IJRPC 2012, 2(3) Parvathi ISSN: 22312781

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Available online at www.ijrpc.com Review Article

INTRANASAL DRUG DELIVERY TO BRAIN: AN OVERVIEW

M. Parvathi
Raghavendra Institute of Pharmaceutical Sciences and Research, Anantapur,
Andhra Padesh, India

ABSTRACT
As the people have been suffering from many CNS disorders like Multiple sclerosis, Alzheimer’s
disease, Parkinson’s disease many drugs have been developed but they failed in showing the
concentration required for action. But nose to brain drug delivery the drug directly enter into the
brain. The objective of this review is to provide overview of nose on an physiological, anatomical
and, barriers related to nasal drug delivery, physicochemical, biological and factors affecting nasal
drug delivery system and its advantages.

Keywords: Intranasal drug delivery, Barriers to intranasal delivery, Brain targeting.

INTRODUCTION especially against respiratory infections such

Despite good progress in neurosciences and a as influenza, is attracting interest from vaccine
corresponding high interest in brain delivery delivery scientists3. Bjerre et al. showed that
technologies, very few drugs have been the sedative propiomazine, for which a rapid
marketed for the treatment of CNS disorders. onset of action is desirable. and it absorbed
Nasal applications for delivery to the brain within 5 minutes after nasal administration to
4
have not been pursued by the pharmaceutical rats . Currently, nasal administration is used
industry since the 1980s. Currently, Nasal therapeutically for the systemic absorption of
drug delivery has been recognized as a very drugs in a variety of indications, including
promising route for delivery of therapeutic sumatriptan for migraine , the antidiuretic
compounds including biopharmaceuticals . desmopressin5 for the treatment of diabetes
The nasal mucosa used for delivering the insipidus and oxytocin for secretion of milk in
drugs for CNS disorders and systemic response to suckling during breast feeding or
administration of analgesics, sedatives, contraction of the uterine muscle to hasten
hormones, cardiovascular drugs, and childbirth by nasal delivery. the dopamine
vaccines, corticosteroid hormones The agonist apomorphine for patients with
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anatomy and physiology of the nasal passage Parkinsonism .
indicate that nasal administration has potential
practical advantages for the introduction of Advantages of intranasal drug delivery
therapeutic drugs into the systemic circulation.  Rapid drug absorption via highly-
The concentration-time profiles achieved after vascularized mucosa
nasal administration are often similar to those  Ease of administration, non-invasive
after intravenous administration, resulting in a  Improved bioavailability
1
rapid onset of pharmacological activity .  Improved convenience and
Drugs ranging from small chemicals to large compliance
macromolecules including peptide/protein  Self-administration
therapeutics, hormones, and vaccines, are  Large nasal mucosal surface area for
being delivered through the nasal cavity. dose absorption
Marketed products include a range of  Avoidance of the gastrointestinal tract
antimigraine drugs (e.g.,sumatriptan, and first-pass metabolism
zolmitriptan) as well as some peptides
2  Rapid onset of action
(e.g.,calcitonin, desmopressin) . Later the use
 Lower side effects
of the nasal route for delivery of vaccines,

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 Drugs which cannot be absorbed to the nasopharynx. Both symmetrical halves

orally may be delivered to the consist of four areas (nasal vestibule, atrium,
Systemic circulation through respiratory region and olfactory region) that
nasal drug delivery system. are distinguished according to their anatomic
 Convenient route when compared with and histological characteristics.
parenteral route for long term therapy.
 Bioavailability of larger drug molecules
can be improved by means of
absorption enhancer or other
approach.

Disadvantages of intranasal drug delivery

 Some drugs may cause irritation to
the nasal mucosa
 Nasal congestion due to cold or
allergies may interfere with absorption
of drug.
 Drug delivery is expected to decrease
with increasing molecular weight.
 Frequent use of this route leads to
mucosal damage
 The amount of drug reaches to RESPIRATORY REGION
different regions of the brain and The respiratory epithelium is made of with four
spinal cord, varies with each agent types of cells are non-ciliated and ciliated
columnar cells, basal cells and goblet cells.
NASAL CAVITY These cells facilitate active transport
ANATOMY AND PHYSIOLOGY processes such as the exchange of water and
In humans the functions of the nasal cavity are ions between cells and motility of cilia and also
7
breathing and olfaction . It also affords an to prevent drying of the mucosa by Trapping
important protective activity once it filters, heat moisture in order to facilitate mucociliary
and humidify the inhaled air before reaching clearance. A viscous gel layer, the mucus
the lowest airways. Nasal cavity is lined with blanket floats on the serous fluid layer. The
mucus layer and hairs which are involved in viscous gel layer is moved along by the hook
those functions are trapping inhaled particles shaped cilia termini during the energy
and pathogens. Moreover, mucociliary dependent ‘effective stroke’ phase of the
clearance, immunological activities and ciliary motion Cilia are up to 7mm in length
metabolism of endogenous substances are when fully extended but can fold to half this
also essential functions of nasal structures . length during the recovery stroke where the
The nasal cavity is a space situated above the hook terminus detaches from the gel layer and
oral cavity and hard palate and below the skull moves immersed in the sol layer in the
base and intracranial compartment. The nasal opposite direction to the gel layer movement
septum consists of cartilage in its front end The cilia beat with a frequency of 1000 strokes
and bone towards the back of the nose. The per min. Hence the mucus moves only in one
perpendicular plate of the ethmoid bone, direction from the anterior to the posterior part
vomer bone, and maxilla bone these three of the nasal cavity to the nasopharynx.
gives nasal septum. The nasal septum is
sometimes crooked or off-midline, which leads OLFACTORY REGION
to narrowing of one or both sides of the nasal Smell allows humans and animals with
cavity. The left and right nasal cavities become olfactory receptors to identify food, mates,
continuous in the back of the nose via the predators, and provides both sensual pleasure
opening to the nasopharynx is called as the as well as warnings of danger . The olfactory
choana. In this area, the nasal cavity region of the two nasal passages in humans
transitions into the nasopharynx. The is a area of about 2.5 square centimeters
nasopharynx contains a collection of centrally containing in total of about 50 million primary
located lymphoid tissue called the adenoids. . sensory receptor cells. The olfactory region
The human nasal cavity has a total volume of consists of cilia projecting down out of the
15-20mL and a total surface area of 150 cm2 . olfactory epithelium into a layer of mucous
It is divided by middle septum into two which is about 60 microns thick. This mucous
symmetrical halves, each one opening at the layer is a lipid-rich secretion that bathes the
face through nostrils and extending posterior surface of the receptors at the epithelium

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surface. The mucous layer is produced by the to some extent, the enzymes present in nasal
11
Bowman’s glands which reside in the olfactory mucosa provides a pseudo-first-pass effect .
epithelium. The mucous lipids assist in The role of the enzymatic barrier is to protect
transporting the odorant molecules as only the lower respiratory airways from toxic
volatile materials that are soluble in the agents. In addition, there are various barriers
mucous can interact with the olfactory in the nasal membrane for protection from the
receptors and produce the signals that our microorganisms, allergens and irritating
8
brain interprets as odor . substances from the environment that must be
overcome by drugs before they can be
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absorbed into the systemic circulation .

Mucociliary clearance
Particles entrapped in the mucus layer are
transported and cleared from the nasal cavity.
The combined action of the mucus layer and
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cilia is called mucociliary clearance . This is
an defence mechanism of the respiratory tract
to protect against noxious inhaled materials.
Mucus traps the particles of dust, bacteria and
drug substances and is transported towards
the nasopharynx at a speed of 5 - 8 mm/min
where it is swallowed. The normal mucociliary
MECHANISM OF DRUG ABSORPTION
FROM NOSE transit time in humans has been reported to be
14
The initial step in the absorption of drug from 13 to 15 min .
the nasal cavity is passage through the
Protective barriers
mucus, large/charged particles may find it
small molecular weight and Uncharged
more difficult to cross. But Small unchanged
substances can easily pass through this layer.
particles easily pass through this layer. The
But larger or charged particles are difficult to
mechanisms for absorption through the nasal
cross. Mucin, the protein in the mucus, has the
mucosa. These include paracellular transport
potential to bind to solutes, hindering diffusion.
via movement between cell and transcytosis
Additionally, structural changes in the mucus
by vesicle carriers .transcellular or simple
layer are possible as a result of environmental
diffusion across the membrane. 15
changes such as pH, temperature etc . The
1. The first mechanism includes aqueous route
nasal membrane is a physical barrier and the
of transport, which is also called as the
mucociliary clearance is a temporal barrier to
paracellular route. This is slow and passive
drug absorption across the nasal epithelium16.
route. inverse log-log relation ship between
intranasal absorption and the molecular
weight of water-soluble compounds. Poor FACTORS INFLUENCING NASAL DRUG
bio-availability was observed for drugs with ABSORPTION
Various factors affecting the systemic
a molecular weight greater than
9 bioavailability of drugs that are administered
1000Daltons .
through the nasal route. Those are
2. The second mechanism is transport
physiochemical properties of the drugs, the
through a lipoidal route is known as
anatomical and physiological properties of the
transcellular process and is responsible for
nasal cavity and the type and characteristics of
the transport of lipophilic drugs that show a
rate dependency on their lipophilicity. Drugs selected nasal drugs delivery system.
also cross cell membranes by an active
1. Physiochemical properties of drug.
transport route via carrier-mediated means
Molecular size
or transport through the opening of tight
Enzymatic degradation in nasal cavity
junctions. For example, Chitosan, a natural
Lipophilic-hydrophilic balance.
biopolymer opens tight junctions between
10 2. Delivery Effect
epithelial cells to facilitate drug transport .
Formulation (Concentration, pH)
Viscosity
Barriers for nasal drug absorption
Enzymatic barrier Drugs distribution and deposition.
3. Nasal Effect
The nasal mucosa contains enzymes such as
Environmental pH
cytochrome P450-dependent monooxygenase,
Cold, rhinitis.
carboxyl esterase and amino peptidase. nasal
Membrane permeability.
delivery avoids hepatic first-pass metabolism

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Molecular size formulations interfere with the normal functions

The molecular size of the drug influence like ciliary beating or mucociliary clearance
absorption of the drug through the nasal route. and thus alter the permeability of drugs.
The lipophilic drugs have direct relationship
between the molecular weight and drug Drugs distribution and deposition
permeation whereas water soluble compounds The drug distribution in the nasal cavity affect
have inverse relationship. The rate of the efficiency of nasal absorption. The mode of
permeation is highly sensitive to molecular drug administration could effect the distribution
17 .
size for compounds with MW ≥ 300 Daltons of drug in nasal cavity, which in turn will
determine the absorption efficiency of a drug.
Enzymatic degradation in nasal cavity The absorption and bioavailability of the nasal
Nasal cavity having exo-peptidases and endo- dosage forms depends on the site of
peptidases, exo-peptidases. Exo-peptidases disposition. The anterior portion of the nose
capability to cleave peptides at their N and C provides a prolonged nasal residential time for
terminal and endo-peptidases such as serine disposition of formulation, it enhances the
and cysteine, which can attack internal peptide absorption of the drug. The posterior chamber
bonds .Drugs like peptides and proteins are of nasal cavity will use for the deposition of
having low bio-availability across the nasal dosage form and drug is eliminated by the
cavity, so these drugs may have possibility to mucociliary clearance process and hence
20
undergo enzymatic degradation of the drug shows low bioavailability . The site of
molecule in the lumen of the nasal cavity or disposition and distribution of the dosage
during passage through the epithelial barrier18. forms are depends on delivery device, mode
of administration, physicochemical properties
Lipophilic-hydrophilic balance of drug molecule.
The HLB nature of the drugs affects the
absorption process. By increasing lipophilicity, Environmental pH
the permeation of the compound normally The environmental pH also affect the
increases through nasal mucosa. Although the efficiency of nasal drug absorption. The
nasal mucosa was found to have some nonionised lipophilic form crosses the nasal
hydrophilic character, it appears that these epithelial barrier via transcellular route,
mucosae are primarily lipophilic in nature and whereas the more lipophilic ionized form
the lipid domain plays an important role in the passes through the aqueous paracellular
21
barrier function of these membranes. route .
Lipophilic drugs like naloxone, buprenorphine,
testosterone and 17a-ethinyl- oestradiol are Membrane permeability
almost completely absorbed when Nasal membrane permeability is the important
administered intranasal route. factor which affect the absorption of the drug
through the nasal route. The water soluble
Formulation (pH, Concentration) drugs and particularly large molecular weight
The pH of the formulation can affect a drug’s drugs like peptides and proteins are having the
permeation. To avoid nasal irritation, the pH of low membrane permeability are mainly
the nasal formulation should be adjusted to absorbed through the endocytotic transport
4.5–6.5 because lysozyme is found in nasal and by passive diffusion through the aqueous
22
secretions, which is responsible for destroying pores (i.e. tight junctions) .
certain bacteria at acidic pH. Under alkaline
conditions, lysozyme is inactivated and the Cold, rhinitis
tissue is susceptible to microbial infection. In The symptoms are hyper secretion, itching
addition to avoiding irritation, it results in and sneezing mainly caused by the viruses,
obtaining efficient drug permeation and bacteria or irritants. Rhinitis is a most
prevents the growth of bacteria. frequently associated common disease, it
23
Concentration gradient plays very important influence the bioavailability of the drug . It is
role in the permeation process of drug through caused by chronic or acute inflammation of the
the nasal membrane due to nasal mucosal mucous membrane of the nose. These
damage19. conditions affect the absorption of drug
through the mucus membrane due the
24
Viscosity inflammation .
A higher viscosity of the formulation increases
contact time between the drug and the nasal NASAL FORMULATIONS
mucosa thereby increasing the time for The selection of delivery system depends
permeation. At the same time, highly viscous upon the drug being used, proposed

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indication, patient population and marketing second extracellular transport based route,
preference. intranasal administered substances may be
transported along trigeminal nerve to by pass
Nasal Drops BBB. After reaching the olfactory bulb of
Nasal drops are one of the most simple and trigeminal region the substances may enter in
convenient systems developed for nasal to other regions of brain by diffusion, which
delivery. The main disadvantage of this may also be facilitated by perivascular pump
system is the lack of dose precision. It has that is driven by arterial pulsation.
been reported that nasal drops deposit human Delivery of drugs to the central nervous
serum albumin in the nostrils more efficiently system (CNS) remains a challenge in the
than nasal sprays. development of therapeutic agents for central
targets due to the impenetrable nature of the
Nasal Sprays drug through blood-brain barrier (BBB). The
Both solution and suspension formulations can BBB obstruct the substrate penetration based
be formulated into nasal sprays. Due to the on several characteristics, including
availability of metered dose pumps and lipophilicity, molecular size and specificity for
actuators, a nasal spray can deliver an exact a variety of ATP-dependent transport systems.
dose from 25 to 200 µL. Injection of dyes in the ventricles of rabbits
and monkeys showed that the cerebrospinal
Nasal Gels fluid (CSF) is drained via the olfactory neurons
Nasal gels are high-viscosity thickened into the olfactory neurons, originating from the
solutions or suspensions. The advantages of a olfactory bulb, connect the brain with the nasal
nasal gel include the reduction of post-nasal cavity by penetrating the cribriform plate,
drip due to high viscosity, reduction of taste which brings the neurons into the nasal
impact due to reduced swallowing, reduction mucosa. This coined the idea that this
of anterior leakage of the formulation, transport route could also exist in the opposite
reduction of irritation by using soothing direction, which would imply direct access
excipients and target delivery to mucosa for from the nasal cavity to the brain, thus
better absorption. circumventing the BBB26.

Nasal Powders NEEDS AND FUTURE PROSPECTIVE OF

This dosage form may be developed if solution NASAL DRUG DEIVERY
and suspension dosage forms cannot be In the field of drug delivery, drug delivery
developed due to lack of drug stability. The technologies will play a key role in the success
advantages to the nasal powder dosage form of the industry. The need for non-invasive drug
are the absence of preservative and superior delivery systems continues due to poor
stability of the formulation. Eventhough the acceptance and compliance with the existing
suitability of the powder formulation is delivery systems. The current needs of the
dependent on the solubility, particle size, industry are improved solubility/stability,
aerodynamic properties and nasal irritancy of biological half-life and bioavailability
25
the active drug and excipients . enhancement of poorly absorbed drugs. Key
issues facing the biopharma industry are to
INTRA NASAL DRUG DELIVERY TO BRAIN improve safety, improve efficacy for organ
There are three mechanisms underlying the targeting, and improved compliance via
direct nose to brain drug delivery, one is sustained release or increasing residence time
intracellular transport mediated route and two of drug at the site of application. New
extracellular transport mediated routes. The technologies include improved nasal
intracellular transport mediated route is a formulations; site specific release, carrier-
relatively slow process, taking hours for intra based systems, advanced spray formulations,
nasally administered substances to reach the atomized mist technology, preservative free
olfactory bulb. The two extracellular transport system and integrated formulation
mediated routes could underlie the rapid development are strictly needed for success of
entrance of drug into the brain which can drug delivery through nasal mucosa.
occur within minutes of intranasal drug For success of nasal drug delivery
administration. In the first extracellular Researchers has to on:
transport based route intranasally  Development of delivery technologies
administered substances could first cross the to increase efficacy and reduce side
gas between the olfactory neurons in the effects by target delivery with
olfactory epithelium which are subsequently variations potential of the drug
transported in to the olfactory bulb. In the

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 Development of new technologies to 10. Dodane V, Khan MA and Merwin JR.

deliver macromolecules with utilization Effect of chitosan on epithelial
of biotechnology and high technology permeability and structure. Int J
 Development of integrated/improved Pharm. 1999;182:21-32.
nasal formulations 11. Soane RJ, Frier M, Perkins AC, Jones
 Development of integrated device NS and Davis SS. Illum L Evaluat ion
development for successful delivery of the clearance charact erist ics of
of therapeutics bioadhesive systems in humans. Int J
Pharm.1999; 178: 55-65.
CONCLUSION 12. Morimoto K, Miyazaki M and Kakemi
The identification of ways to increase the M. Effect s of proteolytic enzyme
bioavailability of drugs in the brain opens inhibit ion on nasal absorption of
possibilities for the causal treatment of salmon calcitonin in rat s. Int J
diseases associated with a deficiency in Pharm.1995;133:1-8.
neurosteroids and neurotransmitters in the 13. Illum L, Mathiowit ZE and Chickering
brain. Despite several limitations, intranasal DE. Bioadhesive formulations for
delivery seems to be the most promising nasal peptide delivery: Fundamentals,
application to improve CNS disorders, Novel Approaches and Development.
including Multiple sclerosis, brain injuries, by New York: Marcel Dekker. 1999;507-
medicine. 539.
14. Kublik H and Vidgren MT. Nasal
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