Despite poor absorption properties, delivery to the colon of bioactive compounds administered by the oral route has become a focus of pharmaceutical research over the last few decades. In particular, the high prevalence of Inflammatory Bowel Disease has driven interest because of the need for improved pharmacological treatments, which may provide high local drug concentrations and low systemic exposure. Colonic release has also been explored to deliver orally biologics having gut stability and permeability issues. For colon delivery, various technologies have been proposed, among which time-dependent systems rely on relatively constant small intestine transit time. Drug delivery platforms exploiting this physiological feature provide a lag time programmed to cover the entire small intestine transit and control the onset of release. Functional polymer coatings or capsule plugs are mainly used for this purpose, working through different mechanisms, such as swelling, dissolution/erosion, rupturing and/or increasing permeability, all activated by aqueous fluids. In addition, enteric coating is generally required to protect time-controlled formulations during their stay in the stomach and rule out the influence of variable gastric emptying. In this review, the rationale and main delivery technologies for oral colon delivery based on the time-dependent strategy are presented and discussed.

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.

Four-dimensional printing (4DP) is emerging as an innovative research topic. It involves the use of smart materials for three-dimensional printing (3DP) of items that change their shape after production, in a programmed way over time, when exposed to appropriate external non-mechanical stimuli (moisture, electric or magnetic fields, UV, temperature, pH or ion composition). In the performance of 4D printed devices, time is involved as the 4th dimension. 4D smart structures have been known for many years in the scientific literature, well before the advent of 3D printing, and the concepts of shape evolution as well as self-assembly have been applied to drug delivery at the nano-, micro- and macro-scale levels. The neologism "4DP" was coined by Tibbits, Massachusetts Institute of Technology, in 2013, who also showed the earliest examples of 4D printed objects. Since then, smart materials have often been combined with additive manufacturing, which makes production of complex shapes easy to achieve: going beyond 3DP, 4D printed items are no static objects. Two main categories of raw materials have been employed for 4DP: shape memory polymers (SMPs) and shape morphing hydrogels (SMHs). In principle, all types of 3D printers could be used for 4DP. In this article, examples of systems for use in the biomedical field, such as stents and scaffolds, and in drug delivery are reviewed, with special emphasis on indwelling devices for retention in the urinary bladder and in the stomach.