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

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Mette Thing, Li Agårdh, Susan Larsen, Rune Rasmussen, Jakob Pallesen, Nina Mertz, Jesper Langgaard Kristensen, Martin Hansen, Jesper Ostergaard, Claus Selch Larsen

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 (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 μg 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 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
Volume103
Issue number12
Pages (from-to)4021–4029
Number of pages10
ISSN0022-3549
DOIs
Publication statusPublished - 2014

ID: 126172627