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PERSPECTIVE

Nose-to-brain drug delivery approach: growth factor (NGF), essential fibroblast growth factor
(bFGF), S14G-humanin, oxytocin, melatonin, vitamin B-12
a key to easily accessing the brain for and many more (Frey et al., 1997).
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the treatment of Alzheimer’s disease Drug transport mechanism from nose to the brain: The
upper region of the nasal cavity (known as an olfactory
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region) remains directly connected to the brain (frontal

Alzheimer’s disease (AD): AD, a neurodegenerative dis- cortex; especially olfactory bulb) via olfactory nerves. Along
order and a significant cause of dementia throughout the
with this, the middle and the largest region of the nasal
world mostly affects the older adults but sometimes also
cavity (the respiratory region) remain supplied with the tri-
seen in young age (early state AD) (Agrawal et al., 2017). As
geminal sensory neurons and blood vessels. When the drug
per the Alzheimer Association report 2017, AD remains to
administered into the nasal cavity, firstly it has to pass the
be considered as the 6th leading cause of death which near-
mucociliary clearance in the vestibular region. Further, the
ly touches around 5.5 million people only in the USA and
drug molecule reaches to the internal portion of the nasal
the data is similar throughout the world (approximately 37
cavity where it comes in contact with the blood vessels (re-
million people suffers from AD) (Alzheimer’s Association,
spiratory epithelium) and neuronal network (olfactory and
2017). On the other hand, the treatments are insufficient,
respiratory epithelium) (Crowe et al., 2018). From the blood
and the available therapies do not claim the complete cure
vessels, the drug entered into the systemic circulation and
of disease. Instead, they relieve the symptoms in the prelim-
distributed throughout the body as per the relative volume
inary stage. Also, AD therapies are very costly, mostly unaf-
of distribution. This systemic bioavailability remains as the
fordable for an average income population. Such constraint
minor route of drug transport to the brain in which the drug
is due to the inaccessibility of the brain. The human brain
entered the brain via BBB. While another route (primary
is the most complex and delicate organ, highly protected by
route) of brain drug delivery is the direct neuronal path-
various physiological shields primarily the blood-brain-bar-
rier (BBB). The BBB upholds the homeostasis of the brain way, in which the drug follow intracellular and extracellular
and restricts the entry of most of the foreign components transport mechanism to enter into the different regions of
including lipids, peptides, and essential nutrients. Thus, the brain via olfactory and trigeminal sensory neurons (Fig-
the entry of almost all the drugs and bioactive to the brain ure 1) (Lochhead and Thorne, 2012). The exact mechanism
remains complicated (Agrawal et al., 2018b). The intranasal of drug transport from the nasal cavity to the brain is still a
(IN) route offers an alternative approach for drug delivery to different issue among scientists although; it was supposed to
the brain without the interference of the BBB. In our previ- follow the combined way to enter into the brain. Moreover,
ous article (Agrawal et al., 2018a), we have discussed various the drug transport mechanism depends upon various factors
innovative approaches, describing the novel techniques, effi- such as nature of the drug, type of delivery system or dosage
ciency, limitations, clinical investigations, patents, FDA sta- form, a device used for IN application, formulation parame-
tus, current scenario and future possibilities of direct nose- ters, experimental and physiological conditions. It remained
to-brain drug delivery. observed that the excipients added to the formulation to im-
prove the drug retention time (like a gelling agent, and mu-
Intranasal route: The current AD therapy mainly concerns coadhesive polymers), a permeation enhancer, and the drug
about the systemic delivery of anti-AD drug to the brain carrier system significantly affect the drug concentration
via the oral route and intravenous injection. The major in the brain. Additionally, the drug absorption through the
drawback of these approaches is poor drug concentration, neuronal pathway more promptly happens if the formula-
reduced therapeutic efficacy, and greater peripheral side tion remains targeted to the posterior upper region (olfactory
effects. Also, other common strategies utilize surgical pro- region) of the nasal cavity (Dhuria et al., 2010).
cedures and intracerebroventricular injection which seem
highly invasive, painful and inconvenient for the patients. Current research and available therapies: Nowadays, the
In this context, the IN route provides a direct and non-in- direct nose-to-brain drug delivery appears as an innovative,
vasive route which by-passes the BBB, increases the drug convenient and effective strategy for the treatment of vari-
concentration in the brain, reduces the systemic side effect, ous brain disorders. A considerable research database (in-
painless, patient-friendly and improves the drug perfor- cluding on-going research, preclinical investigations, clinical
mance (Agrawal et al., 2018a). The first concept of IN drug studies and various patents) promises the potency of the IN
delivery to the brain was introduced in 1989, by William approach for the treatment of AD and other brain disorders
H. Fery II. They discovered that IN administration of drugs (Dhuria et al., 2010). Presently, the AD therapy is limit-
could achieve the active targeting of therapeutic agents to ed to only few FDA approved conventional symptomatic
the brain for the treatment of neurodegenerative disorders drugs like galantamine, donepezil, rivastigmine, memantine
(like an AD, Parkinson’s disease (PD)) and stroke. However, and tacrine (tacrine: discontinued in the USA due to side
various successful attempts made by researchers through- effects) (Agrawal et al., 2018a, b). The available therapy is
out the world. These researchers designate the IN route, a very costly and effective only in mild to the moderate AD.
suitable route for delivery of various therapeutic agents like Also, the patient experience severe side effects. Thus various
insulin, piperine, quercetin, curcumin, H102-peptide, nerve researches are carried out to deliver the therapeutic agents

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 Alexander A, Saraf S (2018) Nose-to-brain drug delivery approach: a key to easily accessing the brain for the treatment of Alzheimer’s disease.
Neural Regen Res 13(12):2102-2104. doi:10.4103/1673-5374.241458
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Figure 1 Drug transport from the nasal cavity to the brain primarily through the neuronal pathway via olfactory and trigeminal sensory
neurons and secondly through the systemic circulation.
The neuronal pathway is a direct route of drug transfer to the brain while the drug entered into the systemic circulation needs to cross the blood-
brain barrier (BBB) (Adapted with permission from Agrawal et al., 2018a).

directly from nose-to-brain (Khan et al., 2017). Mostly, the investigation rest are still under preclinical examination. Al-
research strategy utilizes a suitable carrier system including though, the preclinical studies of various drugs (galantamine,
polymeric nanoparticles (Alexander et al., 2016), liposomes, donepezil, tacrine, memantine, risperidone, curcumin, and
lipid nanocarriers (solid lipid nanoparticles (SLN), nano- quercetin) and peptides (NGF, S14G-humanin, VIP, bFGF,
structured lipid carriers (NLC), microemulsion, nanoemul- and melanocortins) on different AD animal models demon-
sion), hydrogel, in-situ gelation (Alexander et al., 2015), etc., strated improved memory, cognition and behavioral func-
for the treatment of the AD. These carrier systems enhance tions of the animal. Along with this (Agrawal et al., 2018a),
the nasomucosal permeability of the drug, protects the drug histochemical analysis and fluorescence, as well as radio
from enzymatic degradation in nasal cavity; reduces the imaging of the extracted brain, show a decrease in amyloid
nasomucosal clearance; improves the drug retention time; β plaque in the brain. However, after all these successful
increases the bioavailability in the brain, drug targeting preclinical investigations very few studies reproduce satis-
to a specific region of the brain to reduce the side effects. factory results in clinical investigations. The obtained results
Sometimes, nasal solution or powder or mucoadhesive may occur due to various limitations of IN route (limited
formulation (Alexander et al., 2011) seems suitable for ef- drug permeability, nasomucosal clearance, and low reten-
fective nose-to-brain drug delivery. In the present scenario, tion time) and lack of a suitable device to deliver the drug
scientists have explored a lot on galantamine, donepezil, ri- at the particular region (olfactory region) in the nose (Dhu-
vastigmine, risperidone, tacrine, deferoxamine, tarenflurbil, ria et al., 2010). Scientists are working to resolve this issue
insulin, insulin-like growth factor, curcumin, piperine, quer- and hopeful for the success in the development of IN drug
cetin, NGF, bFGF, wheat germ agglutinin, H102 peptide, delivery system for the treatment of AD soon. In our previ-
erythropoietin, vasoactive intestinal peptide (VIP), V24P, ous review work, we have described the detailed insights of
melanocortins, various anti-amyloid β antibodies, stem cells on-going IN researches for the treatment of AD (Agrawal et
for nerve regeneration and various genes or genetic factors al., 2018a).
for the treatment of the AD.
From the full range of bioactive or drug molecules (with Research boundaries: After the entire successful lab (pre-
anti-AD activity), the extensive research using the IN route clinical and clinical) results, it remained observed that
limited to only 19 molecules among these, only two drug not even one IN therapy is available in the market for the
substances (insulin and rivastigmine) are under clinical treatment of AD. This shortcoming may be due to a lack

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 Alexander A, Saraf S (2018) Nose-to-brain drug delivery approach: a key to easily accessing the brain for the treatment of Alzheimer’s disease.
Neural Regen Res 13(12):2102-2104. doi:10.4103/1673-5374.241458

of successful clinical investigations particularly the human Amit Alexander, Shailendra Saraf*
trials. Most of the time, the results of preclinical stages and Rungta College of Pharmaceutical Sciences and Research,
clinical studies are contradictory or does not found signifi- Bhilai, Chhattisgarh, India (Alexander A)
cantly useful in human trials. The contradiction may be due Durg University, Govt. Vasudev Vaman Patankar Girls’ P.G.
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to the variable physiological responses and in vivo pharmaco- College Campus, Raipur Naka, Durg, Chhattisgarh, India;
kinetic and pharmacodynamic behaviors. The use of various University Institute of Pharmacy, Pt. Ravishankar Shukla
additives, the nature of the drug, formulation parameters University, Raipur, Chhattisgarh, India (Saraf S)
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and experimental conditions also affects the drug bioavail- *Correspondence to: Shailendra Saraf, PhD,
ability in the brain. Therefore, a suitable delivery device is [email protected].
required to directly target the drug to the olfactory region orcid: 0000-0002-8384-9370 (Shailendra Saraf)
of the nasal cavity which further facilitates the absorption Received: 2018-05-14
Accepted: 2018-08-08
of the drug through neuronal channels. Moreover, there are
some incidences of contradictory results of the similar studies doi: 10.4103/1673-5374.241458
conducted in different laboratories by a different group of re- Copyright license agreement: The Copyright License Agreement has
searchers. The reason behind these contradictory results is the been signed by all authors before publication.
non-uniformity of the experimental methodology (Agrawal et Plagiarism check: Checked twice by iThenticate.
al., 2018a). Furthermore, the pathophysiology and target site Peer review: Externally peer reviewed.
Open access statement: This is an open access journal, and articles are
of various brain disorders is not exactly clear, and the move- distributed under the terms of the Creative Commons Attribution-Non-
ment of the drug inside the brain is also not confirmed which Commercial-ShareAlike 4.0 License, which allows others to remix,
affect the development of a promising system. Together, all tweak, and build upon the work non-commercially, as long as appropri-
these data suggest the need for a more precise study to under- ate credit is given and the new creations are licensed under the identical
stand the brain responses and pathologies of brain disorders terms.
Open peer reviewer: Salvatore Guarini, University of Modena and
and development of standard experimental procedures for Reggio Emilia, Italy.
reproducibility of the results (Dhuria et al., 2010). Additional file: Open peer review report 1.

Conclusion and future perspective: The healthcare societies References

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will lead to the development of successful IN formulation.

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