Microbiota-sensitive drug delivery systems based on natural polysaccharides for colon targeting

Inflammatory bowel disease (IBD) is characterized by recurrent episodes of inflammation of the GIT, with periods of remission from symptoms, such as abdominal pain, rectal bleeding, unintentional weight loss, and diarrhea. IBD affects more than 3 million people across Europe and North America.

Although the causes of IBD are not yet fully understood,¹ recent research suggests that persistent intestinal inflammation resulting from inappropriate immune responses caused by interactions between genetic factors, gut microbiota, and environmental factors, are involved. Unfortunately, treatment of the diseased colon, IBD, as well as colon cancer via the oral route is difficult because most drugs are absorbed or denatured (e.g., protein and polypeptide-based drugs) in the upper GIT before reaching the colon, causing adverse effects. Thus, different approaches to improve colon drug targeting have been developed, including pH-dependent and time-dependent systems. Another interesting approach is the use of the metabolic potential of the unique microbiota community in the human colon. This strategy has been used to split prodrugs into their active components, such as sulfasalazine by colonic azoreductase activity into 5-aminosalicylic acid (5-ASA), the active compound, and sulfapyridine.² A larger metabolic potential exists regarding polysaccharidic breakdown specific to the colonic microbiota ecosystem. Colon targeting might also be useful for the local or systemic treatment of extra-intestinal diseases with fragile biological drugs because of the increased surface area available for drug resorption and decreased metabolic activity.

Most of these approaches are based on polymeric matrices or reservoir systems using film-forming polymers. In both cases, the macromolecular networks should ideally be impermeable to the drug in the upper GIT but permeable once in the distal GIT. To provide such specific drug delivery, the technology can: (i) be sensitive to changes in the pH gradient along the GIT; (ii) be degraded by the microbiota enzymes; or (iii) undergo swelling or/and erosion once the distal portion of GIT is reached.

Recently, novel polymeric film coatings have been developed, allowing colon targeting under the pathophysiological conditions seen in patients with IBD. Several parameters of thin polymeric films have been investigated upon exposure to release media simulating the entire GIT. Desired membrane properties, such as enhanced water uptake, dry mass loss kinetics, and mechanical stability, can be adjusted to the specific requirements of particular disease treatments. The aim is to withstand the harsh conditions in the upper GIT (e.g., different pH levels, shear forces, and hydrostatic pressure). Various polysaccharides have been identified as the most promising and appropriate for this type of advanced drug delivery system: Nutriose FB 06 (a branched dextrin with nondigestible glycoside linkages: α-1,2 and α-1,3), Eurylon 7 A-PG (acetylated and pregelatinized high amylose starch), Eurylon 6 A-PG (an acetylated and pregelatinized high amylose starch), Eurylon 6 HP-PG (a hydroxypropylated and pregelatinized high amylose starch), Lycoat RS 780 (a pregelatinized modified starch), and Glucidex (a maltodextrin).3, 4, 5, 6

In vitro drug release has to be measured through the entire GIT, including incubation with fecal samples from patients and/or healthy subjects, to approximate in vivo reality. 5-ASA release was effectively suppressed in upper GIT conditions but began immediately upon exposure to fecal samples of patients with IBD.³ The in vivo efficacy of these systems has been confirmed in male Wister rats.⁷

Thus, these recently developed systems of colon targeting can be adapted to fit the patient’s physiopathology. In addition, the polysaccharide can also exhibit a prebiotic effect on the colonic microbiota of patients, which can be clinically beneficial to normalize the imbalance colonic bacteria.⁸ In this review, we highlight oral drug delivery technologies based on natural biodegradable polysaccharides for colon targeting.