Development of a digital twin of a tablet that mimics a real solid dosage form: Differences in the dissolution profile in conventional mini-USP II and a biorelevant colon model.

The performance of colon-targeted solid dosage forms is commonly assessed using standardised pharmacopeial dissolution apparatuses like the USP II or the miniaturised replica, the mini-USP II. However, these fail to replicate the hydrodynamics and shear stresses in the colonic environment, which is crucial for the tablet's drug release process. In this work, computer simulations are used to create a digital twin of a dissolution apparatus and to develop a method to create a digital twin of a tablet that behaves realistically. These models are used to investigate the drug release profiles and shear rates acting on a tablet at different paddle speeds in the mini-USP II and biorelevant colon models to understand how the mini-USP II can be operated to achieve more realistic (i.e., in vivo) hydrodynamic conditions. The behaviour of the tablet and the motility patterns used in the simulations are derived from experimental and in vivo data, respectively, to obtain profound insights into the tablet's disintegration/drug release processes. We recommend an "on-off" operating mode in the mini-USP II to generate shear rate peaks, which would better reflect the in vivo conditions of the human colon instead of constant paddle speed.

The virtual physiological human gets nerves! How to account for the action of the nervous system in multiphysics simulations of human organs.

This article shows how to couple multiphysics and artificial neural networks to design computer models of human organs that autonomously adapt their behaviour to environmental stimuli. The model simulates motility in the intestine and adjusts its contraction patterns to the physical properties of the luminal content. Multiphysics reproduces the solid mechanics of the intestinal membrane and the fluid mechanics of the luminal content; the artificial neural network replicates the activity of the enteric nervous system. Previous studies recommended training the network with reinforcement learning. Here, we show that reinforcement learning alone is not enough; the input-output structure of the network should also mimic the basic circuit of the enteric nervous system. Simulations are validated against in vivo measurements of high-amplitude propagating contractions in the human intestine. When the network has the same input-output structure of the nervous system, the model performs well even when faced with conditions outside its training range. The model is trained to optimize transport, but it also keeps stress in the membrane low, which is exactly what occurs in the real intestine. Moreover, the model responds to atypical variations of its functioning with 'symptoms' that reflect those arising in diseases. If the healthy intestine model is made artificially ill by adding digital inflammation, motility patterns are disrupted in a way consistent with inflammatory pathologies such as inflammatory bowel disease.

Tribology provides an in vitro tool that correlated to in vivo sensory data on the mouthfeel of coated tablets.

Tribology is an emerging technique in the pharmaceutical field for texture and mouthfeel studies. Due to its relevance to oral sensory perception, tribology supports the development of novel products in the food industry. This study explores tribology as a tool to optimise the mouthfeel and ease of swallowing of pharmaceutical coatings and coated tablets. We measured the lubricating properties of eight pharmaceutical coatings using two methods: surface tribology and thin film tribology. As food science is more advanced in texture and mouthfeel studies, methods were developed from this field with the intention to mimic tablet ingestion. Further, the link between tribological measurements and the sensory evaluation of the coated tablets obtained by a human panel was explored. We have demonstrated that discrimination of tablets with different coatings using tribology is feasible. The viscosity, solubility and composition of the coating formulations played an important factor in lubrication. For the first time, tribology was used to analyse the lubricating properties of conventional tablet coatings and a linear relationship between tribology and the oral sensory perception, i.e. slipperiness and stickiness, was demonstrated. Tribology has the potential to become a valuable formulation tool to characterise the lubricating behaviour of coated tablets in the context of oral sensory perception.

The duality between particle methods and artificial neural networks.

The algorithm behind particle methods is extremely versatile and used in a variety of applications that range from molecular dynamics to astrophysics. For continuum mechanics applications, the concept of 'particle' can be generalized to include discrete portions of solid and liquid matter. This study shows that it is possible to further extend the concept of 'particle' to include artificial neurons used in Artificial Intelligence. This produces a new class of computational methods based on 'particle-neuron duals' that combines the ability of computational particles to model physical systems and the ability of artificial neurons to learn from data. The method is validated with a multiphysics model of the intestine that autonomously learns how to coordinate its contractions to propel the luminal content forward (peristalsis). Training is achieved with Deep Reinforcement Learning. The particle-neuron duality has the advantage of extending particle methods to systems where the underlying physics is only partially known, but we have observations that allow us to empirically describe the missing features in terms of reward function. During the simulation, the model evolves autonomously adapting its response to the available observations, while remaining consistent with the known physics of the system.

Sensory attributes of coated tablets: Developing a formal lexicon and sensory wheel.

The patient's sensory experience when taking an oral medicine is important in the assessment of its palatability, and acceptability. The aim of this study was to develop tools useful for standardisation of sensory assessment of coated tablets: a lexicon and a sensory wheel. Two randomised, double-blind sensory assessments were performed involving 83 and 52 heathy adult volunteers and two sets of coated tablets. By adapting the principles used by food sciences, a free-text description of conventional, bitter-tasting or tasteless, coated tablets was performed. In the first assessment, volunteers described the sensory attributes of the first set of tablets. The attributes collected were then validated using a second set of tablets in a separate study with different volunteers. The appropriateness and semantics of each sensory attribute was analysed. Twenty attributes most relevant for assessment of coated tablets were selected for the lexicon and associated with explicit definitions. A collection of all attributes that could possibly be triggered by coated tablets were organised in the form of a sensory wheel. This study provides a valuable insight into the sensory experience while taking a coated tablet and presents tools which can accelerate the development of palatable medicines.

Modelling and simulation of the hydrodynamics and mixing profiles in the human proximal colon using Discrete Multiphysics.

The proximal part of the colon offers opportunities to prolong the absorption window following oral administration of a drug. In this work, we used computer simulations to understand how the hydrodynamics in the proximal colon might affect the release from dosage forms designed to target the colon. For this purpose, we developed and compared three different models: a completely-filled colon, a partially-filled colon and a partially-filled colon with a gaseous phase present (gas-liquid model). The highest velocities of the liquid were found in the completely-filled model, which also shows the best mixing profile, defined by the distribution of tracking particles over time. No significant differences with regard to the mixing and velocity profiles were found between the partially-filled model and the gas-liquid model. The fastest transit time of an undissolved tablet was found in the completely-filled model. The velocities of the liquid in the gas-liquid model are slightly higher along the colon than in the partially-filled model. The filling level has an impact on the exsisting shear forces and shear rates, which are decisive factors in the development of new drugs and formulations.

Investigation of the effect of the water to powder ratio on hydraulic cement properties.

OBJECTIVE: The use of rheological properties to determine the optimal water: powder ratio of tricalcium silicate-based prototype materials incorporating alternative radiopacifiers and fillers. Determination of how the proportion of water incorporated affected the physicochemical behaviour of the materials. METHODS: Endodontic cements replaced with 30% radiopacifier, and additions of calcium phosphate and micro-silica were tested. The unmodified cements were mixed with a 0.35 water: powder ratio which served as control. At this water: powder ratio, unmodified Portland cement without any addition had an adequate consistency and furthermore it has been well characterized. Assessment of material rheological properties enabled adjustment of the water: powder ratio in each material to provide comparable viscosity values to those of the pure cement. The flowability, phase analysis and calcium release were measured for both viscosity-matched and the standard 0.35 water: powder ratio blends. The prototype materials with the adjusted water: powder ratios were also characterized by scanning electron microscopy, energy-dispersive spectroscopy and evaluated for radio-opacity. RESULTS: The use of the 0.35 water: powder ratio is not appropriate when changing the radiopacifier and incorporating additives. Zirconium oxide did not vary the water: powder ratio but tantalum oxide and calcium tungstate resulted in an increase and decrease in water demand respectively. Using the standard 0.35 ratio when the mixture had a low water demand resulted in higher flowability values and calcium release in solution. Micro-silica and calcium phosphate altered the hydration of the materials. All materials were adequately radiopaque. SIGNIFICANCE: Rheological assessment is an easy reproducible way to determine the water: powder ratios of materials with varying amounts of additives and radiopacifiers during development. Modifications to the water: powder ratio affects material properties.

Developing methodology to evaluate the oral sensory features of pharmaceutical tablet coatings.

Acceptability of medicines is critical for effective pharmacotherapy. The aim of this study was to investigate the oral sensory properties of tablet coatings to determine how mouthfeel can improve acceptability. A randomised double-blind study was performed in 84 adult volunteers (51% ≥55 years). Each participant received 4 placebo tablets (3 coated and 1 uncoated) to evaluate (i) ease of swallowing and (ii) palatability. Visual analogue scales (VAS) were used to capture sensory parameters. Acceptability was assessed using the following parameters: ease of swallowing; amount of water taken with the tablet; rank order of preference; roughness; adhesiveness and slipperiness. Ease of swallowing was determined to be the most sensitive measure of acceptance. The best coating was the one that was reported to be the most slippery and smooth. The presence of a coating improved ease of swallowing, mouthfeel and overall palatability. This study demonstrates that slippery coatings improve acceptability of tablets. The study also demonstrates the value of VAS to measure the sensory attributes of coated tablets.

Using discrete multi-physics for detailed exploration of hydrodynamics in an in vitro colon system.

We developed a mathematical model that describes the motion of viscous fluids in the partially-filled colon caused by the periodic contractions of flexible walls (peristalsis). In-vitro data are used to validate the model. The model is then used to identify two fundamental mechanisms of mass transport: the surfing mode and the pouring mode. The first mechanism is faster, but only involves the surface of the liquid. The second mechanism causes deeper mixing, and appears to be the main transport mechanism. Based on the gained understanding, we propose a series of measures that can improve the reliability of in-vitro models. The tracer in PET-like experiments, in particular, should not be injected in the first pocket, and its viscosity should be as close as possible to that of the fluid. If these conditions are not met, the dynamics of the tracer and the fluid diverge, compromising the accuracy of the in-vitro data.

New algorithm for the treatment of gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is associated with a variety of typical and atypical symptoms. Patients often present in the first instance to a pharmacist or primary care physician and are subsequently referred to secondary care if initial management fails. Guidelines usually do not provide a clear guidance for all healthcare professionals with whom the patient may consult. AIM: To update a 2002-treatment algorithm for GERD, making it more applicable to pharmacists as well as doctors. METHODS: A panel of international experts met to discuss the principles and practice of treating GERD. RESULTS: The updated algorithm for the management of GERD can be followed by pharmacists, for over-the-counter medications, primary care physicians, or secondary care gastroenterologists. The algorithm emphasizes the importance of life style changes to help control the triggers for heartburn and adjuvant therapies for rapid and adequate symptom relief. Proton pump inhibitors will remain a prominent treatment for GERD; however, the use of antacids and alginate-antacids (either alone or in combination with acid suppressants) is likely to increase. CONCLUSION: The newly developed algorithm takes into account latest clinical practice experience, offering healthcare professionals clear and effective treatment options for the management of GERD.

Observations of biological choruses in the Southern California Bight: A chorus at midfrequencies.

This paper describes the characteristics of an underwater biological chorus recorded in the midfrequency band (1-10 kHz) in the Southern California Bight. The recordings were made in July, 2002 by a large-vertical-aperture, 131-element, 2D billboard array. The chorus, observed predominantly on two consecutive nights during the 8-day experiment, is composed of two bands of energy centered around 1.5 kHz and between 4 and 5 kHz. It causes a complete reversal in the vertical directional characteristics of the mid-frequency ambient sound field between day and nighttime periods; whereas the vertical structure during the day shows a notch in the horizontal direction with levels more than 10 dB below those at higher angles, the nighttime levels in the horizontal can exceed those at other vertical angles by more than 10 dB. These nighttime sounds also are strongly anisotropic in azimuth; they appear to come mainly from a popular Southern California fishing spot where the water depths exceed 75 m. Vertical beam-to-beam coherence squared estimates suggest the chorus source region exists on spatial scales greater than the multipath interference wavelengths of this environment. Individual sounds comprising the chorus, although difficult to separate from the background din, have a fluttering, rasping character.

Feasibility of a bioadhesive drug delivery system targeted to oesophageal tissue.

This contribution examines the feasibility of utilising an oesophageal-adhesive alginate layer to support model drug particles. Such a bioadhesive system offers the prospect of local drug delivery to the oesophagus, which in turn has applications in the treatment of conditions including gastro-oesophageal reflux disease and oesophageal cancer. Surface-modified (amine, carboxylate and sulfate) as well as neutral fluorescent beads were investigated as model drug particles. A fluorescence assay technique was utilised to quantify the extent and duration of adhesion of a fixed dose of these particles to excised porcine oesophageal tissue. Retention of the particles was investigated both from aqueous systems and within an adhesive alginate solution. After 30 min significantly higher adhesion of neutral beads was recorded from the alginate solution as compared to the aqueous suspension (n = 6, P < 0.05). The beads that possessed a negative charge showed significantly greater retention within the alginate carrier (n = 6, P < 0.05). However, the amine-modified beads showed retention profiles that were similar both within the alginate carrier and within the aqueous suspension (n = 6, P > 0.05).

An in vitro mucosal model for prediction of the bioadhesion of alginate solutions to the oesophagus.

This paper discusses the development of an in vitro model utilised to assess the adhesion of alginate solutions to porcine oesophageal tissue. The methodology involved the construction of retention apparatus onto which sections of tissue were mounted. Fluorescently labelled alginate solutions of known rheological profile were dispensed onto the tissue at a concentration of 2% w/v. A washing solution was applied at a specified rate to mimic saliva flow and the eluted material collected. Fluorimetric analysis allowed dose retention to be assessed as a function of time. The effect of the nature of the washing solution and the choice of alginate were investigated. It was found that after 30 min up to 20% of the applied alginate dose remained associated with the tissue, regardless of the alginate selected from the range examined. The nature of the washing medium did not have a significant effect on retention, irrespective of the inherent mucin concentration. Overall this study indicated that the technique presented offers a viable means of studying bioadhesion of liquids and also demonstrates that alginate solutions may have an application as bioadhesive agents for localisation within the oesophagus.