title: In vivo efficacy of microbiota-sensitive coatings for colon targeting: a promising tool for IBD therapy.
abstract: The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is demonstrated in an experimental colitis model with Wister rats. 5-Aminosalicylic acid (5-ASA) pellets were prepared by extrusion-spheronization and coated with Nutriose:ethylcellulose (EC) 1:4 or peas starch:ethylcellulose 1:2 blends. The pellets were mixed with standard chow, and the daily drug dose was 150mg/kg. For reasons of comparison, also commercially available Pentasa pellets and placebo pellets were studied. At day 3 after the beginning of the treatment, colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Animals were sacrificed on day 6. Macroscopic and histological evaluations of colitis were performed blindly. In addition, inflammatory markers were evaluated using ELISA and real-time PCR. Rats receiving TNBS and placebo pellets developed a severe colitis in the distal half of the colon. 5-ASA administered in the form of Pentasa pellets reduced macroscopic inflammation by only 5%. In contrast, the colon lesions were much less severe upon treatment with Nutriose:EC- and peas starch:EC-coated pellets: The macroscopic score was reduced by 25 and 24%, respectively. Decreases of 37 and 38% of the histological lesions confirmed the efficacy of these new colon targeting systems. Also, inflammatory markers (MPO, IL-1β mRNA, TNF mRNA) were significantly decreased in rats receiving Nutriose:EC- and peas starch:EC-coated pellets compared to Pentasa pellets. Furthermore, real-time PCR analysis indicated increased activation of the target receptor PPAR-γ and the HMGCS2 gene in rats upon administration of 5-ASA loaded Nutriose:EC- and peas starch:EC pellets compared to the commercial product. Also, HPLC-MS/MS analysis of plasma samples demonstrated that the level of the main metabolite of the drug (N-acetyl-5-ASA) was much lower upon administration of Nutriose:EC or peas starch:EC coated pellets compared to Pentasa pellets, indicating that undesired premature drug release in the upper gastrointestinal tract was more effectively hindered. In addition to the rat study, in vivo imaging of transgenic mice expressing the luciferase gene evidenced much more pronounced PPAR-γ activation upon 5-ASA administration in the form of Nutriose:EC-coated pellets versus Pentasa pellets. All these results clearly demonstrate the superiority of these microbiota-sensitive polysaccharide-based film coatings for colon targeting in vivo.
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Lille, France. Electronic address: youness.karrout@univ-lille2.fr.
authors.forename: Y
authors.initials: Y
authors.lastname: Karrout
authors.affiliation: INSERM U995, Digestive Inflammatory Diseases, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubuquoy
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U761, Biostructures and Drug Discovery, Lille, France; Institut Pasteur de Lille, Lille, France; PRIM(Pôle de Recherche Interdisciplinaire sur le Médicament), Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Piveteau
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Siepmann
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Moussa
authors.affiliation: Roquette, Biology and Nutrition Department, Lestrem, France.
authors.forename: D
authors.initials: D
authors.lastname: Wils
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U761, Biostructures and Drug Discovery, Lille, France; Institut Pasteur de Lille, Lille, France; PRIM(Pôle de Recherche Interdisciplinaire sur le Médicament), Lille, France.
authors.forename: T
authors.initials: T
authors.lastname: Beghyn
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U995, Digestive Inflammatory Diseases, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Neut
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Lille, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Flament
authors.affiliation: Roquette, Biology and Nutrition Department, Lestrem, France.
authors.forename: L
authors.initials: L
authors.lastname: Guerin-Deremaux
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U995, Digestive Inflammatory Diseases, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubreuil
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U761, Biostructures and Drug Discovery, Lille, France; Institut Pasteur de Lille, Lille, France; PRIM(Pôle de Recherche Interdisciplinaire sur le Médicament), Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Deprez
authors.affiliation: INSERM U995, Digestive Inflammatory Diseases, Lille, France; University of Lille, School of Medicine, Lille, France.
authors.forename: P
authors.initials: P
authors.lastname: Desreumaux
authors.affiliation: University of Lille, College of Pharmacy, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Lille, France. Electronic address: juergen.siepmann@univ-lille2.fr.
authors.forename: J
authors.initials: J
authors.lastname: Siepmann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D003912:Dextrins / Q000737:chemistry; D016503:Drug Delivery Systems; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D019804:Mesalamine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008822:Mice, Transgenic; D064307:Microbiota; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013213:Starch / Q000737:chemistry; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003912:Dextrins; D053583:Interleukin-1beta; C573352:NUTRIOSE; D047495:PPAR gamma; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019804:Mesalamine; C013517:ethyl cellulose; D014302:Trinitrobenzenesulfonic Acid; D002482:Cellulose; D013213:Starch; D009195:Peroxidase; D006904:Hydroxymethylglutaryl-CoA Synthase
keywords: 5-aminosalicylic acid; Colon targeting; Film coatings; In vivo efficacy; Inflammatory bowel diseases