title: Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS).
abstract: We have newly synthesized osteotropic diclofenac with bisphosphonic moiety (DIC-BP) based on the concept of Osteotropic Drug Delivery System (ODDS) and investigated its potency of site-specific and controlled delivery of diclofenac to the bone in rats. After intravenous injection into rats, DIC-BP was predominantly distributed in the skeleton. DIC-BP once incorporated in the bone was gradually eliminated (t(1/2)=9.7 days), releasing diclofenac into the bone compartment. As a result, the bone concentration of regenerated diclofenac was apparently constant over 28 days. Furthermore, we evaluated the anti-inflammatory effects of DIC-BP compared with diclofenac (sodium salt) in adjuvant-induced arthritic rats. The mean effective doses (ED(50)) were 0.55 mg/kg and 1.3 mg/kg for daily oral administration of diclofenac and weekly intravenous injection of DIC-BP, respectively. Considering the frequency of medication of 17 times for diclofenac and 4 times for DIC-BP in the experimental period, ED(50) was corrected to 9.4 and 5.2 mg/kg (per experimental period) for diclofenac and DIC-BP, respectively. Moreover, DIC-BP exhibited no side effects of gastrointestinal damage, typical of non-steroidal anti-inflammatory drugs. Thus, ODDS of diclofenac shows promise as an approach for highly potent and non-toxic therapy of diclofenac, with less frequent medication.
authors.affiliation: Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company, 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan. hideki_hirabayashi@po.fujisawa.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Hirabayashi
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: J
authors.initials: J
authors.lastname: Fujisaki
authors.forename: T
authors.initials: T
authors.lastname: Masunaga
authors.forename: S
authors.initials: S
authors.lastname: Sato
authors.forename: J
authors.initials: J
authors.lastname: Hiroi
authors.forename: Y
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Hata
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001842:Bone and Bones / Q000378:metabolism*; D004008:Diclofenac / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004164:Diphosphonates / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005260:Female; D005269:Femur / Q000378:metabolism; D007275:Injections, Intravenous; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004164:Diphosphonates; D011355:Prodrugs; D004008:Diclofenac