Supersaturating oral delivery systems of poorly water-soluble compounds produced by hot melt extrusion

The field of enabling techniques for poorly water-soluble drugs has been growing over the last decades. Therefore, different formulation strategies and processes have gained relevance within the development of solid pharmaceutical dosage forms for oral drug delivery. A prominent example to manufacture such dosage forms is the process of hot melt extrusion, where mostly combinations of polymers and drugs are melted together and processed to result in an amorphous solid dispersion as a biopharmaceutically enhanced drug delivery system. The final extrudate needs to be further processed downstream for example in a mill or a pelletizer. Processing a drug in an extruded form comes with the advantage of increased apparent solubility and therefore increased amount of dissolved drug available for absorption in the gastrointestinal tract. A crucial quality attribute for this formulation approach is selecting the most suitable polymer in combination with a given drug. To identify the most suitable polymer, a variety of screening approaches can be applied. Some approaches make use of the Flory-Huggins interaction parameter or a comparison of Hansen solubility parameters, while an important experimental alternative is the screening of polymers for amorphous drug stabilization (SPADS) approach. However, a suitable polymer cannot always be found so that a compromise may lead to unbeneficial formulation characteristics. There is current research focusing on the development of new synthetic polymers based on chemical monomer engineering as well as the combination of polymers. Another approach is the addition of a small molecular additive for the stabilization of a drug without the necessary use of a polymer, i.e. so-called co-amorphous systems. In this work, the interaction of an additive and the modification of the polymer are combined in molecularly designed polymeric matrices consisting of interacting small molecular additives and a polymeric excipient. The key aspect of this development is the specifically targeted molecular interaction between polymer and additive, which alters matrix characteristics thereby leading to possible benefits on the level of processing, amorphous stability and/or aqueous dispersion and drug release. The first study consisted of establishing a concept of combining acidic co-formers with a basic polymer to improve processablity as well as drug release. In the beginning of this study, the co-former malic acid was identified to be most beneficial for the formulation with the polymer Eudragit E PO (dimethylaminoethyl methacrylate copolymer). Interactions between the additive and the polymer were confirmed by Fourier transform infrared spectroscopy (FTIR) and 13C-nuclear magnetic resonance spectroscopy (NMR). These interactions were also present after the addition of the drug fenofibrate. In the next step, the amorphous stability of the additive-containing formulation was compared with the corresponding non-additive formulation via atomic force and scanning electron microscopy (SEM). By using energy dispersive X-ray spectroscopy during the SEM measurement, the drug was found to be dispersed homogenously in the malic acid formulation, whereas in the control formulation without additive, drug-rich domains were visible. This finding was supported by an observed phase separation in phasing images of atomic force microscopy using the control formulation. In addition to the improved stability, the additive formulation showed improved drug release compared to the control formulation and the corresponding physical mixture. Since an extruded formulation requires further downstream processes, such as milling or grinding in a mortar, the powderized extrudate should have sufficient flowability to enable any subsequent processing such as tableting. The modified matrix formulation showed also in this technical aspect better flowability than the control formulation or the pure polymer. To conclude in this case study on Eudragit E PO, the addition of malic acid to the polymer showed a specific molecular interaction and resulted in different formulation improvements with regards to amorphous stability, downstream processability as well as drug release. In the second study, a polymer, which is not extrudable in its neat form, was modified in a way to make it applicable for extrusion. Different small molecular additives were investigated each as interacting partner with the polyelectrolyte sodium carboxymethyl cellulose (NaCMC). Studied additives were trometamol, urea, meglumine, and the amino acids lysine, histidine, arginine. These additives were intended to exert strong specific interactions with the macromolecular polyelectrolyte via acid-base-interactions. As manufacturing technique, a combination of solvent evaporation (with and without additive) and subsequent hot melt extrusion was conducted as a two-step process. Such processing served as a model of what an excipient supplier would do to make the modified NaCMC matrix available for a pharmaceutical company to process it together with a drug by hot melt extrusion. Initially, the maximum amount of additive in combination with NaCMC was determined for which an amorphous solid dispersion was still feasible as produced by extrusion. As a result, an excess molar amount of interacting additive was generally needed because amounts of additives below 15 % were shown not to be applicable for improving the extrusion behavior of the polymer. There was on the other hand also a maximum suitable additive concentration given with higher concentrations leading to residual crystallinity after extrusion. The suitable polyelectrolyte matrices, which showed no indication of crystallinity in the laboratory X-ray diffraction analysis, were further investigated for homogeneity and crystallinity by synchrotron X-ray diffraction. Moreover, possible interactions and melting behavior were studied by hot stage microscopy and heat-assisted FTIR. It was shown that the polyelectrolyte matrices containing either meglumine, lysine, or urea resulted in an amorphous homogenous formulation. This finding was in line with the extrusion performance as well as the heat-assisted FTIR spectroscopy. Therefore, the promising meglumine and lysine excipient matrices were analyzed further in a subsequent study using a model drug. In line with the assessment of glass forming ability, the third study was designed for the practical comparison of two crucial enabling techniques i.e. hot melt extrusion and mesoporous silica. Therefore, two drugs, which are instable glass formers, were selected for a stability-based comparison under ICH Q1 accelerated stability conditions. For an increase in measurement sensitivity, the extruded samples were examined at the start of the study and the end using 13C solid-state NMR. This comparison was complemented by drug dissolution studies in biorelevant media at defined time points. In line with theoretical expectations about drugs that are challenging to stabilize in amorphous form, this study confirmed the superior stabilization capabilities of mesoporous silica formulations for which drug was successfully loaded and confined in mesopores. In contrast, the extruded formulations were not able to stabilize the challenging model drugs in their amorphous form over the duration of a three months stability study. These findings were underlined by results of the non-sink dissolution profiles at the defined time points, which showed a comparative decrease in supersaturation for the extruded formulations. The silica formulations, which were lacking the necessary precipitation inhibitor, showed just a “spring-effect” of high supersaturation but they could not sustain it without further excipients to act as a “parachute”. There was no decrease in the initial drug supersaturation visible over the duration of the study, which was in line with the solid-state evaluation. In conclusion, this study shows the advantage of mesoporous silica to formulate drugs that have a high tendency to recrystallize so that classical polymeric solid dispersions exhibit a substantial risk of physical instability. The knowledge gained from the second study formed the basis of the fourth study. The two most promising candidates from the synchrotron study of the modified matrices, which were the lysine and the meglumine formulations, were further investigated regarding their biopharmaceutical properties. Thus, the model drug fenofibrate was selected as quantitative marker for in vitro and in vivo performance. During the pre-evaluation of the solid state, the amorphous form of both formulations was confirmed via powder X-ray diffraction as well as differential scanning calorimetry. Moreover, a possible interaction was investigated via FTIR. The in vitro non-sink experiments in Fasted Simulated Intestinal Fluid (FaSSIF) showed a higher supersaturation and parachute effect for both formulations compared to the corresponding non-modified matrix without additive. The physical mixture only showed a slight drug release in the beginning, which decreased even more over time. Due to high viscosity, which was measured in separate rheological measurements, there was a 30 min delay in drug release observed in the extruded formulations. These findings agreed with results of the subsequent in vivo rat study, which showed a significant difference between the AUCs of the meglumine formulation and the corresponding physical mixture as well as differences in the Cmax values between both formulations and their physical mixtures. Therefore, this study showed the beneficial impact of the selected additives on the biopharmaceutical performance of the model drug fenofibrate. In conclusion, this thesis focused on designing modified polymeric matrices based on targeted molecular interactions of additives and drug carriers. Small molecular additives were used in amorphous solid dispersions with a special emphasis on hot melt extrusion. It could be demonstrated that the careful selection of small molecular additives, which interact with a polymer, could have a beneficial impact on the manufacturing process, the physical stability, and/or biopharmaceutical release properties of a drug from its amorphous form. Different analytical methods supported the view of the intended molecular interactions in the modified matrices but the various technical and biopharmaceutical benefits are currently hard to predict theoretically. While we used molecular simulations occasionally to visualize candidate mixtures for experimental evaluation, a next step would be a more intensive use of in silico tools to predict formulation performance and to screen mixtures in the computer. In line with current research and practice in the pharmaceutical industry, the selection of excipients during the early formulation development is crucial for the successful design of an amorphous drug delivery system on the market. This work showed that the addition of interacting small molecular additives could have a positive impact on the resulting matrix properties and therefore this would broaden the variety of suitable polymer matrices not by any covalent bonds in the synthesis of novel polymers but by virtue of a physical modification of the polymer through the given additive. The presented approach of a modified polymeric matrix therefore holds much promise in future pharmaceutical development of amorphous drug products

Stream segregation of concurrent speech and the verbal transformation effect:influence of fundamental frequency and lateralization cues

Repeating a recorded word produces verbal transformations (VTs); perceptual regrouping of acoustic-phonetic segments may contribute to this effect. The influence of fundamental frequency (F0) and lateralization grouping cues was explored by presenting two concurrent sequences of the same word resynthesized on different F0s (100 and 178 Hz). In experiment 1, listeners monitored both sequences simultaneously, reporting for each any change in stimulus identity. Three lateralization conditions were used – diotic, ±680-μs interaural time difference, and dichotic. Results were similar for the first two conditions, but fewer forms and later initial transformations were reported in the dichotic condition. This suggests that large lateralization differences per se have little effect – rather, there are more possibilities for regrouping when each ear receives both sequences. In the dichotic condition, VTs reported for one sequence were also more independent of those reported for the other. Experiment 2 used diotic stimuli and explored the effect of the number of sequences presented and monitored. The most forms and earliest transformations were reported when two sequences were presented but only one was monitored, indicating that high task demands decreased reporting of VTs for concurrent sequences. Overall, these findings support the idea that perceptual regrouping contributes to the VT effect

Duration of Coherence Intervals in Electrical Brain Activity in Perceptual Organization

We investigated the relationship between visual experience and temporal intervals of synchronized brain activity. Using high-density scalp electroencephalography, we examined how synchronized activity depends on visual stimulus information and on individual observer sensitivity. In a perceptual grouping task, we varied the ambiguity of visual stimuli and estimated observer sensitivity to this variation. We found that durations of synchronized activity in the beta frequency band were associated with both stimulus ambiguity and sensitivity: the lower the stimulus ambiguity and the higher individual observer sensitivity the longer were the episodes of synchronized activity. Durations of synchronized activity intervals followed an extreme value distribution, indicating that they were limited by the slowest mechanism among the multiple neural mechanisms engaged in the perceptual task. Because the degree of stimulus ambiguity is (inversely) related to the amount of stimulus information, the durations of synchronous episodes reflect the amount of stimulus information processed in the task. We therefore interpreted our results as evidence that the alternating episodes of desynchronized and synchronized electrical brain activity reflect, respectively, the processing of information within local regions and the transfer of information across regions

Multistability and metastability: understanding dynamic coordination in the brain

Multistable coordination dynamics exists at many levels, from multifunctional neural circuits in vertebrates and invertebrates to large-scale neural circuitry in humans. Moreover, multistability spans (at least) the domains of action and perception, and has been found to place constraints upon, even dictating the nature of, intentional change and the skill-learning process. This paper reviews some of the key evidence for multistability in the aforementioned areas, and illustrates how it has been measured, modelled and theoretically understood. It then suggests how multistability—when combined with essential aspects of coordination dynamics such as instability, transitions and (especially) metastability—provides a platform for understanding coupling and the creative dynamics of complex goal-directed systems, including the brain and the brain–behaviour relation

Time Scale Hierarchies in the Functional Organization of Complex Behaviors

Traditional approaches to cognitive modelling generally portray cognitive events in terms of ‘discrete’ states (point attractor dynamics) rather than in terms of processes, thereby neglecting the time structure of cognition. In contrast, more recent approaches explicitly address this temporal dimension, but typically provide no entry points into cognitive categorization of events and experiences. With the aim to incorporate both these aspects, we propose a framework for functional architectures. Our approach is grounded in the notion that arbitrary complex (human) behaviour is decomposable into functional modes (elementary units), which we conceptualize as low-dimensional dynamical objects (structured flows on manifolds). The ensemble of modes at an agent’s disposal constitutes his/her functional repertoire. The modes may be subjected to additional dynamics (termed operational signals), in particular, instantaneous inputs, and a mechanism that sequentially selects a mode so that it temporarily dominates the functional dynamics. The inputs and selection mechanisms act on faster and slower time scales then that inherent to the modes, respectively. The dynamics across the three time scales are coupled via feedback, rendering the entire architecture autonomous. We illustrate the functional architecture in the context of serial behaviour, namely cursive handwriting. Subsequently, we investigate the possibility of recovering the contributions of functional modes and operational signals from the output, which appears to be possible only when examining the output phase flow (i.e., not from trajectories in phase space or time)

Complex Processes from Dynamical Architectures with Time-Scale Hierarchy

The idea that complex motor, perceptual, and cognitive behaviors are composed of smaller units, which are somehow brought into a meaningful relation, permeates the biological and life sciences. However, no principled framework defining the constituent elementary processes has been developed to this date. Consequently, functional configurations (or architectures) relating elementary processes and external influences are mostly piecemeal formulations suitable to particular instances only. Here, we develop a general dynamical framework for distinct functional architectures characterized by the time-scale separation of their constituents and evaluate their efficiency. Thereto, we build on the (phase) flow of a system, which prescribes the temporal evolution of its state variables. The phase flow topology allows for the unambiguous classification of qualitatively distinct processes, which we consider to represent the functional units or modes within the dynamical architecture. Using the example of a composite movement we illustrate how different architectures can be characterized by their degree of time scale separation between the internal elements of the architecture (i.e. the functional modes) and external interventions. We reveal a tradeoff of the interactions between internal and external influences, which offers a theoretical justification for the efficient composition of complex processes out of non-trivial elementary processes or functional modes

Dynamic Effective Connectivity of Inter-Areal Brain Circuits

Anatomic connections between brain areas affect information flow between neuronal circuits and the synchronization of neuronal activity. However, such structural connectivity does not coincide with effective connectivity (or, more precisely, causal connectivity), related to the elusive question “Which areas cause the present activity of which others?”. Effective connectivity is directed and depends flexibly on contexts and tasks. Here we show that dynamic effective connectivity can emerge from transitions in the collective organization of coherent neural activity. Integrating simulation and semi-analytic approaches, we study mesoscale network motifs of interacting cortical areas, modeled as large random networks of spiking neurons or as simple rate units. Through a causal analysis of time-series of model neural activity, we show that different dynamical states generated by a same structural connectivity motif correspond to distinct effective connectivity motifs. Such effective motifs can display a dominant directionality, due to spontaneous symmetry breaking and effective entrainment between local brain rhythms, although all connections in the considered structural motifs are reciprocal. We show then that transitions between effective connectivity configurations (like, for instance, reversal in the direction of inter-areal interactions) can be triggered reliably by brief perturbation inputs, properly timed with respect to an ongoing local oscillation, without the need for plastic synaptic changes. Finally, we analyze how the information encoded in spiking patterns of a local neuronal population is propagated across a fixed structural connectivity motif, demonstrating that changes in the active effective connectivity regulate both the efficiency and the directionality of information transfer. Previous studies stressed the role played by coherent oscillations in establishing efficient communication between distant areas. Going beyond these early proposals, we advance here that dynamic interactions between brain rhythms provide as well the basis for the self-organized control of this “communication-through-coherence”, making thus possible a fast “on-demand” reconfiguration of global information routing modalities