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Greifswald, Germany

Koziolek M.,University of Greifswald | Gorke K.,University of Greifswald | Neumann M.,University of Greifswald | Garbacz G.,Physiolution GmbH | Weitschies W.,University of Greifswald
European Journal of Pharmaceutical Sciences

A novel bio-relevant in vitro dissolution device was designed to mimic intragastric conditions after food intake paying particular consideration to mechanical aspects: the Fed Stomach Model (FSM). The FSM represents a fully computer-controlled dynamic flow-through system, in which dosage forms are hosted in so-called gastric vessels. Dosage form movement profiles as well as pressures can be simulated in a physiologically relevant manner. This proof-of-concept study aimed at the investigation of the effects of individual parameters and complex test programs on the drug delivery behavior of diclofenac sodium bilayer extended release tablets. Magnetic marker monitoring experiments demonstrated the applicability of the FSM to simulate intragastric movement velocities of solid oral dosage forms equivalent to in vivo data. Dissolution experiments revealed the relevance of all simulated parameters (i.e. pressure, dosage form movement and pump rate). Moreover, three different test scenarios with test programs specific for fundus, antrum and gastric emptying considered the variability of intragastric transit of solid oral dosage forms after food intake and were confirmed to be reasonable. Dissolution rates were low under conditions specific for fundus owing to low shear stresses. In contrast, higher amounts of the drug were released under high stress conditions simulating antral transit and gastric emptying. Concluding, the FSM can be a valuable tool for bio-relevant dissolution testing due to its potential of precise and reproducible simulation of mechanical parameters characteristic for the fed stomach. © 2013 Elsevier B.V. All rights reserved. Source

Eisenacher F.,Martin Luther University of Halle Wittenberg | Garbacz G.,Physiolution GmbH | Mader K.,Martin Luther University of Halle Wittenberg
European Journal of Pharmaceutics and Biopharmaceutics

Gastroretentive drug delivery systems are retained in the stomach for a sufficient time interval, releasing the drug in a controlled manner. According to literature, the floating principle is the most frequently used formulation approach for gastric retention. However, many publications lack information of the floating forces, the impact of different pH-values and almost no information exist concerning the resistance of the floating performance against physiological relevant stress. Therefore, we evaluated the performance of CO2-generating floating bilayer (drug and floating layer) tablets with respect to robustness, drug release profile, pH dependence and floating behaviour. Bilayer tablets were coated with a flexible and water permeable, but CO2-retaining polymer film of either polyvinyl acetate or ammonio-methacrylate copolymer type A. Metformin-HCl was used as a relevant model drug due to its dose-dependent and saturable absorption from the proximal part of the small intestine. To mimic physiological relevant mechanical stress conditions, recently developed dissolution stress tests with pulsed pressures were applied in addition to release studies according to the pharmacopeia. Bilayer tablets coated with polyvinyl acetate showed short floating lag times, reasonable floating strength values, floating durations of more than 24 h in simulated gastric fluid and a robust and pH independent release of Metformin-HCl. Tablets coated with ammonio-methacrylate copolymer type A showed a higher permeability for the active ingredient combined with a decreased robustness of the inflated tablets. Both polymers can be used for balloon-like floating devices. The appropriate polymer has to be chosen dependent from the properties of the active ingredient and requested application of the delivery device. Furthermore, the dissolution stress test analysis is able to indicate possible safety issues of gastroretentive formulations as well as to characterise the robustness of formulation principles towards mechanical stresses of bio-relevant intensity. © 2014 Elsevier B.V. All rights reserved. Source

Tarnacka M.,University of Silesia | Kolodziejczyk K.,University of Silesia | Dulski M.,University of Silesia | Zakowiecki D.,Pharmaceutical Works Polpharma SA | And 5 more authors.
European Journal of Pharmaceutics and Biopharmaceutics

Different experimental and theoretical techniques were applied to investigate basic physical properties of very stable and homogeneous solid dispersions formed by itraconazole and octaacetylmaltose. Differential scanning calorimetry as well as semi-empirical calculations have indicated that liquid crystalline ordering in itraconazole was completely suppressed in the binary mixtures. Molecular dynamics studies with the use of broadband dielectric spectroscopy have shown that the width of the structural relaxation process becomes smaller and fragility drops in solid dispersions with respect to the pure itraconazole. Moreover, the dynamics of secondary relaxation processes was affected by acetylated maltose. As demonstrated, β- and γ-secondary modes shift to higher and lower frequencies, respectively. On the other hand, aging experiments revealed that isostructural relaxation times in the glassy state become systematically longer with the addition of modified carbohydrate. This is a very important finding in the context of the current discussion on the factors affecting physical stability of easily crystallizing APIs. It seems that beside intermolecular interactions and local reorientation, the global mobility might control the crystallization of amorphous solid dispersions. Finally, we have demonstrated that itraconazole in binary mixtures dissolves faster and to greater extent with respect to the crystalline and amorphous form of this API. © 2014 Elsevier B.V. All rights reserved. Source

Koziolek M.,University of Greifswald | Grimm M.,University of Greifswald | Garbacz G.,Physiolution GmbH | Kuhn J.-P.,University of Greifswald | Weitschies W.,University of Greifswald
Molecular Pharmaceutics

The aim of this magnetic resonance imaging (MRI) study was to investigate gastric emptying after intake of a high-caloric and high-fat standard meal as recommended by FDA and EMA for food-effect bioavailability and fed bioequivalence studies. Twelve healthy human subjects (7 male, 5 female) received the standard meal after an overnight fast. MRI was performed before as well as 15, 25, 35, 45, 55, 65, 105, 195, 275, and 375 min after meal intake using strong T2-weighted sequences and chemical shift imaging. In addition, 30 min after the beginning of meal intake subjects ingested 240 mL of water representing the recommended coadministration of water during drug intake. Gastric content volume was assessed using T2-weighted images, and fat fraction was estimated using a calculation of fat fraction in chemical shift imaging. In addition, the existence of a mechanism allowing fast gastric emptying of water in the fed state was investigated. After a lag phase of 50-90 min, gastric content volume decreased constantly with a rate of 1.7 mL/min. The water ingested 30 min after the start of the meal intake directly reached the antrum and subsequently was emptied quickly from the human stomach. Complete gastric emptying within 6 h was observed in only one out of 12 subjects. The fat fraction of the intragastric chyme decreased from 9.5% directly after meal intake to 6.3% at the end of the experiments. Moreover, the fat fraction in fundus was significantly higher compared to the antrum. This study contributes fundamental data for the assessment of food effects of solid oral dosage forms. © 2014 American Chemical Society. Source

Koziolek M.,University of Greifswald | Grimm M.,University of Greifswald | Becker D.,Vivo Drug Delivery GmbH | Iordanov V.,Medimetrics | And 5 more authors.
Journal of Pharmaceutical Sciences

Gastrointestinal (GI) pH and temperature profiles under fasted-state conditions were investigated in two studies with each 10 healthy human subjects using the IntelliCap® system. This telemetric drug delivery device enabled the determination of gastric emptying time, small bowel transit time, and colon arrival time by significant pH and temperature changes. The study results revealed high variability of GI pH and transit times. The gastric transit of IntelliCap® was characterized by high fluctuations of the pH with mean values ranging from pH 1.7 to pH 4.7. Gastric emptying was observed after 7-202 min (median: 30 min). During small bowel transit, which had a duration of 67-532 min (median: 247 min), pH values increased slightly from pH 5.9-6.3 in proximal parts to pH 7.4-7.8 in distal parts. Colonic pH conditions were characterized by values fluctuating mainly between pH 5 and pH 8. The pH profiles and transit times described in this work are highly relevant for the comprehension of drug delivery of solid oral dosage forms comprising ionizable drugs and excipients with pH-dependent solubility. © 2014 Wiley Periodicals, Inc. Source

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