American Journal of Drug Delivery

, Volume 4, Issue 2, pp 65–77 | Cite as

Oral delivery of hematopoietic factors

Progress with gastrointestinal mucoadhesive patches, microdevices, and other microfabrication technologies
Review Article


As a second wave of biopharmaceuticals, oral protein/peptide delivery systems have been studied and applied to hematopoietic factors such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Many conventional oral drug-delivery systems such as absorption enhancers, emulsions, liposomes, microcapsules and nanocapsules, protein-unfolding technology, protein conjugates, and colon delivery technology have been challenged for the development of oral hematopoietic factor preparations. Those drug-delivery systems were designed to solve two hurdles: hydrolytic degradation by the digestive enzymes and poor membrane permeability of hematopoietic factors due to their three-dimensional structures. Furthermore, all of the trials have faced a hurdle of low bioavailability, because the dilution and spreading of an absorption enhancer in the gastrointestinal tract reduces the effect of the absorption enhancer on hematopoietic factors. To solve these problems, the gastrointestinal mucoadhesive patch system (GI-MAPS) was designed.

The GI-MAPS is based on a patch formulation composed of three layers: (i) a water-insoluble basement membrane; (ii) a drug-carrying layer; and (iii) a pH-sensitive bioadhesive surface membrane. After oral administration, the surface layer dissolves at the targeted intestinal site and adheres to the small intestinal wall, where a closed space is created on the target site of the gastrointestinal mucosa by adhering to the mucosal membrane. As a result, both the drug and the absorption enhancer coexist in the closed space and a high-concentration gradient is formed between inside the system and the enterocytes, which contributes to the enhanced absorption of hematopoietic factors because most drugs are absorbed by a passive-diffusion mechanism. As a result, the absorption enhancer makes full use of its capacity.

The GI-MAPS was applied to both G-CSF and EPO and feasibility studies were performed in rats and dogs. The Eudragit™ L100 GI-MAPS containing both G-CSF and HCO-60™ as an absorption enhancer showed a physiologic availability of 23% in dogs and the total white blood cell count peaked at 170% after administration. The GI-MAPS containing EPO and Labrasol™ as an absorption enhancer showed a bioavailability of 12.1% in rats. Thus, the GI-MAPS proof of concept has been clarified.

As the GI-MAPS is a novel drug-delivery system preparation, the fabrication method is the second hurdle to overcome in the launch of an oral preparation of hematopoietic factors. However, recent advances in microfabrication technology in the semiconductor industry have made it possible to produce many micron-size GI-MAPS. Several approaches to produce the micron-size GI-MAPS are described and the future of these technologies is discussed.


  1. 1.
    Crommelin DJ, Sindelar RD. Pharmaceutical biotechnology. Amsterdam: Harwood Academic Publishers, 1997Google Scholar
  2. 2.
    Szkrybalo W. Emerging trends in biotechnology: a perspective from the pharmaceutical industry. Pharm Res 1987; 4: 361–3PubMedCrossRefGoogle Scholar
  3. 3.
    Bienz-Tadmor B. Biopharmaceuticals go to market: patterns of worldwide development. Biotechnology (NY) 1993; 11: 168–72CrossRefGoogle Scholar
  4. 4.
    Drews J. Intent and coincidence in pharmaceutical discovery: the impact of biotechnology. Arznmittel Forschung 1995; 45: 934–9Google Scholar
  5. 5.
    Vermeij P, Blok D. New peptide and protein drugs. Pharm World Sci 1996; 18: 87–93PubMedCrossRefGoogle Scholar
  6. 6.
    Wilding IR, Davis SS, O’Hagan DT. Targeting of drugs and vaccines to the gut. Pharmacol Ther 1994; 62: 97–124PubMedCrossRefGoogle Scholar
  7. 7.
    Zhou XH. Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs. J Control Release 1994; 29: 239–52CrossRefGoogle Scholar
  8. 8.
    Healey JNC. Enteric coatings and delayed release. In: Hardy JG, Davis SS, Wilson CG, editors. Drug delivery to the gastrointestinal tract. New York: John Wiley & Sons, 1989: 83–96Google Scholar
  9. 9.
    Gomez-Orellana I, Paton DR. Advances in the oral delivery of proteins. Exp Opin Ther Patents 1998; 8: 223–34CrossRefGoogle Scholar
  10. 10.
    Shah RB, Ahsan F, Khan MA. Oral delivery of proteins: progress and prognostication. Crit Rev Ther Drug Carrier Syst 2002; 19: 135–69PubMedCrossRefGoogle Scholar
  11. 11.
    Sayani AP, Chien YW. Systemic delivery of peptides and proteins across absorptive mucosae. Crit Rev Ther Drug Carrier Syst 1996; 13: 85–184PubMedGoogle Scholar
  12. 12.
    Iwabuchi A, Makino K, Kanda M. Influence of gastrointestinal microflora on digestibility and biological value of protein in rats. J Nutr Sci Vitaminol (Tokyo) 1993; 39: 489–96CrossRefGoogle Scholar
  13. 13.
    Bai JPF. Colonic delivery of peptide and protein drugs: consideration of intracellular proteolytic enzymes. STP Pharma Sci 1995; 5: 30–5Google Scholar
  14. 14.
    Bai JPF. Distribution of brush-border membrane peptidases along the rat intestine. Pharm Res 1994; 11: 897–900PubMedCrossRefGoogle Scholar
  15. 15.
    Bai JPF. Subcellular distribution of proteolytic activities degrading bioactive peptides and analogues in the rat small intestinal and colonic enterocytes. J Pharm Pharmacol 1994; 46: 671–5PubMedCrossRefGoogle Scholar
  16. 16.
    Michael S, Thöle M, Dillmann R, et al. Improvement of intestinal peptide absorption by a synthetic bile acid derivative, cholylsarcosine. Eur J Pharm Sci 2000; 10: 133–40PubMedCrossRefGoogle Scholar
  17. 17.
    Chao AC, Nguyen JV, Broughall M, et al. In vitro and in vivo evaluation of effects of sodium caprate on enteral peptide absorption and on mucosal morphology. Int J Pharm 1999; 191: 15–24PubMedCrossRefGoogle Scholar
  18. 18.
    Hochman J, Artursson P. Mechanisms of absorption enhancement and tight junction regulation. J Control Release 1994; 29: 253–67CrossRefGoogle Scholar
  19. 19.
    Lo YL, Huang JD. Effects of sodium deoxycholate and sodium caprate on the transport of epirubicin in human intestinal epithelial caco-2 cell layers and everted gut sacs of rats. Biochem Pharmacol 2000; 59: 665–72PubMedCrossRefGoogle Scholar
  20. 20.
    Mesiha M, Plakogiannis F, Vejosoth S. Enhanced oral absorption of insulin from desolvated fatty acid-sodium glycocholate emulsions. Int J Pharm 1994; 111: 213–6CrossRefGoogle Scholar
  21. 21.
    Rivera TM, Leone-Bay A, Paton DR, et al. Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl) amino] caprylate: pharmacological considerations. Pharm Res 1997; 14: 1830–4PubMedCrossRefGoogle Scholar
  22. 22.
    Amidon GL, Lennernas H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995; 12: 413–20PubMedCrossRefGoogle Scholar
  23. 23.
    Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutics classification system: the central role of dose/solubility ratio. Pharm Res 2003; 20: 1917–25PubMedCrossRefGoogle Scholar
  24. 24.
    Dantzig AH. Oral absorption of β-lactams by intestinal peptide transport proteins. Adv Drug Deliv Rev 1997; 23: 63–76CrossRefGoogle Scholar
  25. 25.
    Lee VHL, Yamamoto A, Kompella UB. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit Rev Ther Drug Carrier Syst 1991; 8: 91–192PubMedGoogle Scholar
  26. 26.
    Schreier S, Malheiros SVP, de Paula E. Surface active drugs: self-association and interaction with membranes and surfactants: physicochemical and biological aspects. Biochem Biophys Acta 2000; 1508: 210–34PubMedCrossRefGoogle Scholar
  27. 27.
    Takada K, Ushirogawa Y. Effect of pH, dietary proteins and trypsin inhibitors on the hydrolytic rates of human granulocyte colony-stimulating factor (G-CSF) by rat digestive enzymes. J Pharmacobiodyn 1991; 14: 363–70PubMedCrossRefGoogle Scholar
  28. 28.
    Ushirogawa Y, Nakahigashi Y, Kiriyama A, et al. Effect of organic acids, trypsin inhibitors and dietary protein on the pharmacological activity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats. Int J Pharm 1992; 81: 133–41CrossRefGoogle Scholar
  29. 29.
    Friedman DI, Amidon GL. Oral absorption of peptides: influence of pH and inhibitors on the intestinal hydrolysis of leu-enkephalin and analogues. Pharm Res 1991; 8: 93–6PubMedCrossRefGoogle Scholar
  30. 30.
    Ohtani S, Ogawara K, Higaki K, et al. Casein enhances stability of peptides in intestinal lumen: role of digested products of casein. Pharm Res 2003; 20: 1746–51PubMedCrossRefGoogle Scholar
  31. 31.
    Fujii S, Yokoyama T, Ikegaya Y, et al. Promoting effect of the new chymotrypsin inhibitor FK-448 on the intestinal absorption of insulin in rats and dogs. J Pharm Pharmacol 1985; 37: 545–9PubMedCrossRefGoogle Scholar
  32. 32.
    Liu H, Tang R, Pan W, et al. Potential utility of various protease inhibitors for improving the intestinal absorption of insulin in rats. J Pharm Pharmacol 2003; 55: 1523–9PubMedCrossRefGoogle Scholar
  33. 33.
    Bai JPF. Effects of bile salts on brush-border and cytosolic proteolytic activities of intestinal enterocytes. Int J Pharm 1994; 111: 147–52CrossRefGoogle Scholar
  34. 34.
    Shah RB, Khan MA. Protection of salmon calcitonin breakdown with serine proteases by various ovomucoid species for oral drug delivery. J Pharm Sci 2004; 93: 392–406PubMedCrossRefGoogle Scholar
  35. 35.
    Cho MJ, Scieszka JF, Burton PS. Citric acid as an adjuvant for transepithelial transport. Int J Pharm 1989; 52: 79–81CrossRefGoogle Scholar
  36. 36.
    Hayashi M, Sakai T, Hasegawa T, et al. Physiological mechanism for enhancement of paracellular drug transport. J Control Release 1999; 62: 141–8PubMedCrossRefGoogle Scholar
  37. 37.
    Unigene Inc [online]. Available from URL: [Accessed 2004]
  38. 38.
    Nishimura K, Nozaki Y, Yoshimi A, et al. Studies on the promoting effects of carboxylic acid derivatives on the rectal absorption of β-lactam antibiotics in rats. Chem Pharm Bull (Tokyo) 1985; 33: 282–91CrossRefGoogle Scholar
  39. 39.
    Fix JA, Gardner CR. Rectal drug delivery: a viable alternative? Pharm Int 1986; 272–5Google Scholar
  40. 40.
    Hoogdalem EJV, Stijnen AM, Boer AGD, et al. Rate-controlled absorption enhancement of rectally administered cefazolin in rats by a glyceride mixture (MGK). J Pharm Pharmacol 1988; 40: 329–32PubMedCrossRefGoogle Scholar
  41. 41.
    Anderberg EK, Lindmark T, Artursson P. Sodium caprate elicits dilatations in human intestinal tight junctions and enhances drug absorption by the paracellular route. Pharm Res 1993; 10: 857–64PubMedCrossRefGoogle Scholar
  42. 42.
    Shima M, Kimura Y, Adachi S, et al. Recovery of caco-2 cell monolayers to normal from the transport-enhanced state induced by capric acid sodium salt and its monoacylglycerol. Biosci Biotechnol Biochem 1999; 63: 680–7CrossRefGoogle Scholar
  43. 43.
    Thanou M, Verhoef JC, Junginger HE. Trimethylated chitosan derivatives are effective and safe penetration enhancers for oral peptide drug delivery and absorption. S T P Pharm Sci 2000; 10: 315–9Google Scholar
  44. 44.
    Thanou M, Verhoef JC, Junginger HE. Oral drug absorption enhancement by chitosan and its derivatives. Adv Drug Deliv Rev 2001; 52: 117–26PubMedCrossRefGoogle Scholar
  45. 45.
    Mizuno A, Ueda M, Kawanishi G. Effects of salicylate and other enhancers on rectal absorption of erythropoietin in rats. J Pharm Pharmacol 1992; 44: 570–3PubMedCrossRefGoogle Scholar
  46. 46.
    Moriya H, Maitani Y, Shimoda N, et al. Pharmacokinetic and pharmacological profiles of free and liposomal recombinant human erythropoietin after intravenous and subcutaneous administrations in rats. Pharm Res 1997; 14: 1621–8PubMedCrossRefGoogle Scholar
  47. 47.
    Maitani Y, Morita H, Shimoda N, et al. Distribution characteristics of entrapped recombinant human erythropoietin in liposomes and its intestinal absorption in rats. Int J Pharm 1999; 185: 13–22PubMedCrossRefGoogle Scholar
  48. 48.
    Maitani Y, Hazawa M, Tojo Y, et al. Oral administration of recombinant human erythropoietin in liposomes in rats: influence of lipid composition and size of liposomes on bioavailability. J Pharm Sci 1996; 85: 440–5PubMedCrossRefGoogle Scholar
  49. 49.
    Patel HM, Stevenson RW, Parson JA, et al. Use of liposomes to acid intestinal absorption of entrapped insulin in normal and diabetic dogs. Biochim Biophys Acta 1982; 716: 186–93CrossRefGoogle Scholar
  50. 50.
    Brayden DJ, O’Mahony DJ. Novel oral drug delivery gateways for biotechnology products: polypeptides and vaccines. Pharm Sci Technol Today 1998; 7: 291–9CrossRefGoogle Scholar
  51. 51.
    Woodley JF. Liposomes for oral administration of drugs. Crit Rev Ther Drug Carrier Syst 1985; 2: 1–18PubMedGoogle Scholar
  52. 52.
    Choudhari KB, Labhasetwar V, Dorle AK. Liposomes as a carrier for oral administration of insulin: effect of formulation factors. J Microencapsul 1994; 11: 319–25PubMedCrossRefGoogle Scholar
  53. 53.
    Mathiowitz E, Jacob JS, Jong YS, et al. Biologically erodible microspheres as potential oral drug delivery systems. Nature 1997; 386: 410–4PubMedCrossRefGoogle Scholar
  54. 54.
    Eyles JE, Alpar HO, Conway BR, et al. Oral delivery of poly(lactic acid) micro-sphere-encapsulated interferon in rats. J Pharm Pharmacol 1997; 49: 669–74PubMedCrossRefGoogle Scholar
  55. 55.
    Jenkins PG, Howard KA, Blackhall NW, et al. The quantitation of the absorption of microparticles into the intestinal lymph of Wistar rats. Int J Pharm 1994; 102: 261–6CrossRefGoogle Scholar
  56. 56.
    Sinko PJ, Lee Y-H, Makhey V, et al. Biopharmaceutical approach for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT). Pharm Res 1999; 16: 527–33PubMedCrossRefGoogle Scholar
  57. 57.
    Lee YH, Perry B, Sutyak JP, et al. Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin absorption in dogs. Pharm Res 2000; 17: 284–90PubMedCrossRefGoogle Scholar
  58. 58.
    Johnston TP, Rahman A, Alur H, et al. Permeation of unfolded basic fibroblast growth factor (bFGF) across rabbit buccal mucosa: does unfolding of bFGF enhance transport? Pharm Res 1998; 15: 246–53PubMedCrossRefGoogle Scholar
  59. 59.
    Jensen-Pippo KE, Whitcomb KL, DePrince RB, et al. Enteral bioavailability of human granulocyte colony stimulating factor conjugated with poly(ethylene glycol). Pharm Res 1996; 13: 102–7PubMedCrossRefGoogle Scholar
  60. 60.
    Russell-Jones GJ, Westwood SW, Habberfield AD. Vitamin B12 mediated oral delivery systems for granulocyte-colony stimulating factor and erythropoietin. Bioconjug Chem 1995; 6: 459–65PubMedCrossRefGoogle Scholar
  61. 61.
    Habberfield A, Jensen-Pippo K, Ralph L, et al. Vitamin B12-mediated uptake of erythropoietin and granulocyte colony stimulating factor in vitro and in vivo. Int J Pharm 1996; 145: 1–8CrossRefGoogle Scholar
  62. 62.
    Lim C-J, Shen W-C. Comparison of monomeric and oligomeric transferring as potential carrier in oral delivery of protein drugs. J Control Release 2005; 106: 273–86PubMedCrossRefGoogle Scholar
  63. 63.
    Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9: 249–304PubMedGoogle Scholar
  64. 64.
    Russell-Jones GJ. Use of vitamin B12 conjugates to deliver protein drugs by the oral route. Crit Rev Ther Drug Carrier Syst 1998; 15: 557–86PubMedCrossRefGoogle Scholar
  65. 65.
    Hovgaard D, Mortensen BT, Schifter S, et al. Comparative pharmacokinetics of single-dose administration of mammalian and bacterially-derived recombinant human granulocyte-macrophage colony-stimulating factor. Eur J Haematol 1993; 50: 32–6PubMedCrossRefGoogle Scholar
  66. 66.
    Wilding I. Site-specific drug delivery in the gastrointestinal tract. Crit Rev Ther Drug Carrier Syst 2000; 17: 557–620PubMedCrossRefGoogle Scholar
  67. 67.
    Saffran M, Kumar GS, Savariar C, et al. A new approach to the oral administration of insulin and other peptide drugs. Science 1986; 233: 1081–4PubMedCrossRefGoogle Scholar
  68. 68.
    Van den Mooter G, Maris B, Samyn C, et al. Use of azo polymers for colon-specific drug delivery. J Pharm Sci 1997; 86: 1321–7PubMedCrossRefGoogle Scholar
  69. 69.
    Ashford M, Fell JT. Targeting drugs to the colon: delivery systems for oral administration. J Drug Target 1994; 2: 241–58PubMedCrossRefGoogle Scholar
  70. 70.
    Haupt S, Rubinstein A. The colon as a possible target for orally administered peptide and protein drugs. Crit Rev Ther Drug Carrier Syst 2002; 19: 499–551PubMedCrossRefGoogle Scholar
  71. 71.
    Fish NW, Bloor JR. Drug delivery to the colon. Exp Opin Ther Patents 1999; 9: 1515–21CrossRefGoogle Scholar
  72. 72.
    Niwa K, Takaya T, Morimoto T, et al. Preparation and evaluation of a time-controlled release capsule made of ethylcellulose for colon delivery of drugs. J Drug Target 1995; 3: 83–9PubMedCrossRefGoogle Scholar
  73. 73.
    Takaya T, Ikeda C, Imagawa N, et al. Development of a colon delivery capsule and the pharmacological activity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in beagle dogs. J Pharm Pharmacol 1995; 47: 474–8PubMedCrossRefGoogle Scholar
  74. 74.
    Stevens HNE, Wilson CG, Welling PG, et al. Evaluation of Pulsincap™ to provide regional delivery of dofetilide to the human GI tract. Int J Pharm 2002; 236: 27–34PubMedCrossRefGoogle Scholar
  75. 75.
    Wilson CG, Bakhshaee M, Stevens HNE, et al. Evaluation of a gastro-resistant pulsed release delivery system (Pulsincap™) in humans. Drug Deliv 1997; 4: 201–6CrossRefGoogle Scholar
  76. 76.
    Dorkoosh FA, Verhoef JC, Borchard G, et al. Development and characterization of a novel peroral peptide drug delivery system. J Control Release 2001; 71: 307–18PubMedCrossRefGoogle Scholar
  77. 77.
    Dorkoosh FA, Verhoef JC, Verheijden JHM, et al. Peroral absorption of octreotide in pigs formulated in delivery systems on the basis of superporous hydrogel polymers. Pharm Res 2002; 19: 1532–6PubMedCrossRefGoogle Scholar
  78. 78.
    Dorkoosh FA, Verhoef JC, Borchard G, et al. Intestinal absorption of human insulin in pigs using delivery systems based on superporous hydrogel polymers. Int J Pharm 2002; 247: 47–55PubMedCrossRefGoogle Scholar
  79. 79.
    Schnurch B, Walker G. Multifunctional matrices for oral peptide delivery. Crit Rev Ther Drug Carrier Syst 2001; 18: 459–501Google Scholar
  80. 80.
    Eiamtrakarn S, Itoh Y, Kishimoto J, et al. Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein. Biomaterials 2002; 23: 145–52PubMedCrossRefGoogle Scholar
  81. 81.
    Takada K, Venkatesan N. Oral administration of erythropoietin (EPO) using gastro-intestinal mucoadhesive patch system (GI-MAPS). Proceedings of 2004 AAPS Annual Meeting; 2004 Nov 10; Baltimore (MD).Google Scholar
  82. 82.
    Whitehead K, Shen Z, Mitragotri S. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J Control Release 2004; 98: 37–45PubMedCrossRefGoogle Scholar
  83. 83.
    Eaimtrakarn S, Itoh Y, Kishimoto J, et al. Retention and transit of intestinal mucoadhesive films in rat small intestine. Int J Pharm 2001; 224: 61–7PubMedCrossRefGoogle Scholar
  84. 84.
    Eaimtrakarn S, Rama Prasad YV, Puthli SP, et al. Evaluation of gastrointestinal transit characteristics of oral patch preparation using caffeine as a model drug in human volunteers. Drug Metab Pharmacokinet 2002; 17: 284–91PubMedCrossRefGoogle Scholar
  85. 85.
    Shen Z, Mitragotri S. Intestinal patches for oral drug delivery. Pharm Res 2002; 19: 391–5PubMedCrossRefGoogle Scholar
  86. 86.
    Ahmed A, Bonner C, Desai TA. Bioadhesive microdevices with multiple reservoirs: a new platform for oral drug delivery. J Control Release 2002; 81: 291–306PubMedCrossRefGoogle Scholar
  87. 87.
    Tao SL, Lubeley MW, Desai TA. Bioadhesive poly(methyl methacrylate) microdevices for controlled drug delivery. J Control Release 2003; 88: 215–28PubMedCrossRefGoogle Scholar
  88. 88.
    Lehr C-M. Bioadhesion technology for the delivery of peptide and protein drugs to the gastrointestinal tract. Crit Rev Ther Drug Carrier Syst 1994; 11: 119–60PubMedGoogle Scholar
  89. 89.
    Tao SL, Desai TA. Gastrointestinal patch systems for oral drug delivery. Drug Discov Today 2005; 10: 909–15PubMedCrossRefGoogle Scholar
  90. 90.
    Venkatesan N, Yoshimitsu J, Ito Y, et al. Liquid filled nanoparticles as a drug delivery tool for protein therapeutics. Biomaterials 2005; 26: 7154–63PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of PharmacokineticsKyoto Pharmaceutical UniversityKyotoJapan

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