More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility.

In vivo studies of formulation performance with in vitro and/or in silico simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative PhysioCell apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (n = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other in vitro-in vivo predictions involving immediate-release oral dosage forms.

PhysioCell®; - a Novel, Bio-relevant Dissolution Apparatus: Hydrodynamic Conditions and Factors Influencing the Dissolution Dynamics.

The physiologically relevant dissolution apparatuses simulate various aspects of gastrointestinal physiology and help to understand and predict the in vivo behavior of an oral dosage form. In this paper, we present and characterize for the first time a novel bio-relevant dissolution apparatus - PhysioCell®;. We evaluated the impact of several factors on the hydrodynamic conditions in the key vessel of the apparatus - the StressCell. We observed that the medium flow rate, but not the glass beads' size or amount, significantly influenced the dissolution rate. The relationship was disproportional: the increase in the flow rate from 4.6 to 9.0 mL/min reduced the dissolution time of 85% (T85) of the NaCl tablet by 46%, but from 134 to 300 mL/min decreased the T85 only by 24%. At the same time, the contractions of the StressCell's elastic walls promoted the content mixing and enhanced the dissolution rate of the paracetamol tablets: even very rare mixing contractions (1 per 10 min) decreased the T85 over twofold for the flow rate of 8 mL/min. In conclusion, the hydrodynamic conditions in the StressCell affect the dissolution of solid dosage forms and the understanding of these effects is crucial for modeling physiologically-based test conditions in the novel apparatus. Combinations of the unique PhysioCell®;features - adjustable medium flow, temperature control, controllable pH gradients and predefined mechanical agitation - can create a set of dissolution test scenarios for characterization of oral dosage forms and, in the future, making the in vitro-in vivo predictions. Graphical Abstract.

A novel open source tool for ELISA result analysis.

ELISA has become a standard analytical tool in the numerous branches of science and industry. Processing of the ELISA results may be a multistep process, often requiring a prior adaptation, using proprietary software, or exporting the results into external internet platforms. It may be problematic in the light of good documentation practices and maintaining good data integrity. In this paper, we present the development and application of the ELISA Tool software. The program is based on a Python scripting programming language and is available under an open-source license. The ELISA Tool allows users to fully control and validate the calculation procedure through a user-friendly graphical user interface. The modular architecture of the software allows its application in other information technology (IT) projects used for data processing in research laboratories. We successfully applied the ELISA Tool for the analysis of real-life samples. The ELISA Tool allowed import of the measurement data, an approximation of the calibration curves with two different algorithms, exploration and diagnostics of the model fit, and generation of the final report with the calculations while maintaining the raw data file unchanged. We report here for the first time the implementation of the idea of full control over data processing, from measured raw data to the final report. We obtained a transparent, open, registered system of data processing control, independent of third parties. The modular and flexible architecture of the created software encourages its further development following the individual demands of the users.

A dynamic system for the simulation of fasting luminal pH-gradients using hydrogen carbonate buffers for dissolution testing of ionisable compounds.

The hydrogen carbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions and covers the physiological pH range of the luminal fluids from pH 5.5 to about pH 8.4. The pH value of a hydrogen carbonate buffer is the result of a complex and dynamic interplay of the concentration of hydrogen carbonate ions, carbonic acid, the concentration of dissolved and solvated carbon dioxide and its partial pressure above the solution. The complex equilibrium between the different ions results in a thermodynamic instability of hydrogen carbonate solutions. In order to use hydrogen carbonate buffers with pH gradients in the physiological range and with the dynamics observed in vivo without changing the ionic strength of the solution, we developed a device (pHysio-grad®) that provides both acidification of the dissolution medium by microcomputer controlled carbon dioxide influx and alkalisation by degassing. This enables a continuous pH control and adjustment during dissolution of ionisable compounds. The results of the pH adjustment indicate that the system can compensate even rapid pH changes after addition of a basic or acidic moiety in amounts corresponding up to 90% of the overall buffer capacity. The results of the dissolution tests performed for a model formulation containing ionizable compounds (Nexium 20mg mups) indicate that both the simulated fasting intraluminal pH-profiles and the buffer species can significantly affect the dissolution process by changing the lag time prior to initial drug release and the release rate of the model compound. A prediction of the in vivo release behaviour of this formulation is thus most likely strongly related to the test conditions such as pH and buffer species.

An automated system for monitoring and regulating the pH of bicarbonate buffers.

The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO(2)) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO(2) loss must be completely avoided or the escaped CO(2) has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.