Intranasal Introduction to Laboratory Animals

DOI: 10.29296/2618723X-2019-02-09

A.E. Katelnikova, K.L. Kryshen, A.A. Zueva, M.N. Makarova

Institute of Preclinical Studies,
3, Zavodskaya St., Build. 245, Kuzmolovsky Urban-Type Settlement, Vsevolozhsky District, Leningrad Region, 188663, Russia
Е-mail: [email protected]

Keywords: respiratory tracts toxicity anesthesia anatomy of the nose rodents

For citation:

Katelnikova A.E., Kryshen K.L., Zueva A.A., Makarova M.N. Intranasal Introduction to Laboratory Animals. Laboratory Animals for Science. 2019; 2.


The intranasal drug delivery has been become increasingly interesting not only for the treatment of acute and chronic nasal cavity diseases but mainly for drug delivery to the central nervous system and/or systemic blood over the past decades. The high permeability and vascularization of nasal mucosa, coupled with the preventing of the first-pass metabolism and/or drug destruction into gastro-intestinal tract, is provided by intranasal administration. In that regard, such delivery ensures more effective absorption of a tested object than via oral route. The using intranasal delivery of larger molecules not absorbed via oral route (such as peptide-protein drugs and vaccines) has also become a reality even though the nasal absorption of these compounds decreases with their molecular weight. As the demand for drugs with the intranasal administration grows, there is increased need for assessment of pharmacodynamics and toxic properties of drug before pharmaceutical marketing. This article presents an overview of the intranasal administration to laboratory animals. For optimizing the delivery of the agent to the animal and minimizing potential adverse experiences from the procedure it is required a detailed consideration and planning of administration of tested object to laboratory animals. The overview covers the volume of administration, equipment, as well as interspecific nose structure differences, surface area and physiology that need to be taken into account while planning the experiment. To accomplish targeting it may be manipulated variables such as the equipment of administration, volume and pharmaceutical dosage form (liquid, gas, vapor, powder), particle size, chemical properties and composition. The design of research of intranasal administration of tested objects should take into account the volume of administration and the using of anesthesia affecting the delivery performance. These two important factors will determine the relative distribution of the delivered substance to the upper and lower respiratory tracts and entry into the gastrointestinal tract.

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  1. Fortuna A., Alves G., Serralheiro A., Sousa J., Falcao A. Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules. Eur. J. Pharm. Biopharm. 2014. Vol. 88 (1): 8–27. doi: 10.1016/j.ejpb.2014.03.004.
  2. Grassin-Delyle S., Buenestado A., Naline E., Faisy C., Blouquit-Laye S., Couderc L., Le Guen M., Fischler M., Devillier P. Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids. Pharmacol. Ther. 2012. Vol. 134 (3): 366–79. doi: 10.1016/j.pharmthera.2012.03.003.
  3. Jadhav K., Gambhire M., Shaikh I., Kadam V.J., Pisal S.S., Nasal Drug Delivery System-Factors Affecting and Applications. Curr. Drug Ther. 2007. Vol. 2 (1): 27–38. doi:
  4. Pires A., Fortuna A., Alves G., Falcão A. Intranasal drug delivery: how, why and what for? J. Pharm. Pharm. Sci. 2009. Vol. 12 (3): 288–311.
  5. Privalova A.M., Gulyaeva N.V., Bukreeva T.V. Intranazal`noe vvedenie perspektivny`j sposob dostavki lekarstvenny`x veshhestv v mozg. Nejroximiya. 2012; 29 (2): 93.
  6. Bitter C., Suter-Zimmermann K., Surber C. Nasal drug delivery in humans. Curr. Probl. Dermatol. 2011. Vol. 40: 20–35. doi: 10.1159/000321044.
  7. Illum L. Nasal drug delivery – recent developments and future prospects. J. Control. Release. 2012. Vol. 161(2): 254–63. doi: 10.1016/j.jconrel.2012.01.024.
  8. Bhise S.B., Yadav A.V., Avachat A.M., Malayandi R. Bioavailability of intranasal drug delivery system. Asian J. Pharm. 2008. Vol. 2 (4): 201–15. doi:
  9. Emami A., Tepper J., Short B., Yaksh T. L., Bendele A.M., Ramani T., Mellon R.D. Toxicology evaluation of drugs administered via uncommon routes: intranasal, intraocular, intrathecal/intraspinal, and intra-articular. Int. J. Toxicol. 2018. Vol. 37 (1): 4–27. doi: 10.1177/1091581817741840.
  10. Dallaire F., Ouellet N., Bergeron Y., Turmel V., Gauthier M.C., Simard M., Bergeron M.G. Microbiological and inflammatory factors associated with the development of pneumococcal pneumonia. J. Infect. Dis. 2001. Vol. 184 (3): 292–300. doi:10.1086/322021.
  11. Munster V.J., de Wit E., Feldmann H. Pneumonia from human coronavirus in a macaque model. N. Engl. J. Med. 2013. Vol. 368 (16): 1560–2. doi: 10.1056/NEJMc1215691.
  12. Miller M.A., Stabenow J.M., Parvathareddy J., Wodowski A.J., Fabrizio T.P., Bina X.R., Zalduondo L., Bina J.E. Visualization of murine intranasal dosing efficiency using luminescent Francisella tularensis: effect of instillation volume and form of anesthesia. PloS one. 2012. Vol. 7(2): e31359. doi: 10.1371/journal.pone.0031359.
  13. Bao Y., Gao Y., Koch E., Pan X., Jin Y., Cui X. Evaluation of pharmacodynamic activities of EPs® 7630, a special extract from roots of Pelargonium sidoides, in animals models of cough, secretolytic activity and acute bronchitis. Phytomedicine. 2015. Vol. 22 (4): 504–9. doi: 10.1016/j.phymed.2015.03.004.
  14. Beigelman A., Mikols C.L., Gunsten S.P., Cannon C.L., Brody S.L., Walter M.J. Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis. Respir. Res. 2010. Vol. 11(1): 90. doi: 10.1186/1465-9921-11-90.
  15. Harkema J.R. Comparative anatomy and epithelial cell biology of the nose. In: Parent RA, ed. Comparative Biology of the Normal Lung. 2nd ed. San Francisco, CA: Elsevier; 2015:7-18. Chapter 2.
  16. Gizurarson S. Animal models for intranasal drug delivery studies. A review article. Acta. Pharm. Nord. 1990. Vol. 2 (2): 105–22.
  17. M´enache M.G., Hanna L.M., Gross E.A., Lou S.R. Zinreich S.J., Leopold D.A., Jarabek A.M., Miller F.J. Upper respiratory tract surface areas and volumes of laboratory animals and humans: considerations for dosimetry models. J. Toxicol. Environ. Health. 1997. Vol. 50(5): 475–506. doi:10.1080/00984109708984003.
  18. Gross E., Morgan K. Architecture of the nasal passages and larynx. In: Parent RA. Comparative Biology of the Normal Lung: A Treatise on Pulmonary oxicology. 1992. Vol. 1: 7–25.
  19. Morgan K.T. Approaches to the identification and recording of nasal lesions in toxicology studies. Toxicol. Pathol. 1991. Vol. 19(4): 337–51.
  20. Witschi H., Espiritu I., Pinkerton K.E. Pulmonary cell kinetics and morphometry after ozone exposure: day versus night and dose response in rats. Am. J. Physiol. 1997. Vol. 272(6): L1152-L1160. doi:10.1152/ajplung.1997.272.6.L1152.
  21. Gizurarson S., Bechgaard E., Hjortkjær R.K. Two intranasal administration techniques give two different pharmacokinetic results. Scand. J. Lab. Anim. Sci. 2006. Vol. 33 (1): 35–8. doi:
  22. Morton D.B., Jennings M., Buckwell A., Ewbank R., Godfrey C., Holgate B., Inglis I., James R., Page C., Sharman I., Verschoyle R., Westall L., Wilson A.B. Refining procedures for the administration of substances. Lab. Anim. 2001. Vol. 35 (1): 1–41. doi:10.1258/0023677011911345.
  23. Wolff R.K. Toxicology studies for inhaled and nasal delivery. Mol. Pharm. 2015. Vol. 12 (8): 2688–96. doi: 10.1021/acs.molpharmaceut.5b00146.
  24. Southam D.S., Dolovich M., O'Byrne P.M., Inman M. D. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am. J. Physiol. Lung Cell Mol. Physiol. 2002. Vol. 282(4): L833-L839 doi: 10.1152/ajplung.00173.2001.
  25. IACUC Routes of Administration Guidelines. URL:
  26. Makarenko I.E., Avdeeva O.I., Vanatiev G.V., Ry`bakova A.V., Xod`ko S.V., Makarova M.N., Makarov V.G. Vozmozhny`e puti i ob``emy` vvedeniya lekarstvenny`x sredstv laboratorny`m zhivotny`m. Mezhdunarodny`j vestnik veterinarii. 2013; 3: 78–84.
  27. Turner P.V., Brabb T., Pekow C., Vasbinder M.A. Administration of substances to laboratory animals: routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci. 2011. Vol. 50 (5): 600–13.
  28. Tebbey P.W., Unczar C.A., LaPierre N.A., Hancock G.E. A novel and effective intranasal immunization strategy for respiratory syncytial virus. Viral. Immunol. 1999. Vol. 12 (1): 41–5. doi:10.1089/vim.1999.12.41.
  29. Charpoval S., Nabozny G., Marietta E.V., Raymond E.L., Krco C.J., Andrivet P. Short ragweed allergen induces eosinophilic lung disease in HLA-DQ transgenic mice. J. Clin. Invest. 1999. Vol. 103 (12): 1707–17. doi:10.1172/JCI6175.
  30. Tsuyuki S., Tsuyuki J., Einsle K., Kopf M., Coyle A.J. Costimulation through B7–2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (Th2) immune response and altered airway responsiveness. J. Exp. Med. 1997. Vol. 185 (9): 1671–9. doi:10.1084/jem.185.9.1671.
  31. Eyles J.E., Williamson E.D., Alpar H.O. Immunological responses to nasal delivery of free and encapsulated tetanus toxoid: studies on the effect of vehicle volume. Int. J. Pharmaceut. 2000. Vol. 189 (1): 75–9.
  32. Takafuji S., Suzuki S., Koizumi K., Tadokoro K., Miyamoto T., Ikemori R., Muranka M. Diesel exhaust particulates inoculated by the intranasal route have an adjuvant activity for IgE production in mice. J. Allergy. Clin. Immunol. 1987. Vol. 79 (4): 639–45.
  33. Visweswaraiah A., Novotny L.A., Hjemdahl-Monsen E.J., Bakaletz L.O., Thanavala Y. Tracking the tissue distribution of marker dye following intranasal delivery in mice and chinchillas: a multifactorial analysis of parameters affecting nasal retention. Vaccine. 2002. Vol. 20 (25–26): 3209–20.
  34. Ebino K., Lemus R., Karol M.H. The importance of the diluent for airway transport of toluene diisocyanate following intranasal dosing of mice. Inhal. Toxicol. 1999. Vol. 11 (3): 171–85. doi:10.1080/089583799197131.
  35. Guideline I. C. H. H. T. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3 (R2). International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. 2009. URL:
  36. Guideline I. C. H. H. T. Preclinical safety evaluation of biotechnology-derived pharmaceuticals S6 (R1). Proceedings of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2011. URL:
  37. US Food and Drug Administration. Guidance for Industry and Review Staff: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route. 2015. URL:
  38. Rattazzi L., Cariboni A., Poojara R., Shoenfeld Y., D’Acquisto F. Impaired sense of smell and altered olfactory system in RAG-1(-/-) immunodeficient mice. Front Neurosci. 2015. Vol. 9: 318. doi: 10.3389/fnins.2015.00318.
  39. Yang M., Crawley J.N. Simple behavioral assessment of mouse olfaction. Curr. Protoc. Neurosci. 2009. Chapter 8: Unit 8.24. doi:10.1002/0471142301.ns0824s48.
  40. American Society for Testing and Materials. Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals. ASTM E 981: 2019.
  41. Kuwabara Y., Alexeeff G.V., Broadwin R., Salmon A.G. Evaluation and application of the RD50 for determining acceptable exposure levels of airborne sensory irritants for the general public. Environ Health Perspect. 2007. Vol. 115(11):1609-1616. doi:10.1289/ehp.9848.
  42. Harkema J.R., Carey S.A., Wagner J.G. The nose revisited: a brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol. Pathol. 2006. Vol. 34 (3): 252–69. doi:10.1080/01926230600713475.
  43. Rao D.B., Little P.B., Malarkey D.E., Herbert R.A., Sills R.C. Histopathological evaluation of the nervous system in National Toxicology Program rodent studies: a modified approach. Toxicol. Pathol. 2011. Vol. 39 (3): 463–70. doi: 10.1177/0192623311401044.
  44. Tepper J.S., Kuehl P.J., Cracknell S., Nikula K.J., Pei L., Blanchard J.D. Symposium summary: “breathe in, breathe out, its easy: what you need to know about developing inhaled drugs”. Int. J. Toxicol. 2016. Vol. 36 (4): 376–92. doi: 10.1177/1091581815624080.

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