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A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone

  • Anna Maria Piras
  • Ylenia Zambito
  • Susi Burgalassi
  • Daniela Monti
  • Silvia Tampucci
  • Eleonora Terreni
  • Angela Fabiano
  • Federica Balzano
  • Gloria Uccello-Barretta
  • Patrizia Chetoni
Biomaterials Synthesis and Characterization Original Research
Part of the following topical collections:
  1. Biomaterials Synthesis and Characterization

Abstract

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.

Notes

Acknowledgements

We gratefully acknowledge the financial support from P.R.A. 2017 by the University of Pisa.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10856_2018_6048_MOESM1_ESM.pdf (545 kb)
Supplementary Material

References

  1. 1.
    Liu L, Zhu S. A study on the supramolecular structure of inclusion complex of β-cyclodextrin with prazosin hydrochloride. Carbohydr Polym. 2007;68:472–6.  https://doi.org/10.1016/j.carbpol.2006.11.007.CrossRefGoogle Scholar
  2. 2.
    Marques HMC, Hadgraft J, Kellaway IW. Studies of cyclodextrin inclusion complexes. I. The salbutamol-cyclodextrin complex as studied by phase solubility and DSC. Int J Pharm. 1990;63:259–66.  https://doi.org/10.1016/0378-5173(90)90132-N.CrossRefGoogle Scholar
  3. 3.
    Yang JS, Yang L. Preparation and application of cyclodextrin immobilized polysaccharides. J Mater Chem B. 2013;1:909–18.  https://doi.org/10.1039/c2tb00107a.CrossRefGoogle Scholar
  4. 4.
    Hansch C, Lao A, Hoekman D. Exploring QSAR. Hydrophobic, electronic and steric constants. Crit Rev Toxicol. 1995;25:67–89.CrossRefGoogle Scholar
  5. 5.
    Rodríguez Villanueva J, Rodríguez Villanueva L, Guzmán Navarro M. Pharmaceutical technology can turn a traditional drug, dexamethasone into a first-line ocular medicine. A global perspective and future trends. Int J Pharm. 2017;516:342–51.CrossRefGoogle Scholar
  6. 6.
    Loftsson T, Stefánsson E Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye. Int J Pharmaceut. 2017.  https://doi.org/10.1016/j.ijpharm.2017.04.010.
  7. 7.
    Di Colo G, Zambito Y, Zaino C, Sansò M. Selected polysaccharides at comparison for their mucoadhesiveness and effect on precorneal residence of different drugs in the rabbit model. Drug Dev Ind Pharm. 2009;35:941–9.CrossRefGoogle Scholar
  8. 8.
    Fabiano A, Chetoni P, Zambito Y. Mucoadhesive nano-sized supramolecular assemblies for improved pre-corneal drug residence time. Drug Dev Ind Pharm. 2015;41:2069–76.CrossRefGoogle Scholar
  9. 9.
    Piras AM, Sandreschi S, Maisetta G, Esin S, Batoni G, Chiellini F. Chitosan nanoparticles for the linear release of model cationic peptide. Pharm Res. 2015;32:2259–65.  https://doi.org/10.1007/s11095-014-1615-9.CrossRefGoogle Scholar
  10. 10.
    Dash M, Samal SK, Douglas TEL, Schaubroeck D, Leeuwenburgh SC, Van Der Voort P, et al. Enzymatically biomineralized chitosan scaffolds for tissue-engineering applications. J Tissue Eng Regen Med. 2017;11:1500–13.  https://doi.org/10.1002/term.2048 CrossRefGoogle Scholar
  11. 11.
    Piras AM, Maisetta G, Sandreschi S, Gazzarri M, Bartoli C, Grassi L, et al. Chitosan nanoparticles loaded with the antimicrobial peptide temporin B exert a long-term antibacterial activity in vitro against clinical isolates of Staphylococcus epidermidis. Front Microbiol. 2015;6(APR).  https://doi.org/10.3389/fmicb.2015.00372.
  12. 12.
    Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J. Bioadhesion of hydrated chitosans: an in vitro and in vivo study. Int J Pharm. 1996;145:231–40.  https://doi.org/10.1016/S0378-5173(96)04776-X.CrossRefGoogle Scholar
  13. 13.
    Lehr C-M, Bouwstra JA, Schacht EH, Junginger HE. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm. 1992;78:43–8.  https://doi.org/10.1016/0378-5173(92)90353-4.CrossRefGoogle Scholar
  14. 14.
    Tamer TM, Hassan MA, Omer AM, Valachova K, Eldin MSM, Collins MN. et al. Antibacterial and antioxidative activity of O-amine functionalized chitosan. Carbohydr Polym. 2017;169:441–50.  https://doi.org/10.1016/j.carbpol.2017.04.027.CrossRefGoogle Scholar
  15. 15.
    Prabaharan M, Mano JF. Chitosan derivatives bearing cyclodextrin cavitiesas novel adsorbent matrices. Carbohydr Polym. 2006;63:153–66.  https://doi.org/10.1016/j.carbpol.2005.08.051.CrossRefGoogle Scholar
  16. 16.
    Chaleawlert-umpon S, Nuchuchua O, Saesoo S, Gonil P, Ruktanonchai UR, Sajomsang W. et al. Effect of citrate spacer on mucoadhesive properties of a novel water-soluble cationic β-cyclodextrin-conjugated chitosan. Carbohydr Polym. 2011;84:186–94.  https://doi.org/10.1016/j.carbpol.2010.11.017.CrossRefGoogle Scholar
  17. 17.
    Laine V, Coste-Sarguet A, Gadelle A, Defaye J, Perly B, Djedaini-Pilard F. Inclusion and solubilization properties of 6-S-glycosyl-6-thio derivatives of [small beta]-cyclodextrin. J Chem Soc, Perkin Trans. 1995;2:1479–87.  https://doi.org/10.1039/P29950001479.CrossRefGoogle Scholar
  18. 18.
    Zambito Y, Felice F, Fabiano A, Di Stefano R, Di Colo G. Mucoadhesive nanoparticles made of thiolated quaternary chitosan crosslinked with hyaluronan. Carbohydr Polym. 2013;92:33–9.  https://doi.org/10.1016/j.carbpol.2012.09.029.CrossRefGoogle Scholar
  19. 19.
    Zambito Y, Uccello-Barretta G, Zaino C, Balzano F, Di Colo G. Novel transmucosal absorption enhancers obtained by aminoalkylation of chitosan. Eur J Pharm Sci. 2006;29:460–9.  https://doi.org/10.1016/j.ejps.2006.09.001.CrossRefGoogle Scholar
  20. 20.
    Zambito Y, Zaino C, Uccello Barretta G, Balzano F, Di Colo G. Improved synthesis of quaternary ammonium–chitosan conjugates (N+–Ch) for enhanced intestinal drug permeation. Eur J Pharm Sci. 2008;33:343–50.CrossRefGoogle Scholar
  21. 21.
    Jansook P, Loftsson T. CDs as solubilizers: effects of excipients and competing drugs. Int J Pharm. 2009;379:32–40.CrossRefGoogle Scholar
  22. 22.
    Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59:645–66.CrossRefGoogle Scholar
  23. 23.
    Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4:117–212.Google Scholar
  24. 24.
    Hassan E, Gallo J. A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharm Res. 1990;7:491–5.CrossRefGoogle Scholar
  25. 25.
    Chetoni P, Monti D, Tampucci S, Matteoli B, Ceccherini-Nelli L, Subissi A, et al. Liposomes as a potential ocular delivery system of distamycin A. International. J Pharm. 2015;492:120–6.Google Scholar
  26. 26.
    Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol. 2010;62:1607–21.CrossRefGoogle Scholar
  27. 27.
    Gonil P, Sajomsang W, Ruktanonchai UR, Pimpha N, Sramala I, Nuchuchua O. et al. Novel quaternized chitosan containing β-cyclodextrin moiety: synthesis, characterization and antimicrobial activity. Carbohydr Polym. 2011;83:905–13.  https://doi.org/10.1016/j.carbpol.2010.08.080.CrossRefGoogle Scholar
  28. 28.
    Song LX, Teng CF, Xu P, Wang HM, Zhang ZQ, Liu QQ. Thermal decomposition behaviors of β-cyclodextrin, its inclusion complexes of alkyl amines, and complexed β-cyclodextrin at different heating rates. J Incl Phenom Macrocycl Chem. 2007;60:223–33.  https://doi.org/10.1007/s10847-007-9369-1.CrossRefGoogle Scholar
  29. 29.
    Burgalassi S, Nicosia N, Monti D, Falcone G, Boldrini E, Chetoni P. Larch arabinogalactan for dry eye protection and treatment of corneal lesions: investigations in rabbits. J Ocul Pharmacol Ther. 2007;23:541–50.CrossRefGoogle Scholar
  30. 30.
    Rassu G, Gavini E, Jonassen H, Zambito Y, Fogli S, Breschi MC. et al. New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration. J Pharm Sci. 2009;98:4852–65.  https://doi.org/10.1002/jps.21751.CrossRefGoogle Scholar
  31. 31.
    Uccello-Barretta G, Balzano F, Aiello F, Senatore A, Fabiano A, Zambito Y. Mucoadhesivity and release properties of quaternary ammonium-chitosan conjugates and their nanoparticulate supramolecular aggregates: an NMR investigation. Int J Pharm. 2014;461:489–94.  https://doi.org/10.1016/j.ijpharm.2013.12.018.CrossRefGoogle Scholar
  32. 32.
    Kono H, Teshirogi T. Cyclodextrin-grafted chitosan hydrogels for controlled drug delivery. Int J Biol Macromol. 2015;72:299–308.CrossRefGoogle Scholar
  33. 33.
    Wilson LD, Pratt DY, Kozinski JA. Preparation and sorption studies of β-cyclodextrin–chitosan–glutaraldehyde terpolymers. J Colloid Interface Sci. 2013;393:271–7.  https://doi.org/10.1016/j.jcis.2012.10.046.CrossRefGoogle Scholar
  34. 34.
    Yuan Z, Yeb Y, Gao F, Yuan H, Lan M, Lou K, et al. Chitosan-graft-b-cyclodextrin nanoparticles as a carrier for controlled drug release. Int J Pharm. 2013;446:191–8.CrossRefGoogle Scholar
  35. 35.
    Sajomsang W, Nuchuchua O, Saesoo S, Gonil P, Chaleawlert-umpon S, Pimpha N. et al. A comparison of spacer on water-soluble cyclodextrin grafted chitosan inclusion complex as carrier of eugenol to mucosae. Carbohydr Polym. 2013;92:321–7.  https://doi.org/10.1016/j.carbpol.2012.08.106.CrossRefGoogle Scholar
  36. 36.
    Concheiro A, Alvarez-Lorenzo C. Chemically cross-linked and grafted cyclodextrin hydrogels: from nanostructures to drug-eluting medical devices. Adv Drug Deliv Rev. 2013;65:1188–203.CrossRefGoogle Scholar
  37. 37.
    Salmaso S, Semenzato A, Bersani S, Matricardi P, Rossi F, Caliceti P. Cyclodextrin/PEG based hydrogels for multi-drug delivery. Int J Pharm. 2007;345:42–50.  https://doi.org/10.1016/j.ijpharm.2007.05.035.CrossRefGoogle Scholar
  38. 38.
    Ma B, Lee W-C. A modified Curtius reaction: an efficient and simple method for direct isolation of free amine. Tetrahedron Lett. 2010;51:385–6.CrossRefGoogle Scholar
  39. 39.
    Liu X-M, Lee H-T, Reinhardt RA, Marky LA, Wang D. Novel biomineral-binding cyclodextrins for controlled drug delivery in the oral cavity. J Control Release. 2007;122:54–62.CrossRefGoogle Scholar
  40. 40.
    Magnusdottir A, Másson M, Loftsson T. Self association and cyclodextrin solubilization of NSAIDs. J Incl Phenom. 2002;44:213–8. https://doi.org/101023/A:1023079322024.CrossRefGoogle Scholar
  41. 41.
    Vianna RFL, Bentley MVLB, Ribeiro G, Carvalho FS, Neto AF, de Oliveira DCR, et al. Formation of cyclodextrin inclusion complexes with corticosteroids. Int J Pharm. 1998;167:205–13.CrossRefGoogle Scholar
  42. 42.
    Buranaboripan W, Lang W, Motomura E, Sakairi N. Preparation and characterization of polymeric host molecules,b-cyclodextrin linked chitosan derivatives having different linkers. Int J Biol Macromol. 2014;69:27–34.CrossRefGoogle Scholar
  43. 43.
    Mateen R, Hoare T. Carboxymethyl and hydrazide functionalized beta-cyclodextrin derivatives: a systematic investigation of complexation behaviours with the model hydrophobic drug dexamethasone. Int J Pharm. 2014;472:315–26.  https://doi.org/10.1016/j.ijpharm.2014.06.046.CrossRefGoogle Scholar
  44. 44.
    Simões SMN, Rey-Rico A, Concheiro A, Alvarez-Lorenzo C. Supramolecular cyclodextrin-based drug nanocarriers. Chem Commun. 2015;51:6275–89.  https://doi.org/10.1039/c4cc10388b.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Anna Maria Piras
    • 1
  • Ylenia Zambito
    • 1
  • Susi Burgalassi
    • 1
  • Daniela Monti
    • 1
  • Silvia Tampucci
    • 1
  • Eleonora Terreni
    • 1
  • Angela Fabiano
    • 1
  • Federica Balzano
    • 2
  • Gloria Uccello-Barretta
    • 2
  • Patrizia Chetoni
    • 1
  1. 1.Department of PharmacyUniversity of PisaPisaItaly
  2. 2.Department of Chemistry and Industrial ChemistryUniversity of PisaPisaItaly

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