title: Modification of concomitant drug release from oil vehicles using drug-prodrug combinations to achieve sustained balanced analgesia after joint installation.
abstract: Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. mette.thing@sund.ku.dk
authors.forename: Mette
authors.initials: M
authors.lastname: Thing
authors.forename: Sabrine Smedegaard
authors.initials: SS
authors.lastname: Jensen
authors.forename: Claus
authors.initials: C
authors.lastname: Larsen
authors.forename: Jesper
authors.initials: J
authors.lastname: Østergaard
authors.forename: Susan Weng
authors.initials: SW
authors.lastname: Larsen
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000737:chemistry; D000698:Analgesia / Q000379:methods; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry*; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D007270:Injections, Intra-Articular; D009288:Naproxen / Q000008:administration & dosage / Q000737:chemistry*; D010949:Plasma / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D000077212:Ropivacaine; D012995:Solubility; D013582:Synovial Fluid / Q000737:chemistry; D014280:Triglycerides / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D011355:Prodrugs; D014280:Triglycerides; D009288:Naproxen; D000077212:Ropivacaine