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NASAL DRUG DELIVARY SYSTEM

(An Emerging Drug Delivary System)

- ABSTRACT

The nasal route is a potential alternative route for systemic availability of drugs restricted
to intravenous administration, such as peptide and protein drugs and vaccines. This route
is also advisable for drugs undergoing extensive first pass effect .Besides this, intranasal
route has also been successfully exploited for bypassing the blood brain barrier [BBB]
and subsequently delivering drug molecules to central nervous system [CNS]. The nasal
mucosa has been considered as a potential administration route to achieve faster and
higher level of drug absorption. This is due to the large surface area, porous endothelial
membrane, high total blood flow, the avoidance of first-pass metabolism, and ready
accessibility. The nasal administration of drugs, including numerous compounds, peptide
and protein drugs, for systemic medication. Attempts have been made in the recent past
to increase the residence time of drug formulations in the nasal cavity, resulting in
improved nasal drug absorption. Researchers became interested in the nasal route for the
systemic delivery of medication due to high degree of vascularization and permeability of
the nasal mucosa. In a nut shell, the advantages of intranasal delivery are numerous and
very importantly it is rapid and non-invasive. It reduces systemic exposure and thus
reduces the side effects. Taking into consideration the current research interest in nasal
delivery and positive outcomes from the clinical trials through out the world it won’t be
wrong to expect a wide range of nasal products reaching the market in the near future.

- INTRODUCTION
The nasal mucosa has been considered as a potential administration route to achieve
faster and higher level of drug absorption. This is due to the large surface area, porous
endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and
ready accessibility. The nasal administration of drugs, including numerous compounds,
peptide and protein drugs, for systemic medication. However, the major limitation with
nasal route administration is the poor contact of the formulations with the nasal mucosa.
Many attempts have been made to increase the residence time of drug formulations in the
nasal cavity, resulting in improved nasal drug absorption. Researchers became interested
in the nasal route for the systemic delivery of medication due to high degree of
vascularization and permeability of the nasal mucosa. Several researchers have studied
the anatomical and physiological aspects of the nasal membrane, including its vascular
nature, as they relate to drug delivery. The nose is divided into two nasal cavities via the
septum. The volume of each cavity is approximately 7.5mL and has a surface area around
75 cm2 . There are three distinct functional regions in the nose- the vestibular,
respiratory, and olfactory. Among these, the respiratory region is the most important for
systemic drug delivery . The respiratory epithelium consists of basal, mucus- containing
goblet, ciliated columnar and nonciliated columnar cell types . The cilia move in a
wavelike fashion to transport particles to the pharynx area for ingestion . Additionally,
the cells in this region are covered by nearly 300 microvilli, providing a large surface
area for absorption.Below the epithelium is the lamina propria. This is where blood
vessels, nerves, serous glands, and mucus secre-tory glands may be found. The lamina
propria also houses a dense network of capillaries, through which drug absorption takes
place. The nasal passage epithelium is covered by a mucus layer that is renewed every 10
to 15 minutes. The pH of the mucosal secretions ranges from 5.5 to 6.5 in adults and 5.0
and 6.7 in children. The mucus layer entraps particles, which are then cleared from the
nasal cavity by the cilia. The mucus moves through the nose at an approximate rate of 5
to 6 mm/ min resulting in particle clearance within the nose every 20 minutes . The nasal
cavity also houses numerous enzymes. In humans, cytochrome P450 enzyme isoforms
have been identified and they are CYP1A, CYP2A and CYP2E. Other enzymes detected
in the human nose include carboxylesterases and glutathione S- transeferases .

- MECHANISM OF DRUG ABSORPTION

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. However, large or
charged particles may find it more difficult to cross. Mucin, the principle protein in the
mucus, has the potential to bind to solutes, hindering diffusion. Additionally, structural
changes in the mucus layer are possible as a result of environmental changes (i.e. pH,
temperature, etc.). Subsequent to a drug’s passage through the mucus, there are several
mechanisms for absorption through the mucosa . These include transcellular or simple
diffusion across the membrane, paracellular transport via movement between cell and
transcytosis by vesicle carriers. Obstacles to drug absorption are potential metabolism
before reaching the systemic circulation and limited residence time in the cavity. Several
mechanisms have been proposed but the following two mechanisms have been
considered predominantly. The first mechanism involves an aqueous route of transport,
which is also known as the paracellular route. This route is slow and passive. There is an
inverse log-log correlation between intranasal absorption and the molecular weight of
water-soluble compounds. Poor bioavailability was observed for drugs with a molecular
weight greater than 1000 Daltons. 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 junctions.
- ADVANTAGES OF NASAL DRUG DELIVERY SYSTEMS
1) Easy accessibility and needle free drug application without the necessity of trained
personnel facilitates self medication, thus improving patient compliances compared to
parenteral routes

2) Good penetration of, especially lipophilic, low molecular weight drugs through the
nasal mucosa. For instance the absolute nasal bioavailability of fentanyl is about 80%.

3) Rapid absorption and fast onset of action due to relatively large absorption surface and
high vascularization. Thus the Tmax of fentanyl after nasal administration was less than
or equal to 7 minute comparable to intravenous [i.v] . Nasal administration of suitable

4) Avoidance of the harsh environmental conditions in the gastrointestinal tract (chemical


and enzymatic degradation of drugs).

5) Avoidance of hepatic first pass metabolism and thus potential for dose reduction
compared to oral delivery.
6) Potential for direct delivery of drug to the central nervous system via the olfactory
region, thus by-passing the blood brain barrier.

7) Direct delivery of vaccine to lymphatic tissue and induction of a secretory immune


response at distant mucosal site.

- FACTORS INFLUENCING NASAL DRUG ABSORPTION

A) FACTORS RELATED TO DRUG

a) Lipophilicity -On increasing lipophilicity, the permeation of the compound normally


increases through nasal mucosa. Although the nasal mucosa was found to have some
hydrophilic character, it appears that these mucosae are primarily lipophilic in nature and
the lipid domain plays an important role in the barrier function of these membranes.

b) Chemical Form - The chemical form of a drug can be important in determining


absorption. For example, conversion of the drug into a salt or ester form can alter its
absorption.

c) Polymorphism - Polymorphism is known to affect the dissolution rate and solubility


of drugs and thus their absorption through biological membranes.

d) Solubility & Dissolution Rate - Drug solubility and dissolution rates are important
factors
in determining nasal absorption from powders and suspensions.

B) FACTORS RELATED TO FORMULATION


1) Physicochemical Properties of the Formulation

a) pH and Mucosal Irritancy - The pH of the formulation, as well as that of nasal


surface,
can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal formulation
should be adjusted to 4.5–6.5.

b) Osmolarity - The effect of osmolarity on the absorption of secretin in rats and found
that absorption reached a maximum at a sodium chloride concentration of 0.462 M ,
because shrinkage of the nasal epithelial mucosa was observed at this salt concentration.

2) Dosage form Used for Developing the Formulation - The selection of dosage
form depends upon the drug being used, proposed indication, patient population and last
but not least, marketing preferences. Some of these delivery systems and their important
features are summarized below:

a) Nasal Drops
Nasal drops are one of the most simple and convenient systems developed for nasal
delivery.
b) Nasal Sprays
Both solution and suspension formulations can be formulated into nasal sprays.

c) Nasal Gels
Nasal gels are high-viscosity thickened solutions or suspensions.

d) Nasal Powders
This dosage form may be developed if solution and suspension dosage forms cannot be
developed e.g., due to lack of drug stability.

- Application of Nasal Drug Delivery System


1 ) Delivery of Vaccines Through Nasal Route

2 ) Delivery of Drugs to Brain Through Nasal Cavity

3 ) Delivery of Peptide and Non-Peptide Drugs Through


Nasal Route for Systemic Effect

- CONCLUSION

In a nut shell, the advantages of intranasal delivery are numerous and very importantly it
is rapid and non-invasive. It reduces systemic exposure and thus reduces the side effects.
It also bypasses the BBB and delivers the drug directly into the CNS. It acts as an
alternative to parenteral and oral route for delivery of some drugs. Taking into
consideration the current research interest in nasal delivery and positive outcomes from
the clinical trials through out the world it wont be wrong to expect a wide range of nasal
products reaching the market in the near future. However, still some research needs to be
conducted in delivery of peptide and protein and vaccines through nasal delivery and
delivery of drug from nose to brain.

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Document By
SANTOSH BHARADWAJ REDDY
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