title: Conjugate between chondroitin sulfate and prednisolone with a glycine linker: preparation and in vitro conversion analysis.
abstract: A conjugate between prednisolone (PD) and chondroitin sulfate (CS) with glycine as a linker was prepared in order to obtain an effective macromolecular prodrug against inflammatory disease, especially rheumatoid arthritis. First, PD was converted to the N-trityl-glycine ester (Tr-GP), and the glycine ester of PD (GP) was obtained by detritylation of Tr-GP. Then, GP and CS were condensed with water-soluble carbodiimide to yield CS-GP. The obtained conjugate had a PD content of 2.24% (w/w). Conversion characteristics were investigated for GP and CS-GP to evaluate their potential as a prodrug. In the stability test of GP, PD was released well in the buffer at pH 6-7.4, but degraded rapidly at pH 8 without sufficient release of PD. As to CS-GP, PD was released more slowly than in GP, and the release rate rose with the increase in the medium pH. PD was released gradually from CS-GP over 24 h at a physiological pH. The conversion profiles of both GP and CS-GP almost followed pseudo-first order kinetics. The calculated conversion rate constants supported the gradual and effective release from CS-GP. The release rate of PD from GP and CS-GP was accelerated by the addition of rat plasma, but the promotion of release from CS-GP was small, suggesting that PD should be released gradually from CS-GP in the systemic circulation. It was demonstrated from the preliminary pharmacological study using rats with adjuvant-induced arthritis that CS-GP had high anti-inflammatory potential against arthritis.
authors.affiliation: Department of Drug Delivery Research, Hoshi University.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Onishi
authors.forename: Mototaka
authors.initials: M
authors.lastname: Matsuyama
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002809:Chondroitin Sulfates / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D006868:Hydrolysis; D008297:Male; D011239:Prednisolone / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D002809:Chondroitin Sulfates; D011239:Prednisolone; D005998:Glycine