The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, entailing a gastroresistant film to prevent early interaction of the inner coat with gastric fluids and enabling the attainment of a lag phase matching the small intestinal transit time. Over the years, various multiple-step manufacturing processes have been tested for the fabrication of the Chronotopic™ system in both its configurations. This work focused on the evaluation of 3D printing by fused deposition modeling in view of its potential towards product personalization, on demand one-step manufacturing and efficient scale down of batches. The feasibility of each part of the Chronotopic™ system was independently investigated starting from in-house made filaments, characterizing the resulting specimens for physico-technological and performance characteristics. The printing parameters identified as suitable during the set-up phase were then used to fabricate prototypes either in a single step for the pulsatile configuration or following two different fabrication approaches for the colon-targeting one.

A new type of colon targeting system is presented, combining time-controlled and enzyme-triggered approaches. Empty capsule shells were prepared by injection molding of blends of a high-amylose starch and hydroxypropyl methylcellulose (HPMC) of different chain lengths. The dissolution/erosion of the HPMC network assures a time-controlled drug release, i.e., drug release starts upon sufficient shell swelling/dissolution/erosion. In addition, the presence of high-amylose starch ensures enzyme-triggered drug release. Once the colon is reached, the local highly concentrated bacterial enzymes effectively degrade this polysaccharide, resulting in accelerated drug release. Importantly, the concentration of bacterial enzymes is much lower in the upper gastrointestinal tract, thus enabling site-specific drug delivery. The proposed capsules were filled with acetaminophen and exposed to several aqueous media, simulating the contents of the gastrointestinal tract using different experimental setups. Importantly, drug release was pulsatile and occurred much faster in the presence of fecal samples from patients. The respective lag times were reduced and the release rates increased once the drug started to be released. It can be expected that variations in the device design (e.g., polymer blend ratio, capsule shell geometry and thickness) allow for a large variety of possible colon targeting release profiles.

Retentive drug delivery systems (DDSs) are intended for prolonged residence and release inside hollow muscular organs, to achieve either local or systemic therapeutic goals. Recently, formulations based on shape memory polymers (SMPs) have gained attention in view of their special ability to recover a shape with greater spatial encumbrance at the target organ (e.g., urinary bladder or stomach), triggered by contact with biological fluids at body temperature. In this work, poly(vinyl alcohol) (PVA), a pharmaceutical-grade SMP previously shown to be an interesting 4D printing candidate, was employed to fabricate expandable organ-retentive prototypes by hot melt extrusion. With the aim of improving the mechanical resistance of the expandable DDS and slowing down relevant drug release, the application of insoluble permeable coatings based on either Eudragit^® RS/RL or Eudragit^® NE was evaluated using simple I-shaped specimens. The impact of the composition and thickness of the coating on the shape memory, swelling, and release behavior as well as on the mechanical properties of these specimens was thoroughly investigated and the effectiveness of the proposed strategy was demonstrated by the results obtained.

This paper focuses on recent advancements in the development of 4D printed drug delivery systems (DDSs) for the intravesical administration of drugs. By coupling the effectiveness of local treatments with major compliance and long-lasting performance, they would represent a promising innovation for the current treatment of bladder pathologies. Being based on a shape-memory pharmaceutical-grade polyvinyl alcohol (PVA), these DDSs are manufactured in a bulky shape, can be programmed to take on a collapsed one suitable for insertion into a catheter and re-expand inside the target organ, following exposure to biological fluids at body temperature, while releasing their content. The biocompatibility of prototypes made of PVAs of different molecular weight, either uncoated or coated with Eudragit^®-based formulations, was assessed by excluding relevant in vitro toxicity and inflammatory response using bladder cancer and human monocytic cell lines. Moreover, the feasibility of a novel configuration was preliminarily investigated, targeting the development of prototypes provided with inner reservoirs to be filled with different drug-containing formulations. Samples entailing two cavities, filled during the printing process, were successfully fabricated and showed, in simulated urine at body temperature, potential for controlled release, while maintaining the ability to recover about 70% of their original shape within 3 min.

Film-coating is widely applied in pharmaceutics to enhance aspect/taste and mechanical properties of dosage forms, to protect them from the environment and to modify their release performance. In this respect, a film-coating process was recently involved in the development of 4D printed prolonged-release systems intended for organ retention. During coating processes, liquid formulations are sprayed onto moving cores, whose shape, weight and surface characteristics are essential to attain a homogeneous film. Devices of complex shapes, composed of smart materials and fabricated by hot-processing techniques, such as extrusion and fused deposition modeling 3D printing, might be poorly compatible with the requirements of traditional coating methods, e.g., need for spherical substrates with smooth surface and stable under process temperatures. This work was aimed at evaluating, at a small scale level, the feasibility of a versatile equipment for film-coating of rod-shaped extruded and printed prototypes with different section. Equipment design and set up of process parameters were performed starting from polymeric solutions and suspensions and selecting as cores 50 mm-long rod-shaped samples based on shape memory poly(vinyl alcohol). Integrity and thickness of the applied layer and its impact on shape memory and release performance of prototypes were investigated.