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Synthesis and in Vitro Evaluation of a Novel Chitosan–Glutathione Conjugate

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Purpose

It was the aim of this study to synthesize and characterize a novel chitosan–glutathione (GSH) conjugate providing improved mucoadhesive and permeation-enhancing properties.

Methods

Mediated by carbodiimide and N-hydroxysuccinimide, glutathione was covalently attached to chitosan via the formation of an amide bond. The adhesive properties of chitosan–GSH conjugate were evaluated in vitro on freshly excised porcine mucosa via tensile studies and the rotating cylinder method. The cohesive properties and stability of the resulting conjugate were evaluated by disintegration test and by oxidation experiments, respectively. The permeation-enhancing effect of the chitosan–GSH/GSH system was evaluated in Ussing chambers by using rhodamine 123 as model compound.

Results

The obtained conjugate displayed 265.5 μmol immobilized free thiol groups and 397.9 μmol disulfide bonds per gram polymer. Because of the formation of disulfide bonds within the polymer, the stability of matrix tablets could be strongly improved. In tensile studies, the total work of adhesion of the conjugate was determined to be 9.9-fold increased in comparison to unmodified chitosan. Results from the rotating cylinder method showed more than 55-fold increase in the adhesion time of thiolated chitosan vs. unmodified chitosan. In addition, the conjugate in combination with GSH displayed a 4.9-fold higher permeation-enhancing effect compared with unmodified chitosan.

Conclusions

Because of the improved mucoadhesive and cohesive properties, and the strong permeation-enhancing effect of the chitosan–GSH conjugate/GSH system, the novel thiolated chitosan seems to represent a promising multifunctional excipient for various drug delivery systems.

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References

  1. A. Bernkop-Schnürch V. Schwarz S. Steininger (1999) ArticleTitlePolymers with thiol groups: a new generation of mucoadhesive polymers? Pharm. Res. 16 876–881 Occurrence Handle10.1023/A:1018830204170 Occurrence Handle10397608

    Article  PubMed  Google Scholar 

  2. A. Bernkop-Schnürch C. E. Kast D. Guggi (2003) ArticleTitlePermeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems J. Control. Rel. 93 95–103 Occurrence Handle10.1016/j.jconrel.2003.05.001

    Article  Google Scholar 

  3. A. Bernkop-Schnürch H. Zarti G. F. Walker (2001) ArticleTitleThiolation of polycarbophil enhances its inhibition of soluble and intestinal brush border membrane bound aminopeptidase N J. Pharm. Sci. 90 1907–1914 Occurrence Handle10.1002/jps.1140 Occurrence Handle11745748

    Article  PubMed  Google Scholar 

  4. V. M. Leitner G. F. Walker A. Bernkop-Schnürch (2003) ArticleTitleThiolated polymers: evidence for the formation of disulphide bonds with mucus glycoproteins Eur. J. Pharm. Biopharm. 56 207–214 Occurrence Handle10.1016/S0939-6411(03)00061-4 Occurrence Handle12957634

    Article  PubMed  Google Scholar 

  5. A. Bernkop-Schnürch M. Hoffer K. Kafedjiiski (2004) ArticleTitleThiomers for oral delivery of hydrophilic macromolecular drugs Expert Opin. Drug Deliv. 1 IssueID1): 87–98 Occurrence Handle10.1517/17425247.1.1.87

    Article  Google Scholar 

  6. A. E. Clausen C. E. Kast A. Bernkop-Schnürch (2002) ArticleTitleThe role of glutathione in the permeation enhancing effect of thiolated polymers Pharm. Res. 19 602–608 Occurrence Handle10.1023/A:1015345827091 Occurrence Handle12069161

    Article  PubMed  Google Scholar 

  7. A. Bernkop-Schnürch D. Guggi Y. Pinter (2004) ArticleTitleThiolated chitosans: development and in vivo evaluation of a mucoadhesive permeation enhancing oral drug delivery system J. Control. Rel. 94 177–186 Occurrence Handle10.1016/j.jconrel.2003.10.005

    Article  Google Scholar 

  8. D. Guggi A. Bernkop-Schnürch (2005) ArticleTitleImproved paracellular uptake by the combination of different types of permeation enhancers Int. J. Pharm. 288 141–150 Occurrence Handle10.1016/j.ijpharm.2004.09.023 Occurrence Handle15607266

    Article  PubMed  Google Scholar 

  9. A. Krezel W. Bal (2003) ArticleTitleStructure–function relationships in glutathione and its analogues Org. Biomol. Chem. 1 3885–3890 Occurrence Handle|10.1039/b309306a Occurrence Handle14664379

    Article  PubMed  Google Scholar 

  10. R. F. Hebert. US 2002/ 0002136 A1 (2002).

  11. A. Habeeb (1973) ArticleTitleA sensitive method for localization of disulfide containing peptides in column effluents Anal. Biochem. 56 60–65 Occurrence Handle10.1016/0003-2697(73)90169-3 Occurrence Handle4797196

    Article  PubMed  Google Scholar 

  12. C. E. Kast A. Bernkop-Schnürch (2001) ArticleTitleThiolated polymers–thiomers: development and in vitro evaluation of chitosan–thioglycolic acids conjugates Biomaterials 22 2345–2352 Occurrence Handle10.1016/S0142-9612(00)00421-X Occurrence Handle11511031

    Article  PubMed  Google Scholar 

  13. A. Bernkop-Schnürch M. Hornof T. Zoidl (2003) ArticleTitleThiolated polymers–thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates Int. J. Pharm. 260 229–237 Occurrence Handle10.1016/S0378-5173(03)00271-0 Occurrence Handle12842342

    Article  PubMed  Google Scholar 

  14. Z. Grabarek J. Gergely (1990) ArticleTitleZero-length crosslinking procedure with the use of active esters Anal. Biochem. 185 131–135 Occurrence Handle10.1016/0003-2697(90)90267-D Occurrence Handle2344038

    Article  PubMed  Google Scholar 

  15. D. Guggi M. K. Marschütz A. Bernkop-Schnürch (2004) ArticleTitleMatrix tablets based on thiolated poly(acrylic acid): pH-dependent variation in disintegration and mucoadhesion Int. J. Pharm. 274 97–105 Occurrence Handle10.1016/j.ijpharm.2003.06.001 Occurrence Handle15072786

    Article  PubMed  Google Scholar 

  16. S. A. Mortazavi J. D. Smart (1993) ArticleTitleAn investigation into the role of water movement and mucus gel dehydration in mucoadhesion J. Control. Rel. 25 197–203 Occurrence Handle10.1016/0168-3659(93)90078-J

    Article  Google Scholar 

  17. F. Ferrari M. Bertoni M. C. Bonferoni S. Rossi A. Gazzaniga U. Conte C. Caramella (1995) ArticleTitleInfluence of porosity and formula solubility on disintegration in tablets STP Pharma Sci. 5 116–121

    Google Scholar 

  18. K. Kafedjiiski A. H. Krauland M. H. Hoffer A. Bernkop-Schnürch (2005) ArticleTitleSynthesis and in vitro evaluation of a novel thiolated chitosan Biomaterials 26 819–826 Occurrence Handle10.1016/j.biomaterials.2004.03.011 Occurrence Handle15350788

    Article  PubMed  Google Scholar 

  19. M. Roldo M. Hornof P. Galiceti A. Bernkop-Schnürch (2004) ArticleTitleMucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation Eur. J. Pharm. Biopharm. 57 115–121 Occurrence Handle10.1016/S0939-6411(03)00157-7 Occurrence Handle14729087

    Article  PubMed  Google Scholar 

  20. P. Artursson T. Lindmark S. S. Davis L. Illum (1994) ArticleTitleEffect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2) Pharm. Res. 11 1358–1361 Occurrence Handle10.1023/A:1018967116988 Occurrence Handle7816770

    Article  PubMed  Google Scholar 

  21. A. Bernkop-Schnürch D. Guggi Y. Pinter (2004) ArticleTitleThiolated chitosans: development and in vivo evaluation of a mucoadhesive permeation enhancing oral drug delivery system J. Control. Rel. 94 177–186 Occurrence Handle10.1016/j.jconrel.2003.10.005

    Article  Google Scholar 

  22. A. Bernkop-Schnürch U. M. Brandt A. E. Clausen (1999) ArticleTitleSynthesis and in vitro evaluation of chitosan–cysteine conjugates Sci. Pharm. 67 196–208

    Google Scholar 

  23. A. E. Clausen A. Bernkop-Schnürch (2000) ArticleTitleIn vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil J. Pharm. Sci. 89 1253–1261 Occurrence Handle10.1002/1520-6017(200010)89:10<1253::AID-JPS3>3.0.CO;2-8 Occurrence Handle10980500

    Article  PubMed  Google Scholar 

  24. W. C. Barrett J. P. DeGnore S. Konig H. M. Fales Y. F. Keng Z. Y. Zhang M. B. Yim P. B. Chock (1999) ArticleTitleRegulation of PTP1B via glutathionylation of the active site cysteine 215 Biochemistry 38 6699–6705 Occurrence Handle10.1021/bi990240v Occurrence Handle10350489

    Article  PubMed  Google Scholar 

  25. N. Langoth. Development of buccal drug delivery systems for peptide drugs. Thesis, University of Vienna (2003).

  26. L. A. Dominey K. Kustin (1983) ArticleTitleKinetics and mechanism of Zn (II) complexation with reduced glutathione J. Inorg. Biochem. 18 153–160 Occurrence Handle10.1016/0162-0134(83)80018-X Occurrence Handle6854316

    Article  PubMed  Google Scholar 

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Acknowledgment

This work was supported by Grant “P 15373-MOB” from the Fonds zur Förderung der wissenschaftlichen Forschung (FWF) to Andreas Bernkop-Schnürch.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef Möller Haus, A-6020, Innsbruck, Austria

    Krum Kafedjiiski, Florian Föger & Andreas Bernkop-Schnürch

  2. ThioMatrix GmbH, Research Center, Mitterweg 24, 6020 Innsbruck, Austria

    Martin Werle

Authors
  1. Krum Kafedjiiski
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  2. Florian Föger
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  3. Martin Werle
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  4. Andreas Bernkop-Schnürch
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Correspondence to Andreas Bernkop-Schnürch.

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Kafedjiiski, K., Föger, F., Werle, M. et al. Synthesis and in Vitro Evaluation of a Novel Chitosan–Glutathione Conjugate. Pharm Res 22, 1480–1488 (2005). https://doi.org/10.1007/s11095-005-6248-6

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  • DOI: https://doi.org/10.1007/s11095-005-6248-6

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