Skip to main content
SpringerLink
Log in

Multilayer nanostructured system for oral insulin delivery

  • Original Paper
  • Published:
Journal of Polymer Research Aims and scope Submit manuscript

Abstract

A method to obtain a multilayer insulin-containing composition in a nanostructured form consisting of layers: gold-chitosan-insulin-chitosan nanoparticles was developed. The size of the fully formed multicomponent system was 178 nm.The outer layer of chitosan protects insulin from the damaging effects of low pH-medium and proteolytic enzymes of the gastrointestinal tract when the composition is taken orally. Chitosan simultaneously performs a transport function to deliver insulin into the bloodstream. In experiments on experimental animals with artificially induced type 1 diabetes, it was found that the effectiveness and duration of hypoglycemic action of the composition depends on the amount of insulin in the dose. The composition containing 50 IU of insulin per dose provides a rapid decrease glucose level in the blood and maintains it at the level of the intact group for 3 h. After 6 h the efficacy of the composition is comparable to that of insulin injection. A fundamentally important indicator of the effectiveness of the composition is a constant content of glycated hemoglobin in the blood within 10 days.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Scheme 1
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Gorska-Ciebiada M, Masierek M, Ciebiada M (2020) Improved insulin injection technique, treatment satisfaction, and glycemic control: Results from a large cohort education study. J Clin Transl Endocrinol 19:100217. https://doi.org/10.1016/j.jcte.2020.100217

    Article  PubMed  PubMed Central  Google Scholar 

  2. Pan Y, Li YJ, Zhao HY, Zheng JM, Xu H, Wei G, Hao JS, Cui F (2002) Bioadhesive polysaccharides in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 249:139–147. https://doi.org/10.1016/j.jcte.2020.100217

    Article  CAS  PubMed  Google Scholar 

  3. Makhlof A, Tozuka Y, Takeuchi H (2011) Design and evaluation of novel pH-sensitive chitosan nanoparticles for oral insulin delivery. Eur J Pharm Sci 42:445–451. https://doi.org/10.1016/j.ejps.2010.12.007

    Article  CAS  PubMed  Google Scholar 

  4. Yin L, Ding J, He C, Cui L, Tang C, Yin C (2009) Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomater 30:5691–5700. https://doi.org/10.1016/j.biomaterials.2009.06.055

    Article  CAS  Google Scholar 

  5. Sedyakina N, Kuskov A, Velonia K, Feldman N, Lutsenko S, Avramenko G (2020) Modulation of entrapment efficiency and in vitro release properties of BSA-loaded chitosan microparticles cross-linked with citric acid as a potential protein–drug delivery system. Mater 13(8):1989. https://doi.org/10.3390/ma13081989

    Article  CAS  Google Scholar 

  6. Bhumkar D, Joshi H, Sastry M, Pokharkar V (2007) Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin. Pharm Res 24(8):1415–1426. https://doi.org/10.1007/s11095-007-9257-9

    Article  CAS  PubMed  Google Scholar 

  7. Jintapattanakit A, Junyaprasert V, Mao S, Sitterberg J, Bakowsky U, Kissel T (2007) Peroral delivery of insulin using chitosan derivatives: A comparative study of polyelectrolyte nanocomplexes and nanoparticles. Int J Pharm 342:240–249. https://doi.org/10.1016/j.ijpharm.2007.05.015

    Article  CAS  PubMed  Google Scholar 

  8. Chalasani KB, Russell-Jones GJ, Jain AK, Diwan PV, Jain SK (2007) Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles. J Control Release 122:141–150. https://doi.org/10.1016/j.jconrel.2007.05.019

    Article  CAS  PubMed  Google Scholar 

  9. Chalasani KB, Russell-Jones GJ, Yandrapu SK, Diwan PV, Jain SK (2007) A novel vitamin B12-nanosphere conjugate carrier system for peroral delivery of insulin. J Control Release 117(3):421–429. https://doi.org/10.1016/j.jconrel.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  10. Sarmento B, Ribeiro A, Veiga F, Ferreira D (2006) Development and characterization of new insulin-containing polysaccharide nanoparticles. Colloids Surf B Biointerfaces 53:193–202. https://doi.org/10.1016/j.colsurfb.2006.09.012

    Article  CAS  PubMed  Google Scholar 

  11. Sarmento B, Ribeiro AJ, Veiga F, Ferreira DC, Neufeld RJ (2007) Insulin-loaded nanoparticles are prepared by alginate ionotropic pre-gelation followed by chitosan polyelectrolyte complexation. J Nanosci Nanotechnol 7(8):2833–2841. https://doi.org/10.1166/jnn.2007.609

    Article  CAS  PubMed  Google Scholar 

  12. Woitiski B, Neufeld RJ, Veiga F, Carvalho RA, Figueiredo IV (2010) Pharmacological effect of orally delivered insulin facilitated by multilayered stable nanoparticles. Eur J Pharm Sci 41:556–563. https://doi.org/10.1016/j.ejps.2010.08.009

    Article  CAS  PubMed  Google Scholar 

  13. Sonaje K, Chen YJ, Chen HL, Wey SP, Juang JH, Nguyen HN, Hsu CW, Lin KJ, Sung HW (2010) Enteric-coated capsules filled with freeze-dried chitosan/poly(gamma-glutamic acid) nanoparticles for oral insulin delivery. Biomater 31:3384–3394. https://doi.org/10.1016/j.biomaterials.2010.01.042

    Article  CAS  Google Scholar 

  14. Han L, Zhao Y, Yin L, Li R, Liang Y, Huang H, Pan S, Wu C, Feng M (2012) Insulin-loaded pH-sensitive hyaluronic acid nanoparticles enhance transcellular delivery. AAPS PharmSciTech 13:836–845. https://doi.org/10.1208/s12249-012-9807-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fonte P, Araújo F, Silva C, Pereirad C, Reisa S, Santos HA, Sarmento B (2015) Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. Biotechnol Adv 33(6/3):1342–1354. https://doi.org/10.1016/j.biotechadv.2015.02.010

    Article  CAS  PubMed  Google Scholar 

  16. Cheung RCF, Ng TB, Wong JH, Chan WY (2015) Chitosan: An Update on Potential Biomedical and Pharmaceutical Applications. Mar Drugs 13(8):5156–5186. https://doi.org/10.3390/md13085156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Varlamov VP, Il’ina AV, Shagdarova BT, Lunkov AP, Mysyakina IS (2020) Chitin/Chitosan, and Its Derivatives: Fundamental Problems and Practical Approaches. Biochem(Moscow) 85:154–176. https://doi.org/10.1134/S0006297920140084

  18. Moran HBT, Turley JL, Andersson M, Lavelle EC (2018) Immunomodulatory properties of chitosan polymers. Biomater 184:1–9. https://doi.org/10.1016/j.biomaterials.2018.08.054

    Article  CAS  Google Scholar 

  19. Sogias IA, Williams AC, Khutoryanskiy VV (2008) Why is chitosan mucoadhesive? Biomacromol 9(7):1837–1842. https://doi.org/10.1021/bm800276d

    Article  CAS  Google Scholar 

  20. Sonaje K, Chuang EY, Lin KJ, Yen TC, Su FY, Tseng MT, Sung HW (2012) Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations. Mol Pharm 9(5):1271–1279. https://doi.org/10.1021/mp200572t

    Article  CAS  PubMed  Google Scholar 

  21. Pechenkin MA, Balabushevich NG, Zorov IN, Staroseltseva LK, Mikhalchik EV, Izumrudov VA, Larionova NI (2011) Design, in vitro and in vivo characterization of chitosan – dextran sulfate microparticles for oral delivery of insulin. J Bioequiv Availab 3(10):244–250. https://doi.org/10.4172/jbb.1000094

    Article  CAS  Google Scholar 

  22. Larionova NI, Zubaerova DK, Guranda DT, Pechyonkin MA, Balabushevich NG (2009) Colorimetric assay of chitosan in presence of proteins and polyelectrolytes by using ophthalaldehyde. Carbohydr Polym 75(4):724–727. https://doi.org/10.1016/j.carbpol.2008.10.009

    Article  CAS  Google Scholar 

  23. Balabushevich NG, Pechenkin MA, Zorov IN, Shibanova ED, Larionova NI (2011) Mucoadhesive polyelectrolyte microparticles containing recombinant human insulin and its analogs aspart and lispro. Biochem(Moscow) 76(3):327–331. https://doi.org/10.1134/S0006297911030059

  24. Balabushevich N, Pechenkin M, Shibanova E, Volodkin D, Mikhalchik E (2013) Multifunctional polyelectrolyte microparticles for oral insulin delivery. Macromol Biosci 13(10):1379–1388. https://doi.org/10.1002/mabi.201300207

    Article  CAS  PubMed  Google Scholar 

  25. He Z, Santos JL, Tian H, Huang H, Hu Y, Liu L, Leong KW, Chen Y, Mao HQ (2017) Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin. Biomater 130:28–41. https://doi.org/10.1016/j.biomaterials.2017.03.028

    Article  CAS  Google Scholar 

  26. Mukhopadhyay P, Chakraborty S, Bhattacharya S, Mishra R, Kundu PP (2015) pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery. Int J Biol Macromol 72:640–648. https://doi.org/10.1016/j.ijbiomac.2014.08.040

    Article  CAS  PubMed  Google Scholar 

  27. Finotelli PR, Silva D, Sola-Penna M, Rossi AL, Farina M, Andrade LR, Takeuchi AY, Rocha-Leão MH (2010) Microcapsules of alginate/chitosan containing magnetic nanoparticles for controlled release of insulin. Colloids Surf B Biointerfaces 81:206–211. https://doi.org/10.1016/j.colsurfb.2010.07.008

    Article  CAS  PubMed  Google Scholar 

  28. Dykman L, Khlebtsov N (2012) Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev 41:2256–2282. https://doi.org/10.1039/C1CS15166E

    Article  CAS  PubMed  Google Scholar 

  29. Khlebtsov NG, Dykman LA (2011) Biodistribution and toxicity of gold nanoparticles. Nanotechnol Russ 6(1–2):17–42. https://doi.org/10.1134/S1995078011010101

    Article  Google Scholar 

  30. Mochalova AE, Koryagin AS, Salomatina EV, Apryatina KV, Smirnova LA (2014) Chitosan-Coated Gold Nanoparticles as Promising Nanosystem for Directional Drug Delivery to Target Organs. J Nanotech Diagn Treat 2:34–41. https://doi.org/10.12974/2311-8792.2014.02.02.3

  31. Glazova I, Smirnova L, Zamyshlyayeva O, Zaitsev S, Avdoshin A, Naumov V, Ignatov S (2019) Interpolymer interaction in insulin-chitosan complexes. Supramol Chem 31(6):412–423. https://doi.org/10.1080/10610278.2019.1614180

    Article  CAS  Google Scholar 

  32. Koryagin AS, Mochalova AE, Salomatina EV, Eshkova OYU, Smirnova LA (2013) Adaptogenic effects of chitosan-gold nanocomposites under simulated hypoxic conditions. Inorg Mater Appl Res 4:127–130. https://doi.org/10.1134/S2075113313020081

    Article  Google Scholar 

  33. Smirnova LA, Gracheva TA, Mochalova AE, Kuz’micheva TA, Fedoseeva EN (2010) Peculiarities of gold nanoparticle formation in chitosan solutions doped with HAuCl4. Nanotechnol Russ 5(1–2):78–82. https://doi.org/10.1134/s1995078010010088

    Article  Google Scholar 

  34. Nieto-Suarez M, Vila-Romeu N, Prieto I (2008) Behavior of insulin Langmuir monolayers at the air–water interface under various conditions. Thin Solid Films 516(24):8873–8879. https://doi.org/10.1016/j.tsf.2007.11.062

    Article  CAS  Google Scholar 

  35. Tarazona NA, Machatschek R, Schulz B, Prieto MA, Lendlein A (2019) Molecular insights into the physical adsorption of amphiphilic protein PhaF onto copolyester surfaces. Biomacromol 20(9):3242–3252. https://doi.org/10.1021/acs.biomac.9b00069

    Article  CAS  Google Scholar 

  36. Soenen SJ, Manshian B, Montenegro JM, Amin F, Meermann B, Thiron T, Cornelissen M, Vanhaecke F, Doak S, Parak WJ, De Smedt S, Braeckmans K (2012) Cytotoxic effects of gold nanoparticles: A multiparametric study. ACS Nano 6(7):5767–5783. https://doi.org/10.1021/nn301714n

    Article  CAS  PubMed  Google Scholar 

  37. Apryatina KV, Gribanova MV, Markin AV, Sologubov SS, Smirnova LA (2016) Silver nanoparticle–chitosan complexes and properties of their composites. Nanotechnol Russ 11:766–775. https://doi.org/10.1134/S1995078016060033

    Article  CAS  Google Scholar 

  38. Gracheva TA, Kuz’micheva TA, Perevezentsev VN, Smirnova LA, Mochalova AE, Salomatina EV (2015) Peculiarities of the kinetics of UV-induced formation of gold nanoparticles in chitosan solutions doped with HAuCl4. Tech Phys Lett 41:235–237. https://doi.org/10.1134/S1063785015030062

    Article  CAS  Google Scholar 

  39. Nguyen HH, Brûlet A, Goudounèche D, Saint-Aguet P, Lauth-de Viguerie N, Marty JD (2015) The effect of polymer branching and average molar mass on the formation, stabilization and thermoresponsive properties of gold nanohybrids stabilized by poly(N-isopropylacrylamides). Polym Chem 6(32):5838–5850. https://doi.org/10.1039/C5PY00659G

    Article  CAS  Google Scholar 

  40. Daniel MC, Astruc D (2004) Gold nanoparticles: assembly, supramolecular chemistry, quantum–size–related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev 104:293–346. https://doi.org/10.1021/cr030698+

    Article  CAS  PubMed  Google Scholar 

  41. Link S, El-Sayed MA (1999) Size and temperature dependence of the plasmon absorption of colloidal gold nanoparticles. J Phys Chem B 103(21):4212–4217. https://doi.org/10.1021/jp984796o

    Article  CAS  Google Scholar 

  42. Fong KE, Yung LYL (2013) Localized surface plasmon resonance: a unique property of plasmonic nanoparticles for nucleic acid detection. Nanoscale 5:12043–12071. https://doi.org/10.1039/C3NR02257A

    Article  CAS  PubMed  Google Scholar 

  43. Hunter RJ (1981) Zeta potential in colloid science. Academic Press, New York

    Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Russian Science Foundation No. 21-73-00188 and partly financial support via State assignment in the Research scientific laboratory of "Chemistry of natural products and their synthetic analogues" of Scientific Educational Centre "Technoplatform 2035".

Author information

Authors and Affiliations

  1. Department of Macromolecular Compounds and Colloid Chemistry, Faculty of Chemistry, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia

    Kristina V. Apryatina, Irina A. Glazova, Alexander S. Koryagin, Sergey D. Zaitsev & Larisa A. Smirnova

Authors
  1. Kristina V. Apryatina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina A. Glazova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander S. Koryagin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sergey D. Zaitsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Larisa A. Smirnova
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Conceptualization: [LA Smirnova], Data curation: [AS Koryagin], Writing – original draft: [IA Glazova], Project administration: [SD Zaitsev], Writing – review & editing [KV Apryatina].

Corresponding author

Correspondence to Kristina V. Apryatina.

Ethics declarations

Ethics approval

We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.

Conflicts of interest

All authors confirm that there are no known conflicts of interest associated with this publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Apryatina, K.V., Glazova, I.A., Koryagin, A.S. et al. Multilayer nanostructured system for oral insulin delivery. J Polym Res 29, 378 (2022). https://doi.org/10.1007/s10965-022-03225-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10965-022-03225-w

Keywords

Search

Navigation