World Journal of Pharmaceutical Research

Karpagavalli et al. SJIFResearch

World Journal of Pharmaceutical Impact Factor 7.523

Volume 6, Issue 02, 400-415. Review Article ISSN 2277 7105

AN OUTLOOK ON NASAL DRUG DELIVERY SYSTEM

L. Karpagavalli1*, K. Gopalasatheeskumar1, N. Narayanan1, A. Isakki Raj1, J. Hari

Priya1 and S. Janarthanan

Jaya College of Paramedical Sciences, College of Pharmacy, Thiruninravur, Tamilnadu,

India.

ABSTRACT
Article Received on
15 Dec. 2016,
The history of nasal drug delivery dates back to earlier topical
Revised on 06 Jan. 2017, applications of drugs intended for local effects. Nasal therapy also
Accepted on 27 Jan. 2017
called Nasya karma has been recognized form of treatment in the
DOI: 10.20959/wjpr20172-7796
Ayurvedic system of Indian medicines. In this review was study of the
nasal drug delivery system as these system is have better systemic
*Corresponding Author bioavailability through nasal route as compared to oral route of
L. Karpagavalli
administration. The main benefit of using nasal delivery is prevention
Jaya College of Paramedical
of first pass metabolism, high permeability of some drugs in nasal
sciences, College of
Pharmacy, Thiruninravur, epithelium, quick drug absorption across this membrane, rapid onset of
Tamilnadu, India. action, better patient compliance and comfort, sustained and prolonged
action in comparison to other drug delivery systems. Nasal route is
alternative to parenteral therapy and also useful for long term therapy. In this review was
concentrated on anatomy and physiology of nose, advantages, disadvantages, limitations,
mechanism of drug delivery to the nose, types of dosage form for nasal delivery, factors
influencing nasal absorption, advancement in nasal dosage form and novel nasal drug
formulations.

KEYWORDS: Nasal route, Mucoadhesion, Novel dosage form, CNS Delivery, first pass
metabolism.

INTRODUCTION
The history of nasal drug delivery dates back to earlier topical applications of drugs intended
for local effects. Nasal therapy also called Nasya karma has been recognized form of
treatment in the Ayurvedic system of Indian medicines.[1] The early 1980s saw the

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introduction of nasal route as a promising systemic delivery alternative to other conventional

drug delivery routes.[2]

Nasal route is easily accessible, convenient, and reliable with a porous endothelial membrane
and a highly vascularised epithelium that provides a rapid absorption of compounds into the
systemic circulation, avoiding the hepatic first pass elimination. In addition, intranasal drug
delivery enables dose reduction, rapid attainment of therapeutic blood levels, quicker onset of
pharmacological activity, and fewer side effects.[3,4] The low metabolic environment of nose
has potential to overcome the limitation of oral route and duplicate the benefit of intravenous
administration. In addition to that, nasal administration minimizes the lag time associated
with oral drug delivery and offers non-invasiveness, self-administration, patient comfort, and
patient compliance, which are the hurdles in intravenous drug therapy.[5] It was reported that
lipophilic drugs are generally well absorbed from the nasal cavity with pharmacokinetic
profiles, which are often identical to those obtained after an intravenous injection with a
bioavailability approaching 100%.[1] On the other hand absorption of hydrophilic drugs can
be increased by means of absorption enhancers.[2] Drugs ranging from small chemicals to
large macromolecules including peptide/protein therapeutics, hormones, and vaccines are
being delivered through the nasal cavity.[6] The nasal delivery seems to be a favorable way to
circumvent the obstacles for blood-brain barrier (BBB) allowing the direct drug delivery in
the bio phase of central nervous system (CNS) active compounds. It has also been considered
for the administration of vaccines.[7] For many years drugs have been administered nasally for
both topical and systemic action. Topical administration includes the treatment of congestion,
rhinitis, sinusitis and related or chronic condition and has resulted in a variety of different
medications including corticoids, antihistamines, anticholinergic and vasoconstrictors. In
recent years, increasing investigations of the nasal route have focused especially on nasal
application for systemic delivery. For nasal drug delivery various systems such as nasal gels,
nasal spray, nasal pumps, micro emulsion, suspensions, powders and thermoreversable
mucoadhesive gel have been studied.

Intranasal delivery is currently being employed in treatments of migraine, smoking cessation,

Acute pain relief, osteoporosis, nocturnalenuresis and vitamin-B12 deficiency. Other
examples of therapeutic areas under development or with potential for nasal delivery include
cancer therapy, epilepsy, antiemetics, rheumatoid arthritis and insulin dependent diabetes.

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During the past several decades, the feasibility of drug delivery via the nasal route has
received increasing attention n from pharmaceutical scientists and clinicians.[8,9]

Nasal drug delivery system

Intranasal (IN) delivery is suitable for the local and systemic delivery of diverse therapeutic
compounds. Among the non-invasive routes, nasal administration offers promising potential
as a viable alternative for the delivery of some drugs. Hence there has been a surge of interest
that has led to many investigations involving the nasal cavity as a feasible site for the
administration of much therapeutic agents.[11,12]

The nasal epithelium is thin, porous and highly vascularised. This ensures high degree of
absorption and rapid transport of absorbed substances into the systemic circulation for
initiation of therapeutic action.
A porous endothelial basement membrane that poses no restriction to transporting the
drug into general circulation.
Absorbed substances are transported directly into the systemic circulation thereby
avoiding the first pass metabolic effect generally experienced following oral drug
administration.
Drugs can be absorbed directly into the CNS after nasal administration by passing the
tight blood brain barrier.
The enzymatic activity of the nasal epithelium is lower than that of the GIT or liver and
higher bioavailability of drugs especially proteins and peptides can be achieved. In
addition, enzyme inhibitors are more effective following nasal than oral application
[10]
because of a higher degree of dilution in the latter than in the former.
Realization of pulsatile delivery of some drugs like human growth hormone, insulin,
etc.is higher with NDD.
The nose is amenable to self-medication that not only lowers the cost of therapy but
improves patient compliance as well. The risk of overdosage is low and nasal lavage can
be used to remove unabsorbed excess drug.
Reformulation of existing drugs as NDD products offers companies the possibility to
extend the life cycle of their products.

Advantages
Drugs unabsorbed orally can be delivered to the systemic circulation by means of nasal
drug delivery.[11-14]

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Hepatic first pass metabolism is avoided.

Easy accessibility.
Self-medication is possible.
Improved patient compliance.
Drug degradation observed in the gastrointestinal tract is absent.
Improved bioavailability.
Rapid drug absorption.
Quick onset of action can be achieved.
The nasal bioavailability for smaller drug molecules is good.
Drug possessing poor stability in GIT fluids are given by nasal route.
Studies so far carried out indicate that the nasal route is an alternate to parenteral route,
especially, for protein and peptide drugs.[44]
Polar compound exhibiting poor oral absorption may be particularly suited for this route
of delivery.
Convenient for the patients, especially for those on long term therapy, when compared
with parenteral medication.

Disadvantages
Nasal cavity provides smaller absorption surface area when compared to GIT.[15-17]
Relatively inconvenient to patient when compared to oral delivery system since there is a
possibility of irritation.
There is a risk of local side effects and irreversible damage of the cilia on the nasal
mucosa, both from the substance and from constituents added to the dosage form.
There could be a mechanical loss of the dosage form into the other parts of the respiratory
tract like lungs because of improper technique of administration.
Certain surfactants used as chemical enhancers may disrupt and even dissolve the
membrane in high concentration.

Limitations
Only a limited amount of the formulation can be administered intranasally.
Application of large quantities will disturb the normal functioning of the nose (olfaction
and humidification of inspired air).
Dosing regimen as a result of drainage of the solution or expulsion of the dose due to
sneezing varies.

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High porosity of the nasal epithelium is insufficient for absorption of all compounds as
hydrophilic ones and large molecules like proteins.[18]

Anatomy and physiology of nose

Figure.1: Anatomy of nasal cavity

The nasal cavity is divided into two halves by the nasal septum and extends posterior to the
nasopharynx, while the most anterior part of the nasal cavity, the nasal vestibule, opens to the
face through the nostril. Breathing and olfaction are the major function of human nose.

Nasal cavity has mucus layer and hairs, those helpful in filtration of particles trapped in
inhaled air. Additionally metabolism of endogenous substances, mucociliary clearance also a
function of nose. The human nasal cavity has a total volume of about 16 to 19 ml, and a total
surface area of about 180 cm2, and is divided into two nasal cavities via the septum. The
volume of each cavity is approximately 7.5 ml, having a surface area around 75 cm2.[19,20,21]
Three regions can be distinguished in each part.

The Respiratory region

The respiratory region is the largest having the highest degree of vascularity and is mainly
responsible for systemic drug absorption. The respiratory epithelium is composed of four
types of cells, namely, non-ciliated and ciliated columnar cells, basal cells and goblet cells.
These cells facilitate active transport processes such as the exchange of water and ions
between cells and motility of cilia (where applicable). They may also serve to prevent drying
of the mucosa by trapping moisture.[22,23]

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Olfactory region
It is of about 10 cm2 in surface area and it plays a vital role in transportation of drugs to the
brain and the CSF. The olfactory region is located on the roof of the nasal cavities, just below
the cribriform plate of the ethmoid bone, which separates the nasal cavities from the cranial
Cavity. The olfactory tissue is often yellow in color, in contrast to the surrounding pink
tissue. Humans have relatively simple noses, since the primary function is breathing, while
other mammals have more complex noses better adapted for the function of olfaction. The
olfactory epithelial layer predominantly contains three cell types: the olfactory neural cells,
the subtentacular (also known as supporting) cells and the basal cells.[24,25]

The Vestibular region

It is anterior part of nasal cavity. Surface area is 0.6 cm 2 nasal portion is covered by a
stratified squamous keratinized epithelial with sebaceous gland. It is located at the opening of
nasal passages and is responsible for filtering out the air borne particles. Drug absorption is
very difficult in this region but it afforded high resistance against toxic environment. It is
considered to be the least important of the three regions with regards to drug absorption.[26,27]

Mucus Membrane of Nose and Its Composition

The nasal mucus layer is only 5 m thick and it is organized in two distinct layers: an
external, viscous and dense, and an internal, fluid and serous. Overall, nasal mucus layer
consists of 95% of water, 2.5-3% of mucin and 2% of electrolytes, proteins, lipids, enzymes,
antibodies, sloughed epithelial cells and bacterial products.

Epithelial cells
Basically there are two functions of these cells,
1. Provide a physical barrier to the invasion of infectious microorganisms and allergic
particles.
2. Work in conjunction with mucus glands and cilia to secrete and remove mucus and
foreign particles from the nasal cavity.[28]

Theories of mucoadhesion
Electronic Theory
The adhesive polymer and mucus typically have different electronic characteristics. When
these two surfaces come in contact, a double layer of electrical charge forms at the interface

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and then adhesion develops due to the attractive force from electron transfer across the
electrical double layer.[29]

Adsorption Theory
The adsorption theory of bioadhesion proposes that adhesion of a polymer to a biological
tissue results from (i) primary chemical bonds that are somewhat permanent and therefore
undesirable in bioadhesion (ii) Vander Waals, hydrogen, hydrophobic and electrostatic forces
which form secondary chemical bonds.

Wetting Theory
Primary application to liquid bioadhesive system, the wetting theory emphasizes the intimate
contact between the adhesive and mucus. Thus, a wetting surface is controlled by structural
similarity, degree of cross linking of the adhesive polymer or use of a surfactant.

Diffusion Theory
The essence of this theory is that chains of the adhesive and the substrate interpenetrate one
another to a sufficient depth to create a semi-permanent adhesive bond. The penetration rate
depends on the diffusion coefficient of both interacting polymers and the diffusion coefficient
is known to depend on molecular weight and cross-linking density.

Mechanism of Drug Absorption through Nose:

The first step in the absorption of drug from the nasal cavity is passage through the mucus.
Small unchanged particles easily pass through this layer. Large or charged particles may find
it more difficult to cross.

Figure 2: Cell type of the nasal epithelium

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Ciliated cell (A), non-ciliated cell (B), goblet cells (C), mucous gel-layer (D),
sol layer (E), basal cells (F) and basement membrane (G)

These include trans-cellular or simple diffusion across the membrane, paracellular transport
via movement between cell and transcytosis by vesicle carriers.

The first mechanism involves an aqueous route of transport, which is also known as the
paracellular route. This route is slow and passive. Poor bio-availability was observed for
drugs with a molecular weight greater than 1000 Daltons.[27,28]

The second mechanism involves transport through a lipoidal route that is also known as
the transcellular process and is responsible for the transport of lipophilic drugs that show
a rate dependency on their lipophilicity. Drugs also cross cell membranes by an active
transport route via carrier-mediated means or transport through the opening of tight
junction.[30,31]

Different factors affecting nasal drug absorption

Factors influencing absorption are related to nasal physiology, physic chemical
characteristics of drugs and formulation aspects.[4,32]

1. Biological Factors
a) Structural features.
b) Biochemical changes.
c) Physiological factors.
d) Blood flow.
e) Nasal secretions.
f) pH of the nasal cavity.
g) Mucociliary clearance and ciliary beat frequency.
h) Pathological conditions.
i) Environmental conditions.
j) Temperature.
k) Humidity.

2. Physicochemical Properties of Drugs

a) Molecular weight.
b) Size.

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c) Solubility.
d) Lipophilicity.
e) pka and partition coefficient.

3. Physicochemical Properties of Formulation

a) Dosage form.
b) Viscosity.
c) pH and mucosal irritancy.
d) Osmolarity.
e) Volume of solution applied.

4. Device Related Factors

a) Particle size of the droplet.
b) Size and pattern of disposition.

Novel drug formulations

Several claims have been made in favour of developing nasal formulations containing
liposomes, microspheres and nanoparticles for intranasal drug delivery. These systems
include, besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and
mucoadhesive polymers in order to improve the stability, membrane penetration and retention
time in nasal cavity.

Liposomes
Liposomes are phospholipids vesicles composed by lipid bilayers enclosing one or more
aqueous compartments and wherein drugs and other substances can be included. Liposomal
drug delivery systems present various advantages such as the effective encapsulation of small
and large molecules with a wide range of hydrophilicity and pKa values. In fact, they have
been found to enhance nasal absorption of peptides such as insulin and calcitonin by
increasing their membrane penetration. This has been attributed to the increasing nasal
retention of peptides. Protection of the entrapped peptides from enzymatic degradation and
mucosal membrane disruption.

Microspheres
Microsphere technology has been widely applied in designing formulations for nasal drug
delivery. Microspheres are usually based on mucoadhesive polymers (chitosan, alginate),

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which present advantages for intranasal drug delivery. Furthermore, microspheres may also
protect the drug from enzymatic metabolism and sustain drug release, prolonging its effect.

Nanoparticles
Nanoparticles are solid colloidal particles with diameters ranging from 1-1000 nm.[34] They
consist of macromolecular materials and can be therapeutically used as adjuvant in vaccines
or as drug carriers, in which the active substance is dissolved, entrapped, encapsulated,
adsorbed or chemically attached. Nanoparticles may offer several advantages due to their
small size, but only the smallest nanoparticles penetrate the mucosal membrane by
paracellular route and in a limited quantity because the tight junctions.

Application of nasal drug delivery system

Local delivery
For the treatment of topical nasal disorders the drug is administered through nasal route.
Among the most common examples are antihistamines and corticosteroids for rhino sinusitis,
and nasal decongestants for cold symptoms. Relatively low doses are effective when
administered through nasal route with less systemic toxic effects.[33]

Systemic delivery
The intranasal administration of drugs is an effective way for systemic availability of drugs as
compared to oral and intravascular routes. Examples include analgesics (morphine),
cardiovascular drugs as propranolol and carvedilol, hormones such as levonorgestrel,
progesterone and insulin, antiinflammatory agents as indomethacin and ketorolac, and
antiviral drugs (acyclovir). Some examples which are available in the market include
zolmitriptan and sumatriptan for the treatment of migraine and cluster headaches.[35,36,37]

Nasal vaccines
Nasal mucosa is the first site of contact with inhaled antigens and its use for vaccination,
especially against respiratory infections, has been extensively evaluated. Nasal vaccination is
a promising alternative to the classic parenteral route, because it is able to enhance the
systemic levels of specific immunoglobulin G and nasal secretary immunoglobulin A. [38,39]

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Examples
Intranasal vaccines includes Influenza A and B virus, proteosomainfluenza,
adenovirusvectored influenza, group B meningococcal native, attenuated respiratory
syncytial virus and Para influenza 3 virus.

CNS Delivery through Nasal Route

Intranasal route has promising approaches for delivery of drugs to the brain. The delivery of
drugs to the CNS from the nasal route may occur via olfactory neuroepithelium. The
transport via trigeminal nerve system from the nasal cavity to CNS has also been described.

Examples
Drug delivery through nasal route into CNS has been reported for Alzheimers disease, brain
tumors, epilepsy, pain and sleep disorders.

Methods to Improve Nasal Absorption

Followings are some approaches which have been used successfully for the improvement of
nasal drug absorption.[40]

Permeation enhancers: Various types of permeation enhancers have been investigated

to improve the nasal absorption like fatty acids, bile salts, phospholipids, surfactants,
cyclodextrins etc.
Prodrugs approach: Prodrugs are the inactive chemical moiety which becomes active at
the target site. This approach is mainly used to improve the physicochemical properties
such as taste, solubility, stability etc. of formulation.
In situ gel: These formulations generally controlled the problems of administration along
with conversion into gel by the influence of stimuli includes temperature, pH and ionic
concentration etc.
Nasal enzymes inhibitors: Enzymes inhibitor like protease and peptidase are used as
inhibitors for the formulation of peptide and protein molecules.
Structural modification: Drug structure can be modified without changing the
pharmacological activity to improve the nasal absorption. Chemical modifications are
mainly used to modify the drug structure.
Mucoadhesion: Mucoadhesion can be defining as the state in which two materials held
together for long period. Mucoadhesive polymers make intimate contact with biological
membrane, after the establishment of contact and penetrate into the tissue surface.

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Table 1: Challenge for nasal delivery systems

PROBLEM CHALLENGE SOLUTION
Enzymatic degradation Inhibit nasal enzymes Enzyme inhibitor, prodrugs
Deposit formulation in
Mucociliary clearance Overcome it
anterior cavity
Enhance drug permeation, Permeation enhancer,
Less permeation
modify the membrane Prodrugs
Poor physico-chemical
Improve it Prodrugs, co solvents.
properties of drug

Advancement in nasal dosage form

1. Nasal Drops
Nasal drops are one of the most simple and convenient systems developed for nasal delivery.
Due to ease of self-administration it is becoming more popular. The main disadvantage of
this system is the lack of dose precision.
Ex: Otrivin nasal drops.

2. Nasal Sprays: Both solution and suspension formulations can be formulated into nasal
sprays. Due to the availability of metered dose pumps and actuators, a nasal spray can
deliver an exact dose. These are preferred over powder sprays because powder results in
mucosal irritation.
Ex: Asthalin nasal sprays.

3. Nasal Powders: These formulations are developed when there is problem with stability.
However, the suitability of the powder formulation is dependent on the solubility, particle
size, aerodynamic properties and nasal irritancy of the active drug.
Ex: Onzetraxsail ( sumatriptan nasal powder)

4. Nasal Gels: The nasal gel showed growing interest due to reduction of post-nasal drip,
high viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior
leakage of the formulation, reduction of irritation by using soothing/emollient
excipientsand target delivery to mucosa for better absorption.
Ex: Nascobal(Cynocobalamine), Natesto (Testosterone)

5. Nasal Inserts: Nasal inserts are novel, bioadhesive, solid dosage forms for prolonged
systemic drug delivery via the nasal route. The principle of the dosage form is to imbibe
nasal fluid from the mucosa after administration and to form a gel in the nasal cavity to
avoid foreign body sensation.

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Ex: Brez nasal inserts.

Novel Nasal Drug Formulations

This includes the following formulations enlisted as;[42,43]
Nanoparticle - e.g. Vaccine
Liposomes - e.g. Desmopressin
Microsphere - e.g. Insulin
Micro emulsion - e.g. Zolmitriptan

Table 2: List of available nasal products

DRUG BRAND SUPPLIER MAIN INDICATION
Beclomethasone Beconase GlaxoSmithKline Rhinosinusitis
Budesonide Suprefact Sanofi-Aventis Treatment of prostate Cancer
Cynocobalamine Nascobal Strativa pharma Vit B12 deficiency
Control of dehydration
Desmopressin Desmospray Ferring pharma
in diabetes insipid us
Fentanyl Instany Nyco med Pharma Pain management
Mometazone Nasonex Scharing-plough Scharing-plough
Eradication of nasal
Mupirocine Bactroban GlaxoSmithKline
Staphylococci

CONCLUSION
Nasal drug delivery system offers the main requirement for a successful controlled release of
many drugs which leads to improve patient compliance. Manipulation of controlled release of
various drugs provides a number of advantages over conventional dosage forms. Sustained or
controlled or prolonged release of the drug, good stability and biocompatibility characteristics
make the nasal drug delivery systems very reliable. Hence it can be concluded that many
researches had investigated on nasal drug delivery system and much more studies are need to
be investigated for the further improvement in the nasal drug delivery system.

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