M.Alagusundara et al. | Int. J. Res. Pharm. Sci.

Vol-1, Issue-4, 454-465, 2010

ISSN: 0975-7538
Review Article
www.ijrps.pharmascope.org

Nasal drug delivery system - an overview

1 1 1 1 1
M.Alagusundaram* , B.Chengaiah , K.Gnanaprakash , S.Ramkanth , C.Madhusudhana Chetty ,
2
D.Dhachinamoorthi
1
Department of Pharmaceutics, Annamacharya College of Pharmacy, New Boyanapalli, Rajampet– 516 126,
Kadapa, Andhra Pradesh, India
2
QIS College of pharmacy, Ongole, Andhra Pradesh, India
ABSTRACT

The use of the nasal route for the delivery of challenging drugs such as small polar molecules, vaccines, hormones,
peptides and proteins has created much interest in nowadays. Due to the high permeability, high vasculature, low
enzymatic environment of nasal cavity and avoidance of hepatic first pass metabolism are well suitable for sys-
temic delivery of drug molecule via nose. Many drug delivery devices for nasal application of liquid, semisolid and
solid formulation are investigated to deliver the drugs to the treat most crisis CNS diseases (i.e., Parkinson’s dis-
ease, Alzheimer’s disease) because it requires rapid and/or specific targeting of drugs to the brain. It is well suita-
ble for the delivery of biotechnological products like proteins, peptides, hormones, DNA plasmids for DNA vac-
cines to give enhanced bioavailability. This review sets out to discuss some factors affecting nasal absorption, bio-
availability barriers, strategies to improve nasal absorption, new developments in nasal dosage form design and
applications of nasal drug delivery system.
Keywords: Nose; peptides and proteins; vaccines; bioavailability; nasal drug delivery.
INTRODUCTION et al., 2007). The nasal route circumvents hepatic first
pass elimination associated with the oral delivery: it is
Nasal mucosa has been considered as a potential ad-
easily accessible and suitable for self-medication. Dur-
ministration route to achieve faster and higher level of
ing the past several decades, the feasibility of drug
drug absorption because it is permeable to more com-
delivery via the nasal route has received increasing
pounds than the gastrointestinal tract due to lack of
attention from pharmaceutical scientists and clinicians.
pancreatic and gastric enzymatic activity, neutral pH of
Drug candidates ranging from small metal ions to large
the nasal mucus and less dilution by gastrointestinal
macromolecular proteins have been tested in various
contents (Krishnamoorthy R et al., 1998; Kisan R et al.,
animal models (Chien YW et al., 1989). It has been do-
2007). In recent years many drugs have been shown to
cumented that nasal administration of certain- hor-
achieve better systemic bioavailability through nasal
mones and steroids have resulted in a more complete
route than by oral administration. Nasal therapy, has
absorption (Hussain AA. et al., 1979; Hussain AA et al.,
been recognized form of treatment in the Ayurvedic
1981). This indicates the potential value of the nasal
systems of Indian medicine, it is also called “NASAYA
route for administration of systemic medications as
KARMA” (Chien YW et al., 1989).
well as utilizing this route for local effects.
Nasal drug delivery – which has been practiced for
For many years drugs have been administered nasally
thousands of years, has been given a new lease of life.
for both topical and systemic action. Topical adminis-
It is a useful delivery method for drugs that are active
tration includes the treatment of congestion, rhinitis,
in low doses and show no minimal oral bioavailability
sinusitis and related allergic or chronic conditions, and
such as proteins and peptides. One of the reasons for
has resulted in a variety of different medications in-
the low degree of absorption of peptides and pro-
cluding corticoids, antihistamines, anti-cholinergic and
teins via the nasal route is rapid movement away
vasoconstrictors. In recent years, increasing investiga-
from the absorption site in the nasal cavity due to
tions of the nasal route have focused especially on
the mucociliary clearance mechanism (Mahalaxmi R
nasal application for systemic drug delivery (Kublik H et
al., 1998). Only a few nasal delivery systems used in
experimental studies are currently on the market to
* Corresponding Author
deliver therapeutics into the nasal cavities, i.e. nasal
Email: [email protected]
Contact: +91-9989530761 drops as multiple or single-dose formulation, aqueous
Received on: 21-07-2010 nasal sprays, a nasal gel pump, pressurized MDIs and
Revised on: 13-09-2010 dry powder inhalers. Intranasal delivery is currently
Accepted on: 15-09-2010 being employed in treatments for migraine, smoking
cessation, acute pain relief, osteoporosis, nocturnal
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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

enuresis and vitamin-B12 deficiency. Other examples of like lungs because of the improper technique of
therapeutic areas under development or with potential administration.
for nasal delivery include cancer therapy, epilepsy, an-
ANATOMY & PHYSIOLOGY OF NASAL CAVITY
ti-emetics, rheumatoid arthritis and insulin-dependent
diabetes. The nasal cavity is divided into two halves by the nasal
septum and extends posterior to the nasopharynx,
This review article provides a brief overview of the ad-
while the most anterior part of the nasal cavity, the
vantages and limitations of nasal drug delivery system
nasal vestibule, opens to the face through the nostril.
and anatomy of nasal cavity, mechanism of nasal ab-
The nasal cavity consists three main regions are nasal
sorption, barriers to nasal absorption, strategies to
vestibule, olfactory region and respiratory region. The
improve nasal absorption, nasal drug delivery formula- 2
surface area in the nose can be enlarges about 150cm
tion issues and applications of nasal drug delivery sys-
by the lateral walls of the nasal cavity includes a folded
tems.
structure, it is a very high surface area compared to its
ADVANTAGES (Aulton M.E et al., 2002, small volume. This folded structure consists of three
Krishnamoorthy R et al., 1998) turbinates: the superior, the median and the inferior
(Michael et al., 2005).The main nasal airway having the
1) Drug degradation that is observed in the
narrow passages, usually it has 1-3mm wide and these
gastrointestinal tract is absent.
narrows structures are useful to nose to carryout its
2) Hepatic first pass metabolism is avoided.
main functions.
3) Rapid drug absorption and quick onset of action
can be achieved. The nasal cavity is covered with a mucous membrane
4) The bioavailability of larger drug molecules can be which can be divided into two areas; nonolfactory and
improved by means of absorption enhancer or olfactory epithelium, in this non-olfactory area includes
other approach. the nasal vestibule which is covered with skin-like
5) The nasal bioavailability for smaller drug molecules stratified squamous epithelium cells, where as
is good. respiratory region, which has a typical airways
6) Drugs that are orally not absorbed can be epithelium covered with numerous microvilli, resulting
delivered to the systemic circulation by nasal drug in a large surface area available for drug absorption
delivery. and transport (Sarkar MA, 1992). In this way the mucus
7) Studies so far carried out indicate that the nasal layer is propelled in a direction from the anterior to-
route is an alternate to parenteral route, wards the posterior part of the nasal cavity. The goblet
especially, for protein and peptide drugs. cells are present in the mucus membrane which covers
8) Convenient for the patients, especially for those the nasal turbinate and the atrium; it secretes the mu-
on long term therapy, when compared with cus as mucus granules which are swelling in the nasal
parenteral medication. fluid to contribute to the mucus layer.
9) Drugs possessing poor stability in g.i.t. fluids are
The mucus secretion is composed of about 95% water,
given by nasal route.
2 % mucin, 1% salts, 1% of other proteins such as al-
10) Polar compounds exhibiting poor oral absorption
bumin, immunoglobulin s, lysozyme and lactoferrin,
may be particularly suited for this route of deli-
and b 1% lipids (Kaliner M et al., 1984). The mucus se-
very.
cretion gives immune protection against inhaled bacte-
LIMITATIONS (Hirai S et al., 1993; Kadam SS et al., ria and viruses.It also performs a number of physiologi-
1981) cal functions. (1) It covers the mucosa, and physically
and enzymatically protects it. (2) The mucus has water-
1) The histological toxicity of absorption enhancers
holding capacity. (3) It exhibits surface electrical activi-
used in nasal drug delivery system is not yet clearly
ty. (4) It permits efficient heat transfer. (5) It acts as
established.
adhesive and transport s particulate matter towards
2) Relatively inconvenient to patients when
the nasopharynx(Bernstein JM et al., 1997).
compared to oral delivery systems since there is a
possibility of nasal irritation. MECHANISM OF NASAL ABSORPTION
3) Nasal cavity provides smaller absorption surface
The absorbed drugs from the nasal cavity must pass
area when compared to GIT.
through the mucus layer; it is the first step in absorp-
4) There is a risk of local side effects and irreversible
tion. Small, unchanged drugs easily pass through this
damage of the cilia on the nasal mucosa, both
layer but large, charged drugs are difficult to cross it.
from the substance and from constituents added
The principle protein of the mucus is mucin, it has the
to the dosage form.
tendency to bind to the solutes, hindering diffusion.
5) Certain surfactants used as chemical enhancers
Additionally, structural changes in the mucus layer are
may disrupt and even dissolve membrane in high
possible as a result of environmental changes (i.e. pH,
concentration.
temperature, etc.) (Illum L et al., 1999). So many ab-
6) There could be a mechanical loss of the dosage
sorption mechanisms were established earlier but only
form into the other parts of the respiratory tract
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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

two mechanisms have been predominantly used, such BARRIERS TO NASAL ABSORPTION
as:
Nasal drug delivery system is considered has a profita-
a) First mechanism- It involves an aqueous route of ble route for the formulation scientist because it has
transport, which is also known as the paracellular easy and simple formulation strategies. Intra-nasally
route but slow and passive. There is an inverse log- administered drug products therapeutic efficacy and
log correlation between intranasal absorption and toxicities are influenced by number of factors (Remeo
the molecular weight of water-soluble com- VD et al., 1998). Following factors are the barriers to
pounds. The molecular weight greater than 1000 the absorption of drugs through nasal cavity.
Daltons having drugs shows poor bioavailability
i) Low bioavailability Lipophilic drugs are generally well
(Aurora J et al., 2002).
absorbed from the nasal cavity compared to polar
b) Second mechanism- It involves transport through drugs. The pharmacokinetic profiles of lipophilic drugs
a lipoidal route and it is also known as the are often identical to those obtained after an intraven-
transcellular process. It is responsible for the ous injection and bioavailability approaching 100%. A
transport of lipophilic drugs that show a rate good examples of this is the nasal administration of
dependency on their lipophilicity. Drug also cross Fentanyl where the Tmax for both intravenous and
cell membranes by an active transport route via nasal administration have been shown to be very rapid
carrier-mediated means or transport through the (7 min or less) and the bioavailability for nasal anterior
opening of tight junctions (Aurora J et al., 2002). part of the nasal cavity can decrease clear- administra-
tion was near 80% ( Striebel HW et al., 1993). The most
For examples: chitosan, a natural biopolymer from
important factor limiting the nasal absorption of polar
shellfish, opens tight junctions between epithelial cells
drugs and especially large molecular weight polar drugs
to facilitate drug transport (Dodane V et al., 1999).
such as peptides and proteins is the low membrane
permeability. Drugs can cross the epithelial cell mem-
brane either by the transcellular route exploiting sim-
ple concentration gradients, by receptor mediated or
vesicular transport mechanisms, or by the paracellular
route through the tight junctions between the cells.
Polar drugs with molecular weights below 1000 Da will
generally pass the membrane using the latter route
(McMartin C et al., 1987). Larger peptides and proteins
have been shown to be able to pass the nasal mem-
brane using an endocytotic transport process but only
in low amounts (Inagaki M et al., 1985).
ii) Low membrane transport Another importance fac-
tor is low membrane transport is the general rapid
clearance of the administered formulation from the
Figure 1: Parts of nasal cavity consists of a – nasal ves- nasal cavity due to the mucociliary clearance mechan-
tibule, b – palate, c–inferior turbinate, d-middle tur- ism. This is especially the case for drugs that are not
binate, e – superior turbinate (olfactory mucosa),f – easily absorbed across the nasal membrane. It has
nasopharynx been shown that for both liquid and powder formula-
tions, that are not mucoadhesive, the half life of clear-
ance is in the order of 15–20 min (Illum L et al., 1987;
Soane RJ, 1999). It has further been suggested that the
deposition of a formulation in the anterior part of the
nasal cavity can decrease clear- ance and promote ab-
sorption as compared to deposition further back in the
nasal cavity (Harris AS et al 1986). Most nasal sprays of
various makes have been shown to deliver the formu-
lation to a limited area in the anterior part of the nasal
cavity as opposed to nasal drops which will be deli-
vered to a larger area further back in the nasal cavity.
The use of bioadhesive excipients in the formulations is
an approach to overcome the rapid mucociliary clear-
Figure 2: Cell types of the nasal epithelium showing ance. The clearance may also be reduced by depositing
ciliated cell (A), non-ciliated cell(B), goblet cells(C), gel the formulation in the anterior, less ciliated part of the
mucus layer (D), sol layer (E), basal cell (F) and base- nasal cavity thus leading to improved absorption (Kub-
lik H et al., 1998 ; Harris AS et al., 1986).
ment membrane (G)

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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

iii) Enzymatic Degradation- Another contributing (but Lipophilic-hydrophilic balance

normally considered less important) factor to the low
The hydrophilic and lipophilic nature of the drug also
transport of especially peptides and proteins across the
affects the process of absorption. By increasing lipophi-
nasal membrane is the possibility of an enzymatic de-
licity, the permeation of the compound normally in-
gradation of the molecule either within the lumen of
creases through nasal mucosa. Although the nasal mu-
the nasal cavity or during passage across the epithelial
cosa was found to have some hydrophilic character, it
barrier. These sites both contain exo-peptidases such
appears that these mucosae are primarily lipophilic in
as mono- and di-aminopeptidases that can cleave pep-
nature and the lipid domain plays an important role in
tides at their N and C termini and endopeptidases such
the barrier function of these membranes. Lipophilic
as serine and cysteine, which can attack internal pep-
drugs like naloxone, buprenorphine, testosterone and
tide bonds (Lee VHL, 1988). The use of enzyme inhibi-
17a-ethinyl- oestradiol are almost completely absorbed
tors and/or saturation of enzymes may be approaches
when administered intranasal route (Bawarshi RN et
to overcome this barrier (Morimoto K et al., 1995).
al., 1989; Hussain A et al., 1991).
FACTORS INFLUENCING NASAL DRUG ABSORPTION
Enzymatic degradation in nasal cavity
Several factors affect the systemic bioavailability of
In case of peptides and proteins are having low bio-
drugs which are administered through the nasal route.
availability across the nasal cavity, so these drugs may
The factors can be affecting to the physiochemical
have possibility to undergo enzymatic degradation of
properties of the drugs, the anatomical and
the drug molecule in the lumen of the nasal cavity or
physiological properties of the nasal cavity and the
during passage through the epithelial barrier. These
type and characteristics of selected nasal drugs
both sites are having exo-peptidases and endopepti-
delivery system. These factors play key role for most of
dases, exo-peptidases are mono-aminopeptidases and
the drugs in order to reach therapeutically effective
di-aminopeptidases. These are having capability to
blood levels after nasal administration. The factors
cleave peptides at their N and C termini and endopep-
influencing nasal drug absorption are described as
tidases such as serine and cysteine, which can attack
follows.
internal peptide bonds (Lee V.H.L, 1988).
1) Physiochemical properties of drug.
2) Nasal effect factors
 Molecular size.
Membrane permeability
 Lipophilic-hydrophilic balance.
Nasal membrane permeability is the most important
 Enzymatic degradation in nasal cavity. factor, which affect the absorption of the drug through
the nasal route. The water soluble drugs and particu-
2) Nasal Effect
larly large molecular weight drugs like peptides and
 Membrane permeability. proteins are having the low membrane permeability.
H So the compounds like peptides and proteins are main-
 Environmental p
ly absorbed through the endocytotic transport process
 Mucociliary clearance in low amounts (Inagaki M et al., 1985). Water-soluble
high molecular weight drugs cross the nasal mucosa
 Cold, rhinitis.
mainly by passive diffusion through the aqueous pores
3) Delivery Effect (i.e. tight junctions).
H H
 Formulation (Concentration, p , osmolarity) Environmental p
 Delivery effects The environmental pH plays an important role in the
efficiency of nasal drug absorption. Small water-soluble
 Drugs distribution and deposition.
compounds such as benzoic acid, salicylic acid, and
 Viscosity alkaloid acid show that their nasal absorption in rat
occurred to the greatest extent at those pH values
1) Physiochemical properties of drug
where these compounds are in the nonionised form.
Molecular size However, at pH values where these compounds are
partially ionized, substantial absorption was found.
The molecular size of the drug influence absorption of
the drug through the nasal route. The lipophilic drugs This means that the nonionised lipophilic form crosses
have direct relationship between the MW and drug the nasal epithelial barrier via transcellular route, whe-
permeation whereas water- soluble compounds depict reas the more lipophilic ionized form passes through
the aqueous paracellular route (Franz MR et al.,1993.).
an inverse relationship. The rate of permeation is high-
ly sensitive to molecular size for compounds with MW Mucociliary clearance
≥ 300 Daltons (Corbo DC et al., 1990).
Mucociliary clearance is a one of the functions of the
upper respiratory tract is to prevent noxious sub-

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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

stances (allergens, bacteria, viruses, toxins etc.) from maximum absorption was achieved by 0.462 M sodium
reaching the lungs. When such materials adhere to, or chloride concentration; the higher concentration not
dissolve in, the mucus lining of the nasal cavity, they only causes increased bioavailability but also leads to
are transported towards the nasopharynx for eventual the toxicity to the nasal epithelium (Ohwaki K et al.,
discharge into the gastrointestinal tract (Armengot M 1985).
et al., 1990). Clearance of this mucus and the ad-
Drugs distribution and deposition
sorbed/dissolved substances into the GIT is called the
MCC. This clearance mechanism influence the absorp- The drug distribution in the nasal cavity is one of the
tion process due to the dissolved drugs in the nasal important factors, which affect the efficiency of nasal
cavity are discharge by the both the mucus and the absorption. The mode of drug administration could
cilia, which is the motor of the MCC and the mucus effect the distribution of drug in nasal cavity, which in
transport rate is 6 mm/min. It is of utmost importance turn will determine the absorption efficiency of a drug.
that the MCC is not impaired in order to prevent lower The absorption and bioavailability of the nasal dosage
respiratory tract infections (Jorissen M et al., 1995). forms mainly depends on the site of disposition. The
anterior portion of the nose provides a prolonged nasal
Cold, rhinitis
residential time for disposition of formulation, it
Rhinitis is a most frequently associated common enhances the absorption of the drug. And the posterior
disease, it influence the bioavailability of the drug. It is chamber of nasal cavity will use for the deposition of
mainly classified into allergic rhinitis and common, the dosage form; it is eliminated by the mucociliary
symptoms are hyper secretion, itching and sneezing clearance process and hence shows low bioavailability
mainly caused by the viruses, bacteria or irritants. (Gizurarson S et al., 1991). The site of disposition and
Allergic rhinitis is the allergic airway disease, which distribution of the dosage forms are mainly depends
affects 10% of population. It is caused by chronic or on delivery device, mode of administration,
acute inflammation of the mucous membrane of the physicochemical properties of drug molecule.
nose. These conditions affect the absorption of drug
Viscosity
through the mucus membrane due the inflammation.
A higher viscosity of the formulation increases contact
3) Delivery effect factors
time between the drug and the nasal mucosa thereby
Factors that affect the delivery of drug across nasal increasing the time for permeation. At the same time,
mucosa such as surfactants, dose pH, osmolarity, highly viscous formulations interfere with the normal
viscosity, particle size and nasal clearance, drug functions like ciliary beating or mucociliary clearance
structure can be used to advantage to improve and thus alter the permeability of drugs.
absorption.
STRATEGIES TO IMPROVE NASAL ABSORPTION
Formulation (Concentration, pH, Osmolarity)
Various strategies used to improve the bioavailability
The pH of the formulation and nasal surface, can affect of the drug in the nasal mucosa which includes
a drug’s permeation. To avoid nasal irritation, the pH of
1. To improve the nasal residence time
the nasal formulation should be adjusted to 4.5–6.5
because lysozyme is found in nasal secretions, which is 2. To enhance nasal absorption
responsible for destroying certain bacteria at acidic pH.
3. To modify drug structure to change
Under alkaline conditions, lysozyme is inactivated and
physicochemical properties.
the tissue is susceptible to microbial infection. In addi-
tion to avoiding irritation, it results in obtaining effi- Any one or combination of above approaches are used
cient drug permeation and prevents the growth of bac- for the enhancing the absorption and bioavailability of
teria (Arora P et al., 2002). the formulations. Several methods have been used to
facilitate the nasal absorption of drugs includes:
Concentration gradient plays very important role in
the absorption / permeation process of drug through Nasal enzyme inhibitors
the nasal membrane due to nasal mucosal damage.
Nasal metabolism of drugs can be eliminated by using
Examples for this are nasal absorption of L-Tyrosine
the enzyme inhibitors. Mainly for the formulation of
was shown to increase with drug concentration in
proteins and peptide molecule development enzyme
nasal perfusion experiments. Another is absorption of
inhibitors like peptidases and proteases are used (Hus-
salicylic acid was found to decline with concentration.
sain MA et al., 1990). The absorption enhancers like
This decline is likely due to nasal mucosa damage by
salts and fusidic acid derivatives also shows enzyme
the permanent (Satish BB et al., 2008).
inhibition activity to increase the absorption and bio-
The osmolarity of the dosage form affects the nasal availability of the drug (Donnelly A et al., 1998). The
absorption of the drug; it was studied in the rats by other enzyme inhibitors commonly used for the enzy-
using model drug. The sodium chloride concentration matic activity are tripsin, aprotinin, borovaline, amas-
of the formulation affects the nasal absorption. The tatin, bestatin and boroleucin inhibitors.

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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

Permeation enhancers Cyclodextrins: α, ß, and γ- cyclodextrins and their de-

rivatives
The permeation enhancers are mainly used for the
enhancement of absorption of the active medicament. Glycols: n- glycofurols and n- ethylene glycols
Generally, the absorption enhancers act via one of the
Prodrug approach
following mechanisms:
Prodrug approach is mainly meant for optimizing fa-
Inhibit enzyme activity;
vorable physicochemical properties such as solubility,
Reduce mucus viscosity or elasticity; taste, odor, stability, etc. Prodrug is usually referred as
promoiety, it is to cover the undesired functional
Decrease mucociliary clearance; groups with another functional groups. This prodrug
Open tight junctions; and approach is mainly for improving the nasal bioavailabil-
ity especially for the proteins and peptides to enhance
Solubilize or stabilize the drug. the membrane permeability along with increased en-
The mechanism of action of absorption enhancer is zymatic stability (Martin E et al., 1997). The prodrug
increasing the rate at which drug passes through the undergoes enzymatic transformation to release the
nasal mucosa. Many enhancers act by altering the active medicament, when it crosses the enzymatic and
structure of epithelial cells in some way, but they membrane barrier. The absorption of peptides like
should accomplish this while causing no damage or angiotensin II, bradykinin, caulein, carnosine, enkepha-
permanent change to nasal mucosa. General lin, vasopressin and calcitonin are improved by pre-
requirement of an ideal penetration enhancer are as pared into enamine derivatives, these agents showed
follows. absorption enhancement with prodrug approach.

1. It should lead to an effective increase in the Structural modification

absorption of the drug. Modification of drug structure without altering
2. It should not cause permanent damage or pharmacological activity is one of the lucrative ways to
alteration to the tissues improve the nasal absorption. The chemical modifica-
tion of drug molecule has been commonly used to
3. It should be non irritant and nontoxic. modify the physicochemical properties of a drug such
4. It should be effective in small quantity as molecular size, molecular weight, Pka and solubility
are favorable to improve the nasal absorption of drug.
5. The enhancing effect should occur when Example, chemical modification of salmon calcitonin to
absorption is required ecatonin (C-N bond replaces the S-S bond) showed
6. The effect should be temporary and reversible better bioavailability than salmon calcitonin (Hofstee
BH., 1952).
7. It should be compatible with other excipients.
Particulate drug delivery
Various types of penetration enhancers have been
evaluated for organic drugs including surfactants, bile Particle design is an increasingly important role in ab-
salts, chelators, fatty acid salts, phospholipids, sorption enhancement. Microspheres, nanoparticles
glycyrrhetenic acid derivatives, cyclodextrins and and liposomes are all systems which can be used as
glycols. carriers to encapsulate an active drug. The properties
of these can be varied to maximize therapeutic effica-
Classification of chemical penetration enhancer cy. Overall, this can result in increased absorption effi-
includes (Ramesh RP et al., 2009): cacy and stability and reduced toxicity of the active
Surfactants: Polyozyethylene-9-lauryl ether (Laureth- ingredient. Systems can be designed to be mucoadhe-
9), Saponin sive to increase the retention time and facilitate sus-
tained release.
Bile salts: Trihydroxy salts (glycol- and taurocholate),
Fusidic acid derivatives (STDHF) Microspheres are mainly increase the absorption and
bioavailability by adhering to the nasal mucosa and
Chelators: Salicylates, Ethylenediaminetetraacetic acid increase the nasal residence time of drug (Edman P et
(EDTA) al., 1992). The microspheres prepared by using poly-
Fatty acid salts: Oleic acid, Caprylate (C8), Caprate mers like dextran, chitosan, biodegradable starch mi-
(C10), Laurate (C12) crospheres successfully improved the bioavailability of
various drugs. Liposomes are amphiphilic in nature are
Phospholipids: Lysophosphatidylcholine (lyso-PC), Di- well characterized for favorable permeation of drugs
decanoyl – PC through the biological membranes, so the water so-
Glycyrrhetinic acid derivates: Carbenozolone, Glycyr- luble drugs have been delivered to nasal drugs. Catio-
rhizinate nic liposomes are having good permeation capacity

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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

than negatively charged anionic liposomes (Chien YW intake routes This device is not suitable for the
et al., 1987). systemic delivery of drug by patient himself.
NASAL DRUG DELIVERY SYSTEM DOSAGE FORMS 3. Squeezed bottle
The selection of dosage form depends upon the drug Squeezed nasal bottles are mainly used as delivery de-
being used, proposed indication, patient population vice for decongestants. They include a smooth plastic
and last but not least, marketing preferences. Four bottle with a simple jet outlet. While pressing the plas-
basic formulations must be considered, i.e. solution, tic bottle the air inside the container is pressed out of
suspension, emulsion and dry powder systems. the small nozzle, thereby atomizing a certain volume.
By releasing the pressure again air is drawn inside the
LIQUID NASAL FORMULATIONS
bottle. This procedure often results in contamination
Liquid preparations are the most widely used dosage of the liquid by microorganisms and nasal secretion
forms for nasal administration of drugs. They are main- sucked inside. Dose accuracy and deposition of liquids
ly based on aqueous state formulations. Their humidi- delivered via squeezed nasal bottles are strongly de-
fying effect is convenient and useful, since many aller- pendent on the mode of administration. The differenc-
gic and chronic diseases are often connected with es between vigorously and smoothly pressed applica-
crusts and drying of mucous membranes. Microbiologi- tion influence the dose as well as the droplet size of
cal stability, irritation and allergic rhinitis are the major the formulation. Thus the dose is hard to control.
drawbacks associated with the water-based dosage Therefore squeezed bottles with vasoconstrictors are
forms because the required preservatives impair mu- not recommended to be used by children (Mygind N et
cociliary function (Zia H et al., 1993) and the reduced al., 1978).
chemical stability of the dissolved drug substance and
4. Metered-dose pump sprays
the short residence time of the formulation in the nasal
cavity are major disadvantages of liquid formulations Most of the pharmaceutical nasal preparations on the
(Illum L et al., 1987; Hardy JC et al., 1985). The several market containing solutions, emulsions or suspensions
types dosage forms available in liquid form are de- are delivered by metered-dose pump sprays. Nasal
scribed below. sprays, or nasal mists, are used for the nasal delivery of
a drug or drugs, either locally to generally alleviate cold
1. Instillation and rhinyle catheter
or allergy symptoms such as nasal congestion or
Catheters are used to deliver the drops to a specified systemically, see nasal administration. Although
region of nasal cavity easily. Place the formulation in delivery methods vary, most nasal sprays function by
the tube and kept tube one end was positioned in the instilling a fine mist into the nostril by action of a hand-
nose, and the solution was delivered into the nasal operated pump mechanism. The three main types
cavity by blowing through the other end by mouth available for local effect are: antihistamines,
(Hughes BL et al., 1993; Harris AS et al., 1986). Dosing corticosteroids, and topical decongestants Metered-
of catheters is determined by the filling prior to admin- dose pump sprays include the container, the pump
istration and accuracy of the system and this is mainly with the valve and the actuator. The dose accuracy of
used for experimental studies only. metered-dose pump sprays is dependent on the sur-
face tension and viscosity of the formulation. For solu-
2. Compressed air nebulizers
tions with higher viscosity, special pump and valve
Nebulizer is a device used to administer medication in combinations are on the market.
the form of a mist inhaled into the lungs. The
POWDER DOSAGE FORMS
compressed air is filling into the device, so it is called
compressed air nebulizers. The common technical Dry powders are less frequently used in nasal drug de-
principal for all nebulizers, is to either use oxygen, livery. Major advantages of this dosage form are the
compressed air or ultrasonic power, as means to break lack of preservatives and the improved stability of the
up medical solutions/ suspensions into small aerosol formulation. Compared to solutions, the administration
droplets, for direct inhalation from the mouthpiece of of powders could result in a pro- longed contact with
the device (Knoch M et al., 2002). Nebulizers accept the nasal mucosa. The types of powder dosage forms
their medicine in the form of a liquid solution, which is are described below:
often loaded into the device upon use. Corticosteroids
1. Insufflators
and Bronchodilators such as salbutamol (Albuterol
USAN) are often used, and sometimes in combination Insufflators are the devices to deliver the drug sub-
with ipratropium (Hickey AJ, 2004). The reason these stance for inhalation; it can be constructed by using a
pharmaceuticals are inhaled instead of ingested is in straw or tube which contains the drug substance and
order to target their effect to the respiratory tract, sometimes it contains syringe also. The achieved par-
which speeds onset of action of the medicine and ticle size of these systems is often increased compared
reduces side effects, compared to other alternative to the particle size of the powder particles due to
insufficient deaggregation of the particles and results

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in a high coefficient of variation for initial deposition NASAL GELS

areas. Many insufflator systems work with pre-dosed
Nasal gels are high-viscosity thickened solutions or
powder doses in capsules (Hughes BL et al., 1993).
suspensions. Until the recent development of precise
2. Dry powder inhaler dosing devices, there was not much interest in this
system. The ad- vantages of a nasal gel include the re-
Dry powder inhalers (DPIs) are devices through which a
duction of post-nasal drip due to high viscosity, reduc-
dry powder formulation of an active drug is delivered
tion of taste impact due to reduced swallowing, reduc-
for local or systemic effect via the pulmonary route.
tion of anterior leakage of the formulation, reduction
Dry powder inhalers are bolus drug delivery devices
of irritation by using soothing/emollient excipients and
that contain solid drug, suspended or dissolved in a
target delivery to mucosa for better absorption (Jun-
non polar volatile propellant or in dry powder inhaler
ginger HE, 1956).
that is fluidized when the patient inhales (Alagusunda-
ram M et al., 2010).These are commonly used to treat The deposition of the gel in the nasal cavity depends
respiratory diseases such as asthma, bronchitis, on the mode of administration, because due to its vis-
emphysema and COPD and have also been used in the cosity the formulation has poor spreading abilities.
treatment of diabetes mellitus. The medication is Without special application techniques it only occupies
commonly held either in a capsule for manual loading a narrow distribution area in the nasal cavity, where it
or a proprietary form from inside the inhaler. Once is placed directly. Recently, the first nasal gel contain-
loaded or actuated, the operator puts the mouthpiece ing Vitamin B12 for systemic medication has entered
of the inhaler into their mouth and takes a deep the market.
inhalation, holding their breath for 5-10 seconds. There
APPLICATIONS
are a variety of such devices. The dose that can be
delivered is typically less than a few tens of milligrams 1. Delivery of non-peptide pharmaceuticals
in a single breath since larger powder doses may lead
Low molecular weight (below 1000 daltons) small non-
to provocation of cough (Finlay, 2001).
peptide lipophilic drugs are well absorbed through the
PRESSURIZED MDIs nasal mucosa even though absence of permeation en-
hancer. Nasal membrane containing epithelium is high-
A metered-dose inhaler (MDI) is a device that delivers
ly vascularized and it contains large surface area it is
a specific amount of medication to the lungs, in the
readily accessible for drug absorption because pres-
form of a short burst of aerosolized medicine that is
ence of nasal turbinates.
inhaled by the patient. It is the most commonly used
delivery system for treating asthma, chronic Drugs with extensive pre-systemic metabolism, such as
obstructive pulmonary disease (COPD) and other progesterone, estradiol, propranolol, nitroglycerin,
respiratory diseases. The medication in a metered dose sodium chromoglyate can be rapidly absorbed through
inhaler is most commonly a bronchodilator, the nasal mucosa with a systemic bioavailability of ap-
corticosteroid or a combination of both for the proximately 100% (Ramaprasad YV et al., 1996; Hus-
treatment of asthma and COPD. Other medications less sain AA et al., 1980). These drugs can reach widespread
commonly used but also administered by MDI are mast circulation within few minutes after dosing, as the
cell stabilizers, such as (cromoglicate or nedocromil) venous blood passes from the nose directly into the
(Hickey AJ., 2004).The advantages of MDIs are their systemic circulation. In fact, many drugs that are admi-
portability and small size, availability over a wide do- nistered intranasally are often absorbed faster and
sage range per actuation, dose consistency, dose accu- more efficiently than hose from oral administration
racy, protection of the contents and that they are translating into a quick uptake
quickly ready for use(Newhouse MT., 1991).
Some of non-peptide drugs being studied for nasal
To use the inhaler the patient presses down on the top delivery and have shown good bioavailability by this
of the canister, with their thumb supporting the lower route includes:
portion of the actuator. The propellant provides the
1) Adrenal corticosteroids
force to generate the aerosol cloud and is also the
2) Sex hormonses: 17ß-estradiol, progesterone, no-
medium in which the active component must be
rethindrone, and testosterone.
suspended or dissolved. Propellants in MDIs typically
3) Vitamins: vitamin B
make up more than 99 % of the delivered dose.
4) Cardiovascular drugs: hydralazine, Angiotensin II
Actuation of the device releases a single metered dose
antagonist, nitroglycerine, isosobide dinitrate,
of the formulation which contains the medication
propanolol, and colifilium tosylate.
either dissolved or suspended in the propellant.
5) Autonomic nervous system:
Breakup of the volatile propellant into droplets,
a. Sympathomimetics: Ephedrine, epinephrine,
followed by rapid evaporation of these droplets,
phenylephrine,
results in the generation of an aerosol consisting of
b. Xylometazoline, dopamine and dobutamine.
micrometer-sized medication particles that are then
c. Parasympathomimetics: nicotine, metacholine
inhaled (Finlay, 2001).
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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

d. Parasympatholytics: scopolamine, atropine, tains immunoglobulins (IgA, IgG, IgM, IgE), protective
ipatropium proteins such as complement as well as neutrophils
e. Prostaglandins and lymphocytes in the mucosa (Mestecky J et al.,
6) Central nervous systems stimulants: cocaine, lido- 1997; Kuper CF et al., 1992; Durrani Z et al 1998). Main
caine reasons for exploiting the nasal route for vaccine deli-
7) Narcotics and antagonists: bupemorphine, nalox- very are 1) the nasal mucosa is the first site of contacts
ane with inhaled pathogens, 2) The nasal passages are rich
8) Histamine and antihistamines: disodium cromog- in lymphoid tissue, 3) Creation of both mucosal and
lycate, meclizine systemic immune responses, 4) Low cost, patient
9) Antimigrane drugs: dierogotamine, ergotamine, friendly, non-injectable, safe.
tartarate
Nasal delivery of vaccines has been reported to not
10) Phenicillin, cephalosporins, gentamycin
only produce systemic immune response, but also local
11) Antivirals : Phenyl-p-guanidine benzoate, envirox-
immune response in the nasal lining, providing addi-
ime.
tional barrier of protection (Mestecky J et al., 1997).
12) Inorganic compounds: Inorganis salts, colloidal
Delivering the vaccine to the nasal cavity itself stimu-
gold, colloidal carbon, colloidal silver.
lates the production of local secretory IgA antibodies
2. Delivery of peptide-based pharmaceuticals as well as IgG, providing an additional first line of de-
fense, which helps to eliminate the pathogen before it
Peptides & proteins have a generally low oral bioavai-
becomes established (Durrani Z et al 1998).
lability because of their physico-chemical instability
and susceptibility to hepato-gastrointestinal first-pass Recently, for the diseases like anthrax and influenza
elimination. Examples are insulin, calcitonin, pituitary are treated by using the nasal vaccines prepared by
hormones etc (O’Hagan DT et al., 1990).These peptides using the recombinant Bacillus anthracis protective
and proteins are hydrophilic polar molecules of rela- antigen (rPA) and chitosan respectively(Read RC et al.,
tively high molecular weight, are poorly absorbed 2005; Soane RJ et al., 2001). The common diseases like
across biological membranes with bioavailabilities ob- measles, pertussis, meningitis and influenza causing
tained in the region of 1–2% concentrations when ad- pathogens are mainly enter into the body through the
ministered as simple solutions. To overcome this prob- nasal mucosal surfaces and hence good candidates for
lem mainly we are using the absorption enhancers like nasal vaccines. Nasally administered vaccines, especial-
sufactants, glycosides, cyclodextrin and glycols to in- ly if based on attenuated live cells or adjuvanted by
crease the bioavailability. Nasal route is proving to be means of an immunostimulator or a delivery system,
the best route for such biotechnological products. can induce both mucosal and systemic (i.e. humoral
and cell-mediated) immune responses.
3. Delivery of Drugs to Brain through Nasal Cavity:
5. Delivery of diagnostic drugs:
This delivery system is beneficial in conditions like Par-
kinson’s disease, Alzheimer’s disease or pain because it Nasal drug delivery system also play very important
requires rapid and/or specific targeting of drugs to the role in the delivery of diagnostic agents for the diagno-
brain. The development of nasal delivery system to sis of various diseases and disorders in the body. Be-
brain will increase the fraction of drug that reach the cause the intranasal route better for systemic release
CNS after nasal delivery. The olfactory region located of medicament into blood circulation, so can get quick
at the upper remote parts of the nasal passages offers results with less toxicity. Phenolsulfonphthalein is a
the potential for certain compounds to circumvent the diagnostic agent used to diagnose the kidney function
blood-brain barrier and enter into the brain. The recent of the patients. Pancreatic disorders of the diabetic
studies express neurotrophic factors such as NGF, IGF- patients were diagnosed by using the ‘Secretin’. And
I, FGF and ADNF have been intranasally delivered to the secretory function of gastric acid was determined
the CNS shows good results to increase the bioavaila- by Pentagastrin, diagnostic agent.
bility of drug in the brain. Studies in humans, with pro-
CONCLUSION
teins such as AVP, CCK analog, MSH/ACTH and insulin
have revealed that they are delivered directly to the Nasal drug delivery system is a promising alternative
brain from the nasal cavity. route of administration for the several systemically
acting drugs with poor bioavailability and it has advan-
4. Delivery of Vaccines through Nasal Route:
tages in terms of improved patient acceptability and
Mucosal sites gives first line of defense against the compliance compared to parenteral administration of
microorganisms entered into the body, nasal mucosa drugs. This delivery system is beneficial in conditions
act by filtering the pathogens from the inspired air by like Parkinson’s disease, Alzheimer’s disease or pain
compaction and mucociliary clearance. Nose with because it requires rapid and/or specific targeting of
nose- associated lymphoid tissue (NALT) acts as an ef- drugs to the brain and it is a suitable route to produce
fective site of immune system, it is called Waldeyer´s immune response against various diseases like anthrax,
Ring in human beings and nasal secretions mainly con- influenza etc., by delivering the vaccines through the

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 M.Alagusundara et al. | Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010

nasal mucosa. In near future, we hope that intranasal nasal absorption of peptides.J Drug Target
products most probably comprise for crisis treatments, 1998;5:121-7
such as erectile dysfunction, sleep induction, acute
Durrani Z, McInterney TL, McLain L, et al. Intranasal
pain (migraine), panic attacks, nausea, heart attacks
immunisa- tion with a plant virus expressing a pep-
and Parkinson’s disease and novel nasal products for
tide from HIV-1 gp41 stimulates better mucosal and
treatment of long-term illnesses, such as diabetes,
systemic HIV-1-specific IgA and IgG than oral immu-
growth deficiency, osteoporosis, fertility treatment and
nization. J Immunol Methods 1998; 220: 93-103.
endometriosis, will also be marketed. The successful
application of these attributes requires careful design Edman P, Bjork E, Ryden L. Microspheres as a nasal
of characteristics of both the drug formulation and delivery system for peptidedrugs j controlled release,
delivery device, and a clear understanding of the ways 1992;21:165-72
in which they impact on each other.
Finlay, Warren H.The mechanics of inhaled
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