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 rapidly 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.

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Materials

5-Aminosalicylic acid (5-ASA) was purchased from AK Scientific, Union city, USA. Xyloglucan 3S was ordered from DSM Gokyo food & chemical, Tokyo, Japan. Caffeine, polyvinylpyrrolidone (PVP) K30, triethyl citrate, calcium chloride, hematin, histidine, iron (II) sulfate heptahydrate, magnesium chloride, and vitamin K3 were supplied by Sigma Aldrich, St. Louis, USA. Primojel (sodium starch glycolate type A) was obtained from DFE Pharma, Goch, Germany. Vivapur 101 (microcrystalline cellulose) was provided from JRS Pharma, Rosenberg, Germany. Pharmacoat 603 (hydroxypropyl methylcellulose HPMC 3 mPa·s) was acquired from Shin-Etsu, Tokyo, Japan. Magnesium stearate, talc and granulac 200 (lactose monohydrate) were purchased from Hänseler Swiss Pharma, Herisau, Switzerland. Eudragit® FS 30 D was kindly donated by Evonik, Essen, Germany. Hydrochloric acid 1 M, potassium dihydrogen phosphate, sodium hydroxide 32%, iron (III) oxide red, D-(+)-glucose, ammonium sulphate, sodium chloride, L-cysteine (free base), and vitamin B12 were ordered from Carl Roth, Karlsruhe, Germany. Iron (III) oxide monohydrate yellow was supplied by Strem Chemicals Inc., Newburyport, USA. Sodium hydroxide 1 M was acquired from Honeywell-Fluka, Morristown, USA. Xyloglucanase (nominal activity 1000 U/mL) was purchased from Megazyme, Irishtown, Ireland. p-Hydroxybenzhydrazide (PAHBAH) was obtained from TCI, Tokyo, Japan.

Viviane Doggwiler, Michael Lanz, Valeria Paredes, Georg Lipps, Georgios Imanidis, Tablet formulation with dual control concept for efficient colonic drug delivery, International Journal of Pharmaceutics, 2022, 122499, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2022.122499.

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