• Archives of Pharmacal Research
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• 제21권2호
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• pp.174-178
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• 1998

As a new colon-specific prodrug of 5-aminosalicylic acid (5-ASA), 5-aminosalicyl-glycine (5-ASA-Gly) was prepared by a simple synthetic route in good yield. Apparent partition coefficients of 5-ASA-Gly were lower than those of 5-ASA, which determined in$ CHCl_{3}$/pH 6.8 buffer or n-octanol/pH 6.8 buffer system. Stability of 5-ASA-Gly by peptidases was investigated by incubation of 5-ASA-Gly with the homogenates of tissue and contents of stomach, proximal small intestine or distal small intestine of rats at $37^{\circ}C$. 5-ASA was not detected, indicating that the prodrug was stable in the upper intestine. The amount of 5-ASA liberated from incubation of the prodrug in cecal or colonic contents of rats was about 65% or 27% in 8 hrs, respectively, which indicated that the prodrug activation took place more readily in the rat cecum whose bacterial counts are high like human colon. Results from in vitro experiments suggested 5-ASA-Gly as a promising candidate of a colon-specific prodrug of 5-ASA.

• Archives of Pharmacal Research
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• 제26권4호
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• pp.264-269
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• 2003

5-Aminosalicylic acid (5-ASA) is an active ingredient of therapeutic agents used for Crohn s disease and ulcerative colitis. Because it is absorbed rapidly and extensively in the upper intestine, delivery of the agent specifically to the colon is necessary. We selected taurine as a colon-specific promoiety and designed 5-aminosalicyltaurine (5-ASA-Tau) as a new colon-specific prodrug of 5-aminosalicylic acid (5-ASA). It was expected that introduction of taurine would restrict the absorption of the prodrug and show additive effect to the anti-inflammatory action of 5-ASA after hydrolysis. 5-ASA-Tau was prepared in good yield by a simple synthetic route. The apparent partition coefficient of 5-ASA-Tau in 1-octanol/pH 6.8 phosphate buffer or $CHCl_3$/pH 6.8 phosphate buffer was 0.10 or 0.18, respectively, at $37^{\circ}C$. To determine the chemical and biochemical stability in the upper intestinal environment, 5-ASA-Tau was incubated in pH 1.2 and 6.8 buffer solutions, and with the homogenates of tissue and contents of stomach or small intestine of rats at $37^{\circ}C$. 5-ASA was not detected from any of the incubation medium with no change in the concentration of 5-ASA-Tau. On incubation of 5-ASA-Tau with the cecal and colonic contents of rats, the fraction of the dose released as 5-ASA was 45% and 20%, respectively, in 8 h. Considering low partition coefficient and stability in the upper intestine, 5-ASA-Tau might be nonabsorbable and stable in the upper intestine. After oral administration, it would be delivered to the colon in intact form and release 5-ASA and taurine. These results suggested 5-ASA-Tau as a promising colon-specific prodrug of 5-ASA.

• 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.

• Archives of Pharmacal Research
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• 제26권4호
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• pp.258-263
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• 2003

Colon-specific delivery of glucocorticoids is highly desirable for the efficient treatment of inflammatory bowel disease. We synthesized prednisolone 21-sulfate sodium (PDS) as a colon-specific prodrug of prednisolone (PD) and investigated its properties using rats as test animals. We expected that introduction of sulfate ester as a sodium salt might increase the hydrophilicity and restrict the absorption in the GI tract. If PDS is stable and nonabsorbable in the upper intestine, it will be delivered to the colon as an intact form, where it hydrolyze by the sulfatase to release PD. Compared with PD, the solubility of PDS increased and the apparent partition coefficient decreased greatly. PDS was stable on incubation with pH 1.2 and 6.8 buffer solutions and with the contents of the stomach and small intestine. On incubation with the cecal contents, PDS decreased to 9.6％ of the dose in 10 h producing PD. The amount of PD increased to give a maximum 54％ of the dose and decreased. As a control, when PD was incubated with the cecal contents, it decreased to 29％ of the dose in 8 h, which implied that reduction of PD proceeded under such conditions. These results suggested that hydrolysis of PDS took place to produce and accumulate PD, which decreased by reduction as the incubation period extended. Our results suggested that PDS can be a promising colon-specific prodrug of PD, and sulfate ester group might serve as a potential colon-specific promoiety, especially for the drugs which are resistant to reduction in the colon.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.232.2-232.2
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• 2002

Corticosteroids have been used most frequently for inflammatory bowel disease. They are well absorbed and only a limited fraction of the dose is delivered to the inflammatory site in the colon. To reduce side effects by the systemic absorption. colon-specific delivery is highly desirable. We designed dexamethasone 21-sulfate sodium (DS) as a cOlon-specific prodrug of dexamethasone (D) expecting that it might be stable and non absorbable in the upper intestine and dissociate in the colon by the sulfatase, an enzyme solely found in the colon. (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.177.3-177.3
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• 2003

Corticosteroids have been used most frequently for inflammatory bowel disease. To reduce side effects by the systemic absorption, colon-specific delivery is highly desirable. We expected that conversion of 21-hydroxyl in glucocorticoids into a sulfate ester sodium will greatly increase the hydrophilicity, which consequently restrict the gastrointestinal absorption. Once delivered to the colon, sulfate ester will be hydrolyzed by the sulfatase originated from microbes and release the parent compound, glucocorticoids. In this study, we prepared methylprednisolone 21-sulfate sodium (MPS) and investigated its suitability as a colon-specific prodrug on methylprednisolone (MP). (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.357.2-357.2
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• 2002

Corticosteroids have been used most frequently for inflammatory bowel disease.They are well absorbed and only a limited fraction of the dose is delivered to the inflammatory site in the colon. To reduce side effects by the systemic absorption. cOlon-specific delivery is highly desirable. We prepared prednisolone 21-sulfate sodium (PDS) and investigated its suitability as a colon-specific prodrug of prednisolone(PD). (omitted)

• 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.

• 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.

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.164.2-165
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• 2000