Advanced Drug Delivery Strategies for Inflammatory Bowel Disease

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of IBD affecting more than 10 million people worldwide. These are chronic and progressive conditions, characterised by destructive inflammation of the intestinal tract. With time, the intestinal wall in IBD patients becomes ‘leaky’, and harmful bacteria from the gut microbiota can enter the blood circulation, triggering an immune response and intensifying gut inflammation (Figure 1).

Symptoms of IBD include fever, anaemia, weight loss, diarrhoea, rectal bleeding, abdominal pain, and the urgency to evacuate the bowels. IBD is recognised to significantly impact the quality of life (QoL) of patients. Presently, IBD is not curable. Much effort has been made in developing therapeutic strategies for the treatment of IBD, aiming to reduce symptoms, maintain clinical and endoscopic remission, and prevent long-term disability. These therapies target the intensified inflammation process by decreasing the body’s immune response (i.e., immunomodulators azathioprine and methotrexate) or blocking the inflammation (i.e., biologics infliximab and ustekinumab). Despite the significant advancements in disease treatment, conventional drugs have major limitations such as severe adverse reactions (e.g., nausea, fever, higher risk of infections, diabetes) due to systemic absorption leading to therapy failure or ineffectiveness. Furthermore, a considerable proportion of IBD patients are unresponsive to the advanced therapies (biologics) or lose the response over the course of the disease. A study carried out by Gibble et al. revealed that over 60 percent of IBD patients responded inadequately to their first advanced therapies within 1 year after initiation. Consequently, over time, surgical removal of the inflamed bowel part is necessary. Approximately 23-45 percent of UC and up to 80 percent of CD patients will require colon surgery at some point during their disease.

The major challenge in developing IBD therapeutic strategies  is the delivery of therapeutics directly to the inflamed colon site. Traditional intestinal delivery systems are stimuli-responsive, meaning that drugs are released following certain stimuli, i.e., changes in pH, temperature, transit time, or presence of enzymes under healthy physiological conditions. However, these stimuli are different in IBD, and it is still unclear how they contribute to disease pathophysiology.

In recent years, a plethora of innovative strategies have been reported for the treatment of IBD, aiming to achieve site-specific drug delivery to the inflamed tissue, thereby reducing adverse drug effects and improving efficacy.

Enteric-coated microneedle pills

Initially developed for the transdermal delivery of small drug molecules and macromolecules, enteric-coated microneedle pills have gained attention in recent years as oral dosage forms. A research team at the Massachusetts Institute of Technology and Massachusetts General Hospital Harvard Medical School developed a capsule coated with drug-loaded microneedles capable of injecting drugs directly into the intestinal lining following ingestion (Figure 2).

Animal studies demonstrate that the dosage form delivered insulin more efficiently compared to subcutaneous administration with no harmful side-effects observed. The microneedle capsules safely passed and were excreted from the  gastrointestinal tract (GIT), making it suitable for use in the inflamed GIT in IBD. The incorporation of enteric coating onto microneedles enables the pills to protect incorporated drugs from the harsh acidic environment of the stomach and deliver them directly to the site where they are required. In a pre-clinical study, Rani Therapeutics tested anenteric-coated microneedle pill loaded with the TNF-αblocker adalimumab. The study results showed that the technology protects adalimumab from the acidic and enzymatic degradation of the GIT and directly delivers it to the site of inflammation, where it slowly releases the drug. In summary, enteric-coated microneedle pills represent a promising drug delivery strategy, especially biological compounds for the therapy of IBD. However, further rigorous research is necessary to evaluate their clinical long-term effectiveness and safety in the management of IBD.

Nano-delivery system strategies

Nanoparticulate (NP) systems represent a promising approach to delivering drugs to inflamed colonic tissues, thereby offering the advantage of reducing the drug dose and systemic side-effects. Macrophages, neutrophils, and M cells that are present in inflamed intestinal regions can easily take up the NPs due to their small size (1-100 nm). Triggered by inflammatory cytokines (e.g., TNF-α, IL-1α, IL-6), in the inflamed colon, the intestinal permeability is increased due to the loss of integrity of intestinal tight junctions, cell-to-cell contacts, and immune cell infiltration that is also referred to as ‘leaky gut’. The loss of intestinal integrity enables the NPs to easily penetrate mucosal tissues and transport drugs to the inflamed colon sites. The NPs can be designed to display distinctive attributes and physicochemical properties (size, surface charge, ligands, targeting moieties) that can contribute to the extended retention of drugs at inflammation sites due to, e.g., nanoparticle adhesion to mucus (Figure 3).

Over the past decade, considerable research efforts have been made to advance nano-delivery system strategies for the treatment of IBD. For example, a study by Ali et al revealed a significant accumulation of 3 nm poly(lactic-co-glycolic acid) (PLGA) NPs on the colonic mucosal surface in mice compared to 250 nm NPs. To date, the data obtained is predominantly based on in vitro, ex vivo tissue binding studies, or in vivo studies following rectal administration using animal models. To further evaluate the NP behaviour in humans, further comprehensive studies are necessary for a definitive conclusion.

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