Greifswald, Germany
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Drechsler M.,Albert Ludwigs University of Freiburg | Garbacz G.,Physiolution GmbH | Thomann R.,Albert Ludwigs University of Freiburg | Schubert R.,Albert Ludwigs University of Freiburg
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014

The aim of the present study was to develop film-coated tablets which release a minor amount of the active pharmaceutical ingredient (API) into the stomach and small intestine, yet show a sharp increase of drug release in the colon. Tablets containing the model drug Diclofenac-Na, microcrystalline cellulose as a filler (MT), as well as tablets consisting of Ludiflash® (LT), both were used as tablet cores, respectively. Either chitosan (CHI) alone or different ratios of chitosan and Kollicoat® Smartseal 30 D (KCSS) were applied onto these cores. The resulting film-coated tablets were analyzed for swelling, drug dissolution and stability. In order to clarify whether the colon release is mainly enzyme-driven or pressure-controlled, the coated tablets were both tested in the colon microflora test (CMT), which simulates the enzyme environment within the colon, and using a bio-relevant dissolution apparatus mimicking the intraluminal pressures and stress conditions present in the gastrointestinal tract (GIT). CHI/KCSS (25:75) coated LTs showed a pressure-controlled site-specific drug release in the large intestine, while remaining intact in the upper GIT. CHI as well as CHI/KCSS (25:75) applied onto MTs, remained stable during the entire simulated bio-relevant dissolution transit of the GIT, but showed enzymatically controlled colon targeting in the CMT. These results could be confirmed for CHI/KCSS (25:75) film-coated MTs top-coated with an additional hydroxypropylmethylcellulose (HPMC) layer and an Eudragit L 30 D-55 (EUL) layer to avoid the dissolution in the fasting stomach. © 2014 Elsevier B.V. All rights reserved.


PubMed | Medimetrics, University of Greifswald, Physiolution GmbH and Vivo Drug Delivery GmbH
Type: Journal Article | Journal: Journal of pharmaceutical sciences | Year: 2015

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.


PubMed | Physiolution GmbH, Polish Academy of Sciences, Wroclaw Medical University, Pedagogical University of Cracow and 2 more.
Type: Comparative Study | Journal: International journal of pharmaceutics | Year: 2016

The purpose of the research was to investigate the effect of the manufacturing process of the controlled release hydrophilic matrix tablets on their hydration behavior, internal structure and drug release. Direct compression (DC) quetiapine hemifumarate matrices and matrices made of powders obtained by dry granulation (DG) and high shear wet granulation (HS) were prepared. They had the same quantitative composition and they were evaluated using X-ray microtomography, magnetic resonance imaging and biorelevant stress test dissolution.Principal results concerned matrices after 2 h of hydration: (i) layered structure of the DC and DG hydrated tablets with magnetic resonance image intensity decreasing towards the center of the matrix was observed, while in HS matrices layer of lower intensity appeared in the middle of hydrated part; (ii) the DC and DG tablets retained their core and consequently exhibited higher resistance to the physiological stresses during simulation of small intestinal passage than HS formulation.Comparing to DC, HS granulation changed properties of the matrix in terms of hydration pattern and resistance to stress in biorelevant dissolution apparatus. Dry granulation did not change these properties-similar hydration pattern and dissolution in biorelevant conditions were observed for DC and DG matrices.


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 | Year: 2014

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.


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 | Year: 2014

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.


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 | Year: 2014

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.


Garbacz G.,University of Greifswald | Garbacz G.,Physiolution GmbH | Cade D.,Capsugel R and D | Benameur H.,Capsugel R and D | Weitschies W.,University of Greifswald
European Journal of Pharmaceutical Sciences | Year: 2014

Current compendial dissolution and disintegrating testing is unable to mimic physiological conditions affecting gastric drug release from immediate release dosage forms. In order to obtain more realistic data, a novel test setup was developed that we term a 'dynamic open flow through test apparatus'. It is based on the previously described dissolution stress test device and attempts to simulate the intra-gastric dissolution conditions pertinent to immediate release dosage forms administered under fasting conditions with respect to flow rates, intra-gastric temperature profiles and gastric motility. The concept of the dynamic open flow through test apparatus has been tested using five different types of hard capsules: conventional hard gelatin capsules (HGC), three hypromellose based capsules (Vcaps, Vcaps Plus and DRcaps) and pullulan based capsules (Plantcaps). These were of different sizes but all contained 100 mg caffeine in each formulation, adjusted to avoid buoyancy by addition of excipient. When the capsules were stressed in the apparatus under the dynamic flow conditions applying mild pressure simulating gastric motility, release from release from Vcaps Plus, Vcaps and Plantcaps capsules was very well comparable to HGC. Capsules are usually swallowed with cold water and the temperature dependency of release from gelatin was noted as a significant factor, since heat exchange in the stomach is slow. © 2013 Elsevier B.V. All rights reserved.


Garbacz G.,Physiolution GmbH | Rappen G.-M.,Physiolution GmbH | Koziolek M.,University of Greifswald | Weitschies W.,University of Greifswald
Journal of Pharmacy and Pharmacology | Year: 2015

Objectives For the treatment of inflammatory bowel disease, the development of pH responsive modified release dosage forms is one of the most common approaches to achieve targeted drug delivery. In this study, the dissolution behaviour of eight different modified release (MR) products containing 800-mg mesalazine was investigated. Methods The performance of the products was compared under simulated fasted state conditions using the paddle apparatus as well as the dissolution stress test device mimicking mechanical stress events of bio-relevant intensity. Key findings The dissolution behaviour of the eight tested different pH-responsive MR tablets containing 800-mg mesalazine was dependent on the test conditions. Phases of mechanical stress with physiological intensity influenced the dissolution characteristics and caused in some cases accelerated drug release indicating possible dose dumping. Conclusion The study demonstrates that besides the investigation of the pH dependency of drug release, the characterisation of the mechanical robustness of the dosage forms is an essential factor determining the dissolution characteristics of such pH-dependent targeted modified release tablets. The susceptibility of 800-mg mesalazine MR tablets towards mechanical stress may be one reason for undesired drug delivery in vivo. © 2014 Royal Pharmaceutical Society.


Koziolek M.,University of Greifswald | Garbacz G.,Physiolution GmbH | Neumann M.,University of Greifswald | Weitschies W.,University of Greifswald
Molecular Pharmaceutics | Year: 2013

Intragastric drug release from solid oral dosage forms can be affected by altered physicochemical and mechanical conditions in the upper gastrointestinal (GI) tract. Food effects may lead to changes of one or more pharmacokinetic parameters and, hence, influence drug plasma levels. This can result in severe consequences such as adverse drug reactions or even therapy failure. This review highlights different examples of drug performance under fed conditions. Various reasons such as delayed gastric emptying and pH-dependent solubility of the API as well as intragastric location and movement profiles of solid dosage forms can account for changed drug dissolution. Over the past years, several biorelevant media (e.g., fed state simulated gastric fluid) have been developed with the aim to approach the physiological situation regarding parameters such as pH, buffer capacity, surface tension, and osmolality. It was shown in different in vitro experiments that all of these factors can have an impact on drug dissolution. Besides the application of complex media such as milk or nutritional drinks, the dynamic changes of the gastric content were depicted in recent studies. The capabilities, limitations, and applicability of newly established test setups for the biorelevant simulation of intragastric drug delivery behavior are discussed. Simple test devices (e.g., rotating beaker or dissolution stress test) are mainly used for the biopharmaceutical evaluation of certain problems such as the impact of pressure or shear forces. On the other hand, complex biorelevant test devices (e.g., TNO TIM-1, Dynamic Gastric Model) have recently been introduced aiming at the simulation of multiple parameters characteristic for the postprandial upper GI tract. The different test methods are reviewed with respect to the spectrum of the simulated physiological factors and the degree of complexity. © 2013 American Chemical Society.


Koziolek M.,University of Greifswald | Garbacz G.,Physiolution GmbH | Neumann M.,University of Greifswald | Weitschies W.,University of Greifswald
Molecular Pharmaceutics | Year: 2013

Food effects on drug release and absorption from solid oral dosage forms are a common biopharmaceutical problem. The fed state is characterized by different motility and secretory activity of the complete gastrointestinal (GI) tract compared to fasting conditions. Due to long gastric transit times, the postprandial stomach plays an essential role for drug release and the appearance of food effects. Therefore, a concise comprehension of the relationship between food intake and its effect on drug release from solid oral dosage forms is essential to understand their dissolution behavior under fed conditions. This review describes important aspects of stomach physiology occurring after meal ingestion with particular reference to the FDA standard breakfast. A brief overview of oral and gastric food processing and their potential influence on drug release is given. The key factors affecting the intragastric dissolution of solid oral dosage forms and their regional distribution in the stomach are discussed. Additionally, the effects of food properties on gastric emptying kinetics are presented. Mechanical aspects such as intragastric pressures and hydrodynamics caused by gastric peristalsis are defined. The initial state and the dynamic changes of the gastric content during digestion are characterized since the different physicochemical aspects such as pH value, buffer capacity, rheological properties or surface tension may be essential for the in vivo dissolution profiles of oral dosage forms. Possible effects of the discrete interplay of the physiological factors on the in vivo drug delivery behavior of solid oral dosage forms are discussed. © 2013 American Chemical Society.

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