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.