Chondroitin sulfate-based anti-inflammatory macromolecular prodrugs.
Macromolecular prodrugs of three non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen, ketoprofen, and naproxen, were prepared by the covalent attachment of the drugs onto chondroitin sulfate (ChS) using PEG 1000 as a spacer. Drug-PEG adducts were synthesized using 1,1'-carbonyl diimidazole as a coupling agent in dimethyl sulfoxide, followed by the reaction with ChS in highly dilute aqueous solution at pH 6.8 via N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) as a conjugation agent. The drug-ChS conjugates were confirmed by FTIR, 1H NMR and 13C NMR and the molar percent of drug substitution onto ChS was characterized by 1H NMR using the peak areas of the three protons of -PhiCHCH3 on the drugs to those of -NHCOCH3 on ChS. All drug-ChS conjugates are water-soluble. The release amounts of the free drugs from their corresponding drug-ChS conjugates were evaluated in the presence or absence of either esterase or chondroitinase, and the both enzymes in pH 7.4 Tris-buffer solutions at 37 degrees C by high performance liquid chromatography (HPLC). Keto-ChS conjugates released approximately 100% ketoprofen within 12h in the presence of esterase, but the combination with chondroitinase did not accelerate the release rate. The degradation of Keto-ChS conjugates by chondroitinase was confirmed by gel permeation chromatography (GPC). The Keto-ChS conjugates still retained the enzymatic recognition even at the substitution of ketoprofen as high as 56 mol%. The inhibition percent of carrageenan-induced edema of Keto-ChS-56 was comparable to that of a simple blend of ChS and ketoprofen, suggesting that biologically active ChS and ketoprofen could be liberated from the conjugate.
Peng
Yu-Shiang
YS
College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Lin
Shih-Chun
SC
Huang
Shih-Jer
SJ
Wang
Yu-Ming
YM
Lin
Ying-Jer
YJ
Wang
Li-Fang
LF
Chen
Jenn-Shing
JS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001168:Arthritis / Q000473:pathology; D002351:Carrageenan; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019765:Chondroitin ABC Lyase / Q000737:chemistry; D002809:Chondroitin Sulfates / Q000008:administration & dosage / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005079:Excipients; D006868:Hydrolysis; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009288:Naproxen / Q000008:administration & dosage / Q000494:pharmacology; D011092:Polyethylene Glycols; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D011355:Prodrugs; D011092:Polyethylene Glycols; D009288:Naproxen; D002351:Carrageenan; D002809:Chondroitin Sulfates; D007660:Ketoprofen; D019765:Chondroitin ABC Lyase; D007052:Ibuprofen