Efficacy and toxicity of Eudragit-coated chitosan-succinyl-prednisolone conjugate microspheres using rats with 2,4,6-trinitrobenzenesulfonic acid-induced colitis.
A targeted delivery system for inflammatory bowel disease (IBD), Eudragit L100 (EuL)-coated chitosan (Ch)-succinyl-prednisolone (SP) conjugate microspheres (Ch-SP-MS/EuL), were designed and examined in vivo for efficacy and toxicity. Their preparation was conducted in the same manner as previously; that is, by synthesis of the conjugate by carbodiimide coupling of Ch and SP, conversion into microspheres (Ch-SP-MS), and coating of Ch-SP-MS with EuL. Experimental colitis was induced by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the colon in rats. Drugs were administered once or twice a day intragastrically for three consecutive days. Visible colitis severity, colon/body weight ratio and myeloperoxidase activity were measured as inflammatory indices. Toxicity was examined from the decrease in the thymus/body weight ratio. Efficacy was dose-dependent and the greatest in the order Ch-SP-MS/EuL>Ch-SP-MS>prednisolone (PD) alone, and Ch-SP-MS/EuL showed excellent recovery of colitis states. Toxicity was the greatest in the order PD>>Ch-SP-MS>Ch-SP-MS/EuL. Ch-SP-MS and Ch-SP-MS/EuL reduced significantly the thymic atrophy caused by PD. It was demonstrated that Ch-SP-MS/EuL enhanced effectiveness of PD and reduced toxic side effects of PD greatly. Also, these results established the prediction by previous in vitro and in vivo studies.
Onishi
Hiraku
H
Department of Drug Delivery Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan. onishi@hoshi.ac.jp
Oosegi
Tomoko
T
Machida
Yoshiharu
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D048271:Chitosan; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D009929:Organ Size / Q000187:drug effects; D010316:Particle Size; D011109:Polymethacrylic Acids; D011239:Prednisolone / Q000008:administration & dosage* / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014302:Trinitrobenzenesulfonic Acid
D000893:Anti-Inflammatory Agents; D011109:Polymethacrylic Acids; C038300:methylmethacrylate-methacrylic acid copolymer; D014302:Trinitrobenzenesulfonic Acid; D048271:Chitosan; D011239:Prednisolone