Prodrugs pp 683-699 | Cite as

Colonic Delivery

  • Fumitoshi Hirayama
  • Kaneto Uekama
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


There are a number of colonic diseases that could be treated more effectively using a colon-specific delivery system. These include ulcerative colitis, colorectal cancer, and Crohn’s disease (Hanauer and Kirsner, 1988; Riley, 1993). The local delivery of drugs such as anti-inflammatory agents, anticancer agents, and antibiotics to the colon should permit lower dosing resulting in fewer side effects and increasing therapeutic efficacy. The principal goals of colon-specific delivery after oral administration are, first, to avoid absorption and biodegradation of drugs in the upper intestine such as in the stomach and small intestine where acidor enzyme-labile drugs are degraded and most small drug molecules are absorbed and, second, to release drugs site-specifically in the lower intestine such as in the cecum and colon. With these goals in mind, many different colon-specific drug delivery systems have been investigated during the last decade (Friend, 1992; Rubinstein, 1995; Hovgaard and Brønsted, 1996; Kinget et al., 1998; Sinha and Kumria, 2001). Among these, the most important are film-coating of drug formulations with pH- or pressure-sensitive polymers, coating with bacterial degradable polymers, delivering drugs from time-dependent formulations or biodegradable matrices, and delivering drugs from small molecule prodrugs or polymeric conjugates. The prod rugapproach to colonic delivery is currently used to treat inflammatory bowel diseases (IBD), in which active drugs are liberated by the action of bacterial enzymes such as azo-reductase, glucosidases, and glucronidases in the colon (Friend, 1992; Sinha and Kumria, 2003).


Ulcerative Colitis Distal Ulcerative Colitis Colonic Delivery Prodrug Approach Colonic Drug Delivery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antenucci RN, and Palmer JK. Enzymatic Degradation of α-and β-Cyclodextrins by Bacteroides in the Human Colon. J Agric Food Chem 1984; 32:1316–1321CrossRefGoogle Scholar
  2. Bai JP, Chang L-L, and Guo J-H. Targeting of Peptide and Protein Drugs to Specific Sites in the Oral Route. CRC Crit Rev Ther Drug Carrier Syst 1995; 12:339–371Google Scholar
  3. Brown JP. Role of Gut Bacterial Flora in Nutrition and Health: A Review of Recent Advances in Bacteriological Technique, Metabolism and Factors Affecting Flora Composition. CRC Crit Rev Food Sci Nutr 1977; 8:229–336PubMedCrossRefGoogle Scholar
  4. Butzner JD, Parmar R, and Dalal CJB. Butyrate Enema Therapy Stimulates Mucosal Repair in Experimental Colitis in the Rat. Gut 1996; 38:568–573PubMedCrossRefGoogle Scholar
  5. Coupe AJ, Davis SS, and Wilding IR. Variation in Gastrointestinal Transit of Pharmaceutical Dosage Forms in Healthy Subjects. Pharm Res 1991; 8:360–364PubMedCrossRefGoogle Scholar
  6. Davis SS, Hardy JG, and Fara J. Transit of Pharmaceutical Dosage Forms through the Small Intestine. Gut 1986; 27:886–892PubMedCrossRefGoogle Scholar
  7. Duchêne D. (Ed.) New Trends in Cyclodextrins and Derivatives. Paris: Editions de Santê; 1991. 635p.Google Scholar
  8. Faigle JW. Drug Metabolism in the Colon Wall and Lumen. In: Bieck PR. Colonic Drug Absorption and Metabolism. New York, NY: Marcel Dekker; 1993:29–54Google Scholar
  9. Flourié B, Molis C, Achour L, Dupas H, Hatat C, and Rambaud JC. Fate of β-Cyclodextrin in the Human Intestine. J Nutr 1993; 123:676–680PubMedGoogle Scholar
  10. Friend DR. (Ed.) Oral Colon-Specific Drug Delivery. Boca Raton, FL: CRC Press; 1992. 268p.Google Scholar
  11. Friend DR. Glycosides in Colonic Drug Delivery. In: Friend DR. Oral Colon-Specific Drug Delivery Boca Raton, FL: CRC Press; 1992:153–187Google Scholar
  12. Friend DR, and Chang GW. Drug Glycosides: Potential Prodrugs for Colonspecific Drug Delivery. J Med Chem 1985; 28:51–57PubMedCrossRefGoogle Scholar
  13. Gruber P, Longer MA, and Robinson JR. Some Biological Issues in Oral, Controlled Drug Delivery. Adv Drug Del Rev 1987; 1:1–18CrossRefGoogle Scholar
  14. Haeberlin B, and Friend DR. Anatomy and Physiology of the Gastrointestinal Tract: Implications for Colonic Drug Delivery. In: Friend DR. Oral Colon-Specific Drug Delivery Boca Raton, FL: CRC Press; 1992:1–43Google Scholar
  15. Hanauer SB, and Kirsner JB. Medical Therapy in Ulcerative Colitis. In: Kirsner JB, and Shorter RG. Inflammatory Bowel Disease. Philadelphia, PA: Lee & Febiger; 1988:431–475Google Scholar
  16. Hawksworth G, Drasar BS, and Hill MJ. Intestinal Bacteria and Hydrolysis of Glucosidic Bond. J Med Microbiol 1971; 4:451–459PubMedGoogle Scholar
  17. Hirayama F, Mimani K, and Uekama K. Evaluation of Biphenylyl Acetic Acid-β-cyclodextrin Conjugates as Colon-targeting Prodrug: Drug Release Behavior in Rat Biological Media. J Pharm Pharmacol 1996; 48:27–31PubMedGoogle Scholar
  18. Hirayama F, Ogata T, Yano H, Arima H, Udo K, Takano M, and Uekama K. Release Characteristics of a Short-chain Fatty Acid, n-Butyric Acid, from Its β-Cyclodextrin Ester Conjugate in Rat Biological Media. J Pharm Sci 2000; 89:1486–1495PubMedCrossRefGoogle Scholar
  19. Hovgaard L, and Brønsted H. Current Applications of Polysaccharides in Colon Targeting. CRC Crit Rev Ther Drug Carrier Syst 1996; 13:185–223Google Scholar
  20. Jung YJ, Lee JS, and Kim YM. Synthesis and In Vitro/In Vivo Evaluation of 5-Aminosalicyl-glycine as a Colon Specific Prodrug of 5-Aminosalicylic Acid. J Pharm Sci 2000; 89:594–602PubMedCrossRefGoogle Scholar
  21. Kamada M, Hirayama F, Udo K, Yano H, Arima H, and Uekama K. Cyclodextrin Conjugate-based Controlled Release System: Repeated-and Prolonged-releases of Ketoprofen after Oral Administration in Rats. J Control Rel 2002; 82:407–416CrossRefGoogle Scholar
  22. Kinget R, Kalala W, Vervoort L, and van den Mooter G. Colonic Drug Targeting. J Drug Target 1998; 6:129–149PubMedCrossRefGoogle Scholar
  23. Kopeček J, and Kopeãekova P. N-(2-Hydoxypropyl)methacrylamide Copolymers for Colon-specific Drug Delivery. In: Friend DR. Oral Colon-Specific Drug Delivery Boca Raton, FL: CRC Press; 1992:189–211Google Scholar
  24. McLeod AD, and Tozer TN. Kinetic Perspectives in Colonic Drug Delivery. In: Friend DR. Oral Colon-Specific Drug Delivery Boca Raton, FL: CRC Press; 1992:85–114Google Scholar
  25. Minami K, Hirayama F, and Uekama K. Colon-specific Drug Delivery Based on a Cyclodextrin Prodrug: Release Behavior of Biphenylylacetic Acid from Its Cyclodextrin Conjugates in Rat Intestinal Tracts after Oral Administration. J Pharm Sci 1998; 87:715–720PubMedCrossRefGoogle Scholar
  26. Nakamura J, Asai K, Nishida K, and Sasaki H. A Novel Prodrug of Salicylic Acid, Salicylic Acid-glutamic Acid Conjugate Utilizing Hydrolysis in Rabbit Intestinal Microorganisms. Chem Pharm Bull 1992a; 40:2164–2168PubMedGoogle Scholar
  27. Nakamura J, Kido M, Nishida K, and Sasaki H. Hydrolysis of Salicylic Acidtyrosine and Salicylic Acid-methionine Prodrugs in Rabbits. Int J Pharm 1992b; 87:59–66CrossRefGoogle Scholar
  28. Nakamura J, Tagami C, Nishida K, and Sasaki H. Unequal Hydrolysis of Salicylic Acid-D-alanine and Salicylic Acid-L-alanine Conjugates in Rabbit Intestinal Microorganisms. Chem Pharm Bull 1992c; 40:547–549PubMedGoogle Scholar
  29. Nilsson Å, Danielsson Å, Löfberg R, Benno P, Bergman L, Fausa O, Florholmen J, Karvonen A-L, Kildebo S, Kollberg B, Lindberg G, Lööf L, Stig R, and Tanghøj H. Olsalazine versus Sulphasalazine for Relapse Prevention in Ulcerative Colitis: A Multicenter Study. Am J Gastoenterol 1995; 90:381–387Google Scholar
  30. Nolen III HN, Fedorak RN, and Friend DR. Budenoside-β-D-glucuronide: A Potential Prodrug for Treatment of Ulcerative Colitis. J Pharm Sci 1995; 84:677–681PubMedCrossRefGoogle Scholar
  31. Nolen III HN, and Friend DR. Menthol-β-D-glucuronide: A Potential Prodrug for Treatment of the Irritable Bowel Syndrome. Pharm Res 1994; 11:1707–1711PubMedCrossRefGoogle Scholar
  32. Nudelman A, Ruse M, Aviram A, Rabizadeh E, Shaklai M, Zimrah Y, and Rephaeli A. Novel Anticancer Prodrugs of Butyric Acid. 2. J Med Chem 1992; 35:687–694PubMedCrossRefGoogle Scholar
  33. Pettersson G, Ahlman H, and Kewenter J. A Comparison of Small Intestinal Transit Times between the Rat and the Guinea-pig. Acta Chir Scand 1976, 142: 537–540PubMedGoogle Scholar
  34. Pouillart P, Ronco G, Cerutti I, Trouvin JH, Pieri F, and Villa P. Pharmacokinetic Studies of n-Butyric Mono-and Polyesters Derived from Monosaccharides. J Pharm Sci 1992; 81:241–244PubMedCrossRefGoogle Scholar
  35. Rathi RC, Kopecekova P, Rihova B, and Kopecek J. N-(2-Hydoxypropyl)methacrylamide Copolymers Containing Pendant Saccharide Moieties: Synthesis and Bioadhesive Properties. J Polymer Sci A: Polymer Chem 1991; 29:1895–1902CrossRefGoogle Scholar
  36. Riley SA. Influence of Disease on Colonic Drug Absorption. In: Bieck PR. Colonic Drug Absorption and Metabolism. New York, NY: Marcel Dekker; 1993:177–195Google Scholar
  37. Rubinstein A. Approaches and Opportunities in Colon-Specific Drug Delivery. CRC Crit Rev Ther Drug Carrier Syst. 1995; 12:101–149Google Scholar
  38. Ryde EM. Low-molecular-weight Azo Compounds. In: Friend DR. Oral Colon-Specific Drug Delivery Boca Raton, FL: CRC Press; 1992:143–152Google Scholar
  39. Saffran M, Kumar GS, Savariar C, Burnham JC, Williams F, and Neckers DC. A New Approach to the Oral Administration of Insulin and Other Drugs. Science 1986; 233:1081–1084PubMedCrossRefGoogle Scholar
  40. Scheline R. Metabolism of Foreign Compounds by Gastrointestinal Microorganisms. Pharmacol Rev 1973; 25:451–523PubMedGoogle Scholar
  41. Scheppach W, Sommer H, Kirchner T, Paganelli G-M, Bertram P, Christl S, Richter F, Dusel G, and Kasper H. Effect of Butyrate Enemas on the Colonic Mucosa in Distal Ulcerative Colitis. Gastroenterol 1992; 103: 51–56Google Scholar
  42. Sinha VR, and Kumria R. Colonic Drug Delivery: Prodrug Approach. Pharm Res 2001; 18:557–564PubMedCrossRefGoogle Scholar
  43. Sinha VR, and Kumria R. Microbially Triggered Drug Delivery to the Colon. Eur J Pharm Sci 2003; 18:3–18PubMedCrossRefGoogle Scholar
  44. Stella VJ, and Rajewski RA. Cyclodextrins: Their Future in Drug Formulation and Delivery. Pharm Res 1997; 14:556–567PubMedCrossRefGoogle Scholar
  45. Tozer TN, Friend DR, and McLeod AD. Kinetic Perspectives on Colonic Delivery. STP Pharma Sci 1995; 5: 5–12Google Scholar
  46. Uekama K. Design and Evaluation of Cyclodextrin-based Drug Formulation. Chem Pharm Bull 2004; 52:900–915PubMedCrossRefGoogle Scholar
  47. Uekama K, Hirayama F, and Irie T. Cyclodextrin Drug Carrier Systems. Chem Rev 1998; 98:2045–2076PubMedCrossRefGoogle Scholar
  48. Uekama K, Minami K, and Hirayama F. 6A-O-[(4-Biphenylyl)acetyl]-α-,-β-, and-γ-cyclodextrins and 6A-Deoxy-6A-[[(4-Biphenylyl)acetyl]amino]-α-,-β-, and-γ-cyclodextrins: Potential Produgs for Colon-specific Delivery. J Med Chem 1997; 40:2755–2761PubMedCrossRefGoogle Scholar
  49. Yano H, Hirayama F, Arima H, and Uekama K. Preparation of Prednisoloneappended α-, β-and γ-Cyclodextrins: Substitution at Secondary Hydroxyl Groups and In Vitro Hydrolysis Behavior. J Pharm Sci 2001; 90:493–503PubMedCrossRefGoogle Scholar
  50. Yano H, Hirayama F, Arima H, and Uekama K. Prednisolone-appended α-Cyclodextrin: Alleviation of Systemic Adverse Effect of Prednisolone after Intracolonic Administration in 2,4,6-Trinitrobenzenesulfonic Acid-induced Colitis Rats. J Pharm Sci 2001; 90:2103–2112PubMedCrossRefGoogle Scholar
  51. Yano H, Hirayama F, Kamada M, Arima H, and Uekama K. Colon-specific Delivery of Prednisolone-appended α-Cyclodextrin: Alleviation of Systemic Adverse Effect after Oral Administration. J Control Rel 2002; 79:103–112CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Fumitoshi Hirayama
    • 1
  • Kaneto Uekama
    • 1
  1. 1.Faculty of Pharmaceutical SciencesSojo UniversityKumamotoJapan

Personalised recommendations