title: Two-Stage Single-Compartment Models to Evaluate Dissolution in the Lower Intestine.
abstract: The purpose was to propose two-stage single-compartment models for evaluating dissolution characteristics in distal ileum and ascending colon, under conditions simulating the bioavailability and bioequivalence studies in fasted and fed state by using the mini-paddle and the compendial flow-through apparatus (closed-loop mode). Immediate release products of two highly dosed active pharmaceutical ingredients (APIs), sulfasalazine and L-870,810, and one mesalamine colon targeting product were used for evaluating their usefulness. Change of medium composition simulating the conditions in distal ileum (SIFileum ) to a medium simulating the conditions in ascending colon in fasted state and in fed state was achieved by adding an appropriate solution in SIFileum . Data with immediate release products suggest that dissolution in lower intestine is substantially different than in upper intestine and is affected by regional pH differences > type/intensity of fluid convection > differences in concentration of other luminal components. Asacol® (400 mg/tab) was more sensitive to type/intensity of fluid convection. In all the cases, data were in line with available human data. Two-stage single-compartment models may be useful for the evaluation of dissolution in lower intestine. The impact of type/intensity of fluid convection and viscosity of media on luminal performance of other APIs and drug products requires further exploration.
authors.affiliation: Faculty of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Markopoulos
authors.affiliation: Faculty of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: Faculty of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Mira
authors.initials: M
authors.lastname: Symillides
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.affiliation: Faculty of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
mesh_terms: D001682:Biological Availability; D003106:Colon / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D019804:Mesalamine / Q000493:pharmacokinetics; D009287:Naphthyridines / Q000493:pharmacokinetics*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012995:Solubility; D012460:Sulfasalazine / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
chemical_list: C489415:L870810; D009287:Naphthyridines; D004364:Pharmaceutical Preparations; D012460:Sulfasalazine; D019804:Mesalamine
keywords: Asacol; Azulfidine; L-870,810; absorption; colon; dissolution; ileum; in vitro methods; mesalamine; sulfasalazine