Advertisement

Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 273–283 | Cite as

Synthesis and characterization of a new cyclodextrin derivative with improved properties to design oral dosage forms

  • Agustina García
  • Josefina Priotti
  • Ana Victoria Codina
  • María Delia Vasconi
  • Ariel D. Quiroga
  • Lucila I. Hinrichsen
  • Dario LeonardiEmail author
  • María Celina LamasEmail author
Original Article
  • 56 Downloads

Abstract

This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evaluate whether albendazole inclusion complexes with the new β-cyclodextrin derivative-improved albendazole dissolution efficiency and its anthelminthic activity. The new derivative was thoroughly evaluated and characterized, and an average degree of substitution of 1.4 per cyclodextrin molecule was observed. Albendazole:itaconyl-β-cyclodextrin complexes were prepared by spray drying procedures and investigated using phase solubility diagrams, dissolution efficiency, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared, scanning electronic microscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Phase solubility diagrams and mass spectrometry studies showed that the inclusion complex was formed in an equimolar ratio. Stability constant values were 602 M−1 in water, and 149 M−1 in HCl 0.1 N. Nuclear magnetic resonance experiments of the inclusion complex showed correlation signals between the aromatic and propyl protons of albendazole and the itaconyl-β-cyclodextrin inner protons. The studies indicated solid structure changes of albendazole included in itaconyl-β-cyclodextrin. The maximum drug release was reached at 15 min, and the inclusion complex solubility was 88-fold higher than that of the pure drug. The in vitro anthelmintic activity assay showed that the complex was significantly more effective than pure albendazole.

Keywords

Cyclodextrins Synthesis Poorly water-soluble drug Albendazole Physicochemical characterization 

Notes

Acknowledgements

J.P. and A.G. are grateful to CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) for a Doctoral and a Posdoctoral Fellowship.

Funding information

This work was supported by the Universidad Nacional de Rosario, CONICET (Project No. PIP 112-201001-00194) and Agencia Nacional de Promoción Científica y Tecnológica (Project No. PICT 2006-1126).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Animal studies

All institutional and national guidelines for the care and use of laboratory animals were followed.

References

  1. 1.
    Sosnik A, Augustine R. Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them. Adv Drug Deliv Sys. 2016;103:105–20.CrossRefGoogle Scholar
  2. 2.
    Sharma P, Garg S. Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs. Adv Drug Deliv Sys. 2010;62:491–502.CrossRefGoogle Scholar
  3. 3.
    Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2016;21:363–8.CrossRefGoogle Scholar
  4. 4.
    Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm. 2013;453:167–80.CrossRefGoogle Scholar
  5. 5.
    Frömming K-H, Szejtli J. Cyclodextrins in pharmacy. In: Topics in inclusion complexes. Volume 5, Chapter 1. Springer Science & Business Media; 1993.Google Scholar
  6. 6.
    Schwarz DH, Engelke A, Wenz G. Solubilizing steroidal drugs by β-cyclodextrin derivatives. Int J Pharm. 2017;531:559–67.CrossRefGoogle Scholar
  7. 7.
    Jansook P, Ogawa N, Loftsson T. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. Int J Pharm. 2018;535:272–84.CrossRefGoogle Scholar
  8. 8.
    Shelley H, Babu RJ. Role of cyclodextrins in nanoparticle based drug delivery systems. J Pharm Sci. 2018;107:1741–53.CrossRefGoogle Scholar
  9. 9.
    García A, Leonardi D, Salazar MO, Lamas MC. Modified β-cyclodextrin inclusion complex to improve the physicochemical properties of Albendazole. Complete in vitro evaluation and characterization. PLoS One. 2014;9:e88234.CrossRefGoogle Scholar
  10. 10.
    García A, Leonardi D, Lamas MC. Promising applications in drug delivery systems of a novel β-cyclodextrin derivative obtained by green synthesis. Bioorg Med Chem Lett. 2016;26:602–8.CrossRefGoogle Scholar
  11. 11.
    García A, Leonardi D, Vasconi MD, Hinrichsen LI, Lamas MC. Characterization of albendazole-randomly methylated-β-cyclodextrin inclusion complex and in vivo evaluation of its antihelmitic activity in a murine model of Trichinellosis. PLoS One. 2014;9:e113296.CrossRefGoogle Scholar
  12. 12.
    Adeoye O, Cabral-Marques H. Cyclodextrin nanosystems in oral drug delivery: a mini review. Int J Pharm. 2017;531:521–31.Google Scholar
  13. 13.
    Codina AV, García A, Leonardi D, Vasconi MD, Di Masso RJ, Lamas MC, et al. Efficacy of albendazole:β-cyclodextrin citrate in the parenteral stage of Trichinella spiralis infection. Int J Biol Macromol. 2015;77:203–6.CrossRefGoogle Scholar
  14. 14.
    Priotti J, Codina AV, Leonardi D, Vasconi MD, Hinrichsen LI, Lamas MC. Albendazole microcrystal formulations based on chitosan and cellulose derivatives: physicochemical characterization and in vitro parasiticidal activity in Trichinella spiralis adult worms. AAPS PharmSciTech. 2017;18:947–56.CrossRefGoogle Scholar
  15. 15.
    Madsen CM, Feng K-I, Leithead A, Canfield N, Jørgensen SA, Müllertz A, et al. Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments. Eur J Pharm Sci. 2018;111:311–9.CrossRefGoogle Scholar
  16. 16.
    Lucio D, Irache JM, Font M, Martínez-Ohárriz MC. Nanoaggregation of inclusion complexes of glibenclamide with cyclodextrins. Int J Pharm. 2017;519:263–71.CrossRefGoogle Scholar
  17. 17.
    Shibata M, Nozawa R, Teramoto N, Yosomiya R. Synthesis and properties of etherified pullulans. Eur Polym J. 2002;38:497–501.CrossRefGoogle Scholar
  18. 18.
    Higuchi T, Connors KA. Phase solubility techniques. Adv Anal Chem Instrum. 1965;4:95.Google Scholar
  19. 19.
    Garcia-Rodriguez J, Torrado J, Bolas F. Improving bioavailability and anthelmintic activity of albendazole by preparing albendazole-cyclodextrin complexes. Parasite. 2001;8:S188–S90.CrossRefGoogle Scholar
  20. 20.
    Castillo J, Palomo-Canales J, Garcia J, Lastres J, Bolas F, Torrado J. Preparation and characterization of albendazole β-cyclodextrin complexes. Drug Dev Ind Pharm. 1999;25:1241–8.CrossRefGoogle Scholar
  21. 21.
    Marques HC, Hadgraft J, Kellaway I. Studies of cyclodextrin inclusion complexes. I. The salbutamol-cyclodextrin complex as studied by phase solubility and DSC. Int J Pharm. 1990;63:259–66.CrossRefGoogle Scholar
  22. 22.
    Bertacche V, Lorenzi N, Nava D, Pini E, Sinico C. Host–guest interaction study of resveratrol with natural and modified cyclodextrins. J Incl Phenom Macrocycl Chem. 2006;55:279–87.CrossRefGoogle Scholar
  23. 23.
    United States Pharmacopoeia Convention. USP 32 NF 27: United States Pharmacopoeia and National Formulary, Volume 1. Rockeville (MD); 2008.Google Scholar
  24. 24.
    García A, Leonardi D, Piccirilli GN, Mamprin ME, Olivieri AC, Lamas MC. SSpray drying formulation of albendazole microspheres by experimental design. In vitro–in vivo studies. Drug Dev Ind Pharm. 2015;41:244–52.Google Scholar
  25. 25.
    Vasconi MDBG, Codina AV, Indelman P, Di Masso RJ, Hinrichsen LI. Phenotypic characterization of the response to infection with trichinella spiralis in genetically defined mouse lines of the CBi-IGE stock. Open J Vet Med. 2015;5:111–22.CrossRefGoogle Scholar
  26. 26.
    García A, Barrera MG, Piccirilli G, Vasconi MD, Di Masso RJ, Leonardi D, et al. Novel albendazole formulations given during the intestinal phase of Trichinella spiralis infection reduce effectively parasitic muscle burden in mice. Parasitol Int. 2013;62:568–70.CrossRefGoogle Scholar
  27. 27.
    O’Neill M, Mansour A, DiCosty U, Geary J, Dzimianski M, McCall SD, et al. An in vitro/in vivo model to analyze the effects of flubendazole exposure on adult female Brugia malayi. PLoS Negl Trop Dis. 2016;10:e0004698.CrossRefGoogle Scholar
  28. 28.
    Pralhad T, Rajendrakumar K. Study of freeze-dried quercetin–cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis. J Pharm Biomed Anal. 2004;34:333–9.CrossRefGoogle Scholar
  29. 29.
    Steiner T, Koellner G. Crystalline. Beta.-cyclodextrin hydrate at various humidities: fast, continuous, and reversible dehydration studied by X-ray diffraction. J Am Chem Soc. 1994;116:5122–8.CrossRefGoogle Scholar
  30. 30.
    Mangolim CS, Moriwaki C, Nogueira AC, Sato F, Baesso ML, Neto AM, et al. Curcumin–β-cyclodextrin inclusion complex: stability, solubility, characterisation by FT-IR, FT-Raman, X-ray diffraction and photoacoustic spectroscopy, and food application. Food Chem. 2014;153:361–70.CrossRefGoogle Scholar
  31. 31.
    Wei M, Wang J, He J, Evans DG, Duan X. In situ FT-IR, in situ HT-XRD and TPDE study of thermal decomposition of sulfated β-cyclodextrin intercalated in layered double hydroxides. Microporous Mesoporous Mater. 2005;78:53–61.CrossRefGoogle Scholar
  32. 32.
    Ficarra R, Tommasini S, Raneri D, Calabro M, Di Bella M, Rustichelli C, et al. Study of flavonoids/β-cyclodextrins inclusion complexes by NMR, FT-IR, DSC, X-ray investigation. J Pharm Biomed Anal. 2002;29:1005–14.CrossRefGoogle Scholar
  33. 33.
    Fernandes CM, Carvalho RA, da Costa SP, Veiga FJ. Multimodal molecular encapsulation of nicardipine hydrochloride by β-cyclodextrin, hydroxypropyl-β-cyclodextrin and triacetyl-β-cyclodextrin in solution. Structural studies by 1H NMR and ROESY experiments. Eur J Pharm Sci. 2003;18:285–96.CrossRefGoogle Scholar
  34. 34.
    Lezcano M, Al-Soufi W, Novo M, Rodríguez-Núñez E, Tato JV. Complexation of several benzimidazole-type fungicides with α-and β-cyclodextrins. J Agric Food Chem. 2002;50:108–12.CrossRefGoogle Scholar
  35. 35.
    Jahed V, Zarrabi A, Bordbar A-K, Hafezi MS. NMR (1H, ROESY) spectroscopic and molecular modelling investigations of supramolecular complex of β-cyclodextrin and curcumin. Food Chem. 2014;165:241–6.CrossRefGoogle Scholar
  36. 36.
    Jullian C, Orosteguis T, Pérez-Cruz F, Sánchez P, Mendizabal F, Olea-Azar C. Complexation of morin with three kinds of cyclodextrin: a thermodynamic and reactivity study. Spectrochim Acta A Mol Biomol Spectrosc. 2008;71:269–75.CrossRefGoogle Scholar
  37. 37.
    Jullian C, Cifuentes C, Alfaro M, Miranda S, Barriga G, Olea-Azar C. Spectroscopic characterization of the inclusion complexes of luteolin with native and derivatized β-cyclodextrin. Bioorg Med Chem. 2010;18:5025–31.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.IQUIR-CONICETRosarioArgentina
  2. 2.Departamento de Farmacia, Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioRosarioArgentina
  3. 3.Instituto de Genética Experimental, Facultad de Ciencias MédicasUniversidad Nacional de RosarioRosarioArgentina
  4. 4.CIC-UNRUniversidad Nacional de RosarioRosarioArgentina
  5. 5.Área Parasitología, Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioRosarioArgentina
  6. 6.Instituto de Fisiología Experimental (IFISE-CONICET)RosarioArgentina
  7. 7.Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioRosarioArgentina

Personalised recommendations