Understanding the Interaction of Thermal, Rheological, and Mechanical Parameters Critical for the Processability of Polyvinyl Alcohol-Based Systems during Hot Melt Extrusion.

Hot melt extrusion (HME) is a common manufacturing process used in the pharmaceutical industry to improve the solubility of poorly soluble active pharmaceutical ingredients (API). The goal is to create an amorphous solid dispersion (ASD) where the amorphous form of the API is stabilized within a polymer matrix. Traditionally, the development of pharmaceutically approved polymers has focused on requirements such as thermal properties, solubility, drug-polymer interactions, and biocompatibility. The mechanical properties of the material have often been neglected in the design of new polymers. However, new downstream methods require more flexible polymers or suitable plasticizer polymer combinations. In this study, two grades of the polymer polyvinyl alcohol (PVA), which is already established for HME, are investigated in terms of their mechanical, rheological, and thermal properties. The mechanical properties of the extruded filaments were tested by the three-point bending test. The rheological behavior was analyzed by oscillating plate measurements. Thermal analysis was performed by differential scanning calorimetry (DSC). In addition, the solid and liquid plasticizers mannitol, sorbitol, triacetin, triethyl citrate, polyethylene glycol, and glycerol were evaluated for use with PVA and their impact on the polymer properties was elaborated. Finally, the effects of the plasticizers are compared to each other, and the correlations are analyzed statistically using principal component analysis (PCA). Thereby, a clear ranking of the plasticizer effects was established, and a deeper understanding of the polymer-plasticizer interactions was created.

Determination of Gastric Water Emptying in Fasted and Fed State Conditions Using a Compression-Coated Tablet and Salivary Caffeine Kinetics.

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.

Influence of Different Diets on the Degradation of Sulfasalazine by Colon Bacteria Determined Using MimiCol3.

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.

Determination of Sugars and Acids in Grape Must Using Miniaturized Near-Infrared Spectroscopy.

An automatic determination of grape must ingredients during the harvesting process would support cellar logistics and enables an early termination of the harvest if quality parameters are not met. One of the most important quality-determining characteristics of grape must is its sugar and acid content. Among others, the sugars in particular determine the quality of the must and wine. Chiefly in wine cooperatives, in which a third of all German winegrowers are organized, these quality characteristics serve as the basis for payment. They are acquired upon delivery at the cellar of the cooperative or the winery and result in the acceptance or rejection of grapes and must. The whole process is very time-consuming and expensive, and sometimes grapes that do not meet the quality requirements for sweetness, acidity, or healthiness are destroyed or not used at all, which leads to economic loss. Near-infrared spectroscopy is now a widely used technique to detect a wide variety of ingredients in biological samples. In this study, a miniaturized semi-automated prototype apparatus with a near-infrared sensor and a flow cell was used to acquire spectra (1100 nm to 1350 nm) of grape must at defined temperatures. Data of must samples from four different red and white Vitis vinifera (L.) varieties were recorded throughout the whole growing season of 2021 in Rhineland Palatinate, Germany. Each sample consisted of 100 randomly sampled berries from the entire vineyard. The contents of the main sugars (glucose and fructose) and acids (malic acid and tartaric acid) were determined with high-performance liquid chromatography. Chemometric methods, using partial least-square regression and leave-one-out cross-validation, provided good estimates of both sugars (RMSEP = 6.06 g/L, R2 = 89.26%), as well as malic acid (RMSEP = 1.22 g/L, R2 = 91.10%). The coefficient of determination (R2) was comparable for glucose and fructose with 89.45% compared to 89.08%, respectively. Although tartaric acid was predictable for only two of the four varieties using near-infrared spectroscopy, calibration and validation for malic acid were accurate for all varieties in an equal extent like the sugars. These high prediction accuracies for the main quality determining grape must ingredients using this miniaturized prototype apparatus might enable an installation on a grape harvester in the future.

Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine.

Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process.

3D Printing of Paracetamol Suppositories: An Automated Manufacturing Technique for Individualized Therapy.

Pharmaceutical compounding using the molding technique is the currently applied method for the on-demand manufacturing of suppositories and pessaries. Potential errors of this method are difficult to detect, and the possibilities of individualization of size and shape of the suppositories are limited. In this study, a syringe-based semi-solid 3D printing technique was developed for the manufacturing of suppositories in three different printing designs with the suppository bases polyethylene glycol (PEG) and hard fat (HF). The 3D printed suppositories were analyzed for their visual appearance, uniformity of mass and content, diametrical dimension, breaking force and release behavior and compared to suppositories of the same composition prepared by a commonly used molding technique. The results showed no adverse properties for the 3D printed suppositories compared to the molded ones. Moreover, the easy adaptation of shape using the 3D printing technique was demonstrated by the printing of different sizes and infill structures. Thus, 3D printing has great potential to complement the available manufacturing methods for compounded suppositories, as it represents an automated system for the individualized manufacturing of suppositories that meet patients' needs.

Characterization of an In Vitro/Ex Vivo Mucoadhesiveness Measurement Method of PVA Films.

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.

4D prints of flexible dosage forms using thermoplastic polyurethane with hybrid shape memory effect.

Thermoplastic polyurethanes are versatile materials due to their flexible and elastic properties. In research, medicine, and pharmacy, they are used in dosage forms, implants or as components of medical devices. To gain a deeper understanding of the influences on unfolding or expanding dosage forms, in this publication, 3D printing was used to produce differently shaped and foldable objects from various technical thermoplastic polyurethane filaments. The shape memory behaviour of the dosage forms was exploited to fold and package them in water-soluble hard gelatin capsules. The unfolding time and dimensional recovery of the 3D printed dosage forms were investigated as a function of material properties and shape. As an example, for the use of flexible dosage forms, 3D models have been designed so that their unfolded size is suitable for possible gastric retention. Depending on the shape and material, different unfolding behaviours could be shown. Over a storage period of 60 days, a time related stress on the 4D printed objects was evaluated, which possibly affects the unfolding process. The results of this work aim to be used to evaluate the behaviour of 3D printed unfolding and expanding dosage forms and how they may be suitable for the development of innovative sustained drug delivery concepts or medicinal devices. The basic principle of a hybrid shape memory effect used here could possibly be applied to other drug delivery strategies besides gastric retention.

An Advanced Bioreactor Simulating Dynamic Physiological Conditions in the Human Ascending Colon: MimiCol3.

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 challenges of drug delivery to the esophagus and how to overcome them.

INTRODUCTION: The incidence of esophageal diseases such as eosinophilic esophagitis, gastroesophageal reflux disease, or esophageal carcinoma has increased significantly in recent years. There is a lack of suitable therapeutic options to enable effective therapy. AREAS COVERED: This review addresses the challenges of drug targeting to the esophagus. It describes the physiology of the esophagus, physiological parameters relevant for drug targeting and the pathophysiology of selected diseases of the esophagus. Furthermore, conventional dosage forms such as glucocorticoid-containing solutions or suspensions, inhaler devices and orodispersible tablets are discussed. Innovative drug delivery systems such as stents, mucoadhesive films and 3D printed devices are also presented. EXPERT OPINION: Drug delivery to the esophagus presents challenges, especially in terms of the short transit time and the rapid clearance. While conventional dosage forms such as solutions or suspensions offer the advantage of being available quickly and patient-specific, innovative drug delivery systems address the problem of the short transit time and can thus enable long-lasting exposure.

Establishment of a Dissolution Test System for the Biorelevant Characterization of Esophageal Applied Dosage Forms.

There is a high demand for drug delivery systems that enable local therapy of esophageal diseases such as eosinophilic esophagitis. For the development of such drug delivery systems, suitable in vitro test procedures are needed that allow a biorelevant characterization of dosage forms. With the help of the new test system presented in this thesis it is now possible to simulate the application site esophagus and to characterize the dissolution behavior of esophageal applied drug delivery systems under special consideration of physiological parameters like salivary flow rate, intensity of peristalsis, and posture of the patient. In this work, the dissolution of mucoadhesive films for esophageal application with the new device was investigated and compared to the results obtained with the compendial standard device (USP 2 apparatus). The results show that the novel test system is a promising tool for the early evaluation of locally applied oral formulations for esophageal application.

Functionality and Acceptance of the EsoCap System-A Novel Film-Based Drug Delivery Technology: Results of an In Vivo Study.

There are no methods for specific local application of active substances to the mucosa of the esophagus to treat eosinophilic esophagitis or other esophageal diseases. This publication describes the principal in vivo functionality and acceptance of a novel modular drug delivery concept, called EsoCap system, by 12 healthy volunteers. For the first time, the EsoCap system enables targeted placement on the esophageal mucosa of a mucoadhesive polymer film. Acceptance was determined by means of a standardized questionnaire after administration and functionality of the device by MRI scans. Two different setups of the EsoCap system were tested: one setup with a density of 0.4 g/cm3 and one with a density of 1.0 g/cm3. Acceptability of the dosage form was also confirmed in addition to functionality, by measuring the applied film length. It was found that acceptance of the variant with the higher density was significantly better. This novel drug delivery technology could enable a targeted, local and long-lasting therapy of the esophagus for the first time, depending on the polymer film used.

SmartSpectrometer-Embedded Optical Spectroscopy for Applications in Agriculture and Industry.

The ongoing digitization of industry and agriculture can benefit significantly from optical spectroscopy. In many cases, optical spectroscopy enables the estimation of properties such as substance concentrations and compositions. Spectral data can be acquired and evaluated in real time, and the results can be integrated directly into process and automation units, saving resources and costs. Multivariate data analysis is needed to integrate optical spectrometers as sensors. Therefore, a spectrometer with integrated artificial intelligence (AI) called SmartSpectrometer and its interface is presented. The advantages of the SmartSpectrometer are exemplified by its integration into a harvesting vehicle, where quality is determined by predicting sugar and acid in grapes in the field.

Influence of the geometry of 3D printed solid oral dosage forms on their swallowability.

3D printing can be used to realise a wide variety of geometries of oral dosage forms. In this work, the swallowability of 3D-printed dosage forms with comparable size and different shape using fused deposition modelling (FDM) from isomalt was investigated in a controlled, randomised crossover study design. To produce the required number of dosage forms, a commercial 3D printer was modified with regard to product safety and production time. The modifications carried out permit the printing of 4 pharmaceutical forms simultaneously as well as the printing of rigid filaments. Six 3D-printed placebo objects and two compressed placebo reference objects were tested by 12 subjects in a blinded design. A questionnaire was used to assess swallowability, foreign body sensation at the moment of swallowing, persistent foreign body sensation after swallowing and pain after swallowing. Furthermore, the amount of additional water drunk after administration was documented. With the modified printer, the required 576 test objects could be printed within a few days with good reproducibility. In all questions, the best results were obtained for the printed and compressed oblong tablets, followed by the printed and compressed round tablets, the football and the sphere. The worst results were obtained for the pyramid closely followed by the cuboctahedron. The study shows that the variety of shapes of oral dosage forms made possible by 3D printing needs to be tested in swallowability studies, as not every shape is also easy to swallow.

Mimicking the dynamic Colonic microbiota in vitro to gain a better understanding on the in vivo metabolism of xenobiotics: Degradation of sulfasalazine.

Due to the potential effects of colonic metabolism, the interest in the composition and action of intestinal microbiota has increased significantly throughout the last 10 years. Recently focus is turning to the development and implementation of in vitro tools closely simulating in vivo colonic metabolic processes suitable for routine use. The aim of the present study is to compare the metabolization of the model drug sulfasalazine utilizing the novel dynamic bioreactor MimiCol and a standard static batch fermenter inoculated with cryopreserved faecal microbiota. Major advantages of the novel bioreactor MimiCol are the smaller media volume which is closer to in vivo conditions, the possibility to perform media changes and the closer simulation of in vivo mixing patterns. The study proved that the MimiCol is able to simulate the dynamic conditions found within the ascending colon. The dynamic conditions within the MimiCol led to an almost 2-fold increase of the metabolization rate constant in comparison to the static batch fermenter. Our study was able to prove that the novel dynamic bioreactor MimiCol is able to closely simulate physiologically relevant conditions.

3D Printing of Mini Tablets for Pediatric Use.

In the treatment of pediatric diseases, suitable dosages and dosage forms are often not available for an adequate therapy. The use of innovative additive manufacturing techniques offers the possibility of producing pediatric dosage forms. In this study, the production of mini tablets using fused deposition modeling (FDM)-based 3D printing was investigated. Two pediatric drugs, caffeine and propranolol hydrochloride, were successfully processed into filaments using hyprolose and hypromellose as polymers. Subsequently, mini tablets with diameters between 1.5 and 4.0 mm were printed and characterized using optical and thermal analysis methods. By varying the number of mini tablets applied and by varying the diameter, we were able to achieve different release behaviors. This work highlights the potential value of FDM 3D printing for the on-demand production of patient individualized, small-scale batches of pediatric dosage forms.

Handheld Spectral Sensing Devices Should Not Mislead Consumers as Far as Non-Authentic Food Is Concerned: A Case Study with Adulteration of Milk Powder.

With the rising trend of consumers being offered by start-up companies portable devices and applications for checking quality of purchased products, it appears of paramount importance to assess the reliability of miniaturized sensors embedded in such devices. Here, eight sensors were assessed for food fraud applications in skimmed milk powder. The performance was evaluated with dry- and wet-blended powders mimicking adulterated materials by addition of either ammonium sulfate, semicarbazide, or cornstarch in the range 0.5-10% of profit. The quality of the spectra was assessed for an adequate identification of the outliers prior to a deep assessment of performance for both non-targeted (soft independent modelling of class analogy, SIMCA) and targeted analyses (partial least square regression with orthogonal signal correction, OPLS). Here, we show that the sensors have generally difficulties in detecting adulterants at ca. 5% supplementation, and often fail in achieving adequate specificity and detection capability. This is a concern as they may mislead future users, particularly consumers, if they are intended to be developed for handheld devices available publicly in smartphone-based applications.

In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery.

In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or Cmax compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol Cmax and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate.

The EsoCap-system - An innovative platform to drug targeting in the esophagus.

For the therapy of esophageal diseases such as eosinophilic esophagitis, there are no possibilities of local targeted therapy. This publication describes a novel, innovative drug delivery concept, that enables a targeted, long-lasting administration of drug substances to the esophageal mucosa. In addition to a comprehensive in-vitro characterization of the dosage form, this work includes a proof-of-concept study with healthy volunteers, which shows the functionality and acceptance of this novel drug delivery concept. This novel drug delivery technology enables for the first time a targeted, local and long-lasting therapy of the esophagus.

Design and characterization of a novel 3D printed pressure-controlled drug delivery system.

The aim of the present work was to explore the feasibility of 3D printing via fused deposition modeling (FDM) in the manufacturing of a pressure-controlled drug delivery system. Eudragit® RS, a brittle polymer with pH-independent solubility, was chosen to be a suitable excipient for the 3D printing of a pressure-sensitive, capsule-like dosage form. A self-constructed piston extruder was used for hot melt extrusion (HME) of filaments made from Eudragit® RS that could be used for 3D printing. Subsequently, the printing parameters were experimentally optimized with the aid of a self-programmed software. This G-code generator allowed the simple adjustment of printing speed, temperature, extrusion multiplier and layer height. By this, capsule-shaped dosage forms with the desired mechanical properties could be obtained. The effect of physiological pressure events on the drug release behaviour from the novel dosage form was finally tested by using a biorelevant stress test device. These in vitro experiments demonstrated the rapid and quantitative release of the probe drug after applying realistic pressure events. This work illustrated that 3D printing can be an interesting technique for the production of pressure-controlled dosage forms as a new concept of oral drug delivery.