Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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In vitro Evaluation of Dextran-5-aminosalicylic Acid Conjugate as a Polymeric Colon-specific Prodrug of 5-aminosalicylic Acid

  • Jung, Yun-Jin (Laboratory of Biomedicinal, College of Pharmacy, Pusan National University) ;
  • Jeon, Hyun-Chu (Laboratory of Biomedicinal, College of Pharmacy, Pusan National University) ;
  • Choi, Dea-Kyu (Laboratory of Biomedicinal, College of Pharmacy, Pusan National University) ;
  • Kim, Young-Mi (Medicinal Chemistry, College of Pharmacy, Pusan National University)
  • Published : 2007.02.21
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Abstract

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.

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References

  1. A. Rubinstein, Microbially controlled drug delivery to the colon, Biopharm. & Drug Disposition, 11, 465-475 (1990) https://doi.org/10.1002/bdd.2510110602
  2. D. M. Andrew, Dextran prodrugs for colonic-specific drug delivery: In Oral Colon Specific Drug Delivery, D. R. Friend (Ed.), CRC press, Boca Raton, FL., pp. 213-231 (1992)
  3. A. Rubinstein, D. Nakar and A. Sintov, Chondroitin sulfate: a potential biodegradable carrier for conlon-specific drug delivery, Int. J Pharm., 84, 141-150 (1992) https://doi.org/10.1016/0378-5173(92)90054-6
  4. E. M. Ryde, Low-molecular-weight azo compounds: In Oral Colon Specific Drug Delivery, D. R. Friend (Ed.), CRC press, Boca Raton, FL., pp. 143-152 (1992)
  5. M. Ashore, J. Fell, D. Astwood, H. Sharma and P. Woodhead, An evaluation of pectin as a carrier for drug targeting to the colon, J. Control. Rei., 26, 213-219 (1993) https://doi.org/10.1016/0168-3659(93)90188-B
  6. C. Larsen, and M. Johansen, Dextrans as carriers for drug compounds-realized and potential applications, Arch. Pharm. Chemi., 92, 809-830 (1985)
  7. T. W. Sery and E. J. Hehre, Degradation of dextrans by enzymes of intestinal bacteria, J. of Bacteriology, 66, 373-380 (1955)
  8. B. Crotty and D. P. Jewell, Drug therapy of ulcerative colitis, Br. J Clin. Pharmacol., 34, 189-198 (1992) https://doi.org/10.1111/j.1365-2125.1992.tb04124.x
  9. S. Ardizzone and G. B. Porro, Inflammatory bowel disease: new insights into pathogenesis and treatment, J Intern. Med., 252, 475-496 (2002) https://doi.org/10.1046/j.1365-2796.2002.01067.x
  10. R. Lofberg, Review article: medical treatment ofmild to moderately active Crohn's disease, Aliment. Pharmacal. Ther, 17 Suppl 2, 18-22 (2003)
  11. B. H. Novis, Z. Korzets, P. Chen and J. Bernheim, Nephrotic syndrome after treatment with 5-aminosalicylic acid. Br. Med. J (Clin. Res. Ed.) 296, 1442 (1988)
  12. V. R. Sinha and R. Kurnria, Colonic drug delivery: prodrug approach, Pharm. Res., 18, 557-564 (2001) https://doi.org/10.1023/A:1011033121528
  13. M. K. Chourasia and S. K. Jain, Pharmaceutical approaches to colon targeted drug delivery systems, J. Pharm. Pharm. Sci., 6, 33-66 (2003)
  14. H. Kim, H. Kong, B. Choi, Y. Yang, Y. Kim, M. J. Lim, L. Neckers and Y. Jung, Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease, Pharm. Res., 22(9), 1499-509 (2005) https://doi.org/10.1007/s11095-005-6250-z
  15. H. Bronsted, L. Hovgaard and L Simons, Dextran hydrogels for colon-specific drug delivery III. In vitro and in vivo degradation, S.T.P. Pharma. Sciences, 5, 60-64 (1995)
  16. Y. Jung, J. S. Lee, H. H. Kim, Y. T. Kim and Y.M. Kim, Synthesis and properties of dextran-5-aminosalicylic acid ester as a potential colon-specific prodrug of 5 aminosalicylic acid, Arch. Pharm. Res., 21, 179-186 (1998) https://doi.org/10.1007/BF02974025
  17. J. S. Lee, Y.J. Jung, M. J. Doh and Y.M. Kim, Synthesis and Properties ofdextran-nalidixic acid as a colon-specific prodrug ofnalidixic acid, Drug Development and Industrial Pharmacy, 27(4), 327-332 (2001)