Veronika A Eberle1, Joachim Schoelkopf2, Patrick A C Gane3, Rainer Alles1, Jörg Huwyler4, Maxim Puchkov1. 1. Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. 2. Omya International AG, 4665 Oftringen, Switzerland. 3. Omya International AG, 4665 Oftringen, Switzerland; School of Chemical Technology, Aalto University, FI-00076 Aalto, Helsinki, Finland. 4. Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.
Abstract
INTRODUCTION: Gastroretentive drug delivery systems (GRDDS) play an important role in the delivery of drug substances to the upper part of the gastrointestinal tract; they offer a possibility to overcome the limited gastric residence time of conventional dosage forms. AIMS: The aim of the study was to understand drug-release and floatation mechanisms of a floating GRDDS based on functionalized calcium carbonate (FCC). The inherently low apparent density of the excipient (approx. 0.6 g/cm(3)) enabled a mechanism of floatation. The higher specific surface of FCC (approx. 70 m(2)) allowed sufficient hardness of resulting compacts. The floating mechanism of GRDDS was simulated in silico under simulated acidic and neutral conditions, and the results were compared to those obtained in vitro. METHODS: United States Pharmacopeia (USP) dissolution methods are of limited usefulness for evaluating floating behavior and drug release of floating dosage forms. Therefore, we developed a custom-built stomach model to simultaneously analyze floating characteristics and drug release. In silico dissolution and floatation profiles of the FCC-based tablet were simulated using a three-dimensional cellular automata-based model. RESULTS: In simulated gastric fluid, the FCC-based tablets showed instant floatation. The compacts stayed afloat during the measurement in 0.1 N HCl and eroded completely while releasing the model drug substance. When water was used as dissolution medium, the tablets had no floating lag time and sank down during the measurement, resulting in a change of release kinetics. CONCLUSIONS: Floating dosage forms based on FCC appear promising. It was possible to manufacture floating tablets featuring a density of less than unity and sufficient hardness for further processing. In silico dissolution simulation offered a possibility to understand floating behavior and drug-release mechanism.
INTRODUCTION: Gastroretentive drug delivery systems (GRDDS) play an important role in the delivery of drug substances to the upper part of the gastrointestinal tract; they offer a possibility to overcome the limited gastric residence time of conventional dosage forms. AIMS: The aim of the study was to understand drug-release and floatation mechanisms of a floating GRDDS based on functionalized calcium carbonate (FCC). The inherently low apparent density of the excipient (approx. 0.6 g/cm(3)) enabled a mechanism of floatation. The higher specific surface of FCC (approx. 70 m(2)) allowed sufficient hardness of resulting compacts. The floating mechanism of GRDDS was simulated in silico under simulated acidic and neutral conditions, and the results were compared to those obtained in vitro. METHODS: United States Pharmacopeia (USP) dissolution methods are of limited usefulness for evaluating floating behavior and drug release of floating dosage forms. Therefore, we developed a custom-built stomach model to simultaneously analyze floating characteristics and drug release. In silico dissolution and floatation profiles of the FCC-based tablet were simulated using a three-dimensional cellular automata-based model. RESULTS: In simulated gastric fluid, the FCC-based tablets showed instant floatation. The compacts stayed afloat during the measurement in 0.1 N HCl and eroded completely while releasing the model drug substance. When water was used as dissolution medium, the tablets had no floating lag time and sank down during the measurement, resulting in a change of release kinetics. CONCLUSIONS: Floating dosage forms based on FCC appear promising. It was possible to manufacture floating tablets featuring a density of less than unity and sufficient hardness for further processing. In silico dissolution simulation offered a possibility to understand floating behavior and drug-release mechanism.
Authors: Gábor Vasvári; Ádám Haimhoffer; László Horváth; István Budai; György Trencsényi; Monika Béresová; Csaba Dobó-Nagy; Judit Váradi; Ildikó Bácskay; Zoltán Ujhelyi; Pálma Fehér; Dávid Sinka; Miklós Vecsernyés; Ferenc Fenyvesi Journal: AAPS PharmSciTech Date: 2019-08-19 Impact factor: 3.246