title: Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings.
abstract: Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope (13)C(6)-glucose as the test compound were administered and the occurrence of (13)CO(2) in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines.
authors.affiliation: Department of Clinical and Hospital Pharmacy, University Medical Center Groningen, The Netherlands. r.c.a.schellekens@apoth.umcg.nl
authors.forename: R C A
authors.initials: RC
authors.lastname: Schellekens
authors.forename: F
authors.initials: F
authors.lastname: Stellaard
authors.forename: D
authors.initials: D
authors.lastname: Mitrovic
authors.forename: F E
authors.initials: FE
authors.lastname: Stuurman
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: H W
authors.initials: HW
authors.lastname: Frijlink
mesh_terms: D000464:Alginates / Q000737:chemistry; D001682:Biological Availability; D002214:Capsules; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002482:Cellulose / Q000737:chemistry; D003106:Colon / Q000378:metabolism*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D005079:Excipients / Q000737:chemistry; D005947:Glucose / Q000008:administration & dosage / Q000493:pharmacokinetics; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption; D019804:Mesalamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D008855:Microscopy, Electron, Scanning; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry; D013213:Starch / Q000031:analogs & derivatives / Q000737:chemistry; D013499:Surface Properties
chemical_list: D000464:Alginates; D002214:Capsules; D003692:Delayed-Action Preparations; D005079:Excipients; D006603:Hexuronic Acids; D011108:Polymers; D011109:Polymethacrylic Acids; C038300:methylmethacrylate-methacrylic acid copolymer; D011092:Polyethylene Glycols; D019804:Mesalamine; D020723:Glucuronic Acid; D002482:Cellulose; D013213:Starch; C048390:sodium starch glycolate; D005947:Glucose; D002266:Carboxymethylcellulose Sodium; C109691:microcrystalline cellulose