Enteric-Coated Capsules Providing Reliable Site-Specific Drug Delivery to the Distal Ileum.

Nefecon, a targeted-release capsule formulation of budesonide approved for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy, targets overproduction of galactose-deficient immunoglobulin A type 1 in the Peyer's patches at the gut mucosal level. To investigate whether the commercial formulation of Nefecon capsules reliably releases budesonide to the distal ileum, a human study was conducted with test capsules reproducing the delayed-release function of Nefecon capsules. Caffeine was included in the test capsules as a marker for capsule opening in the gut since it appears rapidly in saliva after release from orally administered dosage forms. Magnetic resonance imaging with black iron oxide was used to determine the capsule's position in the gut at the time caffeine was first measured in saliva and additionally to directly visualize dispersion of the capsule contents in the gut. In vitro dissolution results confirmed that the test capsules had the same delayed-release characteristics as Nefecon capsules. In 10 of 12 human volunteers, the capsule was demonstrated to open in the distal ileum; in the other two subjects, it opened just past the ileocecal junction. These results compared favorably with the high degree of variability seen in other published imaging studies of delayed-release formulations targeting the gut. The test capsules were shown to reliably deliver their contents to the distal ileum, the region with the highest concentration of Peyer's patches.

Is there a fast track ("Darmstrasse") for fluids in the small intestine? Evidence from magnetic resonance imaging.

BACKGROUND: The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the "Magenstrasse" (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects).

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.

Development of a Hot-Melt-Extrusion-Based Spinning Process to Produce Pharmaceutical Fibers and Yarns.

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 EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms.

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.