Design and development of a stimuli-responsive oral tablet system for the treatment of ulcerative colitis
Date
2011-10-19
Authors
Bawa, Priya
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Abstract
The purpose of this study was to formulate a stimuli-responsive colon-targeted oral tablet
(SROT) that was capable of preventing release of the therapeutic agent mesalamine (5-ASA)
in the upper gastrointestinal tract (stomach and small intestine) thus ensuring the delivery of
a maximal quantity of 5-ASA to the colon. The formulation comprised of 5-ASA-loaded
crosslinked chitosan (CHT) granules dispersed within a matrix of pectin, barium chloride
(BaCl2), carboxymethylcellulose (CMC) and xanthan gum (XG). The combination of matrix
components and granules were compressed into shallow concave tablets and coated with a
combination coating solution of pectin and ethylcellulose. Formulation batches were
prepared according to the Box-Behnken experimental design and each formulation was
evaluated for the in vitro drug release characteristics at various residence times and pH
gradients. The mean dissolution time (MDT) in the presence and absence of the colonic
enzymes was employed in the determination of the optimized SROT. In vitro drug release
studies revealed a distinct responsiveness of the SROT to colonic enzymes with a fractional
release of 0.402 in the presence of enzymes vs. 0.152 in the absence of enzymes, after 24
hours. The commercially available comparator product showed irreproducible release profiles
over the 24 hour period (SD: 0-0.550) compared to the SROT (SD: 0-0.037). FTIR spectra of
the coating showed a disappearance of peaks from 1589-1512cm-1 after exposure to colonic
enzymes. In addition, with increasing exposure time to colonic enzymes there was a
disappearance of peaks between 1646-1132cm-1 of the tablet indicating polymeric cleavage
by colonic enzymes and release of 5-ASA from the tablet. Plasma concentration profiles of
the SROT in the pig model produced a Cmax of only 3.77±1.375μg/mL compared to
10.604±2.846μg/mL from the comparator product. Overall, the SROT proved beneficial over
the commercially available comparator product due to the mechanism of drug release and
responsiveness to colonic enzymes.