In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.

Effect of Compaction Pressure on the Enzymatic Activity of Pancreatin in Directly Compressible Formulations.

Tableting of biomolecules is a challenging formulation phase due to their sensitivity to various process parameters, such as compression pressure, process dynamics, or the temperature generated. In the present study, pancreatin was employed as a model enzyme mixture, which was formulated in tablet form utilizing the synergistic effects of brittle and plastic excipients (dibasic calcium phosphate and microcrystalline cellulose, respectively). The effect of varying compaction pressure and lubricant concentration on the generated temperature and enzymatic activity was evaluated. The tablets were analyzed for pancreatin content and the activity of two enzymes (protease and amylase) using pharmacopoeial tests. This study indicated that the formulations proposed here allow tableting over a wide range of compaction pressures without adversely affecting pancreatin content and its enzymatic activity.

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning.

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule's opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms.

Application of a novel PhysioCell apparatus for biopredictive dissolution tests of oral immediate release formulations - A case study workflow for in vitro-in vivo predictions.

Biorelevant dissolution tests of oral solid dosage forms open the gate to valid in vitro-in vivo predictions (IVIVP). A recently developed apparatus, PhysioCell, allows mimicking the fluid flow and pressure waves occurring in the human fasted stomach. In this work, we used the PhysioCell to perform IVIVP for vortioxetine immediate-release (IR) tablets: the originator (Brintellix) and generic product candidates (VORTIO). The dissolved drug was monitored in the gastric (StressCell) and intestinal (Collection Vessel) compartments that contained biorelevant media. Simulated intermittent gastric stress at 15 min and "housekeeping wave" at 30 min increased the dissolution of Brintellix formulations only. A mechanistic model that best described the observations involved the first-order tablet disintegration with a stress-induced enhancement for Brintellix, dissolution of solid particles in the StressCell, and drug transfer to the Collection Vessel. Then, a semi-mechanistic pharmacokinetic model with dissolution parameters as inputs simulated vortioxetine plasma concentrations in healthy volunteers after single and multiple dosing of Brintellix. Despite different dissolution characteristics, VORTIO provided similar concentration profiles to the originator. In conclusion, PhysioCell dissolution tests, combined with semi-mechanistic IVIVP, can be successfully used to develop IR dosage forms exhibiting gastric stress-related effects.

Conjunction of semi-mechanistic in vitro-in vivo modeling and population pharmacokinetics as a tool for virtual bioequivalence analysis - a case study for a BCS class II drug.

Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator's plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial's failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development.

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.