title: Metronidazole prodrugs: synthesis, physicochemical properties, stability, and ex vivo release studies.
abstract: The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning ((13)C NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 °C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole.
authors: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy. carla.mura@unica.it
authors: Carla
authors: C
authors: Mura
authors: Donatella
authors: D
authors: Valenti
authors: Costantino
authors: C
authors: Floris
authors: Roberta
authors: R
authors: Sanna
authors: Maria Antonietta
authors: MA
authors: De Luca
authors: Anna Maria
authors: AM
authors: Fadda
authors: Giuseppe
authors: G
authors: Loy
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008795:Metronidazole / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000890:Anti-Infective Agents; D011355:Prodrugs; D008795:Metronidazole