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Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin

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Abstract

The development of alternative routes to the conventional subcutaneous administration of insulin is expected to provide an important advance in the management of diabetes. The aim of this work was to produce and characterize chitosan-coated Witepsol 85E solid lipid nanoparticles (SLN) containing insulin, and to evaluate the potential of these colloidal carriers for oral administration. SLN were prepared by a modified solvent emulsification–evaporation method based on a water/oil/water double emulsion followed by chitosan adsorption to SLN surface. Optimized chitosan-coated SLN presented a mean particle size around 450 nm and were positively charged, indicating synergic properties for intestinal absorption. Higher extent of insulin permeation was observed for SLN and chitosan-coated SLN in a Caco-2 cell monolayer model. When comparing both SLN formulations, chitosan coating was shown to provide higher insulin permeation. Also, similar effects were also observed using a Caco-2/HT29 monolayer model, which more closely resemble the intestinal membrane, thus indicating that the mucoadhesive properties and permeation enhancement effect of chitosan may contribute significantly to the enhanced insulin permeation. After oral administration of insulin-loaded SLN to diabetic rats, a considerable hypoglycemic effect was observed for 24 h, which was more pronounced when chitosan-coated SLN were used, resulting in relative pharmacological bioavailabilities of 8% and 17% for uncoated and chitosan-coated SLN, respectively. Also, fluorescently labeled insulin was located on the intestinal walls and internalized into enterocytes after administration in chitosan-coated SLN, thus revealing the effectiveness of this nanocarrier in promoting the intestinal absorption of insulin. In conclusion, the use of chitosan-coated SLN may provide an interesting platform for the development of oral insulin formulations to be used in the management of diabetes.

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References

  1. Beals JM, Kovach P, DJ A, Sindelar RD. Insulin. In: Pharmaceutical Biotechnology. The Netherlands: Harwood Academic Publishers; 1997. p. 229–39.

    Google Scholar 

  2. Hoffman A, Ziv E. Pharmacokinetic considerations of new insulin formulations and routes of administration. Clin Pharmacokinet. 1997;33(4):285–301.

    Article  PubMed  CAS  Google Scholar 

  3. Owens DR. New horizons—alternative routes for insulin therapy. Nat Rev Drug Discov. 2002;1:529–40.

    Article  PubMed  CAS  Google Scholar 

  4. Carino GP, Mathiowitz E. Oral insulin delivery. Adv Drug Deliv Rev. 1999;35:249–57.

    Article  PubMed  CAS  Google Scholar 

  5. Rawat M, Singh D, Saraf S, Saraf S. Nanocarriers: promisin vehicle for bioactive drugs. Biol Pharm Bull. 2006;29(9):1790–8.

    Article  PubMed  CAS  Google Scholar 

  6. Muller RH, Maaen S, Weyhers H, Specht F, Lucks JS. Cytotoxicity of magnetite-loaded polylactide, polylactide/glycolide particles and solid lipid nanoparticles. Int J Pharm. 1996;138(1):85–94.

    Article  Google Scholar 

  7. Muller RH, Ruhl D, Runge S. Biodegradation of solid lipid nanoparticles as a function of lipase incubation time. Int J Pharm. 1996;144:115–21.

    Article  Google Scholar 

  8. Muller RH, Lippacher A, Gohala S. Solid lipid nanoparticles (SLN) as carrier system for the controlled release of drugs. In: Wise DL, editor. Handbook of pharmaceutical controlled release tecnology. New York: Marcel Dekker; 2000. p. 377–91.

    Google Scholar 

  9. Garcia-Fuentes M, Torres D, Alonso MJ. New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin. Int J Pharm. 2005;296:122–32.

    Article  PubMed  CAS  Google Scholar 

  10. Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomed. 2007;2(4):743–9.

    CAS  Google Scholar 

  11. Sogias I, Williams A, Khutoryanskiy V. Why is Chitosan Mucoadhesive? Biomacromolecules. 2008;9(7):1837–42.

    Article  PubMed  CAS  Google Scholar 

  12. Sarmento B, Ribeiro A, Veiga F, Ferreira D, Neufeld R. Oral bioavailability of insulin contained in polysaccharide nanoparticles. Biomacromolecules. 2007;8(10):3054–60.

    Article  PubMed  CAS  Google Scholar 

  13. Sarmento B, Ribeiro A, Veiga F, Sampaio P, Neufeld R, Ferreira D. Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharm Res. 2007;24(12):2198–206.

    Article  PubMed  CAS  Google Scholar 

  14. Reis CP, Veiga FJ, Ribeiro AJ, Neufeld RJ, Damgé C. Nanoparticulate biopolymers deliver insulin orally eliciting pharmacological response. J Pharm Sci. 2008;97:5290–305.

    Article  PubMed  CAS  Google Scholar 

  15. Cui F, Qian F, Zhao Z, Yin L, Tang C, Yin C. Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles. Biomacromolecules. 2009;10:1253–8.

    Article  PubMed  CAS  Google Scholar 

  16. Sandri G, Bonferoni MC, Rossi S, Ferrari F, Gibin S, Zambito Y, et al. Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. Eur J Pharm Biopharm. 2007;65(1):68–77.

    Article  PubMed  CAS  Google Scholar 

  17. Lowe PJ, Temple CS. Calcitonin and insulin in isobutylcyanoacrylate nanocapsules: protection against proteases and effect on intestinal absorption in rats. J Pharm Pharmacol. 1994;46(7):547–52.

    Article  PubMed  CAS  Google Scholar 

  18. Tobio M, Gref R, Sanchez A, Langer R, Alonso MJ. Stealth PLA-PEG nanoparticles as protein carriers for nasal administration. Pharm Res. 1998;15(2):270–5.

    Article  PubMed  CAS  Google Scholar 

  19. Clark MA, Jepson MA, Hirst BH. Exploiting M cells for drug and vaccine delivery. Adv Drug Deliv Rev. 2001;50(1–2):81–106.

    Article  PubMed  CAS  Google Scholar 

  20. Hussain N, Jaitley V, Florence AT. Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics. Adv Drug Deliv Rev. 2001;50:107–42.

    Article  PubMed  CAS  Google Scholar 

  21. des Rieux A, Fievez V, Garinot M, Schneider Y-J, Preat V. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Rel. 2006;116:1–27.

    Article  CAS  Google Scholar 

  22. Tobio M, Sanchez A, Vila A, Soriano I, Evora C, Vila-Jato JL, et al. The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration. Colloids Surf B. 2000;18(3–4):315–23.

    Article  CAS  Google Scholar 

  23. Sarmento B, Mazzaglia D, Bonferoni MC, Neto AP, Monteiro MdC, Seabra V. Effect of chitosan coating in overcoming the phagocytosis of insulin loaded solid lipid nanoparticles by mononuclear phagocyte system. Carbohydr Polym. 2011;84:919–25.

    Article  CAS  Google Scholar 

  24. Garcia-Fuentes M, Torres D, Alonso MJ. Design of lipid nanoparticles for the oral delivery of hydrophilic macromolecules. Colloids Surf B. 2003;27(2–3):159–68.

    Article  CAS  Google Scholar 

  25. Zhang N, Ping Q, Huang G, Xu W, Cheng Y, Han X. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int J Pharm. 2006;327:153–9.

    Article  PubMed  CAS  Google Scholar 

  26. Sarmento B, Ribeiro A, Veiga F, Ferreira D. Development and validation of a rapid reversed-phase HPLC method for the determination of insulin from nanoparticulate systems. Biomed Chromatogr. 2006;20(9):898–903.

    Article  PubMed  CAS  Google Scholar 

  27. Sandri G, Bonferoni MC, Gökçe EH, Ferrari F, Rossi S, Patrini M, et al. Chitosan-associated SLN: in vitro and ex vivo characterization of cyclosporine A loaded ophthalmic systems. J Microencapsul. 2010;27(8):735–46.

    Article  PubMed  CAS  Google Scholar 

  28. Florence A. Issues in oral nanoparticle drug carrier uptake and targeting. J Drug Target. 2004;12(2):65–70.

    Article  PubMed  CAS  Google Scholar 

  29. Yin L, Ding J, He C, Cui L, Tang C, Yin C. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials. 2009;30(29):5691–700.

    Article  PubMed  CAS  Google Scholar 

  30. Cano-Cebrian MJ, Zornoza T, Granero L, Polache A. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Curr Drug Deliv. 2005;2(1):9–22.

    Article  PubMed  CAS  Google Scholar 

  31. Walter E, Janich S, Roessler BJ, Hilfinger JM, Amidon GL. HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium: In vitro–in vivo correlation with permeability data from rats and humans. J Pharm Sci. 1996;85(10):1070–6.

    Article  PubMed  CAS  Google Scholar 

  32. Chen X-M, Elisia I, Kitts DD. Defining conditions for the co-culture of Caco-2 and HT29-MTX cells using Taguchi design. J Pharmacol Toxicol Meth. 2010;61(3):334–42.

    Article  CAS  Google Scholar 

  33. Hu FQ, Yuan H, Zhang HH, Fang M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int J Pharm. 2002;239(1–2):121–8.

    Article  PubMed  CAS  Google Scholar 

  34. Wissing SA, Kayser O, Muller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev. 2004;56:1257–72.

    Article  PubMed  CAS  Google Scholar 

  35. Cui F, Shi K, Zhang L, Tao A, Kawashima Y. Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Control Rel. 2006;114(2):242–50.

    Article  CAS  Google Scholar 

  36. Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao JX, Kissel T. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake? Eur J Pharm Biopharm. 2000;50(1):147–60.

    Article  PubMed  CAS  Google Scholar 

  37. Garcia-Fuentes M, Prego C, Torres D, Alonso MJ. A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly(ethylene glycol) as carriers for oral calcitonin delivery. Eur J Pharm Sci. 2005;25:123–33.

    Article  Google Scholar 

  38. Eldridge JH, Hammond CJ, Meulbroek JA, Staas JK, Gilley RM, Tice TR. Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally administered biodegradable microspheres target the peyer’s patches. J Control Rel. 1990;11(1–3):205–14.

    Article  CAS  Google Scholar 

  39. Das S, Chaudhury A (2011) Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery. AAPS PharmSciTech (in press)

  40. Lin YH, Mi FL, Chen CT, Chang WC, Peng SF, Liang HF, et al. Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules. 2007;8:146–52.

    Article  PubMed  CAS  Google Scholar 

  41. Damge C, Vrancks H, Balschmidt P, Couvreur P. Poly(alkyl cyanoacrylate) nanospheres for oral administration of insulin. J Pharm Sci. 1997;86:1407–500.

    Article  Google Scholar 

  42. Zhang Z, Lv H, Zhou J. Novel solid lipid nanoparticles as carriers for oral administration of insulin. Pharmazie. 2009;64:574–8.

    PubMed  CAS  Google Scholar 

  43. Schipper NGM, Varum KM, Stenberg P, Ocklind G, Lennernas H, Artursson P. Chitosans as absorption enhancers of poorly absorbable drugs 3: influence of mucus on absorption enhancement. Eur J Pharm Sci. 1999;8:335–43.

    Article  PubMed  CAS  Google Scholar 

  44. Ziv E, Bendayan M. Intestinal absorption of peptides through the enterocytes. Microcosp Res Techniq. 2000;49(4):346–52.

    Article  CAS  Google Scholar 

  45. Bendayan M, Ziv E, Gingras D, Ben-Sasson R, Bar-On H, Kidron M. Biochemical and morpho-cytochemical evidence for the intestinal absorption of insulin in control and diabetic rats. Comparison between the effectiveness of duodenal and colon mucosa. Diabetologia. 1994;37(2):119–26.

    Article  PubMed  CAS  Google Scholar 

  46. Artursson P. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res. 1994;11:1358–61.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal (SFRH/BPD/35996/2007 and PTDC/SAU-FCF/70651/2006). The authors wish to thank Lilly Portugal for insulin supply, Abbott Portugal for the Medisense Precision Xceed Kit, and José das Neves for his kind review and useful comments on the manuscript.

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Authors and Affiliations

  1. CICS, Health Sciences Research Center, Department of Pharmaceutical Sciences, Instituto Superior de Ciências da Saúde, Gandra, Portugal

    Pedro Fonte, Tiago Nogueira & Bruno Sarmento

  2. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164 4050-047, Porto, Portugal

    Christiane Gehm, Domingos Ferreira & Bruno Sarmento

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  1. Pedro Fonte
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  2. Tiago Nogueira
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  5. Bruno Sarmento
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Correspondence to Bruno Sarmento.

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Fonte, P., Nogueira, T., Gehm, C. et al. Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. Drug Deliv. and Transl. Res. 1, 299–308 (2011). https://doi.org/10.1007/s13346-011-0023-5

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