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Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (12C) was added to the tablet, while for the ice capsule 13C3 labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters tmax and AUC0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations.
The microbiome of the colon is characterized by its great diversity. This varies not only intra- but also interindividually and is influenced by endogenous and exogenous factors, such as dietary and lifestyle factors. The aim of this work was to investigate the extent to which the degradation of the drug sulfasalazine is influenced by different microbiota. Therefore, the in vitro model MimiCol3 was used, which represents the physiological conditions of the ascending colon. In addition to a representative physiological volume, the pH value, redox potential and an anaerobic atmosphere are important to provide the bacteria with the best possible growth conditions. Stool samples were taken from three healthy subjects, comparing omnivorous, vegetarian and meat-rich diets, and cultured for 24 h. However, the nutrient medium used for cultivation led to the alignment of the bacterial composition of the microbiota. The previously observed differences between the diets could not be maintained. Nevertheless, the similar degradation of sulfasalazine was observed in all microbiota studied in MimiCol3. This makes MimiCol3 a suitable in vitro model for metabolism studies in the gut microbiome.
Application of In Vivo Imaging Techniques and Diagnostic Tools in Oral Drug Delivery Research
(2022)
Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on “Understanding Gastrointestinal Absorption-related Processes (UNGAP)” was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.
Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.
Fibers and yarns are part of everyday life. So far, fibers that are also used pharmaceutically have mainly been produced by electrospinning. The common use of spinning oils and the excipients they contain, in connection with production by melt extrusion, poses a regulatory challenge for pharmaceutically usable fibers. In this publication, a newly developed small-scale direct-spinning melt extrusion system is described, and the pharmaceutically useful polyvinyl filaments produced with it are characterized. The major parts of the system were newly developed or extensively modified and manufactured cost-effectively within a short time using rapid prototyping (3D printing) from various materials. For example, a stainless-steel spinneret was developed in a splice design for a table-top melt extrusion system that can be used in the pharmaceutical industry. The direct processing of the extruded fibers was made possible by a spinning system developed called Spinning-Rosi, which operates continuously and directly in the extrusion process and eliminates the need for spinning oils. In order to prevent instabilities in the product, further modifications were also made to the process, such as a the moisture encapsulation of the melt extrusion line at certain points, which resulted in a bubble-free extrudate with high tensile strength, even in a melt extrusion line without built-in venting.
The absorption of drugs with narrow absorption windows in the upper small intestine can be improved with a mucoadhesive drug delivery system such as enteric films. To predict the mucoadhesive behaviour in vivo, suitable in vitro or ex vivo methods can be performed. In this study, the influence of tissue storage and sampling site on the mucoadhesion of polyvinyl alcohol film to human small intestinal mucosa was investigated. Tissue from twelve human subjects was used to determine adhesion using a tensile strength method. Thawing of tissue frozen at −20 °C resulted in a significantly higher work of adhesion (p = 0.0005) when a low contact force was applied for one minute, whereas the maximum detachment force was not affected. When the contact force and time were increased, no differences were found for thawed tissue compared to fresh tissue. No change in adhesion was observed depending on the sampling location. Initial results from a comparison of adhesion to porcine and human mucosa suggest that the tissues are equivalent.
Transmucosal drug delivery systems can be an attractive alternative to conventional oral dosage forms such as tablets. There are numerous in vitro methods to estimate the behavior of mucoadhesive dosage forms in vivo. In this work, a tensile test system was used to measure the mucoadhesion of polyvinyl alcohol films. An in vitro screening of potential influencing variables was performed on biomimetic agar/mucin gels. Among the test device-specific factors, contact time and withdrawal speed were identified as influencing parameters. In addition, influencing factors such as the sample area, which showed a linear relationship in relation to the resulting work, and the liquid addition, which led to an abrupt decrease in adhesion, could be identified. The influence of tissue preparation was investigated in ex vivo experiments on porcine small intestinal tissue. It was found that lower values of Fmax and Wad were obtained on processed and fresh tissue than on processed and thawed tissue. Film adhesion on fresh, unprocessed tissue was lowest in most of the animals tested. Comparison of ex vivo measurements on porcine small intestinal tissue with in vitro measurements on agar/mucin gels illustrates the inter- and intra-individual variability of biological tissue.
Abstract
Saliva is an attractive sampling matrix for measuring various endogenous and exogeneous substances but requires sample treatment prior to chromatographic analysis. Exploiting supercritical CO2 for both extraction and chromatography simplifies sample preparation, reduces organic solvent consumption, and minimizes exposure to potentially infectious samples, but has not yet been applied to oral fluid. Here, we demonstrate the feasibility and benefits of online supercritical fluid extraction coupled to supercritical fluid chromatography and single‐quadrupole mass spectrometry for monitoring the model salivary tracer caffeine. A comparison of 13C‐ and 32S‐labeled internal standards with external standard calibration confirmed the superiority of stable isotope‐labeled caffeine over nonanalogous internal standards. As proof of concept, the validated method was applied to saliva from a magnetic resonance imaging study of gastric emptying. After administration of 35 mg caffeine via ice capsule, salivary levels correlated with magnetic resonance imaging data, corroborating caffeine's usefulness as tracer of gastric emptying (R2 = 0.945). In contrast to off‐line methods, online quantification required only minute amounts of organic solvents and a single manual operation prior to online bioanalysis of saliva, thus demonstrating the usefulness of CO2‐based extraction and separation techniques for potentially infective biomatrices.
Development of Test Programs for the Biorelevant Characterization of Esophageal-Applied Dosage Forms
(2023)
In the local treatment of the esophageal mucosa, the retention time of the different dosage forms, such as tablets, films or liquids, is of high relevance for the effective treatment of diseases. Unfortunately, there are only few in vitro models describing the esophageal route of administration. To predict the behaviour of an esophageal-applied dosage form, it is necessary to simulate the site of application in a biorelevant way. The aim of this work was to develop two test setups for an esophageal peristalsis model which was described in a previous study. Different parameters such as flow rate, peristalsis, angle of inclination or mucous membrane were varied or introduced into the model. A stimulated and unstimulated modus were developed and tested with two different dosage forms. The time until the dosage form was cleared from the in vitro model was shorter with the stimulated than with the unstimulated modus. Also, esophageal-applied films had a prolonged transit time compared to a viscous syrup. The modification of the simulated esophageal surface made it possible to estimate the retention time of the dosage forms. It could be demonstrated that the residence time of a dosage form depends on different parameters affecting each other.
In recent years, the colon has become a hot topic in biopharmaceutical research as several in vitro models of the human colon have been presented. A major focus is on the characterization of the microbiota and its capabilities. The aim of the present study was to further develop the MimiCol, preserving its properties and accelerating data acquisition. Emphasis was placed on the simplicity of its design and easy scalability. To prove the viability of the concept, degradation of sulfasalazine was investigated, and the bacterial composition during the experiment was assessed by 16S rRNA sequencing. The transfer of the experimental conditions to the new model was successful. Commercially available components were implemented in the setup. The model MimiCol3 represented the colon ascendens satisfactorily in its properties regarding volume, pH value, and redox potential. 16S rRNA sequencing led to further insights into the bacterial composition in the vessels. Degradation of sulfasalazine was in good agreement with in vivo data. The new model of the colon ascendens MimiCol3 enabled us to collect more reliable data, as three experiments were conducted simultaneously under the same conditions.
The EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms
(2021)
An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release.