• Archives of Pharmacal Research
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• 제21권2호
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• pp.179-186
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• 1998

Dextran-5-aminosalicylic acid ester (dextran-5-ASA) was synthesized as a colon-specific prodrug of 5-aminosalicylic acid (5-ASA) which is active against inflammatory bowel diseases. Chemical stability of dextran-5-ASA in the bath of pH 1.2 or 6.8 was investigated at $37^{\circ}C$ for 6 hrs, and 5-ASA was not released on such conditions. Depolymerization (%) of dextran-5-ASA by dextranase with the degree of substitution (DS) of 18, 23, or 30 was 92, 62 or 45 in 8 hrs respectively, but was not affected by the MW of dextran (9,000, 40,600, 80,200 or 580,000). Distribution of 5-ASA in dextran, determined by gel filtration chromatography, appeared to be relatively uniform. Incubation of dextran-5-ASA (DS 18) in cecal contents of rats released 20% (28 g) and 35% (49 g) of 5-ASA in 8 hrs and 24 hrs, respectively, but no 5-ASA was liberated from small intestinal contents.

• 약학회지
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• 제42권1호
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• pp.31-38
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• 1998

Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester(Dextran-5-ESA) was synthesized as a potential colon-specific prodrug of 5-aminosalicylic acid (5-ASA). No free 5-(4-eth oxycarbonylphenylazo) salicylic acid (5-ESA) was detected when the chemical stability of dextran-5-ESA was tested at pH 1.2, or pH 6.8 bath solution, Effects of the degree of substitution (DS) and molecular weight of dextran on the depolymerization by dextranase was investigated. Depolymerization(%) decreased with increasing DS, and was not affected by M.W. of dextran. The extent of prodrug conversion after incubation in the contents of various G.I. Tract segments of rats was evaluated. 5-ASA was released in the cecal contents, but not in the contents of proximal small intestine (PSI) or distal small intestine (DSI). No significant prodrug conversion was observed in the cecal contents of rats pretreated with kanamycin sulfate, which indicated that microbial enzymes were responsible for the cleavage of the prodrug.

• Journal of Pharmaceutical Investigation
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• 제37권1호
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• pp.45-49
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• 2007

Dextran-5-aminosalicylic acid conjugate (dextran-5-ASA) was in vitro-evaluated as a polymeric colon-spe-cific prodrug of 5-aminosalicylic acid (5-ASA). Chemical stability of dextran-5-ASA in the pH 1.2 or 6.8 buffer solutions was investigated at 37 for 6 hrs. The dextran backbone was not degraded and no 5-ASA release was detected. Moreover, dextran-5-ASA neither liberated 5-ASA in the homogenates of the small intestine of rats nor was transported across Caco-2 cell monolayers, suggesting no significant loss of dextran-5-ASA during transit through the upper intestine. Furthermore, incubation of dextran-5-ASA in 10% cecal contents of rats released about 37% and 55% of 5-ASA bound to dextran in 8 hr and 24 hr, respectively. While that with either esterase or dextranase failed to liberate 5-ASA from the polymeric prodrug, incubation of dextran-5-ASA with both esterases and dextranse released 5-ASA up to about 24% of 5-ASA bound to dextran. These results suggest that, after oral administration of dextran-5-ASA, the polymeric prodrug is delivered specifically to and releases 5-ASA in the large intestine, and reveal that the 5-ASA release by cleavage of the ester bond requires precedent depolymerization of the dextran backbone.