Refine
Document Type
- Article (18)
Language
- English (18)
Has Fulltext
- yes (18)
Is part of the Bibliography
- no (18)
Keywords
- - (11)
- caffeine (3)
- salivary tracer technique (3)
- MRI (2)
- biorelevant in vitro model (2)
- colonic microbiota (2)
- dynamic colon model (2)
- in vitro metabolization (2)
- saliva (2)
- sulfasalazine (2)
- 3D printing (1)
- DUOCAP (1)
- FDM (1)
- GastroDuo (1)
- Germany (1)
- HPMC (1)
- LPS (1)
- MRI study (1)
- MimiCol (1)
- MimiCol3 (1)
- SLA 3D-printing (1)
- USP apparatus 4 (1)
- USP apparatus 7 (1)
- abomasum (1)
- acetaminophen (1)
- additive manufacturing (1)
- aspiration (1)
- biopharmaceutics (1)
- calves (1)
- capsule-in-capsule (1)
- carbon dioxide–based separation (1)
- clinical study (1)
- compression-coated tablet (1)
- continuous manufacturing (1)
- diarrhoea (1)
- diet (1)
- dissolution (1)
- dissolution methods (1)
- drug delivery (1)
- drug-eluting implant (1)
- ear canal stenosis (1)
- ease of swallowing (1)
- enteric hard capsule (1)
- eosinophilic esophagitis (1)
- esophageal diseases (1)
- esophageal transport (1)
- esophagus (1)
- esophagus therapy (1)
- ex vivo measurements (1)
- external auditory canal (1)
- fasted and fed state conditions (1)
- films (1)
- formulation design (1)
- gastric emptying (1)
- high-resolution manometry (1)
- hotmelt extrusion (1)
- human intestinal mucosa (1)
- hydroxypropyl methyl cellulose (1)
- hydroxypropyl methyl cellulose acetate succinate (1)
- imaging tools (1)
- in vitro drug release (1)
- in vitro model (1)
- in vitro–ex vivo correlation (1)
- in vivo (1)
- in vivo disintegration (1)
- in vivo study (1)
- indoleamine 2,3-dioxygenase (1)
- intestinal application (1)
- intravitreal implants (1)
- kynurenine pathway (1)
- local drug targeting (1)
- magnetic marker monitoring (1)
- magnetic resonance imaging (1)
- manufacturing science (1)
- materials science (1)
- methyltryptophan (1)
- mini tablets (1)
- mucoadhesion (1)
- mucoadhesive films (1)
- mucoadhesive polymer (1)
- online sample preparation (1)
- oral rehydration solution (1)
- pediatrics (1)
- peristalsis (1)
- personalized implant (1)
- pharmacokinetics (1)
- pig (1)
- porcine small intestine (1)
- preoperative workflow (1)
- propranolol HCl (1)
- saliva flow (1)
- salivary tracer (1)
- scintigraphy (1)
- site-specific application (1)
- site-specific drug delivery (1)
- spinning process (1)
- stable isotope (1)
- supercritical fluid chromatography (1)
- supercritical fluid extraction (1)
- telemetric capsules (1)
- tensile studies (1)
- triamcinolone acetonide (1)
- user perspective (1)
- vitreous substitute (1)
Institute
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.
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.
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.
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.
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.
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.
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.
: An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased
mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be
a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT)
is currently in the interest of research due to its potential inhibitory effects on IDO1 and
immunomodulatory properties. The present study aims to investigate the protective and
immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine
in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan
(TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite
kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils
and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP
to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that
degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide
no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven
interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be
considered for therapeutic applications of 1-MT.
Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear canal implant (EECI) as a postoperative stent after canaloplasty. We designed and pre-clinically tested this novel implant for drug release (by high-performance liquid chromatography), biocompatibility (by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay), bio-efficacy (by the TNF-α (tumor necrosis factor-alpha)-reduction test (DEX) and inhibition zone test (for cipro)), and microbial contamination (formation of turbidity or sediments in culture medium). The EECI was implanted for the first time to one patient with a history of congenital EEC atresia and state after three canaloplasties due to EEC restenosis. The preclinical tests revealed no cytotoxic effect of the used materials; an antibacterial effect was verified against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa, and the tested UV-irradiated EECI showed no microbiological contamination. Based on the test results, the combination of silicone with 1% DEX and 0.3% cipro was chosen to treat the patient. The EECI was implantable into the EEC; the postoperative follow-up visits revealed no otogenic symptoms or infections and the EECI was explanted three months postoperatively. Even at 12 months postoperatively, the EEC showed good epithelialization and patency. Here, we report the first ever clinical application of an individualized, drug-releasing, mechanically flexible implant and suggest that our novel EECI represents a safe and effective method for postoperatively stenting the reconstructed EEC.
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.
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.
Many orally dosed APIs are bioavailable only when formulated as an enteric dosage form to protect them from the harsh environment of the stomach. However, an enteric formulation is often accompanied with a higher development effort in the first place and the potential degradation of fragile APIs during the coating process. Ready-to-use enteric hard capsules would be an easily available alternative to test and develop APIs in enteric formulations, while decreasing the time and cost of process development. In this regard, Lonza Capsugel® Next Generation Enteric capsules offer a promising approach as functional capsules. The in vivo performance of these capsules was observed with two independent techniques (MRI and caffeine in saliva) in eight human volunteers. No disintegration or content release in the stomach was observed, even after highly variable individual gastric residence times (range 7.5 to 82.5 min), indicating the reliable enteric properties of these capsules. Seven capsules disintegrated in the distal part of the small intestine; one capsule showed an uncommonly fast intestinal transit (15 min) and disintegrated in the colon. The results for this latter capsule by MRI and caffeine appearance differed dramatically, whereas for all other capsules disintegrating in the small intestine, the results were very comparable, which highlights the necessity for reliable and complementary measurement methods. No correlation could be found between the gastric residence time and disintegration after gastric emptying, which confirms the robust enteric formulation of those capsules.
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.
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.
Abomasal emptying rate of diarrhoeic and healthy suckling calves fed with oral rehydration solutions
(2020)
Abstract
The aim of the study was to determine the abomasal emptying rate (AER) of calves suffering from naturally occurring diarrhoea compared with that of healthy calves. Furthermore, the effects of an oral rehydration solution (ORS) mixed into milk replacer on the AER were determined. Acetaminophen absorption test (APAT) was performed to estimate the AER. Sixty Holstein–Frisian calves (age < 14 days) were included in the study and divided into groups as follows: healthy calves (H; n = 16), healthy calves fed with ORS (HORS; n = 14), diarrhoeic calves (D; n = 15) and diarrhoeic calves fed with ORS (DORS; n = 15). For the APAT, the calves were fed 2 L of milk replacer containing 50 mg acetaminophen (AP)/kg body weight. Venous blood samples were collected before and after milk replacer and AP intake in 30–60 min intervals for 12 hr. During the APAT, no significant differences in median maximum acetaminophen concentration (Cmax) were observed among all groups. Time to reach maximum acetaminophen concentration (Tmax) in DORS (median 390 min, 25/75 quartiles: 300/480 min) was significantly higher compared with that in H (median: 270 min 25/75 quartiles: 210/315 min) and HORS (median: 300 min (25/75 quartiles: 240/360 min). Non‐linear regression revealed that the calculated abomasal half‐life (AP t1/2) tended to be delayed in DORS (median: 652 min, 25/75 quartiles: 445/795 min, p = .10). The area under the AP curve values (AUC) from 0 to 120 min and 0 to 240 min of the observation period were significantly higher in H than D and DORS. In conclusion, significant differences in the AER indices reflected delayed abomasal emptying in diarrhoeic calves. Furthermore, the hypertonic ORS tended to have an additive delaying impact on the AER, which needs attention for the feeding management of diarrhoeic calves.