What is NASAL Drug

Delivery system?
 NASAL DRUG DELIVERY

INTRODUCTION:

Nasal drug delivery is receiving much attention from the pharmaceutical

industry.

About 2% of the overall drug delivery is administered via the nasal route.

Topical decongestants or anti-inflammatory drugs used to treat a rhinitis or

allergy related indications are well-known drug products.

The nasal route is an attractive alternative to invasive administrations, and

provides a direct access to the systemic circulation.
 MERITS OF NASAL DRUG DELIVERY SYSTEM:

3.A rapid onset of action is possible through nasal route, for the
administration of systemically acting products.
4.Deposition of an active compound in the nasal cavity results in avoidance
of its degradation through the first-pass metabolism.
5.Avoids parentral administration
6.Rapid absorption, peaking generally within 1530 minutes
7.Apparent permeability to some peptides
8.Ease of self-administration/good patient compliance
9.lower doses and less side effects
10.quicker onset of pharmacological activity .
11.Rate of absorption comparable to IV medication.
12.User-friendly, painless, non-invasive, needle-free administration mode.
13.Useful for both local & systemic drug delivery.
14.For CNS drugs, better site for rapid onset of action

Ex. Inhalation anesthesia, Morphine etc.

13.The nose is a very easy access point for medication delivery - even

easier to access than IM or IV sites.


DEMERITS OF NASAL DRUG DELIVERY SYSTEM:

Environmental conditions, infection, and inter-subject variability can lead

to inconsistent absorption.
Short time span is available for absorption due to rapid clearance.
Local metabolism in the nose and instability of compound (especially for
peptide drugs) occur.
Once administered, removal of the therapeutic agent from the site of
absorption is difficult.
The histological toxicity of absorption enhancers used in nasal drug delivery system
is not yet clearly established.
Relatively inconvenient to patients when compared to oral delivery systems since
there is a possibility of nasal irritation.
Nasal cavity provides smaller absorption surface area when compared to GIT.
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.
Certain surfactants used as chemical enhancers may disrupt and even dissolve
membrane in high concentration.
There could be a mechanical loss of the dosage form into the other parts of the
respiratory tract like lungs because of the improper technique of administration.
TRADITIONAL NASAL
DISPENSING SYSTEMS
Traditional application
systems consist of
Nasal drops,
Pipettes,
Squeeze bottles,
Sprays
Nasal drops may be
suitable for infants only.
In adults, drops into
the nasal cavity mostly
lead to a rapid clearance
of the drug along the
floor of the nasal cavity
toward the throat.
Studies demonstrate a
longer duration of
sprayed products on the
nasal mucosa than
formulations
administered as drops.
Compared to drops, sprays results in:
Larger surface area of coverage.
Smaller liquid particle size allowing thin layer to cover
mucosa.
Less run-off out the nasal cavity.

SPRAY PUMP DEVICES

- Multidose - Unidose - Bidose
VARIOUS MULTIDOSE CONTAINERS THE UNIT-DOSE SYSTEM AND THE BI-DOSE SYSTEM

Nasal spray products contain therapeutically active ingredients (drug substances) dissolved or
suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers,
and buffering agents).

These agents can be for local therapy (e.g., established treatments such as corticosteroids for
rhinitis) or for systemic therapy [e.g., migraine therapies such as Imigran.

Absorption of drugs from the nasal mucosa is also influenced by the contact time between drug
and epithelial tissue.
 (MAD)
Mucosal Atomization Device
Atomization results in higher
bioavailability than either spray
or drops.

MAD - Mucosal Atomization device:

Device designed to allow

emergency personnel to delivery
nasal medications as an
atomized spray.

Broad 30-micron spray ensure

excellent mucosal coverage.
 NASAL ANATOMY AND PHYSIOLOGY

The nose actively contributes to two major functions of the

human system.

The first function is the sense of smell (olfaction)

The second is respiration or breathing.

The nasal septum divides the nasal cavity into left and right
halves.

The nasal septum is never a straight vertical separation of the

two cavities.
 The respiratory tract, which includes the

nasal mucosa
hypopharynx
large airways &
small airways

provides a relatively large mucosal surface

area for drug absorption.
The most efficient area for drug
administration is the lateral walls of the
nasal cavity, which consist of highly
vascularized tissue, the mucosa.
 1. The anterior one-third of the
nasal cavity viewed in cross-
section reveals a central
septum dividing the two
cavities. This region, including
the proximal portion of the
inferior and middle turbinates,
is nonciliated .

2. In the posterior two-thirds of

the nasal cavity, clearance of
deposited particles occurs by
slow spreading of the mucus
layer into the ciliated regions
along the inferior and middle
meatuses, followed by a more
rapid mucociliary clearance
into the nasopharynx from
where they are swallowed.

3. Approximately 1 L of mucus
is transported from the anterior
part to the posterior part of the
a nasal vestibule d middle turbinate nose per day. It takes
approximately 2030 min for
b palate e superior turbinate (olfactory the whole mucus layer to be
mucosa) renewed.
c inferior turbinate f nasopharynx
Site of drug
spray &
absorption
POSSIBLE DRUG ABSORPTION PATHWAYS
 Pathways for nasal absorption
Nose brain
pathway
Absorption through the olfactory
neurons
Olfactory mucosa, nerve
- transneuronal absorption. Olfactory
epithelium is considered as a portal for
substances to enter CNS
Brain
CSF
The olfactory mucosa (smelling
area in nose) is in direct contact
with the brain and CSF.
Medications absorbed across the
olfactory mucosa directly enter the
CSF. Highly vascular nasal mucosa
This area is termed the nose brain
pathway and offers a rapid, direct
route for drug delivery to the brain.
 Lipophilicity
Lipid Loving Non-lipophilic molecules

Cellular membranes Lipophilic molecules

are composed of
layers of lipid material.
Cell Membrane
Drugs that are
lipophilic are easily
and rapidly absorbed
across the mucous
membranes. Blood stream
 Absorption
through the
supporting cells
& the
surrounding
capillary bed

- venous
drainage
 Nasal enzymes
Cytochrome P 450 dependent onooxygenases, Lactate dehydrogenase,
Oxidoreductase, Hydrolases, Esterase, lactic dehydogenase, malic enzymes,
lysosomal proteinases, steroid hydroxylases., etc.,

Cytochrome P450 dependent mono oxygenases has been reported to

catalyse the metabolism of xenobiotics, nasal decongestants, nocotine,
cocaine, phenacetin, nitrosamine progesterone etc.,

Insulin zinc free was hydrolysed slowly by leusine aminopeptidase,

PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase

Progesterone and testosterone were metabolized by several steroid

hydroxylases in the nasal mucosa of rats
 Nasal pH
Nasal secretion of adult : 5.5-6.5
Infants and children: 5-6.7
It becomes alkaline in conditions such as
acute rhinitis, acute sinusitis.

Lysozyme in the nasal secretion helps as

antibacterial and its activity is diminished in
alkaline pH
Formulation
Development
Formulation Development

Dosage form

Factors affecting drug absorption

Formulation considerations

Physiological

Pharmaceutical
 Dosage forms

Liquid drop

Liquid spray/nebulizers

Aerosol

Suspension spray/nebulizers

Gel

Sustained release
 Drug concentration

Factors affecting Vehicle of drug delivery

drug absorption
Mucosal contact time

Degree of drugs ionization

pH of the absorption site

Size of the drug molecule

Relative lipid solubility

 Physiological effects

- Drug metabolism in the respiratory tract & reduction of systemic effect

- Protein binding

- Mucociliary transport causing increased or decreased drug residence time

- Local toxic effects of the drug

Ex., edema, cell injury, or altered tissue defenses

- Local or systemic effects of propellants, preservatives, or carriers

1. Effect of particle size

2. Effect of molecular size

3. Effect of solution pH

4. Effect of drug lipophilicity

5. Effect of drug concentration

 1. Effect of particle size

- Large particles (> 7 microns) will be lost in the gastrointestinal tract

- Small particles (< 3 microns) will be lost in exhaled breathe

- Intermediate particles (3 to 7 microns) reach the actual site of action

2. Effect of molecular size

- Higher the molecular size, lower the nasal absorption

- A good systemic bioavailability can be achieved for molecules with a

molecular weight of up to 1000 Daltons when no absorption enhancer is
used
 3. Effect of solution pH

- Nasal absorption is pH dependent

- Absorption is higher at a pH lower than the dissociation constant (pKa) of
the molecule

- Absorption is lower as the pH increases beyond the dissociation constant

4. Effect of drug lipophilicity

- Polar (water soluble) drugs tend to remain on the tissues of the upper airway
- Non-polar (lipid soluble) drugs are more likely to reach distal airways

- Lipid soluble drugs are absorbed more rapidly than water soluble drugs

5. Effect of drug concentration

- Absorption depends on the initial concentration of the drug
- The absorption follows first-order kinetics
For an effective administration of therapeutic drugs through the
nasal mucosa, the following must be taken into consideration:

4.The method and technique of administration.

5.The site of drug deposition
6.Droplet size
7.Spray characteristics
8.The rate of clearance through the ciliary cavity
9.The pathological condition of the nose
10.The speed of mucus flow
11.The presence of infection and atmospheric conditions
[e.g., relative humidity (RH)] will affect the efficacy of nasal
absorption.
 DETERMINATION OF NASAL ABSORPTION BY
INVIVO METHODS:

In Vivo Animal Models

3.Several animal models have been described for

studying drug absorption through the nasal mucosa.
4.The most convenient model is the anesthesized rat
model developed by Hirai et al.
5.For most non-peptide drugs, the results obtained in
rats can accurately reflect the absorption profiles in
humans.
6.Some experimental modifications are possible, with
a similar surgical operation, and can be chosen for
special purposes.
RAT MODEL:

It has the following steps

Rat is anesthetised by IP injection of sodium pentobarbital.

Then an incision is made in the neck, the trachea is cannulated

with a poly ethylene tube another tube is inserted through
oesophagus towards the posterior part of the nasal cavity.

The passage of the nasopalatine tract is sealed surgically to

prevent to prevent the drainage of drug solution from the nasal
cavity in to the mouth. The drug solution is delivered to the nasal
cavity through either nostril or the oesophageal tubing.

The blood samples are then collected from the femoral vein and
analysed for absorbed drug.
RABBIT MODEL:

It has the following steps

A rabbit weighing 3 kg is anaesthetised by an IM injection

of a combination of ketamine and xylazine.

The drug solution is delivered by nasal spray in to each

nostril while the rabbits head is held in an upright position.

The rabbit is permitted to breath normally through nostrils

and body temperature maintained at 37oC by a heating
pad.

The blood samples are collected in the marginal ear

vein. Ex: Progesterone and its hydroxyl derivatives.
In vivoin situ model

3.Following the same surgical operation as in the in vivo model, the drug
remaining in the nasal cavity can be recovered at a predetermined time
and analyzed in this simple model.

5.This method is useful for evaluating both the absorption and the
degradation of peptides.

7.Other than the rat & rabbit model, dogs, monkeys, and sheep are also
used for in vivo studies.

9.In such large animals, the formulation can be administered while the
animal is under anesthesiaor, in some cases, under conscious
conditionsand care should be taken for physical loss of the formulation
because of drainage.

Interspecies differences in nasal drug

absorption
In Vitro Cell Culture Models

Various in vitro systems are currently available, which

include the excised nasal epithelium from different animal
species, primary cell cultures, and cell lines,
of the human nasal epithelium.

Excised nasal mucosae

Excised nasal mucosae from different animal species

(rabbits, dogs, sheep, pigs, cattle, and humans) are used for
studying nasal transport and metabolism.

An experimental set-up using an Ussing chamber is

frequently used for evaluating the permeability of a drug
through the excised mucosa.
 EXVIVO NASAL PERFUSION MODEL

3.During perfusion studies, a funnel is provided

underneath the nose to lead the drug solution, which is
flowing out of nasal cavity in the drug reservoir(37oC) and
circulated through the nasal cavity of the rat by means of a
peristaltic pump.

5.The perfusion solution passes out from the nostril and

through the funnel and flows in to the drug reservoir
solution again. Drug solutions of 320mL are continuously
circulated through the nasal cavity of anesthesized rats.

7.The reservoir is stirred constantly and the amount of

drug absorbed is determined by measuring the drug
concentration remaining in the solution after a period of
perfusion.
1. The obtained disappearance kinetics can be
used for predicting the in vivo rate of drug
absorption.

3. The method is also applicable to the assessment

of the damaging effects of absorption enhancers
on the nasal mucosa.
 Applications

Delivery of non-peptide pharmaceuticals

Delivery of peptide-based pharmaceuticals

Delivery of diagnostic drugs

 1. Delivery of non-peptide pharmaceuticals

Drugs with extensive pre-systemic metabolism, such as

1) Adrenal corticosteroids
2) Sex hormones: 17-estradiol, progesterone, no-rethindrone, and testosterone.
3) Vitamins: vitamin B
4) Cardiovascular drugs: hydralazine, Angiotensin II antagonist, nitroglycerine,
isosobide dinitrate, propanolol, and colifilium tosylate.
5) Autonomic nervous system:

a. Sympathomimetics: Ephedrine, epinephrine, phenylephrine,

b. Xylometazoline, dopamine and dobutamine.
c. Parasympathomimetics: nicotine, metacholine
d. Parasympatholytics: scopolamine, atropine, ipatropium
e. Prostaglandins

can be rapidly absorbed through the nasal mucosa with a systemic

bioavailability of approximately 100%
2. Delivery of peptide-based pharmaceuticals

Peptides & proteins have a generally low oral

bioavailability because of their physico-chemical
instability and susceptibility to hepato-
gastrointestinal first-pass elimination

Eg. Insulin, Calcitonin, Pituitary hormones etc.

Nasal route is proving to be the best route for such

biotechnological products
Basic concepts for achieving
improved nasal peptide and
protein delivery.
3. Delivery of diagnostic drugs

Diagnostic agents such as

Phenolsulfonphthalein kidney function

Secretin pancreatic disorders

Pentagastrin secretory function of gastric acid

 Delivery of Vaccines through Nasal Route:

Nasal delivery of vaccines has been reported to not only

produce systemic immune response, but also local immune
response in the nasal lining, providing additional barrier of
protection
Delivering the vaccine to the nasal cavity itself stimulates
the production of local secretory IgA antibodies as well as
IgG, providing an additional first line of defense, which helps
to eliminate the pathogen before it becomes established

Recently, for the diseases like anthrax and influenza are

treated by using the nasal vaccines prepared by using the
recombinant Bacillus anthracis protective antigen (rPA) and
chitosan respectively
 Conclusions
Multiple drugs can be given IN
Rapid
Immediate access
Can be given to almost anyone
Exception = Nasal mucosal abnormalities.

Atomization is the best method

Cheap, easy to use device
Disposable/single use (MAD)
Appropriate drug concentrations

IN is a true needleless system!

Reduce Level III bloodborne exposures
HIV
Hepatitis B, C
REFERENCES:

1. Encyclopedia of pharmaceutical technology. 3rd Edition . Vol 1. Page

:1201 by JAMES SWARBRICK.

2. Text book of Novel Drug Delivery System by Chien, 2nd Edition.

3. Shaji J and Marathe S.W. NASAL DRUG DELIVERY SYSTEM:

OPPORTUNITIES & CHALLENGES INDIAN DRUGS Vol. 45 No. 5
May 2008 Pg no (345 353)