Mathematical Modeling and Simulation to Investigate the CNS Transport Characteristics of Nanoemulsion-Based Drug Delivery Following Intranasal Administration

  • Ekta Kadakia
  • Dean Bottino
  • Mansoor AmijiEmail author
Research Paper



Despite encouraging preclinical results, mechanisms of CNS drug delivery following intranasal dosing of nanoemulsions remain incompletely understood. Herein, the transport characteristics of intranasally administered nanoemulsions are investigated using mathematical modeling and simulation.


A compartmental model was developed to describe systemic and brain pharmacokinetics of drug solutions following intranasal dosing in rodents. The association between transport processes and CNS drug delivery was predicted using sensitivity analysis. Published pharmacokinetic data for four drugs; dosed as a nanoemulsion and aqueous solution were modeled to characterize differences in transport processes across formulations.


The intranasal model structure performed in a drug agnostic fashion. Sensitivity analysis suggested that though the extent of CNS drug delivery depends on nasal bioavailability, the CNS targeting efficiency is only sensitive to changes in drug permeability across the nasal epithelium. Modeling results indicated that nanoemulsions primarily improve nasal bioavailability and drug permeability across the olfactory epithelium, with minimal effect on drug permeability across the non-olfactory epithelium.


Using mathematical modeling we outlined dominant transport pathways following intranasal dosing, predicted the association between transport pathways and CNS drug delivery, predicted human CNS delivery after accounting for inter-species differences in nasal anatomy, and quantified the CNS delivery potential of different formulations in rodents.

Key words

Blood-brain barrier CNS targeting intranasal drug delivery modeling and simulation nanoemulsions 





2-(phosphonomethyl)pentanedioic acid


Technetium-99 m


The area under the curve (AUC) from the time of dosing to the time of the last observation






Cerebrospinal fluid


Coefficient of variation








Intra arterial




















Molecular weight


Not available


Not estimated






Non-olfactory epithelium


Olfactory epithelium


Polydispersity index


Surface area


Standard deviation








Acknowledgments and Disclosures

This study was partially supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health through a grant R21-NS066984.


  1. 1.
    Vyas TK, Tiwari SB, Amiji MM. Formulation and physiological factors influencing CNS delivery upon intranasal administration. Crit Rev Ther Drug Carrier Syst. 2006;23(4):319–47.CrossRefGoogle Scholar
  2. 2.
    Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654–73.CrossRefGoogle Scholar
  3. 3.
    Hanson LR, Frey WH 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9(Suppl 3):S5.CrossRefGoogle Scholar
  4. 4.
    Ruigrok MJ, de Lange EC. Emerging insights for translational pharmacokinetic and pharmacokinetic-Pharmacodynamic studies: towards prediction of nose-to-brain transport in humans. AAPS J. 2015;17(3):493–505.CrossRefGoogle Scholar
  5. 5.
    Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv. 2014;21(2):75–86.CrossRefGoogle Scholar
  6. 6.
    Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.CrossRefGoogle Scholar
  7. 7.
    Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm. 2009;379(1):146–57.CrossRefGoogle Scholar
  8. 8.
    Phukan K, Nandy M, Sharma RB, Sharma HK. Nanosized drug delivery systems for direct nose to brain targeting: a review. Recent Pat Drug Deliv Formul. 2016;10(2):156–64.CrossRefGoogle Scholar
  9. 9.
    Shah L, Yadav S, Amiji M. Nanotechnology for CNS delivery of bio-therapeutic agents. Drug Deliv Transl Res. 2013;3(4):336–51.CrossRefGoogle Scholar
  10. 10.
    Ganta S, Talekar M, Singh A, Coleman TP, Amiji MM. Nanoemulsions in translational research-opportunities and challenges in targeted cancer therapy. AAPS PharmSciTech. 2014;15(3):694–708.CrossRefGoogle Scholar
  11. 11.
    Yadav S, Gattacceca F, Panicucci R, Amiji MM. Comparative biodistribution and pharmacokinetic analysis of cyclosporine-a in the brain upon intranasal or intravenous administration in an oil-in-water nanoemulsion formulation. Mol Pharm. 2015;12(5):1523–33.CrossRefGoogle Scholar
  12. 12.
    Mahajan HS, Mahajan MS, Nerkar PP, Agrawal A. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting. Drug Deliv. 2014;21(2):148–54.CrossRefGoogle Scholar
  13. 13.
    Stevens J, Ploeger BA, van der Graaf PH, Danhof M, de Lange EC. Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration. Drug Metab Dispos. 2011;39(12):2275–82.CrossRefGoogle Scholar
  14. 14.
    Colombo M, Figueiro F, de Fraga Dias A, Teixeira HF, Battastini AMO, Koester LS. Kaempferol-loaded mucoadhesive nanoemulsion for intranasal administration reduces glioma growth in vitro. Int J Pharm. 2018;543(1–2):214–23.CrossRefGoogle Scholar
  15. 15.
    Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, et al. Selective CNS uptake of the GCP-II inhibitor 2-PMPA following intranasal administration. PLoS One. 2015;10(7):e0131861.CrossRefGoogle Scholar
  16. 16.
    Uchida M, Katoh T, Mori M, Maeno T, Ohtake K, Kobayashi J, et al. Intranasal administration of milnacipran in rats: evaluation of the transport of drugs to the systemic circulation and central nervous system and the pharmacological effect. Biol Pharm Bull. 2011;34(5):740–7.CrossRefGoogle Scholar
  17. 17.
    Kang-Jye Chou MDD. The distribution of local anesthetics into the CSF following intranasal administration. Int J Pharm. 1998;168(2):137–45.CrossRefGoogle Scholar
  18. 18.
    Scott Summerfield PJ, Sahi J, Chen L. Passive diffusion permeability of the BBB—examples and SAR. In: Li Di EHK, editor. Blood-brain barrier in drug discovery: optimizing brain exposure of CNS drugs and minimizing brain side effects for peripheral drugs. Hoboken: Wiley; 2015. p. 95–112.Google Scholar
  19. 19.
    Trapa PE, Belova E, Liras JL, Scott DO, Steyn SJ. Insights from an integrated physiologically based pharmacokinetic model for brain penetration. J Pharm Sci. 2016;105(2):965–71.CrossRefGoogle Scholar
  20. 20.
    Mustafa G, Ahuja A, Al Rohaimi AH, Muslim S, Hassan AA, Baboota S, et al. Nano-ropinirole for the management of parkinsonism: blood-brain pharmacokinetics and carrier localization. Expert Rev Neurother. 2015;15(6):695–710.CrossRefGoogle Scholar
  21. 21.
    Boche M, Pokharkar V. Quetiapine nanoemulsion for intranasal drug delivery: evaluation of brain-targeting efficiency. AAPS PharmSciTech. 2017;18(3):686–96.CrossRefGoogle Scholar
  22. 22.
    Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm. 2008;358(1–2):285–91.CrossRefGoogle Scholar
  23. 23.
    Kumar M, Misra A, Mishra AK, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target. 2008;16(10):806–14.CrossRefGoogle Scholar
  24. 24.
    Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44–52.CrossRefGoogle Scholar
  25. 25.
    Bourganis V, Kammona O, Alexopoulos A, Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. Eur J Pharm Biopharm. 2018;128:337–62.CrossRefGoogle Scholar
  26. 26.
    Kadakia E, Shah L, Amiji MM. Mathematical modeling and experimental validation of nanoemulsion-based drug transport across cellular barriers. Pharm Res. 2017;34(7):1416–27.CrossRefGoogle Scholar
  27. 27.
    Dordevic SM, Santrac A, Cekic ND, Markovic BD, Divovic B, Ilic TM, et al. Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: physicochemical and in vivo performances. Int J Pharm. 2017;533(2):421–30.CrossRefGoogle Scholar
  28. 28.
    Tan SF, Kirby BP, Stanslas J, Basri HB. Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability. J Pharm Pharmacol. 2017;69(11):1447–57.CrossRefGoogle Scholar
  29. 29.
    Yadav S, Gandham SK, Panicucci R, Amiji MM. Intranasal brain delivery of cationic nanoemulsion-encapsulated TNFalpha siRNA in prevention of experimental neuroinflammation. Nanomedicine. 2016;12(4):987–1002.CrossRefGoogle Scholar
  30. 30.
    Meredith ME, Salameh TS, Banks WA. Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J. 2015;17(4):780–7.CrossRefGoogle Scholar
  31. 31.
    Lin T, Liu E, He H, Shin MC, Moon C, Yang VC, et al. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides. Acta Pharm Sin B. 2016;6(4):352–8.CrossRefGoogle Scholar
  32. 32.
    Khan AR, Liu M, Khan MW, Zhai G. Progress in brain targeting drug delivery system by nasal route. J Control Release. 2017;268:364–89.CrossRefGoogle Scholar
  33. 33.
    Dhuria SV, Hanson LR, Frey WH 2nd. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther. 2009;328(1):312–20.CrossRefGoogle Scholar
  34. 34.
    Davis SS, Illum L. Absorption enhancers for nasal drug delivery. Clin Pharmacokinet. 2003;42(13):1107–28.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Translational Modeling & Simulation, Quantitative Clinical PharmacologyTakeda PharmaceuticalsCambridgeUSA

Personalised recommendations