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Nose to Brain: A versatile mode of drug delivery system

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 16

Review Article
Nose to Brain: A versatile mode of drug delivery system
Sagar Savale*, Hitendra Mahajan
Department of Pharmaceutics, R. C .Patel Institute of Pharmaceutical Education and Research, Shirpur, MS,
India

Received: 15 Feb 2017 Revised: 21 Feb 2017 Accepted: 24 Feb 2017

Abstract

Objective: The Aim of present review highlights transport of drug in nose to brain via olfactory and
trigeminal nerve pathway by passing blood brain barrier (BBB). Nose to brain drug delivery has
received a great deal of attention as a non-invasive, convenient and reliable drug delivery system for
the systemic and targeted administration of drugs.
Method: Various reports were taken from research articles published in journals, data from various
books and other online available literature. A summary of various drug deliveries through some drug
transport pathways, factors influencing nasal drug absorption, formulation strategies nose to brain,
colloidal carriers in nose to brain drug delivery systems and nasal delivery devices on nose to brain
drug delivery systems.
Conclusion: Delivery of drugs to the brain is a very challenging approach in current scenario due to
presence of physiological barriers (BBB) that restricts the delivery of drugs to CNS. Thus, since last
few years, intranasal route has attracted a wide attention of researchers as a convenient, non-invasive,
reliable, and safe route to achieve faster and higher levels of drug in the brain via olfactory region by
passing BBB.Keywords: Nose to Brain, Blood-Brain barrier, brain targeting, Nasal drug delivery,
delivery pathways and devices.

Introduction Nasal Mucosa is considered as potential

Nose to brain drug delivery System is a administration route to achieve rapid and
targeted approach in which drug is targeted in higher level of drug absorption (Mittal et al.,
nasal route for systemic effect. Nasal drug 2013). Nasal cavity having a Larger surface
delivery system is recognized as an excellent area, porous endothelial membrane, high total
route of therapeutic compounds including in blood flow and avoidance of problem of first
Pharmaceuticals and Biopharmaceuticals. pass metabolism are this few reasons
Researchers are interested in nasal route for the
*Address for Corresponding Author: systemic delivery of medications due to their
Mr. Sagar Kishor Savale, high degree of permeability of nasal mucosa.
Department of Pharmaceutics, R. C. Patel (Ugwoke et al., 2005) Delivery of drug to the
Institute of Pharmaceutical Education & brain is Major challenge due to Presence of two
Research,Shirpur,425405,Dist.Dhule, Physiological barriers that restricts the delivery
Maharashtra State, India. of drug to the Central Nervous System (CNS),
Mobile No: +91 9960885333 The Blood Brain Barrier (BBB) and Blood
Email ID: [email protected] Cerebrospinal Fluid Barrier (BCSFB).

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 17

Nasal drug delivery system is explored for the up to cranial cavity. In nose to brain approach
conventional and local delivery of drugs for the drug formulation on nasal instillation comes in
treatment of local disorders like nasal allergy, contact with nasal mucosa and it is rapidly
nasal infections and nasal congestion. But, transported directly into the brain. Bypassing
since that few decades Nasal route is attracted a the BBB and achieving very rapid CSF levels
wide attention of researchers as a Convenient, (Garcia et al., 2005). Some amount of
reliable, non-invasive and safe to achieve faster administered drug is reaches to systemic
and maximum level of drug absorption (Garcia circulation by respiratory region and some
et al., 2005). amount of drug is lost to nasal associated
Nose to Brain approach is a great area of lymphoid tissue. The hydrophobic (lipid
interest for direct transport pathway of drugs in soluble) molecules is rapidly enter to the blood
nose to brain through olfactory and trigeminal stream from nasal mucosa and subsequently
nerve cells through nose they can bypassing the reach the CNS by crossing the BBB. But,
BBB and enter brain directly. Olfactory region Maximum pharmaceutical drug is hydrophilic
of the nasal mucosa is direct connection (water soluble), this drug is a rate limiting
between nose and brain explored for CNS barrier for targeting and highly lipid soluble
acting drugs. Improvement in bioavailability of drug molecules show better targeting ability
some drugs and therapeutic proteins and due to higher partition coefficient (higher
peptides was reported (Kumar et al., 2008). For lipophilicity). Hydrophilic drug molecules is
nose to brain delivery, drugs need to permeate also cross the nasal mucosa when, nasal
the BBB from the circulation. To achieve this, mucosa is break down due to local injury
drug or Prodrug is absorbed through active and (Kamble et al., 2013). In the recent years, most
passive transport to cross the tight junctions of of drugs and Proteins and Peptides is delivered
the BBB. Drug applied in nasal pathway is efficiently by using Nose to Brain Delivery.
directly reaches to the brain either by direct This strategy is useful to treat variety of CNS
transport from olfactory region to the brain and disorders including, Brain tumors, Parkinson
from blood to brain or CSF (Tellingen et al., disorder, Multiple Sclerosis, Alzheimer
2015). disorder, Epilepsy and Psychiatric disorders
The olfactory region, next to the (Fernandes et al., 2010; Swartling, 2016).
respiratory region in which, drug is directly This is all the possible pathways for drug
absorbed into the brain by different can reach brain after nasal administration are
mechanisms including transcellular, predominately either by the olfactory or
paracellular, olfactory and trigeminal neural trigeminal region or through systemic
pathways. The olfactory region of nasal circulation is shown in
mucosa contains olfactory cells, which extend
Fig.1.

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 18

Figure 1. Drug instillation to the nasal cavity

Advantages of Nasal Drug Delivery System Rapid elimination of drug substance from
Hepatic first pass metabolism is avoided nasal cavity due to Mucocilliary Clearance
(Hussain, 1998). Rapid drug absorption and (Rahisuddin et al., 2011). Nasal cavity provides
quick onset of action is achieved (Putheti et al., a smaller absorption surface area as compared
2009). Drug degradation in GI tract is avoided to gastrointestinal tract (Hussain, 1998).
(Dey et al., 2011). Some drugs is not absorbed Absorption enhancer may create mucosal
orally can be delivered to systemic circulation toxicity used in formulation (Arora et al.,
by nasal route (Ghori et al., 2015). Transport 2002). Low bioavailability may results from
for the Protein and Peptide drugs (Rahisuddin enzymatic degradation and metabolism at
et al., 2011). It can shows excellent mucosal surface (Ghori et al., 2015).
bioavailability for low molecular weight drugs Mechanical loss of the dosage form could
(Stieber e al., 2011). Bioavailability of larger occur due to improper technique of
molecules is improved by using Absorption administration (Putheti et al., 2009).
Enhancers. Better patient compliance (Parvathi,
2012). Reasons for Optimizations and Development
Limitations of Nasal Drug Delivery System of Nose to Brain Targeted Drug Delivery
System
Nose to brain administration is a novel approach of any pharmaceutical molecule to
approach of any pharmaceutical molecule to direct transport of pharmaceutical molecule.
direct transport of pharmaceutical molecule Nose to brain drug delivery system is
through nose to brain via olfactory or applicable for treatment of various CNS
trigeminal nerve pathways bypassing the BBB. disorder such has brain tumor, Parkinson and
Nose to brain drug delivery system is other neurodegenerative type of disorder. It is
applicable for treatment of various CNS applicable to transport of high molecular
disorder such has brain tumor, Parkinson and weight compounds such has protein and
other neurodegenerative type of disorder. It is peptides. In this drug delivery, pharmaceutical
applicable to transport of high molecular molecule directly goes on systemic circulation
weight compounds such has protein and it can prevent the problem of Presystolic
peptides. In this drug delivery, pharmaceutical metabolism. It is non-invasive and convenient
molecule directly goes on systemic circulation therapy for administration of pharmaceutical
it can prevent the problem of Presystolic molecule (Patel et al., 2012).
metabolism. It is non-invasive and convenient
Nose to brain administration is a novel

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 19

Nasal drug delivery system Comparision brain bypassing the BBB. The nasal drug
between Oral, Parenteral and Transdermal delivery system comparison with oral,
drug delivery system (DDS) parenteral and transdermal drug delivery
Nasal drug delivery system is a novel system is reported in Table 1.
approach of drug delivery system in which,
drug is targeted in nose to brain. It is a unique
approach to target the drug direct from nose to
Table 1: Nasal DDS Comparision between Oral, Parenteral and Transdermal DDS
Parameters Nasal Oral Parenteral Transdermal
Higher Plasma drug levels Yes No Yes Yes
BBB and CSF bypass Yes No No No
Rapid onset Yes No Yes Yes
Pain at the site of No No Yes No
administration
Mucosal irritation No Yes No Yes
Systemic activity Yes No Yes Yes
Self-administration Yes Yes No Yes
Patient compliance High High Low Low
Drug degradation No High No Low
Hepatic first pass metabolism No Yes No No
Targeted delivery Yes No Yes Yes
the airways (Kumar et al., 2013). Nasal hairs
Anatomy and Physiology of Nasal Cavity and mainly nasal mucosa with its sticky mucus
In nasal cavity nose as an important organ. blanket help to prevent xenobiotics (allergens,
Nose is complex multifunctional organ. The pathogens or foreign particles) from reaching
major functions of nasal cavity comprise the lungs. It represents a most efficient first line
cleansing the inhaled air and olfaction. of defense for the bodys airway as it copes with
Moreover, it is exerts protective and supportive more than 500 liters of air that are filtered
activity. It filters, heats and humidifies the hourly into the lungs (Illum et al., 2003) and
inhaled air before it reaches the lower parts of anatomy of nose is shown in Fig.2.

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 20

Figure 2. Anatomy of Nose and Distinct functional areas of nasal cavity

Mucociliary activity is removing mucus conchae and the magnification of mucosa by

towards the nasopharynx, immunological microvilli and cilia. This zone is highly
activities is involving a variety of immune vascularized (Dey et al., 2011). The posterior
competent cells and metabolism of endogenous region of the nasal cavity is the nasopharynx,
substances are further essential functions of its upper region consists of ciliated cells and
nasal cavity. The nasal cavity was connected to lower part consists of squamous epithelium.
other cavities such as the frontal, maxillary This area is also part of mucosal immune
sinus and the ear also serve as resonant body. system, due to rich vascularization, the
There were three distinct functional areas in the olfactory and respiratory zones may serve as an
nasal cavity, vestibules to olfactory and efficient absorption surface for topically
respiratory zones and the distinct functional applied drugs (Falcao et al., 2009).
areas of nasal cavity is shown in Fig.2. The olfactory region with its vicinity to the
The vestibular area approx. 0.6 cm2 serve cerebrospinal fluid (CSF) and direct nervous
as a first barrier against airborne particles with interface to the brain is attracted approach in
low vascularization comprised of stratified researcher’s interest for possible nose to brain
squamous and keratinized epithelial cells with delivery (Bahadur et al., 2012). The respiratory
nasal hairs. Olfactory area is approx. 15 cm2 epithelium or other parts of nasal cavity and
enables olfactory perception is highly airway were lined by superficial epithelium
vascularized (Misra et al., 2012). The consisting primarily of two types of cells, the
respiratory area approx. 130 cm2 serves with its globet cells (20%) and ciliated cells (80%). The
mucus layer produced by highly specialized various cell types of the epithelium were joined
cells as an efficient air cleansing system. The together tight junctions and cell types of nasal
surface of this zone is enlarged by division of epithelium is shown in Fig.3.
the cavity by lateral walls into three nasal

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 21

Figure 3. Cell types of the Nasal Epithelium

Mucus is continuously produced by globet paracellular (extracellular) mechanism is

cells traps inhaled particulates and infectious passive and slow aqueous route of transport
debris while the propulsive force bout 1,000 through intracellular tight junctions or the open
strokes/min) generated by ciliated cells clefts of the epithelial cells of the nasal
transports the mucus towards the nasopharynx mucosa. In nose to brain transport of drug, the
and gastrointestinal tract for elimination. This paracellular transport involves two
effective cleansing mechanism is Mucociliary extracellular routes, first across the olfactory
clearance. The Mucociliary clearance is neurons and the second across the trigeminal
approximately 20 min. but, it subject to great nerve. After reaching the olfactory bulb or
inter subject variability. The Mucociliary trigeminal region the Pharmaceutical agent is
clearance is dependent on the function of the enter other brain regions by simple diffusion,
cilia and the characteristics of the covering facillated diffusion by arterial pulsation driven
mucus which can be influenced by acute and perivascular pump. Paracellular mechanism is
chronic illness (common cold, allergic rhinitis) demonstrated inverse log-log correlation
(Jadhav et al., 2007; Soeda et al., 2008). between intranasal absorption and molecular
Many substances is influences the weight of hydrophilic compounds. Poor
Mucociliary clearance of the airways, either by bioavailability is observed for drugs having
stimulation or inhibition. A stimulatory effect molecular weight greater than 1000 Daltons
of drugs on the Mucociliary clearance is a irrespective of their lipophilicity. Molecules
clinical importance, because these substances like chitosan is tried to manipulate the
can possible used to improve pathological junctions between the nasal epithelium cells to
conditions of mucociliary clearance. facilitate transnasal absorption (Bahadur et al.,
Components (Drug and other ingredients) of 2012; Prajapati et al., 2012).
nasally administered formulation with a too be The second transcellular (intracellular)
pronounced mucociliary clearance impairing mechanism entails transport through a lipoidal
activity may limit their use (Ugwoke et al., route by either by receptor mediated
2005; Basu et al., 2010). endocytosis (passive diffusion, fluid phase
Mechanism of drug absorption across Nasal endocytosis). This Mechanism for the
Mucosa transnasal absorption of both small and large
Drug across nasal mucosa under two lipophilic molecules. Transcellular drug uptake
mechanisms, the paracellular and the is mainly a function of lipophilic nature of drug
transcellular mechanisms. The First molecules with highly lipophilic drugs being
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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 22

expected to have rapid transnasal uptake. Neural pathways

However, the transcellular mechanism is a slow The neural pathways include olfactory and
process for taking hours for nasally trigeminal neural Pathways (Fig.4) which
administered drugs to reach the olfactory bulb provide connection between the nasal mucosa
via intracellular axonal transport by processes and the brain; it is a unique pathway for the
like endocytosis within the olfactory neurons nose to brain delivery of pharmaceuticals and
(Kublik et al., 1998; Nagpal et al., 2013). therapeutics.
Drug Transport Pathways of Nose to the
Brain Delivery

Figure 4. Drug Transport Pathways of Nose to the Brain Delivery

Olfactory neural pathways especially across the Sustentacular cells were

Olfactory neural pathways, drug material is receptor mediated endocytosis, fluid phase
travelled from the olfactory region in the nasal endocytosis or the passive diffusion for the
cavity to CSF or brain parenchyma, It is also lipophilic drugs is mediated rapidly and at a
transverse to the nasal olfactory epithelium. In high rates. This route is mainly responsible for
this pathway, the arachnoid membrane the transport of lipophilic drug molecules and
surrounding the subarachnoid space having a the transport rate is depended in their
three different pathways across the olfactory lipophilicity (Misra et al., 2012).
epithelium, first is transcellular pathways
Second is a paracellular pathway in which, the the molecular weight of drugs up to 6000
tight junctions between Sustentacular cells Dalton with absorption enhancers (Kumar et
having the clefts between Sustentacular cells al., 2008).
and olfactory neurons. Nasal absorption of Third is olfactory nerve pathway in which,
hydrophilic drugs undergo diffusion the drug is taken up to the neuronal cells by
mechanism through aqueous channels or pores. endocytosis or pinocytosis mechanism and
This pathway is slow and it is responsible for transported by the intracellular axonal transport
the transport of hydrophilic drugs under rate to the olfactory bulb. Thus, the different modes
dependency on the molecular mass of the drug of drug transport across the nasal olfactory
material. Drugs with a molecular weight in the epithelium are the transcellular passive
range between 300 - 1000 Dalton shows good diffusion, Paracellular passive diffusion, efflux
bioavailability without absorption enhancer and transport, transcytosis transports (Thorne et al.,
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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 23

2004) and the olfactory region of brain is shown in Fig.5.

Figure 5. Olfactory region of Brain.

Trigeminal neural pathways through the cribriform plate along the olfactory
Trigeminal nerve pathways is the largest pathway, It is difficult to differentiate the nose
nerve pathway among all cranial nerve to brain administered drugs reach the olfactory
pathways in which, innervates the respiratory bulbs and other rostral brain areas (anterior
and olfactory epithelium (Fig.4) of the nasal olfactory nucleus and frontal cortex) via
passages and enters the central nervous system olfactory pathway, brainstem, spinal cord via
(CNS). The small portion of the trigeminal trigeminal pathway and the both extracellular,
nerve pathways is terminates the olfactory intracellular pathways is involved for
bulbs. The trigeminal nerve is communicates in bypassing the BBB (Thorne et al., 2004; Garcia
sensory information from the nasal cavity, oral et al., 2005; Tellingen et al., 2015).
cavity, eyelids and the cornea to CNS via Vascular pathway
ocular, maxillary and the mandibular divisions Pharmaceutical or Therapeutic agents is
of trigeminal nerves. The former two is transported in nose to brain through the blood
sensory functions while later the both sensory vessels supplying the nasal cavity to systemic
and motor functions (Nagpal et al., 2013). circulation following the nasal administration
The ocular and maxillary nerve is (Fig.4). Nose to brain route is utilized to
important for nose to brain delivery as neurons deliver drug to the systemic circulation through
from these branches passed directly through the absorption into the capillary blood vessels
nasal mucosa. The unique feature of the underlying the nasal mucosa. The nasal mucosa
trigeminal nerve is that enters the brain from is highly vascularised for receiving blood
the respiratory epithelium of the nasal passages supply from branches of both the internal and
at the two sites first through anterior lacerated external carotid artery, including the branches
foramen near the pons and second through of the facial artery and maxillary artery. The
cribriform plate near olfactory bulb is creating olfactory mucosa was received blood from the
the entry points into the both caudal and rostral anterior and posterior ethmoidal artery
brain areas following the nose to brain (smallest artery of ocular cavity), where the
administrations. Since the portion of the respiratory mucosa is received the blood from
trigeminal nerve pathway enters the brain the sphenopalatine artery (they are branches of

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 24

the maxillary artery). The relative density of This pathway is connected to the
the blood vessels is greater in the respiratory subarachnoid space containing CSF, perineural
mucosa than the olfactory mucosa, making the spaces encompassing olfactory nerves and the
former an ideal region for adsorbtion of drug nasal lymphatics (Fig.4). The CSF circulation
into the systemic circulation (Schaefer et al., and drainage provide access for nose to brain
2002). administered therapeutics to the CSF and other
The respiratory region is the combination areas of the brain. The CSF was produced by
of the continuous and fenestrated endothelium secretion at the four choroid plexi, especially at
that allowing the egress of both small and large the fourth and lateral ventricles. CSF is a
molecules into the blood subsequent transport secretory fluid produced by the choroid plexi to
cross the BBB to the brain. This is especially cushion the brain. The tracers is injected into
true for small lipophilic drugs which more the CSF in the cerebral ventricles or
easily enter to the blood stream and it can cross subarachnoid space drain to the underside of
the BBB compared to large hydrophilic the olfactory bulbs into channels associated
molecules such as proteins and peptides or high with olfactory nerves traversing the cribriform
molecular weight compounds. The therapeutics plate that reach the nasal lymphatic system and
is distributed throughout the systemic cervical lymph nodes. Hence CSF flows along
circulation and it enter in the blood supply to the olfactory sub mucosa in the roof of the
the nasal passages to be rapidly transferred to nasal cavity (Tellingen et al., 2015).
that carotid arterial blood supply to the brain Nose to brain administration of drugs is a
and spinal cord, this process known as counter- same pathways from the nasal cavity to CSF
current transfer (Schaefer et al., 2002). into the brain interstitial spaces and
The drug material is enter to the brain perivascular spaces for distribution throughout
through the perivascular spaces in the nasal the brain. In nose to brain administration is
passages or after reaching the brain demonstrated by the drugs gains direct access
parenchyma to be distributed throughout the to the CSF form the nasal cavity followed by
brain. The perivascular spaces is act as a subsequent distribution to the brain and spinal
lymphatic system for the brain, where the cord. The transport is dependent on the
neuron derived substance is cleared from brain lipophilicity, molecular weight and degree of
interstitial fluid by entering perivascular ionization of drug molecules (Dey et al., 2011;
channels associated with cerebral blood vessel. Mittal et al., 2013).
This pathway is involving perivascular Lymphatic pathways
channels associated with blood vessel as a The CSF production via choroid plexus
potential for nose to brain drug transport and its absorption via arachnoid villi to the
mechanism. Perivascular transport is a bulk cerebral venous sinuses had remained widely
flow mechanism rather than the diffusing alone accepted. The functional and anatomical
the arterial pulsations were driving forces for connection between the extracranial lymphatics
the perivascular transports. The high level of (Fig.4) (nasal submucosa and cervical
drug in the walls of cerebral blood vessels and lymphatics) and subarachnoid spaces via the
carotid arteries, even after removal of blood by perineural spaces to the cribriform plate. Nasal
saline perfusion, that suggested to nose to brain submucosa is consist of dense vascular network
delivery of the drugs gain access to the that leads to systemic circulation and dense
perivascular spaces (Basu et al., 2010). network of lymphatics that communicates
Cerebrospinal fluid (CSF) pathway directly with the subarachnoid spaces (Misra et
al., 2012).The nasal submucosal lymphatics

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 25

leads directly to the subarachnoid space via a Phenylephrine and fenoterolare is shown to
perineural route to the cribriform plate. Nasal increases the blood flow, this effect is
lymphatics is offers a direct transport through important in determining the nasal drug
the subarachnoid space and have been absorption due to their effect on blood flow
proposed as a potential pathways for the (Ugwoke et al., 2005; Mittal et al., 2013).
invasion of the pathogens such as S. Enzymatic activity
pneumoniae, N. meningitis or H. influenza Nasal administration of drugs in
responsible for bacterial meningitis (Kumar et circumvent gastrointestinal and hepatic first
al., 2013; Fernandes et al., 2010). pass effect. The drug is significantly
Factors Influencing Nasal Drug Absorption metabolized in lumen of nasal cavity and the
There were several factor that affect the passage across the nasal epithelial barrier due
permeation of drugs is administered through to the presence of cytochrome P450 dependant
nasal route. The factor affecting nasal Monooxygenase, lactose dehydrogenase,
absorption of drugs, The Biological, oxidoreductase, hydrolase, acid phosphatase
Physicochemical and formulation factor. and esterase (Soni et al., 2004). The
Biological factors which affect nasal drug cytochrome P450 isoenzyme metabolized the
absorption Nasal blood flow drug such as cocaine, nicotine, alcohols,
Nasal mucosa is supplied by rich progesterone and decongestants. The
vasculature and presents a large surface area proteolytic enzymes (aminopeptidases and
making an optimal drug absorption. The blood protease) were found they are belived to be the
flow is influences significantly the systemic major barrier against the absorption of protein
nasal absorption of drugs that enhanced the and peptide drugs such as, calcitonin, insulin
drug is passing through the membrane reaching and Desmopressin. This enzymes is exist in the
to the general circulation. Drug absorption is nasal mucosa may affect the pharmacokinetic
take placed by the diffusion, the optimal blood and pharmacodynamics profile of nasally
flow is essential to maintain the concentration administered drugs (Jain et al., 2010).
gradient from the site of absorption to blood. Mucociliary clearance
The vasodilation and vasoconstriction may Mucociliary clearance is important
determine the blood flow and the rate extent of function to removal of foreign substances and
drug to be absorbed (Soni et al., 2004). particles from the nasal cavity consequently
The blood vessels in the nasal mucosa is preventing them from reaching the lower
surrounded by adrenergic nerves which act as airways. Nasal administration of formulation is
an alpha adrenoreceptor stimulation of these cleared from the nasal cavity with a half-life of
receptors is shows to decreases blood flow and clearance about 15 min. with the result of
blood content in the nose of the humans and limiting time available for absorption (Hussain,
animals. The nasal blood flow is affected by 1998).
the external and physiological factors such as The normal mucociliary transit time of
ambient temperature, humidity, vasoactive humans 12-15 min. having a rapid mucociliary
drugs, trauma and inflammation. The clearance of drug formulations that are
psychological factors such as emotion, fear, deposited in the nasal cavity. It is an important
anxiety and frustration. The Nasal flow was factor underlying the low bioavailability of
sensitive to different locally or systemically nose to brain administration of drugs. Most of
acting drugs, such as oxymetazoline and drug having hormonal changes in the body,
clonidine decreases the blood flow of pathological conditions and formulation factors
histamines, albuterol, isoproterenol, especially rheology to affect mucociliary

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 26

clearance and turn to exert significant influence The nasal membrane is predominantly
on drug permeability (Prajapati et al., 2012). lipophilic, hence the drug absorption is
Physical condition of the nasal mucosa diminish with decreases in lipophilicity. Thus
The physical condition of nasal mucosa is the polar drug is not easily transported across
important effect on the drug absorption. There nasal mucosa. The lipophilicity is too high, the
were times when the mucosa is crushing, drug does not dissolved in the aqueous
blending or dry. The infection may be suffering environment of nasal cavity. In general, the
from rhinorrhoea, sinitis and nasal infection. In passage across bio membranes is affected not
any person suffering from several nasal only by lipophilicity/ hydrophilicity but also by
allergies as an excessive nasal secretions away the amount of drug existing as uncharged
the formulation before the drug is chance to species, it was observed that absorption rate
getting absorbed through the mucosa before increases linearly with increase in partition
acting locally. coefficient (Schaefer et al., 2002).
Physiochemical Factors Influencing Nasal Solubility
Drug Absorption Molecular Weight Drug Solubility is a major factor for
The compound having a molecular weight determining the rate and extent in absorption of
less < 300 Dalton in solution are quickly and drug in nasal physiological pH. The
efficiently absorbed across the nasal membrane relationship between the drug solubility and its
in aqueous channels having a 100% absorption via the nasal route. As nasal
bioavailability. Molecular weight of lipophilic secretion are more watery in nature, a drug
drugs is more than 1000 Dalton, the nasal having an appropriate water solubility for
absorption is reduced. The therapeutic agent increased dissolution rate. The several
molecular weight 1000-6000 Dalton achieve approaches that may increase solubility of
good bioavailability with the help of absorption poorly soluble drugs for nasal administration,
enhancers (Misra et al., 2012). the Prodrug, salt forms, co-solvency and
Lipophilicity Complexation (cyclodextrines Complexation)
Lipophilicity is a major physicochemical (Lalani et al., 2014).
factor that limits the transport of therapeutics Polymorphism
on nasal administration. On increasing Polymorphism is affect the dissolution rate
lipophilicity of the compounds, the permeation and solubility of drug molecule and thus their
of the compounds normally increases through absorption through biological membranes. It is
nasal mucosa. The lipid domain plays an important to study polymorphic stability and
important role in the barrier function of these purity of drugs for nasal powders and
membranes (Jain et al., 2010). suspensions (Hussain, 1998).
Dissociation constant Formulation factors for Nasal Drug
The Nasal absorption is depends on the Absorption pH and mucosal irritancy
dissociation constant (pKa) of the drug and on The pH of the formulation and nasal
the pH of the nasal absorption site (5.0-6.5). surface is affect the drug permeation, to avoid
pKa is depends in degree of ionization and nasal irritation, the pH of the nasal formulation
degree of non-ionization. The nasal absorption should be adjusted to 4.5-6.5. In addition to
of weak electrolytes depends on their degree of avoiding irritation, it result in obtaining
ionization and the highest absorption occurs for efficient drug permeation and prevents the
the no ionized species (Dhuria et al., 2010). growth of bacteria (Tellingen et al., 2015).
Partition coefficient Osmolarity

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 27

The osmolarity of formulations, between time that will affect the total absorption of drug
285 and 310 mOsmol/l for nasal drug delivery and improve bioavailability (Alagusundaram et
to avoid the nasal mucosal irritations, precisely al., 2010).
the tonic effects. The isotonic solutions with 4. Formulation Strategies for Nose to Brain
osmolarity of 308 mOsmol/l were preferred for Drug Delivery System
safe and effective drug administration The Nasal route is efficient for CNS and
(Kulkarni et al., 2013). systemic delivery of wide range of drugs, most
Viscosity of the drugs exhibit low bioavailability even
The viscosity of the formulation intended when administered by this route. The low
for nasal drug delivery ensured the proper bioavailability may be due to the low solubility
contact time between the drug formulation and of drugs, rapid enzymatic degradation in nasal
nasal mucosa. The viscosity is increases, cavity, poor membrane permeability and rapid
increases the contact time and increases the mucociliary clearance. Several strategies is
time of permeation. The viscosity of employed to overcome these limitations
formulation not too high its optimum because it include, (Fig.6) Prodrug approach, enzymatic
can interfere the normal functions such as inhibitor, structural modifications, absorption
ciliary beating or mucociliary clearance and it enhancers and mucoadhesive drug delivery
alter the permeability of drug. Hence viscosity system.
of formulation is optimum, higher the residence

Figure 6. Formulation Strategies for Nose to Brain Drug Delivery System

Prodrug approach membrane, However they are poorly water

In Prodrug approach, the drugs that soluble drugs. So the Prodrug approach may be
administered in the form of solution undergo utilized to get of higher hydrophilic character
dissolution prior to absorption. Lipophilic that can made as aqueous formulation of
drugs get easily absorbed through nasal hydrophobic drugs. It should be also focused,
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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 28

when that formulation reaches to systemic Co-solvent

circulation, Prodrug must be converted to the This approach is used to increases the
parent drug molecule. L-dopa is a poorly water solubility of the drugs. Mostly used co-solvent
soluble drug, but when administered as Prodrug includes glycerol, ethanol, propylene glycol
its solubility is increases significantly in and ethylene glycol, since these are nontoxic,
Comparision with parent drug molecules. non-irritant to nasal mucosa and
Similar results were obtained with testosterone, pharmaceutical acceptable (Bahadur et al.,
which is a poor water-soluble drug but in the 2012).
Prodrug form with higher lipophilic nature, Absorption enhancer
Permeation increases through the membrane. Absorption enhancer, in which the poor
This approach is applicable to inhibit the permeability of hydrophilic drugs may be
enzymatic degradation of drugs in nasal overcome by the used of absorption enhancers
mucosa and to render the formulation for that induces reversible modification of
maintaining the enzymatic stability. L- epithelial barrier. The absorption enhancer is
aspartate--b-ester Prodrug of acyclovir is more used in nasal delivery were surfactant (SLS,
permeable and more stable toward enzymatic Poloxamer, tweens, spans), bile salts (sodium
degradation (it is an example of Prodrug glycodeoxycholate,sodium taurodeoxycholate),
approach). Prodrug approach is a powerful fatty acids (taurodihydrofusidate, oleic acid,
approach for enhancement of bioavailability of ethyl oleate), Chelators (EDTA, citric acid),
large molecular weight compounds such as peppermint oil and polymers. Some examples
protein and peptides drugs by this drug delivery of polymers such as cyclodextrines and
(Wu et al., 2008; Nasare et al., 2014). methylated cyclodextrines, chitosan and
Enzymatic inhibitors trimethyl chitosan, carbopol, starch and
Nasal mucus layer and nasal mucosa is act animated gelatine. This is responsible to
as enzymatic barriers for nasal drug delivery changes the permeability of epithelial layers of
system (they have a wide variety of enzymes). nasal mucosa by modifying phospholipids
Several approaches was used to avoid the bilayer and also changes fluidity or reversible
enzymatic degradation, including the use of openings of tight junctions between epithelial
protease and peptidases inhibitors. Bestatin and cells and increases paracellular transport of
comostate amylose were used as drug molecule (Kulkarni et al., 2013). The
aminopeptidases inhibitor and leupeptine, high molecule weight polymeric absorption
Aprotinin as tyrosine inhibitors is probably enhancers were not absorbed and reduced the
involved in the degradation of calcitonin. The systemic toxicity in comparison with low
bacitracin, amastatin, boroleucin and molecular weight. Chitosan can interact with
puromycin is used to avoid the enzymatic protein kinase C and its open tight junctions
degradations of drugs such as leucine, between epithelial cells to increases the
encephalin and human growth harmone. paracellular transport of polar drugs, its
Finally enzymatic inhibition can be achieved strongly interact with the nasal mucous layer
by using certain absorption enhancers such as and increases the contact time to overcome
bile salts and fusidic acid. Disodium ethylene- mucociliary clearance, thus it can widely used
diamine-tetra acetic acid, an absorption in intranasal dosage forms (Soni et al., 2004).
enhancer that reduces enzymatic degradation of Cyclodextrines complexes interact with the
beta sheet peptide, used for the treatment of lipophilic components of natural biological
Alzheimer’s disease (Bahadur et al., 2012; membrane and increase the permeability of
Swartling, 2016). drugs to increase the absorption. Although

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 29

cyclodextrines are widely used for nasal drug Chitosan surface modification
delivery, some local and systemic toxicity was Chitosan surface modification is one of the
reported. The Novel formulations such as important formulation Strategy for improving
mucoadhesive, micro and nanoemulsion, the solubility profile of pharmaceutical
microspheres and nanoparticles containing molecules. Chitosan molecules are the alkaline
absorption enhancers are demonstrated to better hydrolytic derivative of the chitin molecules.
for bypassing the BBB (Nagpal et al., 2013). Chitosan molecule having an ability to enhance
Structural Modification the solubility profile of pharmaceutical
Modification of structure of drug without molecules. They having a minimum
altering pharmacological activity, it is one of Crystallinity and particular from of the
the important factor to improve the Nasal drug chemical structural modifications due to its
absorption. On structural modification of drug chemically highly reactive functional group
molecule, the physicochemical characteristics such as acetamide, hydroxyl and amine
that are commonly modified, the molecular functional groups. The chemical structural
weight, molecular size, partition coefficient and modifications is not affect the fundamental
solubility, all favourable for nasal drug structure of chitosan molecules. The chemical
absorption. Examples of structural modification structural modifications is included
in which, the chemical modification of salmon carboxylation, Biochemical or Enzymatic
calcitonin into ecatonin (C-N bond replaced by modifications and copolymerization or graft
an S-S bond) was help to improved copolymerization. Chitosan surface
bioavailability when compared with parent modification is an excellent approach for
drug molecule (Wong et al., 2012; Fernandes et pharmaceutical, biochemical, biotechnological
al., 2010). and biopharmaceutical field (Patel et al., 2012).
PEG surface modification proteins and peptides in nanoparticulate
It is a surface modification approach to systems (Patel et al., 2012).
improve the solubility of pharmaceutical Lectin surface modification
molecules. The kDa monopolymeric PEG It is class of surface modification is
surface modification system having a surface important to improve the solubility of
110-200 nm particle size of the nanoparticles pharmaceutical molecules. Lectin is a class of
and the diffusion coefficient of the proteins and glycoproteins polymeric system
nanoparticulate system having 20 and the 380 and other purified sources of plants includes
times. This approach is maximum relevant, in jack bean, tomatoes. Lectin is obtained from
which the low molecular mass of PEG the sugar residue on the biological surfaces and
molecule and the high surface modification of it is applicable for the intranasal drug delivery
PEG molecule is responsible for high (Patel et al., 2012).
penetration capacity to that mucus PEG Colloidal Carriers in Nose to Brain Drug
molecule is rapidly absorbed in the surface of Delivery Systems
the particle. The longer chins of PEG Colloidal drug carriers include
molecules are having a maximum ability to microemulsion, nanoemulsion, nanoparticle,
interact the mucus fibers to reducing the polymeric micelles, liposomes, mucoadhesive
mucosal movements of nanoparticulate system. solutions and microspheres. The intent behind
The surface charge of nanoparticulate system use of colloidal drug carriers for nose to brain
responsible for composition of core of drug delivery was to increases the specifically
nanoparticulate system. PEG surface towards cell or tissue to increases
modification is applicable for transport of bioavailability of drugs by increasing their

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 30

diffusion through the biological membranes have been prepared from biodegradable nd
and protect against enzymatic degradations biocompatible blocks of copolymers.
(Jaiswal et al., 2015). Polymeric micelles are characterized by core
Microemulsion shell structure (Kwon et al., 1996; Nishiyama
Microemulsion is a clear, stable, isotropic et al., 2006). Mitra et al. have reported that
mixture of oil, water and surfactant are mixed micelles of bile salts and fatty acid have
frequently in the combination with co- a synergistic effect on the nasal absorption of
surfactants these approach is interested to the peptides.
pharmaceutical scientist because of their Nanoparticles
considerable potential to act as drug delivery Nanoparticle is a nanosized particle range
vehicle by incorporating of wide range drug size range of 1-1000 nm. It is applicable to
molecules. They offer the advantages of improve the solubility of poorly soluble drugs
spontaneous formation, easy manufacturing and permeability of drug molecules (Dingler et
and scale up, thermodynamic stability and it’s al., 1999). This nanoparticulate system is based
important to improve the solubilization and on biodegradable polymers, have been
bioavailability. Preparing a pharmaceutically extensive exploited in targeting drug delivery
acceptable dosage from demands a clear as they offer excellent improvement in nose to
understanding of the microemulsion structure, brain delivery by protecting the encapsulated
phase behaviour, factor leading to its drug from biological and chemical degradation,
thermodynamic stability, factors associated the extracellular transport by P-gp efflux
drug release from the formulation and potential system is increases the CNS availability of
uses and limitation of microemulsion system drugs. The poly-lactic acid (PLA), poly-
(Lin & Guo et al., 2011). glycolic acid (PGA), poly-lactide-co-glycolic
Nanoemulsion acid (PLGA), poly-g-caprolactone (PCL), poly-
Nanoemulsion is an isotropic mixture of methyl methacrylate, are the polymers known
oil, surfactant: cosurfactant (Smix) and drug is to be biodegradable, biocompatible and non-
known as nanoemulsion. The colloidal size toxic (Gasco et al., 1997; Ekambaram et al.,
ranges from 50-100 nm are often referred to as 2012). Illum et al. demonstrated that chitosan
Miniemulsion, nanoemulsion, ultrafine based nanoparticles can enhance nose-to-brain
emulsion or the multiple emulsions. These delivery of drugs compared to equivalent drug
nanoemulsion appear transparent and solutions formulations due to the protection of
translucent to the necked eyes and the possess the drug from degradation and/or efflux back
stability against sedimentation or creaming. into the nasal cavity. Seju et al., (2011) have
These properties make nanoemulsion as reported olanzapine-loaded PLGA
carriers of vast interest for fundamental studies nanoparticles for the treatment of psychotic
and practical applications in various fields like illness, schizophrenia, via nose to brain drug
chemical, cosmetic and pharmaceutical and delivery platform.
Biopharmaceutical fields (Bhosale et al., 2014; Liposomes and Proliposomes
Jaiswal et al., 2015; Patel et al., 2016). Liposomes and Proliposomes is a novel
Polymeric micelles approach of drug delivery system is important
Polymeric micelles that may serve as to deliver the various routes. Liposomes can be
nanoscopic drug carriers. Polymeric micelles used for targeting and introduction of
are the self-assemblies of block of co-polymers therapeutic agents to specific site by
and promising nanocarriers for drug and gene conjugation or cross linking of targeting moiety
delivery, for drug delivery, polymeric micelles to the native liposome or by surface

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 31

modification of the fabricated liposomal devices is mainly constructed in the straw or

formulation. Positively charged liposomes tubes which contains the pharmaceutical
possessed maximum bioadhesion prolonging molecules. It is a pre-dose powder capsules.
the residence time within the nasal cavity
thereby improving the bioavailability (Goyal et Dry powder inhaler
al., 2005). Free flowing Proliposomes Dry powder inhalers (DPIs) (Fig.7) are
containing propranolol hydrochloride were devices through which a dry powder
prepared by Shim et al. and evaluated their formulation of an active drug is delivered for
potential for transnasal delivery of propranolol local or systemic effect via the pulmonary
to sustain its plasma concentration. In a study route. Dry powder inhalers are bolus drug
on rats by Wattanathorn et al. intranasal delivery devices that contain solid drug,
liposomes containing quercetin decreased suspended or dissolved in a non-polar volatile
anxiety like behavior and increased spatial propellant or in dry powder inhaler that is
memory. US Patent 6342478 describes a nasal fluidized when the patient inhales. These are
micellar or liposomal preparation for the commonly used to treat respiratory diseases
delivery of fibroblast growth factor to the such as asthma, bronchitis, emphysema and
brain. Vyas et al. have reported multilamellar COPD and have also been used in the treatment
liposomes for intranasal delivery of nifedipine. of diabetes mellitus (Tos et al., 1998).The
Nasal Delivery Devices medication is commonly held either in a
Nasal drug delivery devices is versatile capsule for manual loading or a proprietary
tool for direct drug delivery in nasal cavity by form from inside the inhaler. Once loaded or
using various nasal device. The nasal devices actuated, the operator puts the mouthpiece of
include Powder formulation devices and liquid the inhaler into their mouth and takes a deep
Formulation devices. Liquid formulations inhalation, holding their breath for 5-10
currently completely dominate the nasal drug seconds. There are a variety of such devices.
Market, but nasal powder formulations and The dose that can be delivered is typically less
devices do exist, and more are in development. than a few tens of milligrams in a single breath
Powder formulation devices since larger powder doses may lead to
The powder nasal devices are more provocation of cough (Haruta et al., 2012).
convenient and it is having a maximum Pressurized Metered-Dose Inhale (PMDI)
stability than liquid nasal devices. In powder The pressurized metered dose inhaler is a
nasal devices preservatives are not required for nasal device (Fig.7) to deliver optimum amount
preparation. It is having a larger dose of drug of drug to the lungs, this is a short burst
and they improve stability of formulation. They aerosolized drug that inhaled the patient. It is
can be free from microbial growth. The nasal used for treatment of asthma, COPD and other
powder administration is increases the patient pulmonary disorders. A PMDI devices are
compliances and patient acceptance. Nasal important to deliver the optimum amount of
powder devices are applicable for the number medication to the lungs (Djupesland, 2012).
of proteins, peptides and non-peptide Breath-powered Bi-Directional technology
pharmaceutical molecules. Powder-polymer The Breath-powered Bi-Directional
complex formulation allows easy or convenient technology (Fig.7) is a new concept for
approach to nasal delivery of drugs. delivering the drug molecule to direct nose to
Insufflators brain administration. It is novel approach for
In this nasal devices, (Fig.7) to deliver the delivering the powder and liquid formulation to
pharmaceutical molecule for inhalation. This intranasal administration (Djupesland, 2012).

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 32

Liquid formulation devices bottles. Dose concentration and deposition of

Liquid nasal devices are deliver the liquid phase delivering via Squeezed bottles
aqueous or watery solutions to nasal cavity. they are strongly dependent on mode of
The suspension and emulsions are also administration. Dose and droplet size of that
transported to nasal cavity for intranasal formulation is mainly dependent on pressed
delivery. Liquid formulation devices are useful application of that container (Djupesland,
for chronic nasal disorders (Djupesland, 2012). 2012).
Sprays and Solution Metered-dose pump sprays
The solutions of drug molecule are Marketed nasal formulation such as
administered in nasal cavity is act as a nasal suspension, emulsion, solution are directly
sprays (Fig.7) and nasal solutions. The delivered to intranasal pathway by using
optimum dose of API is based on the amount of metered dose pump sprays (Fig.7). It is
drug molecule or volume of drug in applicable for treatment of nasal
pharmaceutical formulations. It is most hypersensitivity and other nasal disorders. It is
convenient approach for delivering the drug based on hand operated pump mechanism. It is
formulation for nose to brain delivery important to give local effect such as topical
bypassing the BBB (Djupesland, 2012). decongestants, antihistamines. This containers
Instillation and rhinyle catheter can be contain the pump, valve and the
Rhinyle catheter (Fig.7) is a liquid actuator. Dose of metered dose pump sprays
formulation device is important to deliver the depends upon the viscosity and surface tension
formulation by drop by drop in appropriate of that formulations (Djupesland, 2012).
region of nasal cavity. Catheter dosing is Single and duo dose spray devices
measured by the filling prior to admin-istration. Single dose devices (Fig.7) are
This system is applicable for the experimental administered single dose of drug formulation to
studies only (Djupesland, 2012). the intranasal pathway and duo dose device
Compressed air nebulizers administered more than one dose of different or
Nebulizers (Fig.7) are the nasal same drug formulation intranasal cavity. It is
administration devices in which the drug simple convenient and non-invasive mode for
loaded formulation in the gases state deliver to delivering the drug into nasal cavity. It is used
the lungs. It is a compressed air filling devices for treatment of chronic rhinosinusitis and in a
for delivering the drug formulation to nasal vaccine study (Djupesland, 2012).
cavity. This devices is more applicable for ViaNase atomizer
targeting the drug formulation to respiratory A handheld battery-driven atomizer
tract to give rapid on-set of action and reduces (Fig.7) intended for nasal drug delivery has
the toxic effects. This devices is not applicable been introduced (Via Nase by Kurve
for drug delivering into systemic pathways Technology Inc., Lynnwood, WA, USA). This
(Djupesland, 2012). device atomizes liquids by producing a vortical
Squeezed bottle flow on the droplets as they exit the device.
In this devices (Fig.7) are important for The induced vortical flow characteristics can
delivering the decongestants. They are smooth be altered in circular velocity and direction to
plastic bottles with simple jet outlet by pressing achieve different droplet trajectories. As
the bottle air passes in inside the container is discussed above, it is not clear that vortex flow
pressed out of the small nozzle, having the is desirable for penetration past the nasal valve;
optimum volume. After minimizing the however, it has been suggested that this
pressure the air again passes to inside the technology is capable of targeting the sinuses,

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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 33

and some gamma-deposition images suggesting nasal inhalation. However, when insulin is
delivery to the sinuses have been published. delivered with this device, lung deposition is
However, no information related to impact of likely to occur, and some concerns related to
prior surgery or numerical quantification of airway irritation and reduction in pulmonary
nasal or sinus deposition verifying the claimed function have been raised in relation to long-
improved deposition to the upper parts of the term exposure to inhaled insulin when Exubera
nose has been published (Djupesland, 2012). was marketed for a short period as a treatment
The ViaNase device has been used to deliver for diabetes. This example highlights the issue
nasal insulin in patients with early Alzheimer’s of unintended lung delivery, one important
disease (AD), and clinical benefit has been potential clinical problem associated with using
demonstrated. In these studies, delivery of nebulizers and atomizers producing respirable
insulin was performed over a 2-min period by particles for nasal drug delivery.

Figure 7. Nasal delivery devices: Insufflators (A), Dry powder inhaler (B), Pressurized Metered-
Dose Inhale (C), Breath-powered Bi-Directional technology (D), Sprays and Solution (E), Instillation
and rhinyle catheter (F), Compressed air nebulizers (G), Squeezed bottle (H), Metered-dose pump
sprays (I), Single and duo dose spray devices (J), ViaNase atomizer (K)
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 Asian Journal of Biomaterial Research 2017; 3(1):16-38. 34

Conclusion Kumar M, Mishra A, Babbar AK, Mishra AK,

Nose to brain drug delivery bypasses the Mishra P, Pathak K. 2008. Intranasal
BBB to target CNS, reducing systemic nanoemulsion based brain targeting
exposure of drug, thereby reducing the drug delivery system of risperidone.
systemic side effects. It is an attractive option InternationalJournal of Pharmaceutics,
of drug delivery due to its non-invasiveness. 358: 285-291.
These reported findings may be crucial in Tellingen OV, Arik YB, De Gooijer MC,
developing therapeutically efficacious product Wesseling P, Wurdinger T, De Vries
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it would provide useful information and Genes Involved in Brain Tumor
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