title: Controlled delivery of a new broad spectrum antibacterial agent against colitis: In vitro and in vivo performance.
abstract: Coated pellets and mini-tablets were prepared containing a new broad spectrum antibacterial agent: CIN-102, a well-defined, synergistic blend of trans-cinnamaldehyde, trans-2-methoxycinnamaldehyde, cinnamyl acetate, linalool, β-caryophyllene, cineol and benzyl benzoate. The aim was to provide a new treatment method for colitis, especially for Inflammatory Bowel Disease (IBD) patients. Since the simple oral gavage of CIN-102 was not able to reduce the pathogenic bacteria involved in colitis (rat model), the drug was incorporated into multiparticulates. The idea was to minimize undesired drug release in the upper gastrointestinal tract and to control CIN-102 release in the colon, in order to optimize the resulting antibiotic concentration at the site of action. A particular challenge was the fact that CIN-102 is a volatile hydrophobic liquid. Pellet cores were prepared by extrusion-spheronization and coated with polymer blends, which are sensitive to colonic bacterial enzymes. Mini-tablets were prepared by direct compression. The release of the main compound of CIN-102 (cinnamaldehyde, 86.7% w/w) was monitored in vitro. Optimized coated pellets and mini-tablets were also tested in vivo: in seven-week-old, male mice suffering from dextran sodium sulfate induced colitis. Importantly, both types of multiparticulates were able: (i) to significantly reduce the number of luminal and mucosal enterobacteria in the mice (the levels of which are increased in the disease state), and (ii) to improve the clinical course of the intestinal inflammation (decrease in the percentages of mice with bloody stools and diarrhea). Thus, the proposed coated pellets and matrix mini-tablets allowing for controlled CIN-102 release show a promising potential for new treatment methods of colitis.
authors.affiliation: University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM UMR995, LIRIC, University of Lille, College of Medicine, Place Verdun, F-59045 Lille Cedex, France.
authors.forename: M S
authors.initials: MS
authors.lastname: Nieto-Bobadilla
authors.affiliation: University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, 3 Rue du Prof. Laguesse, 59006 Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Siepmann
authors.affiliation: INSERM UMR995, LIRIC, University of Lille, College of Medicine, Place Verdun, F-59045 Lille Cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Djouina
authors.affiliation: INSERM UMR995, LIRIC, University of Lille, College of Medicine, Place Verdun, F-59045 Lille Cedex, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubuquoy
authors.affiliation: Septeos, 12 Avenue de la Grande Armée, 75017 Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Tesse
authors.affiliation: University of Lille, Department of Physics, UMR CNRS 8024, 59655 Villeneuve-d'Ascq, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Willart
authors.affiliation: University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM UMR995, LIRIC, University of Lille, College of Medicine, Place Verdun, F-59045 Lille Cedex, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubreuil
authors.affiliation: University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, 3 Rue du Prof. Laguesse, 59006 Lille, France. Electronic address: juergen.siepmann@univ-lille2.fr.
authors.forename: J
authors.initials: J
authors.lastname: Siepmann
authors.affiliation: University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM UMR995, LIRIC, University of Lille, College of Medicine, Place Verdun, F-59045 Lille Cedex, France. Electronic address: christel.neut@univ-lille2.fr.
authors.forename: C
authors.initials: C
authors.lastname: Neut
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002152:Calorimetry, Differential Scanning; D002934:Cinnamates / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D003092:Colitis / Q000188:drug therapy* / Q000382:microbiology; D003106:Colon / Q000187:drug effects / Q000382:microbiology; D004338:Drug Combinations; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D008297:Male; D008810:Mice, Inbred C57BL; D012995:Solubility; D013499:Surface Properties; D013607:Tablets; D013729:Terpenes / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; C000610527:CIN-102; D002934:Cinnamates; D004338:Drug Combinations; D013607:Tablets; D013729:Terpenes
keywords: Antibiotic; Coated pellet; Colitis; Controlled release; Mini-tablet