title: A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.
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 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.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Thing
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Li
authors.initials: L
authors.lastname: Ågårdh
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Susan
authors.initials: S
authors.lastname: Larsen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Rasmussen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Pallesen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Mertz
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Kristensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Østergaard
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; DepXplora Aps, Gammelbyvej 17, Lejre DK-4320, Denmark. Electronic address: claus.larsen@sund.ku.dk.
authors.forename: Claus Selch
authors.initials: CS
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D004008:Diclofenac / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007270:Injections, Intra-Articular / Q000379:methods; D007719:Knee Joint / Q000187:drug effects*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012996:Solutions / Q000008:administration & dosage / Q000737:chemistry; D013582:Synovial Fluid / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D011355:Prodrugs; D012996:Solutions; D004008:Diclofenac
keywords: drug delivery systems; injectables; joint injection; non-steroidal anti-inflammatory drugs; physicochemical properties; precipitation; prodrugs; suspensions