New insights on the effects of blend composition on the biodegradation and permeability of Inulin-Eudragit RS film coatings for colon drug delivery

The application of a colon-specific delivery system for drugs utilized to treat inflammatory bowel diseases, comprising ulcerative colitis and Crohn’s disease, can prevent the untimely release in the upper gastrointestinal tract, thereby avoiding systemic side effects and providing the desired colon-specific therapeutic efficiency[1], [2]. Based on the specific physiological conditions of the gastrointestinal tract, such as the pH gradient, different transit times required to reach specific sites, and the distribution of various microorganisms, oral therapeutic drugs surrounded by colonic physiological condition-responsive coatings can realize the purpose of colon targeting[3], [4], [5]. A coating system susceptible to degradation by colonic microbiota is a practically promising approach[6], [7]. Numerous polysaccharides and oligosaccharides have been used in the development of colonic microbiota-dependent systems[8].

Inulin and Eudragit RS (ERS) are coating constituent materials that allow to be used in biodegradable colonic drug delivery systems. Inu-ERS coating is a colon-targeted drug delivery strategy triggered by colonic microbial enzymes. The coating component inulin is indigestible by the upper digestive tract[9]. It can be enzymatically degraded by enzymes produced by the human colonic microbiome, which cleaves the β-(2,1)-glycosidic bonds between the fructosyl units, thus destroying the structure of inulin[10]. Based on the degree of polymerization (DP), inulin can be subdivided into oligosaccharide (DP: 2 to 9) or polysaccharide (DP: 10 to 60). ERS is a copolymer of methyl methacrylate, ethyl acrylate and a low content of trimethyl amino ethyl methacrylate chloride. Complementary properties would allow this combination to have sufficiently low drug penetration in the stomach and small intestine for ensuring drug release in the colon as a consequence of specific enzymatic degradability of inulin. This leads to the formation of pores, which facilitates the subsequent release of drugs in the colon. The hydrophobicity of ERS compensates for the poor mechanical properties and high water solubility of polysaccharides[11].

Up until now, considerable research has focused on the development and optimization of microbially triggered colon-specific coatings for drug reservoirs[6], [12], [13], [14]. In spite of the fact that most of the studies concern the permeation properties, mechanical properties of the coated membranes and the efficiency of in vitro and in vivo drug release from the reservoir, only a few studies discuss that drug release across coated membranes is the result of a combined effect of water imbibition and microbial enzymatic degradation[5], [15], [16], [17], [18]. To the best of our knowledge, studies on how enzymes degrade polysaccharides in coated films after exposure to water are lacking so far. The proportion, type, distribution and preparation process of water-soluble polysaccharides and water-insoluble polymers may all be factors that affect the way and extent of enzyme-triggered degradation of polysaccharides in blend films, which in turn affects the drug diffusion rate and drug diffusion mechanism.

The susceptibility of inulin to enzymes adds a consideration to the transport of drugs through blend films, as the extent to which enzymes degrade different molecular weights or different amounts of inulin within the film will also vary. Leakage of inulin is important for drug release from pellet coatings[19]. In the current work, we prepared inulin-ERS composite films by dispersion casting. Isolated films are convenient model systems for studying release properties of film coated pellets, as they facilitate the measurement of permeability using a diffusion device and are adequate as an initial screening method[20].

The purpose of this paper is to study the complex effects of polysaccharide biodegradation in films with various molecular weights and ratios of inulin and ERS on film permeability, hence to understand how the enzyme degrades the polysaccharide within the film and to investigate the effect of component structure on biodegradation, and permeability characteristics of the film.

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