1 Opportunities and Challenges for the Nasal Administration of Nanoemulsions 1 Claurice Comfort 1 , Gabriela Garrastazu 1,2 , Michele Pozzoli 1 , Fabio Sonvico 1 * 2 1 Graduate School of Health – Pharmacy, University of Technology, Sydney, 15 Broadway, Ultimo, NSW, 3 2007, Australia. 4 2 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil 5 6 *Any correspondence should be addressed to: 7 Dr. Fabio Sonvico, Ph.D. 8 Graduate School of Health – Pharmacy 9 15, Broadway 10 NSW 2007 Ultimo 11 Australia 12 Tel: +61 2 95149296 13 Fax: +61 2 95148300 14 Email: [email protected]15 16 17
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Opportunities and Challenges for the Nasal Administration of Nanoemulsions 1
brain transport. Furthermore, the concentration of tacrine in the brain was 2-fold higher following the intranasal 469
19
administration of the TMME formulation compared to the tacrine solution. Those mice treated with the TMME 470
formulation were also the fastest to regain memory [100]. 471
472
3. Conclusions and perspectives 473
Nanoemulsions have a number of significant and unique advantages favourable for drug delivery via a several 474
administration routes. Of note is their ability to increase drugs absorption/permeation and bioavailability. In 475
particular, they have demonstrated great potential in nasal drug delivery, not only as drug carriers for systemic 476
and nose-to-brain delivery but also as an active component of mucosal vaccinations. Currently, nanoemulsions 477
have not been proposed for the treatment of local ailments of the nose, however in the future this may become 478
an area of interest. Another interesting application would be the delivery of peptides and proteins to the CNS 479
using nanoemulsions. However, a better understanding of the mechanisms related to the nanoemulsion 480
absorption enhancement through the nasal mucosa and molecule transport to the brain is required to further 481
advance this formulation approach. Concerning the safety of nanoemulsions, additional in vitro and toxicology 482
studies appears to be necessary to determine the effect of these formulations on the nasal mucosa and cilia. 483
Finally, clinical studies should be conducted in order to confirm the superiority of nanoemulsion formulations 484
over traditional one before nanoemulsion-based nasal products will be available on the market. 485
486
Acknowledgements 487
The authors would like to acknowledge NanoBio Corporation for granting the permission to use images from 488
their website. 489
490
491
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References 492
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Figure 4: Direct nose to brain pathways (modified from [85, 87]). 739
A shows the olfactory nerve pathway whereby the nerves penetrate the epithelial layer of the nasal 740
mucosa providing both axonal (slow) and perineural (fast) absorption pathways. 741
B shows the trigeminal nerve pathway. The nerves do not penetrate the epithelial layer in this case and 742
terminate in the lamina propria, only allowing absorption via axonal (slow) transport. 743
Figure 5: Gamma scintigraphy image showing the distribution of the radioactivity in rats after the 744 administration of (A) risperidone nanoemulsion intravenously (RNE), (B) riepseridone mucoadhesive 745 nanoemulsion intranasally (RME), (C) risperidone nanoemulsion intranasally (RNE) (reproduced with 746 permission from [90]). 747
28
Table 1. Advantages and limitations of nasal drug delivery (adapted from [1, 4-7]). 748
749
750
ADVANTAGES LIMITATIONS
• Highly vascularized
• Highly permeable
• Increased bioavailability of many drugs
• Reliable, safe, non-invasive and
convenient
• Avoidance of first-pass metabolism
o Small dosage volume of only 25-200 µL
o Mucociliary clearance (MCC)
mechanism
o Impaired drug absorption in case of nasal
congestion
o Improper administration technique could
cause inefficient deposition
OPPORTUNITIES UNIQUENESS Large surface area increased by the
presence of microvilli
Fast onset of action
Wide range of options for the delivery of
hydrophobic, hydrophilic and/or high
molecular weight compounds (>1kDa)
Potential differences in absorption and
permeability potential between the
different regions of the nasal cavity
Lower enzyme levels compared to the
gastrointestinal tract and liver
Direct transport from the nose to the
central nervous system (CNS) is possible
bypassing the Blood Brain Barrier
Nasal lavage to remove unabsorbed
excess drug if needed
29
Table 2. Discriminating properties of macro-, nano- and microemulsions. 751