Mechanistic Investigation of Enzyme Triggered Release from a Xyloglucan Matrix Tablet for Controlled Colonic Drug Delivery.

The objective of this study was to investigate the mechanisms underlying drug release from a controlled colonic release (CCR) tablet formulation based on a xyloglucan polysaccharide matrix and identify the factors that control the rate of release for the purpose of fundamentally substantiating the concept and demonstrating its robustness for colonic drug delivery. Previous work demonstrated in vitro limited release of 5-aminosalicylic acid (5-ASA) and caffeine from these tablets in small intestinal environment and significant acceleration of release by xyloglucanase, an enzyme of the colonic microbiome. Targeted colonic drug delivery was verified in an animal study in vivo. In the present work, interaction of the xyloglucan matrix tablets with aqueous dissolution media containing xyloglucanase was found to lead to the spontaneous formation of a hydrated highly viscous gummy layer at the surface of the matrix which had a reduced drug content compared to the underlying regions and persisted with a nearly constant thickness that was inversely correlated to the enzyme concentration throughout the duration of the release process. Enzymatic hydrolysis of xyloglucan was determined to take place at the surface of the matrix leading to matrix erosion and a relation for the rate of enzymatic reaction as a function of bulk enzyme concentration and the concentration of dissolved xyloglucan in the gummy layer was derived. A mathematical model was developed encompassing aqueous medium ingress, matrix metamorphosis due to xyloglucan dissolution and matrix swelling, enzymatic hydrolysis of the polysaccharide and concomitant drug release due to matrix erosion and simultaneous drug diffusion. The model was fitted to data of reducing sugar equivalents in the medium reflecting matrix erosion and released drug amount. Enzymatic reaction parameters and reasonable values of medium ingress velocity, xyloglucan dissolution rate constant and drug diffusion coefficient were deduced that provided an adequate approximation of the data. Erosion was shown to be the overwhelmingly dominant drug release mechanism while the role of diffusion marginally increased at low enzyme concentration and high drug solubility. Changing enzyme concentration had a rather weak effect on matrix erosion and drug release rate as demonstrated by model simulations supported by experimental data, while xyloglucan dissolution was slow and had a stronger effect on the rate of the process. Therefore, reproducible colonic drug delivery not critically influenced by inter- and intra-individual variation of microbial enzyme activity may be projected.

Efficient colonic drug delivery in domestic pigs employing a tablet formulation with dual control concept.

Efficient and reproducible colonic drug delivery remains elusive. The aim of this study was to demonstrate specific colonic delivery in vivo in domestic pigs with a novel tablet formulation based on a dual release control concept using 5-aminosalicylic acid (5-ASA) and caffeine as drug substances. The developed controlled colonic release (CCR) tablet formulation employs a pH-sensitive coating based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, and a xyloglucan-based matrix to inhibit drug release after coating removal in the small intestine and to allow microbiome-triggered drug release by enzymatic action in the colon. CCR tablets were administered to domestic pigs and plasma concentration data was analyzed by physiologically based pharmacokinetic modeling to estimate absorbed amounts from small and large intestine and in vivo drug release rates by model-dependent deconvolution using immediate release (IR) tablets and intravenous solutions as reference. Peak concentration times (tmax) and values (cmax) of CCR 5-ASA and caffeine tablets indicated strongly delayed drug absorption and the deduced absorbed amount as a function of time confirmed absorption overwhelmingly from the large intestine. The microbially cleaved marker molecule sulfasalazine administered alone or together with caffeine in CCR tablets reported, in combination with telemetry measurements, gastrointestinal transit times and site of absorption. Drug release from CCR tablets was inferred to take place predominantly at the site of absorption at a release rate of caffeine that was much larger in the colon than in the small intestine indicating enzymatically triggered release by the colonic microbiome. Xyloglucanase activity in rectal and cecal samples was consistent with release data and compound recovery in fecal droppings was consistent with 5-ASA bioavailability. The results provide evidence that the developed formulation can prevent premature drug release and provide targeted colonic drug delivery. Clinical relevance based on the comparability between pig and man is discussed.

Tablet formulation with dual control concept for efficient colonic drug delivery.

Aim of this study was to develop a tablet formulation for targeted colonic drug release by implementing two control mechanisms: A pH-sensitive coating layer based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, combined with a matrix based on plant-derived polysaccharide xyloglucan to inhibit drug release after coating removal in the small intestine and to allow microbiome triggered drug release in the colon. In vitro dissolution tests simulated the passage through the entire gastrointestinal tract with a four-stage protocol, including microbial xyloglucanase addition in physiologically relevant concentrations as microbiome surrogate to the colonic dissolution medium. Matrix erosion was monitored in parallel to drug release by measurement of reducing sugar equivalents resulting from xyloglucan hydrolysis. Limited drug release in gastric and small intestinal test stages and predominant release in the colonic stage was achieved. The xyloglucan matrix controlled drug release after dissolution of the enteric coating through the formation of a gummy polysaccharide layer at the tablet surface. Matrix degradation was dependent on enzyme concentration in the colonic medium and significantly accelerated drug release resulting in erosion-controlled release process. Drug release at physiologically relevant enzyme concentration was completed within the bounds of colonic transit time. The dual control concept was applicable to two drug substances with different solubility, providing similar release rates in colonic environment containing xyloglucanase. Drug solubility mechanistically affected release, with diffusion of caffeine, but not of 5-ASA, contributing to the overall release rate out of the matrix tablet.