Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10162433 | Journal of Pharmaceutical Sciences | 2014 | 9 Pages |
Abstract
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 mLâ1 at pH 4) and much lower solubility at physiological pH (4.5 μg mLâ1 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.
Keywords
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Mette Thing, Li Ã
gÃ¥rdh, Susan Larsen, Rune Rasmussen, Jakob Pallesen, Nina Mertz, Jesper Kristensen, Martin Hansen, Jesper Ãstergaard, Claus Selch Larsen,