Skip to main content

Phospholipid Magnesome—a nasal vesicular carrier for delivery of drugs to brain

Abstract

The goal of this work was to investigate a new nasal carrier for enhanced drug delivery to brain, we call Phospholipid Magnesome. The system contains soft phospholipid vesicles, composed of phospholipid, water, propylene glycol, magnesium salt, and the mucoadhesive polymer, alginate. The carrier was characterized by various methods: electron microscopy, calorimetry, and dynamic light scattering. The ability of the carrier’s vesicles to entrap various molecules was studied by CLSM and ultracentrifugation combined with HPLC quantification. Mucoadhesivity of the carrier was tested in vitro using porcine nasal mucosa. The delivery of rohdamine 6G, insulin, and epidermal growth factor was estimated by two methods, multiphoton microscopy and near infrared (NIR) imaging. Pharmacodynamic effects of nasal treatment with oxytocin and insulin incorporated in Phospholipid Magnesome were evaluated in animal models. Results show that the system is composed of soft multilamellar nanosized vesicles with the ability to entrap both lipophilic and hydrophilic molecules. The mucoadhesivity test results indicate a prolonged contact time of the drug with the nasal membrane as compared to control. Multiphoton microscopy and NIR imaging of brain show effective delivery of the tested molecules to brain following nasal administration in Phospholipid Magnesome relative to controls. Moreover, the results of the pharmacodynamic study measuring the antinociceptive effect of oxytocin administrated nasally to an animal model indicate the efficiency of the Phospholipid Magnesome as compared to three control systems. Further, nasal administration of insulin resulted in a strong and prolonged hypoglycemic effect for the drug incorporated in the new carrier but not for control systems. Based on the results of the histopathological test, the carrier is safe for local administration on the nasal membrane. In conclusion, the results of this study suggest that Phospholipid Magnesome nasal carrier is able to improve drug effects, probably by a combined mechanism, absorption enhancement, and prolongation of mucosal contact.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

References

  1. 1.

    Touitou E, Illum L. Nasal drug delivery. Drug Deliv Transl Res. 2013;3:1–3.

    Article  PubMed  Google Scholar 

  2. 2.

    Arora P, Sharma S, Garg S. Permeability issues in nasal drug delivery. Drug Discov Today. 2002;7:967–75.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Wolburg H, Wolburg-Buchholz K, Sam H, Horvát S, Deli MA, Mack AF. Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem Cell Biol. 2008;130:127–40.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Illum L. Nasal drug delivery--possibilities, problems and solutions. J Control Release. 2003;87:187–98.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Illum L. Nasal drug delivery - recent developments and future prospects. J Control Release. 2012;161:254–63.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Mittal D, Md S, Hasan Q, Fazil M, Ali A, Baboota S, et al. Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route. Drug Deliv. 2014;23:130–9.

    Article  PubMed  Google Scholar 

  7. 7.

    Corace G, Angeloni C, Malaguti M, Hrelia S, Stein PC, Brandl M, et al. Multifunctional liposomes for nasal delivery of the anti-alzheimer drug tacrine hydrochloride. J Liposome Res. 2014;24:323–35.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Yu C, Gu P, Zhang W, Cai C, He H, Tang X. Evaluation of submicron emulsion as vehicles for rapid-onset intranasal delivery and improvement in brain targeting of zolmitriptan. Drug Deliv. 2011;18:578–85.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Salama HA, Mahmoud AA, Kamel AO, Abdel Hady M, Awad GA. Phospholipid based colloidal poloxamer-nanocubic vesicles for brain targeting via the nasal route. Colloids Surf B Biointerfaces. 2012;100:146–54.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Duchi S, Touitou E, Pradella L, Marchini F, Ainbinder D. Nasal tramadol delivery system: A new approach for improved pain therapy. Eur J Pain Suppl. 2011;5:449–52.

    CAS  Article  Google Scholar 

  11. 11.

    Charlton ST, Davis SS, Illum L. Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery: In vitro characterization studies. J Control Release. 2007;118:225–34.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Duchi S, Ovadia H. Touitou E. Nasal administration of drugs as a new non-invasive strategy for efficient treatment of multiple sclerosis. J Neuroimmunol. 2013;258:32–40.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Touitou E, Natsheh H (2017) Compositions and methods for nasal administration of drugs to brain and for systemic effect. 62/556,509 patent pending

  14. 14.

    Nielsen LS, Schubert L, Hansen J. Bioadhesive drug delivery systems. I. Characterisation of mucoadhesive properties of systems based on glyceryl mono-oleate and glyceryl monolinoleate. Eur J Pharm Sci. 1998;6:231–9.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Santos CA, Jacob JS, Hertzog BA, Freedman BD, Press DL, Harnpicharnchai P, et al. Correlation of two bioadhesion assays: The everted sac technique and the CAHN microbalance. J Control Release. 1999;61:113–22.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Collier HO, Dinneen LC, Johnson CA, Schneider C. The abdominal constriction response and its suppression by analgesic drugs in the mouse. Br J Pharmacol Chemother. 1968;32:295–310.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sierralta F, Naquira D, Pinardi G, Miranda HF. Alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception. Br J Pharmacol. 1996;119:551–4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Touitou E, Godin B, Duchi H (2014) Compositions for nasal delivery. US patent 8,911,751 B2

  19. 19.

    Gross EA, Swenberg JA, Fields S, Popp JA. Comparative morphometry of the nasal cavity in rats and mice. J Anat. 1982;135:83–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes- novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. J Control Release. 2000;65:403–18.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Touitou E, Ainbinde D. 7. Ethosomes - an innovative carrier for enhanced delivery into and across the skin: Original research article: Ethosomes - novel vesicular carriers for enhanced delivery: Characterization skin penetration properties. 2000. J Control Release. 2014;190:44–6.

    Article  PubMed  Google Scholar 

  22. 22.

    Pham QD, Topgaard D, Sparr E. Tracking solvents in the skin through atomically resolved measurements of molecular mobility in intact stratum corneum. Proc Natl Acad Sci U S A. 2017;114:E112–21.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Goodman M, Barry BW. Action of penetration enhancers on human stratum corneum as assessed by differential scanning calorimetry. In: Bronaugh RL, Maibach HI, editors. Percutaneous absorption, mechanisms- methodology- drug delivery. New York: Marcel Dekker, INC; 1989. p. 567–93.

    Google Scholar 

  24. 24.

    Zheng B, Ye L, Zhou Y, Zhu S, Wang Q, Shi H, et al. Epidermal growth factor attenuates blood-spinal cord barrier disruption via PI3K/Akt/Rac1 pathway after acute spinal cord injury. J Cell Mol Med. 2016;20:1062–75.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Schiöth HB, Craft S, Brooks SJ, Frey WH 2nd. Benedict C Brain insulin signaling and Alzheimer's disease: current evidence and future directions. Mol Neurobiol. 2012;46:4–10.

    Article  PubMed  Google Scholar 

  26. 26.

    Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008;58:639–50.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Parker KJ, Buckmaster CL, Schatzberg AF, Lyons DM. Intranasal oxytocin administration attenuates the ACTH stress response in monkeys. Psychoneuroendocrinology. 2005;30:924–9.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Rash JA, Aguirre-Camacho A, Campbell TS. Oxytocin and pain: a systematic review and synthesis of findings. Clin J Pain. 2014;30:453–62.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Mrs. Shatha Boukaileh from Prof. Elka Touitou’s lab for help and assistance in the animal experiments, and Dr. Zakharia Manevitch from The Core of Research Facility, Faculty of Medicine, Hebrew University of Jerusalem for help in the Multiphoton microscopic experiments.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Elka Touitou.

Ethics declarations

All procedures performed on animals were according to The National Institute of Health regulations and were approved by the Committee for Animal Care and Experimental Use of the Hebrew University of Jerusalem.

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Natsheh, H., Touitou, E. Phospholipid Magnesome—a nasal vesicular carrier for delivery of drugs to brain. Drug Deliv. and Transl. Res. 8, 806–819 (2018). https://doi.org/10.1007/s13346-018-0503-y

Download citation

Keywords

  • Phospholipid Magnesome
  • Nasal delivery to brain
  • Oxytocin
  • Insulin
  • Epidermal growth factor