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Novel mucoadhesive system based on sulfhydryl-acrylate interactions

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Abstract

We propose a novel cross-linked mucoadhesive system that can interact covalently with mucin type glycoprotein, thus providing both strong bonding to mucosa as well as ability to function as a sustained release matrix. The strong bonding results from Michael type addition reaction between an acrylate end group on a polymer and the sulfide end group of the mucin type glycoprotein. A proof of concept is provided using a polyehtylene glycol hydrogel formed in situ from polyehtylene glycol di-acrylate (PEG-DA) macromers. The ability of PEG-DA to create interactions with mucin type glycoproteins was verified using nuclear magnetic resonance (NMR) and rheology experiments. NMR studies have detected disappearance of the PEG-DA’s vinyl protons upon mucin addition, whereas rheology measurements have shown a viscosity increase. These results provide an evidence for the formation of mucin-polymer covalent bond. The ability PEG-DA to attach to mucus and promote mucoadhesion was evaluated by tensile measurements. PEG-DA adhered at strength comparable to other covalently interacting mucoadhesive polymers. Furthermore, PEG-DA was found to be a suitable candidate for sustained release of the hydrophilic drug Ibuprofen.

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References

  1. Bernkop-Schnurch A. Mucoadhesive polymers. In: Dumitriu S, Ss Dumitriu, editors. Polymer biomaterial. New York: Marcel Dekker, Inc; 2002. p. 147–65.

    Google Scholar 

  2. Lee JW, Park JH, Robinson JR. Bioadhesive-based dosage forms: the next generation. J Pharm Sci. 2000;89:850–66.

    Article  CAS  PubMed  Google Scholar 

  3. Strous GJ, Dekker J. Mucin-type glycoproteins. Crit Rev Biochem Mol Biol. 1992;27:57–92.

    Article  CAS  PubMed  Google Scholar 

  4. Perez-Vilar J, Hill RL. The structure and assembly of secreted mucins. J Biol Chem. 1999;274:31751–4.

    Article  CAS  PubMed  Google Scholar 

  5. Dekker J, Rossen JWA, Buller HA, Einerhand AWC. The MUC family: an obituary. Trends Biochem Sci. 2002;27:126–31.

    Article  CAS  PubMed  Google Scholar 

  6. Roldo M, Hornof M, Caliceti P, Bernkop-Schnurch A. Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation. Eur J Pharm Biopharm. 2004;57:115–21.

    Article  CAS  PubMed  Google Scholar 

  7. Leitner VM, Walker GF, Bernkop-Schnurch A. Thiolated polymers: evidence for the formation of disulfide bonds with mucus glycoproteins. Eur J Pharm Biopharm. 2003;56:207–14.

    Article  CAS  PubMed  Google Scholar 

  8. Bernkop-Schnuerch A. Thiomers: a new generation of mucoadhesive polymers. Adv Drug Deliv Rev. 2005;57:1569–82.

    Article  CAS  Google Scholar 

  9. Kast CE, Bernkop-Schnurch A. Thiolated polymers—thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates. Biomaterials. 2001;22:2345–52.

    Article  CAS  PubMed  Google Scholar 

  10. Bernkop-Schnurch A, Hornof M, Zoidl T. Thiolated polymers-thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates. Int J Pharm. 2003;260:229–37.

    Article  CAS  PubMed  Google Scholar 

  11. Bernkop-Schnurch A, Scholler S, Biebel RG. Development of controlled drug release systems based on thiolated polymers. J Control Release: Off J Control Release Soc. 2000;66:39–48.

    CAS  Google Scholar 

  12. Davidovich-Pinhas M, Harari O, Bianco-Peled H. Evaluating the mucoadhesive properties of drug delivery systems based on hydrated thiolated alginate. J Control Release. 2009;136:38–44.

    Article  CAS  PubMed  Google Scholar 

  13. Lutolf MP, Tirelli N, Cerritelli S, Colussi L, Hubbell JA. Systematic modulation of michael-type reactivity of thiols through the use of charged amino acids. Bioconjug Chem. 2001;12:1051–6.

    Article  CAS  PubMed  Google Scholar 

  14. Lutolf MP, Hubbell JA. Synthesis and physicochemical characterization of end-linked poly(ethylene glycol)-co-peptide hydrogels formed by Michael-type addition. Biomacromolecules. 2003;4:713–22.

    Article  CAS  PubMed  Google Scholar 

  15. Tortora M, Cavalieri F, Chiessi E, Paradossi G. Michael-type addition reactions for the in situ formation of poly(vinyl alcohol)-based hydrogels. Biomacromolecules. 2007;8:209–14.

    Article  CAS  PubMed  Google Scholar 

  16. Rydholm AE, Bowman CN, Anseth KS. Degradable thiol-acrylate photopolymers: polymerization and degradation behavior of an in situ forming biomaterial. Biomaterials. 2005;26:4495–506.

    Article  CAS  PubMed  Google Scholar 

  17. Seal BL, Panitch A. Viscoelastic behavior of environmentally sensitive biomimetic polymer matrices. Macromolecules. 2006;39:2268–74.

    Article  CAS  ADS  Google Scholar 

  18. Almany L, Seliktar D. Biosynthetic hydrogel scaffolds made from fibrinogen and polyethylene glycol for 3D cell cultures. Biomaterials. 2005;26:2467–77.

    Article  CAS  PubMed  Google Scholar 

  19. Wang Y-Y, Lai SK, Suk JS, Race A, Cone R, Hanes J. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew Chem Int. 2008;47:9726–9.

    Article  CAS  Google Scholar 

  20. Efremova NV, Huang Y, Peppas NA, Leckband DE. Direct measurement of interactions between tethered polyethylene glycol chains and adsorbed mucin layers. Langmuir. 2002;18:836–45.

    Article  CAS  Google Scholar 

  21. Lele BS, Hoffman AS. Mucoadhesive drug carriers based on complexes of poly(acrylic acid) and PEGylated drugs having hydrolyzable PEG-anhydride-drug linkages. J Control Release. 2000;69:237–48.

    Article  CAS  PubMed  Google Scholar 

  22. Bures P, Huang Y, Oral E, Peppas NA. Surface modifications and molecular imprinting of polymers in medical and pharmaceutical applications. J Control Release. 2001;72:25–33.

    Article  CAS  PubMed  Google Scholar 

  23. Yoncheva K, Gomez S, Campanero Miguel A, Gamazo C, Irache Juan M. Bioadhesive properties of pegylated nanoparticles. Expert Opin Drug Deliv. 2005;2:205–18.

    Article  CAS  PubMed  Google Scholar 

  24. Ascentiis AD, deGrazia JL, Bowman CN, Colombo P, Peppas NA. Mucoadhesion of poly(2-hydroxyethyl methacrylate) is improved when linear poly(ethylene oxide) chains are added to the polymer network. J Control Release. 1995;33:197–201.

    Article  CAS  Google Scholar 

  25. Sahlin JJ, Peppas NA. Enhanced hydrogel adhesion by polymer interdiffusion: use of linear poly(ethylene glycol) as an adhesion promoter. J Biomater Sci Polym Ed. 1997;8:421–36.

    Article  CAS  PubMed  Google Scholar 

  26. Huang Y, Leobandung W, Foss A, Peppas NA. Molecular aspects of muco- and bioadhesion: tethered structures and site-specific surfaces. J Control Release. 2000;65:63–71.

    Article  CAS  PubMed  Google Scholar 

  27. Sklenar V, Piotto M, Leppik R, Saudek V. Gradient-tailored water suppression for proton-nitrogen-15 HSQC experiments optimized to retain full sensitivity. J Magn Reson Ser A. 1993;102:241–5.

    Article  CAS  Google Scholar 

  28. Piotto M, Saudek V, Sklenar V. Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. J Biomol NMR. 1992;2:661–5.

    Article  CAS  PubMed  Google Scholar 

  29. Bromberg LE. Interactions between hydrophobically modified polyelectrolytes and mucin. Polym Prepr. 1999;40:616–7.

    CAS  ADS  Google Scholar 

  30. Comyn J. Adhesion science. Cambridge: The royal society of chemistry; 1997.

    Google Scholar 

  31. Schultz J, Nardin M. Theories and mechanisms of adhesion. In: Pizzi A, Mittal KL, editors. Handbook of adhesive technology. New York: Marcel Dekker, Inc.; 1994.

    Google Scholar 

  32. Pocius AV. Adhesion and adhesives technology—an introduction. Cincinnati: Hanser-Gardner; 1997.

    Google Scholar 

  33. Bernkop-Schnurch A, Kast CE, Richter MF. Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine. J Control Release. 2001;71:277–85.

    Article  CAS  PubMed  Google Scholar 

  34. Davidovich-Pinhas M, Bianco-Peled H. Mucoadhesion: a review of characterization techniques. Expert Opin Drug Deliv. 2010;7:259–71.

    Article  CAS  PubMed  Google Scholar 

  35. Rubinstein M, Colby RH. Polymer physics. Oxford: Oxford University Press Inc.; 2003.

    Google Scholar 

  36. Flory PJ. Principles of polymer chemistry, vol. 15. Ithaca, NY: Cornell University; 1953.

    Google Scholar 

  37. Newa M, Bhandari KH, Lee DX, Sung JH, Kim JA, Yoo BK, et al. Enhanced dissolution of ibuprofen using solid dispersion with polyethylene glycol 20,000. Drug Dev Ind Pharm. 2008;34:1013–21.

    Article  CAS  PubMed  Google Scholar 

  38. Newa M, Bhandari KH, Kim J-A, Yoo B-K, Choi H-G, Yong C-S, et al. Preparation and evaluation of fast dissolving ibuprofen-polyethylene glycol 6000 solid dispersions. Drug Deliv. 2008;15:355–64.

    Article  CAS  PubMed  Google Scholar 

  39. Newa M, Bhandari KH, Li DX, Kim JO, Yoo DS, Kim J-A, et al. Preparation and evaluation of immediate release ibuprofen solid dispersions using polyethylene glycol 4000. Biol Pharm Bull. 2008;31:939–45.

    Article  CAS  PubMed  Google Scholar 

  40. Newa M, Bhandari KH, Kim JO, Im JS, Kim JA, Yoo BK, et al. Enhancement of solubility, dissolution and bioavailability of ibuprofen in solid dispersion systems. Chem Pharm Bull. 2008;56:569–74.

    Article  CAS  PubMed  Google Scholar 

  41. Dhawan S, Varma M, Sinha VR. High molecular weight poly(ethylene oxide)-based drug delivery systems. Part I: hydrogels and hydrophilic matrix systems. Pharm Technol. 2005;29(72–74):76–80.

    Google Scholar 

  42. Ritger PL, Peppas NA. A simple equation for description of solute release I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5:23–36.

    Article  CAS  Google Scholar 

  43. Ritger PL, Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release. 1987;5:37–42.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Prof. Seliktar from the department of Biomedical engineering at the Technion, Israel for allowing us to use the PEG-Da synthesis facilities in his lab. The authors also wish to thank Maya Glick and Liran Yerimi for their help in developing the new mucoadhesion test setup.

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Authors and Affiliations

  1. Department of Chemical Engineering, Technion, 32000, Haifa, Israel

    Maya Davidovich-Pinhas & Havazelet Bianco-Peled

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  1. Maya Davidovich-Pinhas
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  2. Havazelet Bianco-Peled
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Correspondence to Havazelet Bianco-Peled.

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Davidovich-Pinhas, M., Bianco-Peled, H. Novel mucoadhesive system based on sulfhydryl-acrylate interactions. J Mater Sci: Mater Med 21, 2027–2034 (2010). https://doi.org/10.1007/s10856-010-4069-6

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  • DOI: https://doi.org/10.1007/s10856-010-4069-6

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