Skip to main content
SpringerLink
Log in
Book cover

Oral Delivery of Macromolecular Drugs pp 65–83Cite as

Strategies to Overcome the Enzymatic Barrier

  • Chapter
  • First Online:

Abstract

Enzymatic degradation of various hydrophilic macromolecules including peptide- or protein drugs by enzymes present in the gastrointestinal tract can be regarded as one main reason for their poor bioavailability after peroral administration. Within the current chapter, strategies to overcome the so-called enzymatic barrier are described. Besides formulations that can protect the drug from enzymatic digestion via, e.g., drug encapsulation and chemical modifications of the drug itself, an emphasis has been put forward on enzyme inhibitors.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Bernkop-Schnürch A, Fragner R (1996) Investigations into the diffusion behaviour of polypeptides in native intestinal mucus with regard to their peroral administration. Pharm Sci 2:361–363

    Google Scholar 

  • Bernkop-Schnürch A, Göckel NC (1997) Development and analysis of a polymer protecting from luminal enzymatic degradation caused by a-chymotrypsin. Drug Dev Ind Pharm 23:733–740

    Article  Google Scholar 

  • Bernkop-Schnürch A, Kast CE, Guggi D (2003) Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer / GSH systems. J Control Release. 2003 Dec 5; 93(2):95–103.

    Google Scholar 

  • Bernkop-Schnürch A (1998) The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins. J Control Release 52(1-2):1–16.

    Google Scholar 

  • Bernkop-Schnürch A, Krajicek ME (1998) Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan-EDTA conjugates. J Control Rel 50:215–223

    Article  Google Scholar 

  • Bernkop-Schnürch A, Marschütz MK (1997) Development and in vivo evaluation of systems to protect peptide drugs from aminopeptidase N. Pharm Res 14:181–185

    Article  Google Scholar 

  • Bernkop-Schnürch A, Paikl C, Valenta C (1997) Novel bioadhesive chitosan-EDTA conjugate protects leucine enkephalin from degradation by aminopeptidase N. Pharm Res 14:917–922

    Article  Google Scholar 

  • Bernkop-Schnürch A, Thaler S (2000) Polycarbophil-cysteine conjugates as platforms for oral (poly)peptide delivery systems. J Pharm Sci 89:901–909

    Article  PubMed  Google Scholar 

  • Bernkop-Schnürch A, Walker G, Zarti H (2001) Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase N. J Pharm Sci 90:1907–1914

    Article  Google Scholar 

  • Biruss B, Valenta C (2006) Skin permeation of different steroid hormones from polymeric coated liposomal formulations. Eur J Pharm Biopharm 62:210–219

    Article  PubMed  CAS  Google Scholar 

  • Brochard G, Luessen HL, Verhoef JC, Lehr CM, de Boer AG, Junginger HE (1996) The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Rel 39:131–138

    Article  Google Scholar 

  • Carmel R (1994) In vitro studies of gastric juice in patients with food-cobalamin malabsorption. Dig Dis Sci 39:2516–2522

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta P, Singh A, Mukherjee R (2002) N-terminal acylation of somatostatin analog with long chain fatty acids enhances its stability and anti-proliferative activity in human breast adenocarcinoma cells. Biol Pharm Bull 25:29–36

    Article  PubMed  CAS  Google Scholar 

  • Delgado C, Francis GE, D. F (1992) The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 9:249–304

    PubMed  CAS  Google Scholar 

  • Drapeau G, Petitclerc E, Toulouse A, Marceau F (1992) Dissociation of the antimicrobial activity of bacitracin USP from its renovascular effects. Antimicrob Agents Chemother 36:955–961

    PubMed  CAS  Google Scholar 

  • Fujii S, Yokohama T, Ikegaya K, Salo F, Yakoo N (1985) Promoting effect of the new chymotrypsin inhibitor FK-448 on the intestinal absorption of insulin in rats and dogs. J Pharm Pharmacol 37:545–549

    Article  PubMed  CAS  Google Scholar 

  • Garner CWJ, Behal FJ (1974) Human liver aminopeptidase. Role of metal ions in mechanism of action. Biochemistry 13:3227–3233

    Article  PubMed  CAS  Google Scholar 

  • Gotoh S, Nakamura R, Nishiyama M, Fujita T, Yamamoto S, Muranishi S (1995) Does bacitracin have an absorption-enhancing effect in the intestine? Biol Pharm Bull 18:794–796

    Article  PubMed  CAS  Google Scholar 

  • Guggi D, Bernkop-Schnürch A (2003) In vitro evaluation of polymeric excipients protecting calcitonin against degradation by intestinal serine proteases. Int J Pharm 252:187–196

    Article  PubMed  CAS  Google Scholar 

  • Guggi D, Krauland AH, Bernkop-Schnürch A (2003) Systemic peptide delivery via the stomach: in vivo evaluation of an oral dosage form for salmon calcitonin. J Control Release 92:125–135

    Article  PubMed  CAS  Google Scholar 

  • He XH, Shaw PC, Tam SC (1999) Reducing the immunogenicity and improving the in vivo activity of trichosanthin by site-directed pegylation. Life Sci 65:355–368

    Article  PubMed  CAS  Google Scholar 

  • Hussain MA, Lim MS, Raghavan KS, Rogers NJ, Hidalgo R, Kettner CA (1992) A phosphinic acid dipeptide analogue to stabilize peptide drugs during their intranasal absorption. Pharm Res 9:626–628

    Article  PubMed  CAS  Google Scholar 

  • Hussain MA, Shenvi AB, Rowe SM, Shefter E (1989) The use of alpha-aminoboronic acid derivatives to stabilize peptide drugs during their intranasal absorption. Pharm Res 6:186–189

    Article  PubMed  CAS  Google Scholar 

  • Ikesue K, Kopecková P, Kopecek J (1993) Degradation of proteins by guinea pig intestinal enzymes. Int J Pharm 95:171–179

    Article  CAS  Google Scholar 

  • Itoh M, Matsuo Y (1994) Gastric ulcer treatment with intravenous human epidermal growth factor: a double-blind controlled clinical study. J Gastroenterol Hepatol 9:78–83

    Article  Google Scholar 

  • Junginger HE (1990) Bioadhesive polymer systems for peptide delivery. Acta Pharm Technol 36:110–126

    CAS  Google Scholar 

  • Kimura T, Sato K, Sugimoto K, Tao R, Murakami T, Kurosaki Y, Nakayama T (1996) Oral administration of insulin as poly(vinyl alcohol)-gel spheres in diabetic rats. Biol Pharm Bull 19:897–900

    Article  PubMed  CAS  Google Scholar 

  • Langguth P, Bohner V, Biber J, Merkle HP (1994) Metabolism and transport of the pentapeptide metkephamid by brush-border membrane vesicles of rat intestine. J Pharm Pharmacol 46:34–40

    Article  PubMed  CAS  Google Scholar 

  • Lee VHL (1990) Protease Inhibitors and Penetration Enhancers as Approaches to Modify Peptide Absorption. J Control Rel 213–223

    Google Scholar 

  • Lehr C-M (1994) Bioadhesion technologies for the delivery of peptide and protein drugs to the gastrointestinal tract. Crit Rev Ther Drug 11:119–160

    CAS  Google Scholar 

  • Lindahl A, Ungell A-L, Knutson L, Lennerna:s H (1997) Characterization of fluids from the stomach and proximal jejunum in men and women. Pharm Res 14:497–502

    Article  PubMed  CAS  Google Scholar 

  • Loretz B, Föger FA, Werle M, Bernkop-Schnürch A (2006) Oral gene delivery: Strategies to improve stability of pDNA towards intestinal digestion. J Drug Targ 14:311–319

    Article  CAS  Google Scholar 

  • Luessen HL, Bohner V, Perard D, Langguth P, Verhoef JC, de Boer AG, Merkle HP, Junginger HE (1996) Mucoadhesive polymers in peroral peptide drug delivery.V. Effect of poly(acrylates) on the enzymatic degradation of peptide drugs by intestinal brush border membrane vesicles. Int J Pharm 141:39–52

    Article  CAS  Google Scholar 

  • Luessen HL, de Leeuw BJ, Langemeyer MW, de Boer AG, Verhoef JC, Junginger HE (1996) Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo. Pharm Res 13:1668–1672

    Article  PubMed  CAS  Google Scholar 

  • Luessen HL, de Leeuw BJ, Perard D, Lehr C-M, de Boer AG, Verhoef JC, Junginger HE (1996) Mucoadhesive polymers in peroral peptide drug delivery. I. Influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes. Eur J Pharm Sci 4:117–128

    Article  CAS  Google Scholar 

  • Luessen HL, Verhoef JC, Borchard G, Lehr CM, de Boer AG, Junginger HE (1995) Mucoadhesive polymers in peroral peptide drug delivery. II. Carbomer and polycarbophil are potent inhibitors of the intestinal proteolytic enzyme trypsin. Pharm Res 12:1293–1298

    Article  PubMed  CAS  Google Scholar 

  • Marschütz MK, Bernkop-Schnürch A (2000) Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials 21:1499–1507

    Article  PubMed  Google Scholar 

  • Marschütz MK, Veronese FM, Bernkop-Schnürch A (2001) Influence of the spacer on the inhibitory effect of different polycarbophil-protease inhibitor conjugates. Eur J Pharm Biopharm 52:137–144

    Article  PubMed  Google Scholar 

  • McCaffrey G, Jamieson JC (1993) Evidence for the role of a cathepsin D-like activity in the release of gal beta 1-4 glnac alpha 2-6 sialyltransferase from rat and mouse liver in whole-cell systems. Comp Biochem Phys C 104:91–94

    CAS  Google Scholar 

  • McClellan JBJ, Garner CW (1980) Purification and properties of human intestine alanine aminopeptidase. Biochim Biophys Acta 613:160–167

    PubMed  CAS  Google Scholar 

  • McConnell RM, Frizell D, Evans ACA, Jones W, Cagle C (1991) New pepstatin analogues: synthesis and pepsin inhibition. J Med Chem 34:2298–2300

    Article  PubMed  CAS  Google Scholar 

  • Okagawa T, Fujita T, Murakami M, Yamamoto A, Shimura T, Tabata S, Kondo S, Muranishi S (1994) Susceptibility of ebiratide to proteolysis in rat intestinal fluid and homogenates and its protection by various protease inhibitors. Life Sciences 55:677–683

    Article  PubMed  CAS  Google Scholar 

  • Plumpton C, Kalinka S, Martin RC, Horton JK, Davenport AP (1994) Effects of phosphoramidon and pepstatin A on the secretion of endothelin-1 and big endothelin-1 by human umbilical vein endothelial cells – measurement by two-site enzyme-linked immunosorbent assay. Clin Sci 87:245–251

    PubMed  CAS  Google Scholar 

  • Raehs SC, Sandow J, Wirth K, Merkle HP (1988) The adjuvant effect of bacitracin on nasal absorption of gonadorelin and buserelin in rats. Pharm Res 5:689–693

    Article  PubMed  CAS  Google Scholar 

  • Ramon J, Saez V, Baez R, Aldana R, Hardy E (2005) PEGylated Interferon-alpha2b: A Branched 40 K Polyethylene Glycol Derivative. Pharm Res 22:1375–1387

    Article  Google Scholar 

  • Reseland JE, Holm H, Jacobsen MB, Jenssen TG, Hanssen LE (1996) Proteinase inhibitors induce selective stimulation of human trypsin and chymotrypsin secretion. J Nutr 126:634–642

    PubMed  CAS  Google Scholar 

  • Saffran M, Bedra C, Kumar GS, Neckers DC (1988) Vasopressin: a model for the study of effects of additives on the oral and rectal administration of peptide drugs. J Pharm Sci 77:33–38

    Article  PubMed  CAS  Google Scholar 

  • Salhanick AI, Clairmont KB, Buckholz TM, Pellegrino CM, Ha S, Lumb KJ (2005) Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide. Bioorg Med Chem Lett 15:4114–4117

    Article  PubMed  CAS  Google Scholar 

  • Sanderink G-J, Artur Y, Siest G (1988) Human aminopeptidase: a review of the literature. J Clin Chem Clin Biochem 26:795–807

    PubMed  CAS  Google Scholar 

  • Sangadala S, Walters FS, English LH, Adang MJ (1994) A mixture of Manduca sexta aminopeptidase and phosphatase enhances Bacillus thuringiensis insecticidal CryIA(c) toxin binding and 86Rb(+)-K+ efflux in vitro. J Biol Chem 269:10088–10092

    PubMed  CAS  Google Scholar 

  • Scott MJ, Huckaby CS, Kato I, Kohr WJ, Laskowski MJ, Tsai MJ, O’Malley BW (1987) Ovoinhibitor introns specify functional domains as in the related and linked ovomucoid gene. J Biol Chem 262:5899–5907

    PubMed  CAS  Google Scholar 

  • Stryer L (1988) Biochemistry. W.H. Freeman and Company, New York

    Google Scholar 

  • Ushirogawa Y (1992) 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 81:133

    Article  CAS  Google Scholar 

  • Valenta C, Christen B, Bernkop-Schnürch A (1998) Chitosan-EDTA conjugate: a novel polymer for topical gels. J Pharm Pharmacol 50:445–452

    Article  PubMed  CAS  Google Scholar 

  • Valenta C, Marschutz M, Egyed C, Bernkop-Schnürch A (2002) Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH. J Pharm Pharmacol 54:603–610

    Article  PubMed  CAS  Google Scholar 

  • Walker B, McCarthy N, Healy A, Ye T, McKervey MA (1993) Peptide gyoxals-a novel class of inhibitor for serine and cysteine proteinases. Biochem J 193:321–323

    Google Scholar 

  • Werle M (2007) Analytical methods for the characterisation of multifunctional polymers for oral drug delivery. Current pharmaceutical analysis 3:111–116

    Article  CAS  Google Scholar 

  • Werle M, Loretz B, Entstrasser D, Föger F (2007) Design and evaluation of a Chitosan-Aprotinin conjugate for the peroral delivery of therapeutic peptides and proteins susceptible to enzymatic degradation. J Drug Targ 15:327–333

    Article  CAS  Google Scholar 

  • Werle M, Schmitz T, Huang H, Wentzel A, Kolmar H, Bernkop-Schnürch A (2006) The potential of cystine-knot microproteins as novel pharmacophoric scaffolds in oral peptide drug delivery. J Drug Targ 14:137–146

    Article  CAS  Google Scholar 

  • Wu ZH, Ping QN, Song YM, Lei XM, Li JY, Cai P (2004) Studies on the insulin-liposomes double-coated by chitosan and chitosan-EDTA conjugates. Yao Xue Xue Bao 39:933–938

    PubMed  CAS  Google Scholar 

  • Yamamoto A, Taniguchi T, Rikyun K, Tsuji T, Fujita T, Murakami M, Muranishi S (1994) Effects of Various Protease Inhibitors on the Intestinal Absorption and Degradation of Insulin in Rats. Pharm Res 11:1496–1500

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Pharmaceutical Engineering, Department of Drug Delivery Technology and Science, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu, Japan

    Martin Werle & Hirofumi Takeuchi

Authors
  1. Martin Werle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirofumi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Werle .

Editor information

Editors and Affiliations

  1. Naturwissenschaftliche Fakultät, Universität Innsbruck, Innrain 52, Innsbruck, 6020, Austria

    Andreas Bernkop-Schnürch

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Werle, M., Takeuchi, H. (2009). Strategies to Overcome the Enzymatic Barrier. In: Bernkop-Schnürch, A. (eds) Oral Delivery of Macromolecular Drugs. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0200-9_4

Download citation

Publish with us

Policies and ethics

Search

Navigation