Polymeric Permeation Enhancers

  • Hans E. JungingerEmail author


There are enough low molecular permeation enhancers available to increase the absorption of hydrophilic drugs, but all of them have the disadvantage of strongly interfering with the phospholipid membranes and of damaging them. Polymeric permeation enhancers are a class of substances which are able to selectively trigger mechanisms to selectively open the watery channels of the tight junctions which allow the passage of hydrophilic drugs alongside the enterocytes. As these polymeric permeation enhancers are hydrophilic polymeric substances they are generally not absorbed and hence show basically no toxicity. They specifically act, e.g. by binding calcium ions (polyacrylates) and the reversible opening of the tight junctions is triggered. Others – like the chitosans and their quaternary analogues like trimethyl chitosan (TMC) – specifically interact with their positive charges of sialic acid or sulphuric acid of the mucosal linings to induce the same effect. As all the polymeric permeation enhancers have to show mucoadhesivity in order to be effective, their residence time on the mucosal surface is increased. This effect is even strongly increased when thiolated polymeric permeation enhancers are used, which are able to even further increase the mucus residence time of the permeation enhancer. Whereas delivery systems containing polymeric permeation enhancers for application at directly accessible mucous membranes are feasible the peroral application is still a challenge.


Tight Junction Peptide Drug Absorption Enhancer Mucoadhesive Property Thiolated Chitosan 
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  1. Allen, A., Hutton, D.A., Pearson, J.P. and Sellers, L.A. et al. (1998) in M. O’Connor (Ed.): Mucus and Mucosa. Ciba Foundation Symposium, London, Vol. 109: p. 1984Google Scholar
  2. Amidon, G.L., Lennernäs, H., Shah, V.P. and Crison, J.R. (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12: 413PubMedCrossRefGoogle Scholar
  3. Artursson, P., Lindmark, T., Davis, S.S. and Illum, L. (1994) Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm. Res. 11: 1358–1361.PubMedCrossRefGoogle Scholar
  4. Avadi, M.R., Zohourian-Mehr, M.J., Younessi, P., Amini, M., Rafieeh-Tehrani, M., and Shafiee, A. (2003) Optimized synthesis and characterization of N-Triethyl Chitosan. J. Bioact. Compat. Polym. 18: 469–480.CrossRefGoogle Scholar
  5. Avadi, M.R., Sadeghi, A., Tahzibi, A., Bayati, K.H. Pouladzadeh, M. Zohourian-Mehr, M.J. and Rafiee-Tehrani, M. (2004) Diethylmethyl chitosan as antimicrobial agent: Synthesis, characterization and antibacterial effects. Eur. J. Polym. 40: 1355–1361.CrossRefGoogle Scholar
  6. Bayat, A., Sadeghi, M.M., Avadi, M.R., Amini, M, Rafiee-Tehrani, M., Shafiee, A. and Junginger, H.E. (2006) Synthesis of N-N dimethyl N-ethyl chitosan as carrier for oral delivery of peptide drugs. J. Bioact. Compat Polym. 21: 433–444.CrossRefGoogle Scholar
  7. Bernkop-Schnürch, A., Brandt, U.M., and Clausen, A.E. (1999) Synthesis and in vitro evaluation of chitosan-cysteine conjugates Sci. Pharm. 67: 196–206.Google Scholar
  8. Bernkop-Schnürch, A. and Steiniger, S. (2000) Synthesis and characterization of mucoadhesive thiolated polymers. Int. J. Pharm. 194: 239–247.PubMedCrossRefGoogle Scholar
  9. Bernkop-Schnürch, A., Scholler, S. and Biebel, R.G. (2000) Development of controlled drug release systems based on thiolated polymers. J. Control. Release 66: 39–48.PubMedCrossRefGoogle Scholar
  10. Bernkop-Schnürch, A. and Hopf, T.E. (2001) Synthesis and in vitro evaluation of chitosan-thioglycolic acid conjugates. Sci. Pharm. 69: 109–118.Google Scholar
  11. Bernkop-Schnürch, A., Hornof, M. and Zoidl, T. (2003) Thiolated polymers- thiomers: modification of chitosan with 2-iminothiolane. Int. J. Pharm. 260: 229–237.PubMedCrossRefGoogle Scholar
  12. Bernkop-Schnürch, A, Hornof, M. and Guggi, D. (2004) Thiolated chitosans. Eur. J. Pharm. Biopharm. 57: 9–17.PubMedCrossRefGoogle Scholar
  13. Bernkop-Schnürch (2005), Thiomers: A new generation of mucoadhesive polymers. Adv. Drug Deliv. Rev. 57: 1569–1582.PubMedCrossRefGoogle Scholar
  14. Borchard, G., Lueßen, H.L., de Boer, A.G., Verhoef, J.C., Lehr, C.-M. and Junginger, H.E. (1996) The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan glutamate and carbomer on the epithelial tight junctions in vitro. J. Control. Release 39: 131–138.CrossRefGoogle Scholar
  15. Carreno-Gomez, B. and Duncan, R. (1997) Evaluation of the biological properties of soluble chitosan and chitosan microspheres. Int. J. Pharm. 148: 231–240.CrossRefGoogle Scholar
  16. Chae, S.Y., Jang, M.-K. and Nah, J.-W. (2005) Influence of molecular weight on oral absorption of water soluble chitosans. J. Control. Release 102: 383–394.PubMedCrossRefGoogle Scholar
  17. Clausen, A.E. and Bernkop-Schnürch, A. (2000) In vitro evaluation of permeation-enhancing effect of thiolated polycarbophil. J. Pharm. Sci. 89: 1253–1261PubMedCrossRefGoogle Scholar
  18. Dodane, V., Khan, A.M. and Merwin, J.R. (1999) Effect of chitosan on epithelial permeability and structure. Int. J. Pharm. 182: 21–32.PubMedCrossRefGoogle Scholar
  19. Dodou, D., Breedveld, P. and Wieringa, P.A. (2005) Mucoadhesives in the gastrointestinal tract: revisiting the literature for novel applications. Eur. J. Pharm. Biopharm. 60: 1–6.PubMedCrossRefGoogle Scholar
  20. Domard, A., Rinaudo, M. and Terrassin, C. (1986) New method for quaternization of chitosan. Int. J. Biol. Macromol. 8: 105–107.CrossRefGoogle Scholar
  21. Dorkoosh, F.A., Verhoef, J.C. Verheijden, J.H.M., Rafiee-Tehrani, M., Borchard, G. and Junginger, H.E. (2002) Peroral absorption of octreotide in pigs formulated in delivery systems on the basis of superporous hydrogel polymers. Pharm. Res. 19: 1532–1536.PubMedCrossRefGoogle Scholar
  22. Dorkoosh, F.A., Stokkel, M.P.M., Blok, D., Borchard, G., Rafiee-Tehrani, M., Verhoef, J.C. and Junginger, H.E. (2004) Feasibility study on the retention of superporous hydrogel (SPH) composite polymer in the intestinal tract of man using scintigraphy. J. Control. Release 99: 199–206.PubMedCrossRefGoogle Scholar
  23. Forstner, J.F. (1978) Intestinal mucins in health and disease. Digestion 17: 234–263PubMedCrossRefGoogle Scholar
  24. Hornof, M.D., Kast, C.E. and Bernkop-Schnürch, A. (2003) In vitro evaluation of the viscoelastic behavior of chitosan –thioglycolic acid conjugates. Eur. J. Pharm. Biopharm. 55: 185–190.PubMedCrossRefGoogle Scholar
  25. Illum. L., Farraj, N.F. and Davis, S.S. (1994) Chitosan as a novel nasal delivery system for peptide drugs. Pharm. Res. 11: 1186–1189.PubMedCrossRefGoogle Scholar
  26. Junginger, H.E. and Verhoef, J.C. (1998), Macromolecules as safe penetration enhancers for hydrophilic drugs – a fiction? Pharm. Sci. Technol. Today 1: 370–376.CrossRefGoogle Scholar
  27. Kast, C.E. and Bernkop-Schnürch, A. (2001) Thiolated polymers – thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates. Biomaterials 22: 2345–2352.PubMedCrossRefGoogle Scholar
  28. Kotzé, A.F., Lueßen, H.L., de Leeuw, B.J., de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (1998) Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J. Control. Release 51: 35–46PubMedCrossRefGoogle Scholar
  29. Kotzé, A.F., Thanou, M.M., Lueßen, H.L., de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (1999) Enhancement of paracellular drug transport with highly quaternized N-trimethyl chitosan chloride in neutral environment: in vitro evaluation in intestinal epithelial cells (Caco-2). J. Pharm. Sci. 88: 253–257.PubMedCrossRefGoogle Scholar
  30. Lehr, C.-M., Poelma, F.G.J., Junginger, H.E. and Tukker, J.J. (1991) An estimate of turnover time of intestinal mucus gel layer in the rat in situ loop. Int. J. Pharm. 70: 235–240.CrossRefGoogle Scholar
  31. Lehr, C.-M., Bouwstra, J.A., Kok, W., de Boer, A.G., Tukker, J.J., Verhoef, J.C., Breimer, D.D. and Junginger, H.E. (1992a) Effects of the mucoadhesive polymer polycarbophil on the intestinal absorption of a peptide drug in the rat. J. Pharm. Pharmacol. 44: 402–407.PubMedCrossRefGoogle Scholar
  32. Lehr, C.-M., Bouwstra, J.A., Schacht, E.H. and Junginger, H.E. (1992b) In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm. 78: 43–48.CrossRefGoogle Scholar
  33. Leitner, V.M., Marschütz, M.K. and Bernkop-Schnürch, A. (2003a) Mucoadhesive and cohesive properties of poly(acrylic acid)-cysteine conjugates with regard to their molecular mass. Eur. J. Pharm. Sci. 18: 89–96.PubMedCrossRefGoogle Scholar
  34. Leitner, .V.M., Walker, G.F. and Bernkop-Schnürch, A. (2003b) Thiolated polymers: evidence for the formation of disulphide bonds with mucus glycoproteins. Eur. J. Pharm. Biopharm. 56: 207–214PubMedCrossRefGoogle Scholar
  35. Lueßen, H.L., de Leeuw, B.J., Langemeijer, M.W.E., de Boer, A. G, Verhoef, J.C. and Junginger, H.E. (1996a) Mucoadhesive polymers in peroral drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo. Pharm. Res. 13: 1668–1672PubMedCrossRefGoogle Scholar
  36. Lueßen, H.L., de Leeuw, B.J., Pérard, D., C.-M. Lehr, de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (1996b) Mucoadhesive polymers in peroral drug delivery. I. Influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes. Eur. J. Pharm. Sci. 4: 117–128.CrossRefGoogle Scholar
  37. Lueßen, H.L., Rentel, C.-O., Kotzé, A.F., de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (1997) Mucoadhesive polymers in peroral peptide drug delivery. IV. Polycarbophil and chitosan are potent enhancers of peptide transport across intestinal mucosae in vitro. J. Control. Release 45: 15–23.CrossRefGoogle Scholar
  38. Muzzarelli, R.A.A., Tanfani, F., Emmanueli, S. and Mariotti, S. (1982) N-(carboxymethylidene)-chitosans and N-(carboxymethyl)-chitosans: novel chelating polyampholytes obtained from chitosan glyoxylate. Carbohydr. Res. 107: 199–214.CrossRefGoogle Scholar
  39. Noach, A.B.J., Kurosaki, Y., Blom-Rosmalen, M.C.M., de Boer, A.G. and Breimer, D.D. (1993) Cell-polarity dependent effect of chelation on the paracellular permeability of confluent Caco-2 cell monolayers. Int. J. Pharm. 90: 229–237.CrossRefGoogle Scholar
  40. Polnok, A., Borchard, G., Verhoef, J.C., Sarisuta, N. and Junginger, H.E. (2004) Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride. Eur. J. Pharm. Biopharm. 57: 77–83.PubMedCrossRefGoogle Scholar
  41. Roldo, M., Hornof, M., Caliceti, P. and Bernkop-Schnürch, A. (2004) Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation. Eur. J. Pharm. Biopharm 57: 115–121.PubMedCrossRefGoogle Scholar
  42. Rossi, S., Ferrari, F. Bonferoni, M.C. and Caramella, C. (2000) Characterization of chitosan hydrochloride-mucin interactions by means of viscosimetric and turbidimetric measurements. Eur. J. Pharm. Sci. 10: 251–257.PubMedCrossRefGoogle Scholar
  43. Sadeghi, A.M.M., Dorkoosh, F.A., Avadi, M.R., Bayat, A., Delie, F., Gurny, R., Rafieeh-Tehrani, M. and Junginger, H.E. (2008a) Permeation enhancer effect of chitosan and chitosan derivatives: comparison of formulations as soluble polymers and nanoparticulate systems on insulin absorption in Caco-2 cells. Eur. J. Pharm. Biopharm. 70: 270–278.Google Scholar
  44. Sadeghi, A.M.M., Amin, A., Avadi, M.R. Siedi, F., Rafiee-Tehrani, M. and Junginger, H.E. (2008b) Synthesis, characterization and antibacterial effects of trimethylated and triethylated 6-NH2-6-deoxy-chitosan. J. Bioact. Compat. Polym. 23: 262–275.Google Scholar
  45. Sieval, A.B., Thanou, M, Kotzé, A.F., Verhoef, J.C., Brussee, J. and Junginger, H.E. (1998) Preparation and NMR-characterization of highly substituted N-trimethyl chitosan hydrochloride. Carbohydr. Polym 36: 157–165.CrossRefGoogle Scholar
  46. Snyman, D., Hamman, J. H,. Kotzé, J.S., Rollings, J.E. and Kotzé, A.F. (2002) The relationship between the absolute molecular weight and the degree of quaternization of N-trimethyl chitosan chloride. Carbohydr. Polym. 50: 145–150.CrossRefGoogle Scholar
  47. Snyman, D., Hamman, J.H. and Kotzé, A.F. (2003) Evaluation of the mucoadhesive properties of N-trimethyl chitosan chloride. Drug Dev. Ind. Pharm. 29: 59–67.CrossRefGoogle Scholar
  48. Thanou, M. (2000) Chitosan Derivatives in Drug Delivery. Trimethylated and Carboxymethylated Chitosan as Safe Enhancers for the Intestinal Absorption of Hydrophilic Drugs, PhD Thesis, Leiden University, Leiden, pp. 91–108.Google Scholar
  49. Thanou, M., Verhoef, J.C. Romeijn, S.G., Nagelkerke, J.F., Merkus, F.W.H.M. and Junginger, H.E. (1999) Effects of N-trimethyl chitosan chloride, a novel absorption enhancer, on Caco-2 intestinal epithelia and the ciliary beat frequency of chicken embryo trachea. Int. J. Pharm. 185: 73–82.PubMedCrossRefGoogle Scholar
  50. Thanou, M.M., Kotzé, A.F. Scharringhausen, T., Lueßen, H.L., de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (2000a). Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers. J. Control. Release 64: 15–25.PubMedCrossRefGoogle Scholar
  51. Thanou, M., Verhoef, J.C., Marbach, P. and Junginger, H.E. (2000b) N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J. Pharm. Sci. 89: 951–957.PubMedCrossRefGoogle Scholar
  52. Thanou, M., Verhoef, J.C., Verheijden, J.H.M. and Junginger, H.E. (2001a) Intestinal absorption of octreotide using trimethyl chitosan chloride: studies in pigs. Pharm. Res. 18: 823–828.PubMedCrossRefGoogle Scholar
  53. Thanou, M., Verhoef, J.C., Nihot, M.-T., Verheijden, J.H.M. and Junginger, H.E. (2001b) Enhancement of the intestinal absorption of low molecular weight heparin (LMWH) in rats and pigs using Carbopol 934P. Pharm. Res. 18: 1638–1641.PubMedCrossRefGoogle Scholar
  54. Thanou, M., Verhoef, J.C. and Junginger, H.E. (2001c) Oral drug absorption enhancement by chitosan and its derivatives. Adv. Drug Deliv. Rev. 52: 117–126.PubMedCrossRefGoogle Scholar
  55. Thanou, M., Nihot, M.T. , Jansen, M., Verhoef, J.C. and Junginger, H.E. (2001d) Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 90: 38–46.PubMedCrossRefGoogle Scholar
  56. Van der Merwe, S.M., Verhoef, J.C. Verheijden, J.H.M., Kotzé, A.F. and Junginger, H.E. (2004a) Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs. Eur. J. Pharm. Biopharm. 58: 225–235.PubMedCrossRefGoogle Scholar
  57. Van der Merwe, Verhoef, J.C., Kotzé, A.F. and Junginger, H.E. (2004b) N-Trimethyl chitosan chloride as absorption enhancer in oral peptide drug delivery. Development and characterization of minitablet and granule formulations. Eur. J. Pharm. Biopharm. 57: 85–91.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutics, Faculty of Pharmaceutical SciencesNaresuan UniversityPhitsanulokThailand

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