Nanomedicines and Nanosimilars: Looking for a New and Dynamic Regulatory “Astrolabe” Inspired System

Abstract

The application of the nanotechnology in medicine and pharmaceutics opens new horizons in therapeutics. Several nanomedicines are in the market and an increasing number is in clinical trials. But which is the advantage of the medicines in nanoscale? The scientists and the regulatory authorities agree that the size and consequently the physiochemical/biological properties of nanomaterials play a key role in their safety and effectiveness. Additionally, all of them agree that a new scientific-based regulatory landscape is required for the establishment of nanomedicines in the market. The aim of this review is to investigate the parameters that the scientists and the regulatory authorities should take into account in order to build up a dynamic regulatory landscape for nanomedicines. For this reason, we propose an “astrolabe-like system” as the guide for establishing the regulatory approval process. Its function is based on the different physicochemical/biological properties in comparison to low molecular weight drugs.

This is a preview of subscription content, access via your institution.

Scheme 1
Fig. 1

Notes

  1. 1.

    European Medicines Agency (EMA), 2006. EMEA/CHMP/79769/2006. Reflection paper on nanotechnology-based medicinal products for human use (29 June). http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_ guideline/2010/01/WC500069728.pdf, Accessed date: 20 August 2018.

  2. 2.

    This “White paper” states the situation of nanomedicines and nanosimilars and suggests new scientific directions that should be considered towards a harmonized regulatory pathway.

References

  1. 1.

    Mühlebach S. Regulatory challenges of nanomedicines and their follow-on versions: a generic or similar approach? Adv Drug Deliv Rev. 2018;131:122–31. https://doi.org/10.1016/j.addr.2018.06.024.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Flühmann B, Ntai I, Borchard G, Simoens S, Mühlebach S. Nanomedicines: the magic bullets reaching their target? Eur J Pharm Sci. 2019;12:73–80. https://doi.org/10.1016/j.ejps.2018.11.019.

    CAS  Article  Google Scholar 

  3. 3.

    Crommelin DJA, Shah VP, Klebovich I, McNeil SE, Weinstein V, Flühmann B, et al. The similarity question for biologicals and non-biological complex drugs. Eur J Pharm Sci. 2015;76:10–7. https://doi.org/10.1016/j.ejps.2015.04.010.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Barenholz Y. Doxil®--the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34. https://doi.org/10.1016/j.jconrel.2012.03.020.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Crommelin DJ, de Vliger JS, Weinstein V, Mühlebach S, Shah VP, Schellekens H. Different pharmaceutical products need similar terminology. AAPS J. 2014;16(1):11–4. https://doi.org/10.1208/s12248-013-9532-0.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Sainz V, Conniot J, Matos AI, Reres C, Zupancic E, Moura L, et al. Regulatory aspects on nanomedicines. Biochem Biophys Res Commun. 2015;468(3):504–10. https://doi.org/10.1016/j.bbrc.2015.08.023.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Schellekens H, Stegemann S, Weinstein V, de Vlieger JS, Flühmann B, Mühlebach S, et al. How to regulate non biological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16(1):15–21. https://doi.org/10.1208/s12248-013-9533-z.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Mühlebach S, Borchard G, Yildiz S. Regulatory challenges and approaches to characterize nanomedicines and their follow-on similar. Nanomedicine (London). 2015;10:659–74.

    Article  Google Scholar 

  9. 9.

    Hussaarts L, Mühlebach S, Shah VP, McNeil S, Borchard G, Flühmann B, et al. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks. Ann N Y Acad Sci. 2017;1407(1):39–49. https://doi.org/10.1111/nyas.13347.

    Article  PubMed  Google Scholar 

  10. 10.

    Ehmann F, Sakai-Kato K, Duncan R, Hernán Pérez de la Ossa D, Pita R, Vidal JM, et al. Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine (London). 2013;8(5):849–56. https://doi.org/10.2217/nnm.13.68.

    CAS  Article  Google Scholar 

  11. 11.

    Di Francesco T, Philipp E, Borchard G. Iron sucrose: assessing the similarity between the originator drug and its intended copies. Ann N Y Acad Sci. 2017;1407(1):63–74. https://doi.org/10.1111/nyas.13517.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Hafner A, Lovrić J, Lakoš GP, Pepić I. Nanotherapeutics in EU: an overview on current state and future directions. Int J Nanomedicine. 2014;9:1005–23. https://doi.org/10.2147/IJN.S55359.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Di Francesco T, Borchard G. A robust and easily reproducible protocol for the determination of size and size distribution of iron sucrose using dynamic light scattering. J Pharm Biomed Anal. 2018;152:89–93. https://doi.org/10.1016/j.jpba.2018.01.029.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Schilt Y, Berman T, Wei X, Barenholz Y, Raviv U. Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs. Biochim Biophys Acta. 1860;2016:108–19. https://doi.org/10.1016/j.bbagen.2015.09.012.

    CAS  Article  Google Scholar 

  15. 15.

    Wibroe PP, Ahmadvand D, Oghanian MA, Yaghmur A, Mofhimi SM. An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome. J Control Release. 2016;221:1–8. https://doi.org/10.1016/j.jconrel.2015.11.021.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Bhattacherjee S. DLS and zeta potential-what they are and what they are not? J Control Release. 2016;235:337–51.

    Article  Google Scholar 

  17. 17.

    Soares S, Souza J, Pais A, Vitorino C. Nanomedicine: principles, properties and regulatory Issues. Front Chem. 2018;6:360. https://doi.org/10.3389/fchem.2018.00360.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Astier A, Barton Pai A, Bissig M, Crommelin DJA, Flühmann B, Hecq JD, et al. How to select a nanosimilar. Ann N Y Acad Sci. 2017;1407(1):50–62. https://doi.org/10.1111/nyas.13382.

    Article  PubMed  Google Scholar 

  19. 19.

    Nicolson GL. The fluid-mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40years. Biochim Biophys Acta. 1838;2014:1451–66.

  20. 20.

    Shannon CE. A mathematical theory of communication. Bell Syst Tech J. 1948;327:27.

    Google Scholar 

  21. 21.

    Naziris Ν, Pippa N, Pispas S, Demetzos C. The role of the information/entropy balance in self-assembly. The structural hierarchy of chimeric drug delivery nanosystems. Pharmakeftiki. 2017;29:77–82.

    Google Scholar 

  22. 22.

    Tsallis C. Introduction to nonextensive statistical mechanisms. Approaching a complex world, Springer Science Business Media, LLC; 2010,

  23. 23.

    Pippa N, Dokoumetzidis A, Demetzos C, Macheras P. On the ubiquitous presence of fractals and fractal concepts in pharmaceutical sciences: a review. Int J Pharm. 2013;456(2):340–52. https://doi.org/10.1016/j.ijpharm.2013.08.087.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Pippa N, Psarommati F, Pispas S, Demetzos C. The shape/morphology balance: a study of stealth liposomes via fractal analysis and drug encapsulation. Pharm Res. 2013;30(9):2385–95. https://doi.org/10.1007/s11095-013-1082-8.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Demetzos C, Pippa N. Fractal analysis as a complementary approach to predict the stability of drug delivery nano systems in aqueous and biological media: a regulatory proposal or a dream? Int J Pharm. 2014;473:213–8. https://doi.org/10.1007/978-3-319-08927-0_27.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Demetzos C, Pippa N. Fractal geometry as a new approach for proving nanosimilarity: a reflection note. Int J Pharm. 2015;483(1–2):1–5. https://doi.org/10.1016/j.ijpharm.2015.02.008.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Demetzos C. Biophysics and thermodynamics: the scientific building blocks of bio-inspired drug delivery systems. AAPS PharmSciTech. 2015;16(3):491–5. https://doi.org/10.1208/s12249-015-0321-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Demetzos C. Pharmaceutical nanotechnology. Fundamentals and practical application. Springer, 2016.

  29. 29.

    Hubbell JA, Chilkoti A. Chemistry. Nanomaterials for drug delivery. Science. 2012;337:303–5.

    Article  Google Scholar 

  30. 30.

    Baars BJ, Edelman DB. Consciousness, biology and quantum hypotheses. Phys Life Rev. 2012;9:285–94.

    Article  Google Scholar 

  31. 31.

    Foffi G, Pastore A, Piazza F, Temussi PA. Macromolecular crowding: chemistry and physics meet biology. Phys Biol. 2013;10(4):040301.

    CAS  Article  Google Scholar 

  32. 32.

    Guisbiers G. Size-dependent materials properties toward a universal equation. Nanoscale Res Lett. 2010;5(7):1132–6. https://doi.org/10.1007/s11671-010-9614-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Mershin A, Nanopoulos DV, Skoulakis EMC. Quantum brain? Proc Acad Athens. 1999;74(A).

  34. 34.

    Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33(10):2373–87. https://doi.org/10.1007/s11095-016-1958-5.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Knoeff J, Flühmann B, Mühlebach S. Medication practice in hospitals: are nanosimilars evaluated and substituted correctly? Eur J Hosp Pharm Sci Pract. 2018;25(2):79–84. https://doi.org/10.1136/ejhpharm-2016-001059.

    Article  Google Scholar 

  36. 36.

    Rosenmayr-Templeton L. Industry update: the latest developments in therapeutic delivery. Ther Deliv. 2013;4(5):1347–52. https://doi.org/10.4155/tde.13.32.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Trikle S, McNeil SE, Mühlebach S, Bawa R, Borchard G, Barenholz YC, et al. Nanomedicines: addressing the scientific and regulatory gap. Ann N Y Acad Sci. 2014;1313:35–56. https://doi.org/10.1111/nyas.12403.

    CAS  Article  Google Scholar 

  38. 38.

    Wolfram J, Zhu M, Yang Y, Shen J, Gentile E, Paolino D, et al. Safety of nanoparticles in medicine. Curr Drug Targets. 2015;16:1671–81.

    CAS  Article  Google Scholar 

  39. 39.

    Lee VC. Progress in nanomedicine: approved and investigational nanodrugs. PT. 2017;42(12):742–55.

    Google Scholar 

  40. 40.

    Marques MRC, Choo Q, Ashtikar M, Rocha TC, Bremer-Hoffmann S, Wacker MG. Nanomedicines-tiny particles and big challenges. Adv Drug Deliv Rev. 2019;In press.https://doi.org/10.1016/j.addr.2019.06.003.

  41. 41.

    Klein K, Stolk P, De Bruin ML, Leufkens HGM, Crommelin DJA, De Vlieger JSB. The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: observations and recommendations. Eur J Pharm Sci. 2019;133:228–35.

    CAS  Article  Google Scholar 

  42. 42.

    Rocco P, Musazzi UM, Franzè S, Minghetti P. Copies of nonbiological complex drugs: generic, hybrid or biosimilar? Drug Discov Today. 2019;24:250–5.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Costas Demetzos.

Additional information

Publisher’s Note

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

“Astrolabe” was an ancient device that has been used as navigator. The Astrolabe is a complex instrument that investigates and discloses the meaning of multicomplex phenomena with precision by using its dynamic and multifunctional abilities (Scheme 1).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Demetzos, C., Kavatzikidou, P., Pippa, N. et al. Nanomedicines and Nanosimilars: Looking for a New and Dynamic Regulatory “Astrolabe” Inspired System. AAPS PharmSciTech 21, 65 (2020). https://doi.org/10.1208/s12249-019-1573-y

Download citation

KEY WORDS

  • astrolabe
  • nanomedicines
  • nanosimilars
  • regulatory issues
  • complex drugs