Section 11
Chapter 10,254

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)

Hirabayashi, H.; Takahashi, T.; Fujisaki, J.; Masunaga, T.; Sato, S.; Hiroi, J.; Tokunaga, Y.; Kimura, S.; Hata, T.

Journal of Controlled Release Official Journal of the Controlled Release Society 70(1-2): 183-191


ISSN/ISBN: 0168-3659
PMID: 11166418
DOI: 10.1016/s0168-3659(00)00355-2
Accession: 010253724

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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.

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