Oral Route of Peptide and Protein Drug Delivery

  • V. H. L. Lee
Conference paper


Designing means to deliver peptide and protein drugs successfully to the systemic circulation by the oral route has been a challenge to scientists in drug delivery for many years [1]. The barriers to peptide and protein absorption from the gastrointestinal tract are well known. There are the enzymatic and penetration barriers [2–4]. Of the two, the enzymatic barrier historically has received more attention and appears to be the rate-limiting step in the intestinal penetration of small peptides such as leucine enkephalin and its analogs [5]. Numerous investigations have focused on the use of protease inhibitors, notably aprotinin [6–8], soy bean trypsin inhibitor [8–10], and amastatin [5] and on the use of formulations, notably microparticulates [11] to protect the encapsulated peptide and protein drugs from luminal proteases.


Protein Drug Hepatic Extraction Penetration Enhancer Paracellular Pathway Peptide Drug 
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. 1.
    Lee VHL, Dodda-Kashi S, Grass GM, Rubas W (1991) Oral route of peptide and protein drug delivery. In. Lee VHL (ed) Peptide and protein drug delivery. Dekker, New York, pp 691–738Google Scholar
  2. 2.
    Lee VHL (1990) Protease inhibitors and penetration enhancers as approaches to modify peptide absorption. J Contr Rel 13:213–223CrossRefGoogle Scholar
  3. 3.
    Lee VHL, Yamamoto A (1990) Penetration and enzymatic barriers to peptide and protein abosrption. Adv Drug Deliv Rev 4:171–207CrossRefGoogle Scholar
  4. 4.
    Schilling RJ, Mitra AK (1991) Degradation of insulin by trypsin and alpha-chymotrypsin. Pharm Res 8:721–727PubMedCrossRefGoogle Scholar
  5. 5.
    Friedman DI, Amidon GL (1991) Oral absorption of peptides: influence of pH and inhibitors on the intestinal hydrolysis of leu-enkephalin and analogues. Pharm Res 8:93–96PubMedCrossRefGoogle Scholar
  6. 6.
    Parsons JA, Rafferty B, Stevenson RW, Zanelli JM (1977) Use of protease inhibitors to protect subcutaneously injected peptide hormones against local degradation. Br J Pharmacol 59: 489P-490PGoogle Scholar
  7. 7.
    Parsons JA, Rafferty B, Stevenson RW, Zanelli JM (1979) Evidence that protease inhibitors reduce the degradation of parathyroid hormone and calcitonin injected subcutaneously. Br J Phannacol 66:25–32Google Scholar
  8. 8.
    Morimoto K, Yamaguchi H, Iwakura Y, Miyazaki M, Nakatani E, Iwamoto T, Ohashi Y, Nakai Y (1991) Effects of proteolytic enzyme inhibitors on the nasal absorption of vasopressin and an analogue. Phann Res 8:1175–1179CrossRefGoogle Scholar
  9. 9.
    Kidron M, Bar-On J, Berry EM, Ziv E (1982) The absorption of insulin from various regions of the rat intestine. Life Sci 31:2837–2841PubMedCrossRefGoogle Scholar
  10. 10.
    Ziv E, Lior O, Kidron M (1987) Absorption of protein via the intestinal wall: a quantitative model. Biochem Phannacol 36:1035–1039CrossRefGoogle Scholar
  11. 11.
    Damge C, Michel C, Aprahamian M, Couvreur P (1988) New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier. Diabetes 37:246–251PubMedCrossRefGoogle Scholar
  12. 12.
    Moore JA, Pletcher SA Ross MJ (1986) Absorption enhancement of growth hormone from the gastrointestinal tract of rats. Int J Phann 34:35–43CrossRefGoogle Scholar
  13. 13.
    Nishihata T, Rytting JH, Kamada A, Higuchi T (1981) Enhanced intestinal absorption of insulin in rats in the presence of sodium 5-methoxysalicylate. Diabetes 30:1065–1067PubMedCrossRefGoogle Scholar
  14. 14.
    Peters GE, Hutchinson LEF, Hyde R, McMartin C, Metcalfe SB (1987) Effect of sodium 5-methoxysalicylate on macromolecule absorption and mucosal morphology in a vascularly perfused rat gut preparation in vivo. J Phann Sci 76:857–861Google Scholar
  15. 15.
    Takada K, Shibata N, Yoshimura H, Masuda Y, Yoshikawa H, Muranishi S, Oka T (1985) Promotion of the selective lymphatic delivery of cyclosporin A by lipid-surfactant mixed micelles. J Pharmacobio-Dyn 8:320–323PubMedCrossRefGoogle Scholar
  16. 16.
    Sekine M, Sasahara K, Kojima T, Hasegawa K, Okada R, Awazu S (1984) Improvement of bioavailability of poorly absorbed drugs. I. Effect of medium chain glyceride base on the rectal absorption of cefmetazole sodium in rats. J Phannacobio-Dyn 7:856–863PubMedCrossRefGoogle Scholar
  17. 17.
    Sekine M, Terashima H, Sasahara K, Nishimura K, Okada R, Awazu S (1985) Improvement of bioavailability of poorly absorbed drugs. II. Effect of medium chain glyceride base on the intestinal absorption of cefmetazole sodium in rats and dogs. J Phannacobio-Dyn 8:286–295CrossRefGoogle Scholar
  18. 18.
    Muranishi S, Muranushi N, Sezaki H (1979) Improvement of absolute bioavailability of normally poorly absorbed drugs: Inducement of the intestinal absorption of streptomycin and gentamicin by lipid-bile salt mixed micelles in rat and rabbit. Int J Phann 2:101–111Google Scholar
  19. 19.
    Bocci V, Naldini A, Corradesc F, Lencioni E (1985) Colorectal administration of human interferon-yo Int J Phann 24:109–114Google Scholar
  20. 20.
    LeCluyse EL, Appel LE, Sutton SC (1991) Relationship between drug absorption enhancing activity and membrane perturbing effects of acylcamitines. Phann Res 8:84–87CrossRefGoogle Scholar
  21. 21.
    Fix JA, Engle K, Porter PA, Leppert PS, Selk SJ, Gardner CR, Alexander J (1986) Acylcamitines: Drug absorption-enhancing agents in the gastrointestinal tract. Am J Physiol 251: G332-G340PubMedGoogle Scholar
  22. 22.
    Ferry DM, Butt TJ, Broom MF, Hunter J, Chadwick VS (1989) Bacterial chemotactic oligopeptides and the intestinal mucosal barrier. Gastroenterology 97:61–67PubMedGoogle Scholar
  23. 23.
    Sutton SC, LeCluyse EL, Cammack L, Fix FA (1992) Enhanced bioavailability of cefoxitin using palmitoyl-L-camitine. I. Enhancer activity in different intestinal regions. Phann Res 9: 191–194CrossRefGoogle Scholar
  24. 24.
    Smith PL, Wall DA, Gochoco CH, Wilson G (1992) Oral absorption of peptides and proteins. Adv Drug Deliv Rev (8:253–290)CrossRefGoogle Scholar
  25. 25.
    Shen WC, Wan J, Ekrami H (1992) Enhancement of polypeptide and protein absorption by macromolecular carriers via endocytosis and transcytosis. Adv Drug Deliv Rev 8: 93–113CrossRefGoogle Scholar
  26. 26.
    Sawchuck RJ, Awni WM (1986) Absorption of cyclosporine from rabbit small intestine in situ. J Phann Sci 75:1151–1156CrossRefGoogle Scholar
  27. 27.
    Jennewein HM, Waldeck F, Konz W (1974) The absorption oftetragastrin from different sites in rats and dogs. Arzneimittelforschung 24:1225–1228PubMedGoogle Scholar
  28. 28.
    Lundin S, Vilhardt H (1986) Absorption of I-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in rabbits. Acta Endocrinol 112: 457–460PubMedGoogle Scholar
  29. 29.
    Kohler E, Duberow DM, Drew J, Ribes G, Loubatieres MMM, Mazer N, Gyr K, Berlinger C (1987) Absorption of an aqueous solution of a new synthetic somatostatin analogue administered to man by gavage. Eur J Clin Phannacol 33:167–171CrossRefGoogle Scholar
  30. 30.
    Grass GM, Morehead WJ (1989) Evidence for site-specific absorption of a novel ACE inhibitor. Phann Res 6:759–765CrossRefGoogle Scholar
  31. 31.
    Lundin S, Pantzar N, Broeders A, Ohlin M, Westrom BR (1991) Differences in transport rate of oxytocin and vasopressin analogues across proximal and distal isolated segments of the small 1.intestine of the rat. Phann Res 8:1274–1280CrossRefGoogle Scholar
  32. 32.
    Kompella UB, Lee VHL (1992) Delivery systems for penetration enhancement of peptide and protein drugs: Design considerations. Adv Drug Deliv Rev 8:115–162CrossRefGoogle Scholar
  33. 33.
    Rubinstein A, Nakar D, Sintov A (1992) Colonic drug delivery: enhanced release of indo- methacin from cross-linked chondroitin matrix in rat cecal content. Pharm Res 9: 276–278PubMedCrossRefGoogle Scholar
  34. 34.
    Salyers AA, O’Brien M (1980) Cellular location of enzymes involved in chondroitin sulfate breakdown by Bacteroides thetaiotaomicron. J Bacterid 143:772–780Google Scholar
  35. 35.
    Saffran M, Kumar GS, Savariar C, Burnham JC, Williams F, Neckers DC (1986) A new approach to the oral administration of insulin and other peptide drugs. Science 23:1081–1084CrossRefGoogle Scholar
  36. 36.
    Heringova A, Koldovsky O, Jirosova V, Uher J, Noack R, Freidrich M, Schenk G (1966) Proteolytic and peptidase activities of the small intestine of human fetuses. Gastroenterology 51:1023–1027PubMedGoogle Scholar
  37. 37.
    Triadou N, Bataille J, Schmitz J (1983) Longitudinal study of the human intestinal brush border membrane proteins. Gastroenterology 85:1326–1332PubMedGoogle Scholar
  38. 38.
    Shoji Y, Lee VHL (1989) Regional differences in the proteolysis of a renin inhibitor in the G.I. tract of the albino rabbit. Pharm Res 6S:31Google Scholar
  39. 39.
    Shoji Y, Lee VHL (1989) Prolyl endoprotease (E.C. activity in the colon and its role in the degradation of thyrotropin releasing hormone in the albino rabbit. Pharm Res 6S: 31Google Scholar
  40. 40.
    Buur A, Yamamoto A, Lee VHL (1990) Penetration of 5-fluorouracil and prodrugs across the intestine of the albino rabbit: evidence for shift in absorption site from the upper to the lower region of the gastrointestinal tract by prodrugs. J Contr Rel 14:43–51CrossRefGoogle Scholar
  41. 41.
    Narawane M, Podder SK, Bundgaard H, Lee VHL (1993) Segmental differences in drug permeability, esterase activity and ketone reductase activity in the albino rabbit intestine. J. Drug Targeting 1:29–39CrossRefGoogle Scholar
  42. 42.
    Conradi RA, Hilgers AR, Ho NFH, Burton PS (1991) The influence of peptide structure on transport across CaCO-2 cells. Pharm Res 8:1453–1460PubMedCrossRefGoogle Scholar
  43. 43.
    Cereijido M, Meza I, Martinez-Palomo A (1981) Occluding junctions in cultured epithelial monolayers. Am J Physiol 240:C96-C102PubMedGoogle Scholar
  44. 44.
    Madara JL, Dharmsathaphorn K (1985) Occluding junction structure-function relationships in a cultured epithelial monolayer. J Cell Biol 101:2124–2133PubMedCrossRefGoogle Scholar
  45. 45.
    Yen WC, Lee VHL (1991) Influence of collagenase on the intestinal transport of a pentapeptide. Proceed Intern Symp Control Rel Bioact Mater 18:95Google Scholar
  46. 46.
    Dolye JW, Wolfe MM, McGuigan JE (1984) Hepatic clearance of gastrin and cholecystokinin peptides. Gastroenterology 87:60–68Google Scholar
  47. 47.
    Gores GJ, LaRusso NF, Miller LJ (1986) Hepatic processing of cholecystokinin peptides. I. Structural specificity and mechanism of hepatic extraction. Am J Physiol 250:G344-G349PubMedGoogle Scholar
  48. 48.
    Sakamoto T, Fujimura M, Newman J, Zhu XG, Greeley GH, Thompson JC (1985) Comparison of hepatic elimination of different forms of cholecystokinin in dogs. J Clin Invest 75:280–285PubMedCrossRefGoogle Scholar
  49. 49.
    Hunter EB, Powers SP, Kost LJ, Pinon DI, Miller LJ, LaRusso NF (1990) Physiochemical determinants in hepatic extraction of small peptides. Hepatology 12:76–82PubMedCrossRefGoogle Scholar
  50. 50.
    Dobrinska MR (1989) Enterohepatic circulation of drugs. J Clin Phar 29:577–580Google Scholar
  51. 51.
    Renston RH, Maloney DG, Jones AL (1980) Bile secretory apparatus: evidence for a vesicular transport mechanism for proteins in the rat, using horseradish peroxidase and (125I) insulin. Gastroenterology 78:1373–1388PubMedGoogle Scholar
  52. 52.
    Renston RH, Jones AL, Christansen WD (1980) Evidence for a vesicular transport mechanism in hepatocytes for biliary secretion of immunoglobulin A. Science 208:1276–1278PubMedCrossRefGoogle Scholar
  53. 53.
    Hinton RH, Dobrota M, Mullock BM (1980) Haptoglobin-mediated transfer of haemoglobin from serum into bile. FEBS Lett 112:247–250PubMedCrossRefGoogle Scholar
  54. 54.
    Lee VHL (1990) Mechanisms and facilitation of corneal drug penetration. J Contr Rel 11: 79–90CrossRefGoogle Scholar
  55. 55.
    Thomas P, Toth CA, Zamcheck N (1982) The mechanism of biliary excretion of ai-acid glycoprotein in the rat: evidence for a molecular weight-dependent, nonreceptor-mediated pathway. Hepatology 2:800–803PubMedCrossRefGoogle Scholar
  56. 56.
    Yen WCY, Lee VHL (1994) Paracellular transport of a proteolytically labile pentapeptide across the colonic and other intestinal segments of the albino rabbit: implications for peptide drag design. J Contr Rel 28:97–109CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • V. H. L. Lee

There are no affiliations available

Personalised recommendations