State-of-the-Art and Future Perspectives in Ingestible Remotely Controlled Smart Capsules for Drug Delivery: A GENEGUT Review

An emerging concern globally, particularly in developed countries, is the rising prevalence of Inflammatory Bowel Diseases (IBDs), such as Crohn’s disease. Oral delivery technologies that can release the active therapeutic cargo specifically at selected sites of inflammation offer great promise to maximise treatment outcomes and minimise off target effects. Therapeutic strategies for IBD have expanded in recent years, with an increasing focus on biologic and nucleic acid-based therapies. Reliable site-specific delivery in the gastrointestinal (GI) tract is particularly crucial for these therapeutics to ensure sufficient concentrations in the targeted cells. Ingestible smart capsules hold great potential for precise drug delivery. Despite previous unsuccessful endeavours to commercialise drug delivery smart capsules, the current rise in demand and recent advancements in component development, manufacturing, and miniaturisation have reignited interest in ingestible devices. Consequently, this review analyses the advancements in various mechanical and electrical components associated with ingestible smart drug delivery capsules. These components include modules for device localisation, actuation and retention within the GI tract, signal transmission, drug release, power supply, and payload storage. Challenges and constraints associated with previous capsule design functionality are presented, followed by a critical outlook on future design considerations to ensure efficient and reliable site-specific delivery for the local treatment of GI disorders.

Introduction

Inflammatory Bowel Diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal (GI) tract that occur in a recurring and remitting pattern (Baldan-Martin et al., 2023). It is estimated that approximately 2.5–3 million individuals in Europe were affected by IBDs in 2022 (Kumar et al., 2023). More specifically, Crohn’s disease has an incidence rate in Western Europe, estimated to be between 1.85 and 10.5 cases per 100,000 person-years (Kumar et al., 2023; Ng et al., 2017). Hence, IBDs impose a substantial financial burden on the healthcare system, with an average cost of 2’609€ per patient-year (Burisch et al., 2020; Kumar et al., 2023). Current IBD therapeutics can be classified into two main categories: non-biologic and biologic. The initial treatment phase typically involves an induction therapy with oral or systemic corticosteroids, such as budesonide, or biologics to achieve remission of the inflammatory process (Roda et al., 2020). Corticosteroids are not recommended for maintenance therapy due to the potential for adverse effects, such as hypertension, associated with prolonged exposure (Torres et al., 2017). The subsequent maintenance phase may employ a range of immunosuppressant therapies, including non-biologic agents like methotrexate or azathioprine, or biologics such as anti-tumour necrosis factor (anti-TNF) therapies (infliximab, adalimumab, and certolizumab pegol) or ustekinumab, or a combination of these (Roda et al., 2020). Moreover, it is anticipated that therapies based on orally administered nucleic acids will offer a promising avenue for the treatment of IBD in the future. Anti-TNF therapies are the primary treatment option for high-risk patients due to their high potency, substantial clinical experience, and low incidence of adverse events (Roda et al., 2020; Torres et al., 2017). However, it has been observed that approximately one-third of Crohn’s disease patients treated with TNF-α inhibitors demonstrate non-adherence (Fidder et al., 2013), which may be associated with the invasive method of administration. Despite the availability of these therapeutic options, IBD has a significant impact on a patient’s social, educational, professional and familial life. This is due to a number of factors, including the symptoms of the disease itself, such as abdominal discomfort, diarrhoea and weight loss, as well as the frequently associated immunosuppressive therapy, hospitalisation and surgery (Roda et al., 2020). Up to 50% of patients with Crohn’s disease require bowel resection within 10 years of diagnosis due to complications associated with the disease (Roda et al., 2020).

In IBD, inflammation may occur in different regions of the GI tract, with the terminal ileum and colon being the most commonly affected areas (Torres et al., 2017). A key approach to improve IBD therapy is therefore the implementation of site-specific drug release at disease locations in the GI tract. The overall exposure of the drug to the systemic circulation can be decreased, while concurrently enhancing its concentration at the desired target site. Thereby, therapeutic efficacy of the treatment can be optimised, while mitigating any potential negative effects. The renewed scientific interest in RNA therapy in recent years (Kim, 2022) has contributed to the demand for site-specific delivery. Particularly for orally administered nucleic acid-based therapies achieving a substantial concentration at the intended site of action is crucial, as the accessibility to the afflicted cells is limited (Hua, 2020; O’Driscoll et al., 2019). Consequently, site-specific drug delivery in the GI tract has become a major objective for the treatment of intestinal diseases. Numerous methodologies have been previously explored in the field of site-specific administration, encompassing prodrugs as well as conventional coatings that rely on factors such as pH alterations, transit time, microbiota, and various combinations thereof (see Tab. 1) (Varum et al., 2020a, 2020b; Yadav et al., 2022). One significant concern of these traditional approaches pertains to the intra- and inter-individual variations in terms of physiological parameters which have resulted in insufficient release from drug delivery systems in previous studies (Ibekwe et al., 2006; Yu et al., 2017). Moreover, it is important to acknowledge that particularly IBD patients, may exhibit deviations from the composition and properties of GI fluids when compared to those of healthy individuals that have the potential to influence the efficacy of drug delivery systems. The potential modifications encompass changes in the pH of the chyme, the size of the accessible bile acid pool, and the composition of the microbiome. These changes are largely dependent on the severity of inflammation (Chikina and Matic Vignjevic, 2021; Effinger et al., 2020; Guo et al., 2022; Roda et al., 2020).

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Table 1: Overview of various strategies employed for the targeted treatment of gastrointestinal (GI) diseases with advantages, disadvantages, and examples; GRAS, generally recognized as safe

Strategy	Advantages	Disadvantages	Examples
pH-dependent polymer coatings	○ Applicable for a wide range of drugs ○ GRAS ingredients	○ Inter- and intraindividual variabilities in pH levels ○ No patient-specific customisation	Eudragit® S, Eudragit® L, Eudragit® FS 30 D, ColoPulse, Duocoat®, CODESTM, Phloral®, OPTICORET
Microbiota-dependent polymer coatings	○ Applicable for a wide range of drugs ○ GRAS ingredients ○ Fibre fermentation function highly conserved in the microbiome	○ Inter- and intraindividual variabilities in microbiome composition ○ No patient-specific customisation	Pectin, guar gum, chitosan, resistant starch, COLALTM, Phloral®, OPTICORETM
Time-dependent polymer coatings	○ Applicable for a wide range of drugs ○ GRAS ingredients	○ Inter- and intraindividual variabilities in transit times ○ No patient-specific customisation	Eudragit® RS 100, Eudragit® RL 100, CODESTM, Chronotropic
Prodrugs	○ Successfully used for almost a century	○ Allergic reactions and adverse events ○ Drug-specific design and therefore lengthy development ○ More complicated market entry as a novel drug	Sulfasalazine, olsalazine, 5-aminosalicylic acid-p-aminobenzyl alcohol-diamine system
Smart capsules	○ Applicable for a wide range of drugs ○ Market entry as a medical device ○ Interaction with the user ○ Complete remote control of point of release ○ Additional features such as sensing ○ Independence from inter- and intraindividual variabilities	○ Insufficient release of particulate formulations and in the colon reported ○ Difficulties with remote capsule activation ○ Substantial dimension and therefore issues with retention ○ Potential toxicity problems related to batteries ○ Lack of sustainability ○ Expensive production	InteliSite®, EnterionTM, IntelliCap®

 

Sophia V. Hoffmann, Joseph P. O’Shea, Paul Galvin, Vincent Jannin, Brendan T. Griffin, State-of-the-Art and Future Perspectives in Ingestible Remotely Controlled Smart Capsules for Drug Delivery: A GENEGUT Review, European Journal of Pharmaceutical Sciences, 2024, 106911, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106911.

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