Challenges for the oral delivery of macromolecules

Key Points

  • Macromolecules comprise a growing group of new pharmaceutical products with the potential to treat diseases that heretofore have had no effective therapeutic options.

  • To date, the therapeutic application of these drugs has been limited because they are effective only when administered parenterally.

  • Since the discovery of insulin and heparin in the early 1900s, there has been keen interest in solving the problem of orally delivering macromolecules safely and effectively. Various approaches have been investigated including altering the intestinal membrane, targeting intestinal transport mechanisms, chemically altering the drug and carrier-assisted transport mechanisms.

  • To date, the most promising approach has been the carrier-assisted approach, which has advanced seven different macromolecules or highly charged small molecules human proof-of-concept testing.

Abstract

The rapid integration of new technologies by the pharmaceutical industry has resulted in numerous breakthroughs in the discovery, development and manufacturing of pharmaceutical products. In particular, the commercial-scale production of high-purity recombinant proteins has resulted in important additions to treatment options for many large therapeutic areas. In addition to proteins, other macromolecules, such as the animal-derived mucopolysacharide heparins, have also seen dramatic growth as injectable pharmaceutical products. To date, macromolecules have been limited as therapeutics by the fact that they cannot be orally delivered. This article will address the current status and future possibilities of oral macromolecular drug delivery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Schematic representation of drug diffusion across a transport barrier.
Figure 2: Pathways of oral drug absorption.
Figure 3: Structure of insulin and hexyl-insulin monoconjugate 2 (HIM2).
Figure 4: Effect of oral insulin, formulated using eligen technology, on fasting plasma glucose in a Phase I clinical study (N = 8).
Figure 5: Results from a Phase I clinical study with Emisphere oral heparin (N = 10).

References

  1. 1

    Brange, J. & Langkjaer, L. in Protein Delivery: Physical Systems (eds Sanders, L. M. & Hendren, R. W.) 343–412 (Plenum, New York, 1997).

    Google Scholar 

  2. 2

    Chetty, D. J. & Chien, Y. W. Novel methods of insulin delivery: an update. Crit. Rev. Ther. Drug Carrier Syst. 15, 629–670 (1998).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Lever, R. & Page, C. P. Novel drug development opportunities for heparin. Nature Rev. Drug Discov. 1, 140–148 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Shah, R. B., Ahsan, F. & Khan, M. A. Oral delivery of proteins: progress and prognostication. Crit. Rev. Ther. Drug Carrier Syst. 19, 135–169 (2002).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Lee, H. J. Protein drug oral delivery: the recent progress. Arch. Pharm. Res. 25, 572–584 (2002).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Sood, A. & Panchagnula, R. Peroral route: an opportunity for protein and peptide drug delivery. Chem. Rev. 101, 3275–3303 (2001). Comprehensive review of approaches for oral delivery of macromolecules

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Gomez-Orellana, I. & Paton, D. R. Advances in the oral delivery of proteins. Exp. Opin. Ther. Patents 8, 223–234 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Gomez-Orellana, I. & Paton, D. R. Advances in the oral delivery of proteins. Update. Exp. Opin. Ther. Patents 9, 247–253 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Donovan, M. D., Flynn, G. L. & Amidon, G. L. Absorption of polyethylene glycols 600 through 2000: the molecular weight dependence of gastrointestinal and nasal absorption. Pharm. Res. 7, 863–868 (1990).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Camenisch, G., Alsenz, J., van de Waterbeemd, H. & Folkers, G. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. Eur. J. Pharm. Sci. 6, 317–324 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Woodley, J. F. Enzymatic barriers for GI peptide and protein delivery. Crit. Rev. Ther. Drug Carrier Syst. 11, 61–95 (1994).

    CAS  PubMed  Google Scholar 

  12. 12

    Rubinstein, A. Approaches and opportunities in colon-specific drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 12, 101–149 (1995).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    van den Mooter, G. & Kinget, R. Oral colon-specific drug delivery: a review. Drug Deliv 2, 81–93 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Tozaki, H. et al. Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: implications in peptide delivery to the colon. J. Pharm. Pharmacol. 49, 164–168 (1997).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Bernkop-Schnurch, A. The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins. J. Control. Release 52, 1–16 (1998). Informative review of different approaches developed to protect protein and peptide drugs from proteolytic degradation in the gastrointestinal tract.

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Bernkop-Schnurch, A. & Walker, G. Multifunctional matrices for oral peptide delivery. Crit. Rev. Ther. Drug Carrier Syst. 18, 459–501 (2001).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Mathiowitz, E. et al. Biologically erodable microspheres as potential oral drug delivery systems Nature 386, 410–414 (1997).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Jung, T. et al. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake?. Eur. J. Pharm. Biopharm. 50, 147–160 (2000). Recent review of polymeric materials used for oral delivery of macromolecules

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Florence, A. T. & Hussain, N. Transcytosis of nanoparticle and dentrimer delivery systems: evolving vistas. Adv. Drug Deliv. Rev. 50, S69–S89 (2001).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Kompella, U. B. & Lee, V. H. L. Delivery systems for penetration enhancement of peptide and protein drugs: design considerations. Adv. Drug Deliv. Rev. 46, 211–245 (2001).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Winiwarter, S. et al. Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J. Med. Chem. 41, 4939–4949 (1998).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Lennernas, H. Human intestinal permeability. J. Pharm. Sci. 87, 403–410 (1998).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Daugherty, A. L. & Mrsny, R. J. Regulation of the intestinal epithelial paracellular barrier. Pharm. Sci. Technol. Today 2, 281–287 (1999). Comprehensive review of paracellular absorption mechanims.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Madara, J. L. Modulation of tight junctional permeability. Adv. Drug Deliv. Rev. 41, 251–253 (2000).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Swenson, E. S. & Curatolo, W. J. Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity. Adv. Drug Deliv. Rev. 8, 39–92 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Daugherty, A. L. & Mrsny, R. J. Transcellular uptake mechanisms of the intestinal epithelial barrier. Part one. Pharm. Sci. Technol. Today 4, 144–151 (1999).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Chao, A. C. et al. Enhancement of intestinal model compound transport by DS-1, a modified Quillaja saponin. J. Pharm. Sci. 87, 1395–1399 (1998).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Fix, J. A. Strategies for delivery of peptides utilizing absorption-enhancing agents. J. Pharm. Sci. 85, 1282–1285 (1996).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Dorkoosh, F. A. et al. Effects of superporous hydrogels on paracellular drug permeability and cytotoxicity studies in Caco-2 cell monolayers. Int. J. Pharm. 241, 35–45 (2002).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Thanou, M., Verhoef, J. C., Junginger, H. E. Oral drug absorption enhancement by chitosan and its derivatives. Adv. Drug Deliv. Rev. 52, 117–126 (2001).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Torres-Lugo, M., Garcia, M., Record, R. & Peppas, N. A. pH-Sensitive hydrogels as gastrointestinal tract absorption enhancers: transport mechanisms of salmon calcitonin and other model molecules using the Caco-2 cell model. Biotechnol. Prog. 18, 612–616 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ward, P. D., Tippin, T. K. & Thakker, D. R. Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm. Sci. Technol. Today 3, 346–358 (2000).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Fasano, A. & Uzzau, S. Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J. Clin. Invest. 99, 1158–1164 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Yamamoto, A. et al. Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs. J. Pharmacol. Exp. Ther. 296, 84–90 (2001).

    CAS  PubMed  Google Scholar 

  35. 35

    Numata, N. et al. Improvement of intestinal absorption of macromolecules by nitric oxide donor. J. Pharm. Sci. 89, 1296–1304 (2000).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Watanabe, Y. et al. Absorption enhancement of a protein drug by nitric oxide donor: effect on nasal absorption of human granulocyte colony-stimulating factor. J. Drug Target. 8, 185–194 (2000).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Yen, W. C. & Lee, V. H. Role of Na+ in the asymmetric paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg across rabbit colonic segments and Caco-2 cell monolayers. J. Pharmacol. Exp. Ther. 275, 114–119 (1995).

    CAS  PubMed  Google Scholar 

  38. 38

    Raoof, A. A. et al. Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs. Eur. J. Pharm. Sci. 17, 131–138 (2002).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Hosny, E. A., Elkheshen, S. A. & Saleh, S. I. Buccoadhesive tablets for insulin delivery: in vitro and in vivo studies. Boll. Chim. Farm. 141, 210–217 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Modi, P., Mihic, M. & Lewin, A. The evolving role of oral insulin in the treatment of diabetes using a novel RapidMist System. Diabetes Metab. Res. Rev. 18, S38–S42 (2002).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Dyer, A. M. et al. Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles. Pharm. Res. 19, 998–1008 (2002).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Callens, C., Pringels, E. & Remon, J. P. Influence of multiple nasal administrations of bioadhesive powders on the insulin bioavailability. Int. J. Pharm. 250, 415–422 (2003).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Sayani, A. P. & Chien, Y. W. Systemic delivery of peptides and proteins across absorptive mucosae. Crit. Rev. Ther. Drug Carrier Syst. 13, 85–184 (1996).

    CAS  PubMed  Google Scholar 

  44. 44

    Williams, G. C. & Sinko, P. J. Oral absorption of the HIV protease inhibitors: a current update. Adv. Drug Deliv. Rev. 39, 211–238 (1999).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Porter, C. J. & Charman, W. N. In vitro assessment of oral lipid based formulations. Adv. Drug Deliv. Rev. 50, S127–S147 (2001).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Rubio-Aliaga, I. & Daniel, H. Mammalian peptide transporters as targets for drug delivery. Trends Pharmacol. Sci. 23, 434–440 (2002).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Swaan, P. W. Recent advances in intestinal macromolecular drug delivery via receptor-mediated transport pathways. Pharm. Res. 15, 826–834 (1998). Informative review of receptor-mediated transport systems available in the gastrointestinal tract and their potential for facilitating macromolecule absorption.

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Oh, D. M., Han, H. K. & Amidon, G. L. Drug transport and targeting. Intestinal transport. Pharm. Biotechnol. 12, 59–88 (1999).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Rouquayrol, M., Gaucher, B., Roche, D., Greiner, J. & Vierling, P. Transepithelial transport of prodrugs of the HIV protease inhibitors saquinavir, indinavir, and nelfinavir across Caco-2 cell monolayers. Pharm. Res. 19, 1704–1712 (2002).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Nielsen, C. U. et al. Dipeptide model prodrugs for the intestinal oligopeptide transporter. Affinity for and transport via hPepT1 in the human intestinal Caco-2 cell line. J. Control. Release 76, 129–138 (2001).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Borchardt, R., Aube, J., Siahaan, T. J., Gangwar, S. & Pauletti, G. M. Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies. Adv. Drug Deliv. Rev. 27, 235–256 (1997).

    Article  Google Scholar 

  52. 52

    Kramer, W. et al. Intestinal absorption of bile acids: paradoxical behaviour of the 14 kDa ileal lipid-binding protein in differential photoaffinity labelling. Biochem. J. 333, 335–341 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Swaan, P. W., Hillgren, K. M., Szoka, F. C. Jr. & Oie, S. Enhanced transepithelial transport of peptides by conjugation to cholic acid. Bioconjug. Chem. 8, 520–525 (1997).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Russell-Jones, G. J., Westwood, S. W. & Habberfield, A. D. Vitamin B12 mediated oral delivery systems for granulocyte-colony stimulating factor and erythropoietin. Bioconjug. Chem. 6, 459–465 (1995).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Russell-Jones, G. J. Use of vitamin B12 conjugates to deliver protein drugs by the oral route. Crit. Rev. Ther. Drug Carrier Syst. 15, 557–586 (1998).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Habberfield, A., Jensen-Pippo, K., Ralph, L., Westwood, S. & Russel-Jones, G. J. Vitamin B12-mediated uptake of recombinant therapeutic proteins from the gut. Int. J. Pharm. 145, 1–8 (1996).

    CAS  Article  Google Scholar 

  57. 57

    Spiekermann, G. M. et al. Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung. J. Exp. Med. 196, 303–310 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Neutra, M. R., Wilson, J. M., Weltzin, R. A. & Kraehenbuhl, J. P. Membrane domains and macromolecular transport in intestinal epithelial cells. Am. Rev. Respir. Dis. 138, S10–S16 (1988).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Russell-Jones, G. J., Arthur, L. & Walker, H. Vitamin B12-mediated transport of nanoparticles across Caco-2 cells. Int. J. Pharm. 179, 247–255 (1999).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Clackson, T. & Wells, J. A. A hot spot of binding energy in a hormone-receptor interface. Science 267, 383–386 (1995).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Wrighton, N. C. et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273, 458–463 (1996).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Maslov, D. L., Lokhov, P. G., Abakumova, O. Y., Tsvetkova, T. A. & Prozorovskiy, V. N. J. New peptidomimetics of insulin. J. Biochem. Mol. Biol. Biophys. 6, 261–265 (2002)

    CAS  PubMed  Google Scholar 

  63. 63

    Cwirla, S. E. et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 276, 1696–1699 (1997).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Clement, S., Still, J. G. & Kosutic, G. Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: The glucose stabilization effects of HIM2. Diabetes Technol. Ther. 4, 459–466 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Kipnes, M., Dandona, P., Tripathy, D., Still, J. G. & Kosutic, G. Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes. Diabetes Care 26, 421–426 (2003).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Asada, H. et al. Absorption characteristics of chemically modified-insulin derivatives with various fatty acids in the small and large intestine. J. Pharm. Sci. 84, 682–687 (1995).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Lee, Y., Nam, J. H., Shin, H. C. & Byun, Y. Conjugation of low-molecular-weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent. Circulation 104, 3116–3120 (2001).

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Uchiyama, T. et al. Development of novel lipophilic derivatives of DADLE (leucine enkephalin analogue): intestinal permeability characateristics of DADLE derivatives in rats. Pharm. Res. 17, 1461–1467 (2000).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Yodoya, E. et al. Enhanced permeability of tetragastrin across the rat intestinal membrane and its reduced degradation by acylation with various fatty acids. J. Pharmacol. Exp. Ther. 271, 1509–1513 (1994).

    CAS  PubMed  Google Scholar 

  70. 70

    Hashizume, M. et al. Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats. J. Pharm. Pharmacol. 44, 555–559 (1992).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Yamada, K., Murakami, M., Yamamoto, A., Takada, K. & Muranishi, S. Improvement of intestinal absorption of thyrotropin-releasing hormone by chemical modification with lauric acid. J. Pharm. Pharmacol. 44, 717–721 (1992).

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Masuda, K., Horie, K., Suzuki, R., Yoshikawa, T. & Hirano, K. Oral delivery of antigens in liposomes with some lipid compositions modulates oral tolerance to the antigens. Microbiol. Immunol. 46, 55–58 (2002).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Lasic, D. D. Novel applications of liposomes. Trends. Biotechnol. 16, 307–321 (1998).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Porter, C. J. Drug delivery to the lymphatic system. Crit. Rev. Ther. Drug Carrier Syst. 14, 333–393 (1997).

    CAS  PubMed  Google Scholar 

  75. 75

    Abbas, R. et al. Oral insulin: pharmacokinetics and pharmacodynamics of human insulin following oral administration of an insulin/delivery agent capsule in healthy volunteers. Diabetes 51, A48 (2002).

    Google Scholar 

  76. 76

    Baughman, R. A. et al. Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans. Circulation 98, 1610–1615 (1998).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Buclin, T., Rochat, M. C., Burckhardt, P., Azria, M. & Attinger, M. Bioavailability and biological efficacy of new oral formulation of salmon calcitonin in healthy volunteers. J. Bone Miner. Res. 17, 1478–1485 (2002).

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Milstein, S. J. et al. Partially unfolded proteins efficiently penetrate cell membranes- implications for oral drug delivery. J. Control. Release 53, 259–267 (1998).

    CAS  Article  PubMed  Google Scholar 

  79. 79

    Engelman, D. M. & Steitz, T. A. The spontaneous insertion of proteins into and across membranes: the helical hairpin hypothesis. Cell 23, 411–422 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Sabatini, D. D., Kreibich, G., Morimoto, T. & Adesnik, M. Mechanisms for the incorporation of proteins in membranes and organelles. J. Cell Biol. 92, 1–22 (1982).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Zimmerman, R. & Meyer, D. I. A year of new insights into how proteins cross membranes. Trends Biochem. Sci. 11, 512–515 (1986).

    Article  Google Scholar 

  82. 82

    van der Goot, F. G., Gonzalez-Manas, J. M., Lakey, J. H. & Pattus, F. A 'molten-globule' membrane-insertion intermediate of the pore-forming domain of colicin A. Nature 354, 408–10 (1991).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Sanz, J. M. & Gimenez-Gallego, G. A partly folded state of acidic fibroblast growth factor at low pH. Eur. J. Biochem. 246, 328–35 (1997).

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Leone-Bay, A. et al. Oral delivery of biologically active parathyroid hormone. Pharm. Res. 18, 964–970 (2001).

    CAS  Article  PubMed  Google Scholar 

  85. 85

    Brayden, D. et al. Heparin absorption across the intestine: Effects of sodium N-[8(2-hydroxybenzoyl) amino]caprylate in rat in situ intestinal instillations and in CACO-2 monolayers. Pharm. Res. 14, 1772–1779 (1997).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Wu, S. -J. & Robinson, J. R. Transcellular and lipophilic complex-enhanced intestinal absorption of human growth hormone. Pharm. Res. 16, 1266–1272 (1999).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Malkov, D., Wang, H., Dinh, S. & Gomez-Orellana, I. Pathway of oral absorption of heparin with sodium N-[8-(2-hydroxylbenzoyl)amino]caprylate. Pharm. Res. 19, 1180–1184 (2002).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Stoll, B. R., Leipold, H., Milstein, S. & Edwards, D. A. A mechanistic analysis of carrier–mediated oral delivery of protein therapeutics. J. Control. Release 64, 217–228 (2000).

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Michael Goldberg or Isabel Gomez-Orellana.

Related links

Related links

DATABASES

LocusLink

Insulin

tissue plasminogen activator

FURTHER INFORMATION

Encyclopedia of Life Sciences

History of insulin

Glossary

BIOAVAILABILITY

The extent to which a drug becomes available in the bloodstream, or at the target tissue, after administration.

LIPOPHILICITY

The extent of insolubility in water or resistance to hydration of a molecule or chemical entity.

HYDROPHILICITY

The extent of solubility in water or the ability to be hydrated of a molecule or chemical entity.

TRANSCYTOSIS

The process by which polarized cells transport certain molecules by engulfing them into vesicles that are released at the opposite side of the cells.

ENTEROCYTES

Epithelial cells that form the gastrointestinal wall.

TIGHT JUNCTION

An intercellular junction that seals together adjacent epithelial cells, preventing the passage of substances through the spaces in between cells.

FUNCTIONAL GROUP

A chemical group with specific properties attached to a molecule.

PHARMACOKINETICS

The way in which drugs are absorbed, distributed, localized in tissues, metabolized and excreted over a period of time.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Goldberg, M., Gomez-Orellana, I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov 2, 289–295 (2003). https://doi.org/10.1038/nrd1067

Download citation

Further reading