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NASAL DRUG DELIVERY SYSTEM: A REVIEW
Sunitha Reddy M.1*
and Manasa Tadi2
Department of Pharmaceutics, Centre for Pharmaceutical Sciences, Institute of Science and
Technology, JNTUH, Kukatpally, Hyderabad, 500085, Telangana, India.
ABSTRACT
Since many years drugs have been administered by the nasal route for
treating local infections such as congestion, rhinitis, sinusitis etc.
several drugs such as corticosteroids, antihistamines, vasoconstrictors
and anticholinergic drugs have been used for local delivery of drugs
through the nasal route. The nasal drug delivery system is a promising
route when compared with the other drug delivery routes thus it will
provides a patient compliance, self-administration, good penetrating
capability, rapid absorption and bypasses first pass metabolism it
requires low dose and gives desirable effects. The nasal route is most
preferred route for the drugs restricted to IV administration because of
large surface area porous endothelial membrane, high blood flow and
ready accessibility from nasal cavity. Recently peptide and protein
drugs are investigated for systemic medication. It is favorable route
because the drugs are rapidly cleared from nasal cavity. It is also well suitable for delivery of
biotechnological products like proteins, peptides, hormones, DNA plasmids for DNA vaccine
delivery.
KEYWORDS: Nose, bioavailability, anatomy, barriers, enhancers, potential pathways,
factors, drug delivery systems and devices.
Definition: Administration of drugs through nasal route is referred as nasal drug
administration. The nasal mucosa present in nose has been considered as a potential
administration route to achieve faster and higher level of drug absorption with possibility of
self-administration. It is an ideal alternative to the parenteral for systemic drug delivery.
Hydrophobic and low molecular drugs can easily penetrate through nasal mucosa with less
degradation, fast absorption can be achieved due to large surface area, high vascularization
World Journal of Pharmaceutical Research SJIF Impact Factor 8.084
Volume 8, Issue 13, 431-450. Review Article ISSN 2277– 7105
Article Received on
03 Oct. 2019,
Revised on 23 Oct. 2019,
Accepted on 13 Nov. 2019,
DOI: 10.20959/wjpr201913-16190
*Corresponding Author
Dr. Sunitha Reddy M.
Department of
Pharmaceutics, Centre for
Pharmaceutical Sciences,
Institute of Science and
Technology, JNTUH,
Kukatpally, Hyderabad,
500085, Telangana, India.
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and low enzymatic environment of nasal cavity. In emergency conditions nasal route can be
used as an alternative route of parenteral. Many drug delivery devices for nasal application of
liquids, semisolids and solid formulations are introduced to deliver the drugs to treat most
crisis CNS diseases (Parkinson‟s, Alzhemer‟s) because it requires rapid and specific onset of
action.
Advantages: Drug degradation is absent in GIT, Absence of hepatic first pass metabolism,
Rapid drug absorption and quick onset of action, simple convenient and easy to administer
which increases Patient compliance, Offers good penetration, Avoidance of harsh
environment, as it requires low doses it is associated with fewer adverse effects, Direct
delivery of drugs to CNS, Minimal aftertaste, drugs that exhibit poor absorption by oral route
or those which are unstable in the presence of GI fluids can be given by nasal route, it can be
used as an alternative to parenteral route for systemic delivery of drugs especially proteins
and peptides, it can be used for patients on long term therapy as it is more convenient then
Parenterals.
Disadvantages: Nasal cavity provides a smaller absorption surface area when compared with
GIT, only small drug volumes can be given through nasal route, not suitable for delivering
high molecular weight compounds, drug permeability may be affected by physiological
mucociliary clearance and beating of cilia, Possibility of irritation compared to oral delivery,
Excipients used in formulation may cause side effects and irreversible damage to cilia on
nasal mucosa, Mechanical loss of dosage form into the other parts of respiratory tracts like
lungs due to improper administration, Surfactants with high concentration leads to dissolution
of membrane, since studies on nasal drug delivery are still in infancy there is limited
understanding of the mechanisms involved and less developed animal models.
ANATOMY
Presently considerable efforts are being made to enable systemic delivery of drugs through
the nasal route as it is highly vascularized. The nasal cavity extends from the nasal vestibule
to the nasopharynx reaching a depth of 12-14cm. The nasal cavity is vertically divided into
two portions by a septum. Each portion is further divided into Vestibule, Olfactory region,
Respiratory region.
a) Vestibule: It is the anterior portion of nasal cavity that lies just behind the nostrils. It has
a surface area of about 0.6cm and is lined by a stratified squamous epithelium cells, it
also contains nasal hairs that filters the inhaled air containing dust particles.
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b) Olfactory region: This region is located at the roof of the nasal cavity, it is made up of
pseudostratified epithelium and also contains specialized cells which helps in olfaction it
has a surface area about 15cm.
c) Respiratory region: It is the largest region of nasal cavity with an area of about 135cm
also called as “conchae” it is composed of pseudostratified columnar epithelial cells,
goblet cells etc. apical surface of epithelial cells contains microvilli and cilia which
increases the surface area for drug absorption. This respiratory region also contains 3
nasal conchae namely, the superior middle and inferior conchae which extend from the
lateral walls of the nasal cavity. This conchae creates twists and turns in the nasal cavity
due to which the inhaled air experiences turbulence. This helps the inhaled air to achieve
good contact with mucous membrane.
Figure 1: Anatomy of nasal cavity.
MECHANISM OF DRUG ABSORPTION: Respiratory region is considered to be major
region from which the drugs may undergo nasal absorption, the mechanism of nasal delivery
was investigated in rats using SS-6 an octapeptide and horseradish peroxidase a protein
molecule; two mechanisms of transport are involved:-
1) Transcellular pathway: This pathway is responsible for the transport of lipophilic drugs
that shows a rate dependency on their lipophilicity.
2) Paracellular pathway: It is the passage of drugs through the pores between the cells, this
is the slow and passive route only those drugs whose molecular weight less than 1000
daltons can easily pass through this route, there is an inverse log-log correlation between
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the intranasal absorption and the molecular weight of water soluble compounds.
3) Carrier mediated pathway: These transport mechanism will transport the drugs through
the opening of tight junctions. Eg: Chitosan.
Fig 2: Carrier mediated pathway.
Table 1: Potential Pathways For Nasal Absorption.
SUBSTANCES POSSIBLE PATHWAYS
Albumin (labeled with Evans blue ad
horseradish peroxidase)
Nasal mucosa-sensory nerve cells of olfactory
epithelium-subarachnoid spaces-blood
stream.
Egg albumin Nasal mucosa-lymphatic stream.
Serum albumin Nasal mucosa-lymphatic stream
Amino acids(arginine, glutamic acid, glycine,
amino butyric acid, proline, serine, tritiated
leueine)
Nasal mucosa-blood vessel (active transport)
Nasal mucosa-olfactory nerve fiber-CNS
Penicilins Nasal membrane-blood stream
Progesterone Nasal membrane-olfactory dendrites-nervous
system-supporting cells in the olfactory
BARRIERS OF NASAL DRUG ABSORPTION: Certain potential barriers which may
decreases the intranasal absorption of drugs and thus their bioavailability have been discussed
below:
1) Low membrane permeability: The nasal membrane is less permeable to polar drugs and
large molecular weight drugs such as proteins and peptides. Lipophilic drugs are well
absorbed from the nasal mucosa exhibiting pharmacokinetic profiles.
2) Mucociliary clearance: The combined action of mucous layer and cilia is said to be
mucociliary clearance, the drug absorbed from nasal cavity are rapidly removed from
nasal mucosa through mucociliary clearance, such clearance is most helpful for the drugs
having low nasal absorption. It has been proposed that deposition of the formulation in
the vestibule may decrease the clearance and hence improves the absorption. The rapid
mucociliary clearance can be overcome by incorporating mucoadhesives in the
formulation.
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Fig 3: Mucociliary clearance.
FACTORS INFLUENCING NASAL DRUG ABSORPTION
Drug permeability through the nasal mucosa is affected by several factors, which can be
broadly classified as:-
1) Biological factors:
a) Structural features
b) Biochemical factors.
2) Physiological factors:
a) Nasal secretions
b) Diseased conditions
c) Neuronal regulation and blood supply
d) Environmental conditions.
3) Formulation factors:
a) Physico-chemical properties of drug
Solubility
Lipophilicity
Molecular weight
pKa and partition co-efficient
b) Physico-chemical properties of formulation.
Dosage form
Osmolarity
Viscosity
pH and mucosal irritancy.
4) Device related factors.
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1) Biological factors
a) Structural features: Nasal vestibule, atrium, respiratory area, olfactory region and
nasopharynx this structural features along with the cell density, surface area, microvilli
and the number of cells influence the nasal drug absorption.
b) Biochemical factors: nasal mucosa present in the nasal cavity acts as enzymatic barrier;
due to the presence of various enzymes like oxidative and conjugative enzymes,
peptidases and proteases. Peptidases and proteases were found to degrade drugs like
insulin, desmopressin, calcitonin and leuteinizing hormone releasing hormone their by
decreasing their absorption.
2) Physiological factors
a) Nasal secretions: nasal cavity produces about 1.5-2ml mucus per day. This mucus layer
is removed due to continuous ciliary movements. Factors which significantly affect the
nasal drug absorption include drug solubility, mucociliary clearance along with pH and
viscosity of nasal secretions.
b) Disease conditions: diseases such as rhinitis, common cold, nasal polyposis and atropic
rhinitis cause irritation of nasal mucosa, leads to improper functioning of mucociliary
clearance and hypo or hypersecreations in nasal cavity. This diseases can affect the nasal
drug absorption.
c) Neuronal regulation and blood supply: parasympathetic stimulation associated with
congestion, leads to increased blood supply which in turn increases the drug permeation.
Sympathetic stimulation is associated with relaxation, leads to decreased blood supply
which in turn decreases the drug permeation.
d) Environmental conditions: as the temperature increases there is a linear increase in the
frequency of ciliary beating which affects the mucous membrane properties.
3) Formulation factors
Physico-chemical properties of the drug as well as the formulation are important for the
bioavailability of nasal formulations:
a) Physico-chemical properties of drug
1. Solubility: since nasal secreations are usually liquid in nature, for a drug to have an
appropriate aqueous solubility to achieve proper dissolution. Eg: prodrugs like N-
dimethylglycinate Hcl and testosterone 17-N were derived.
2. Lipophilicity: on increasing the lipophilicity the drug permeation across the epithelium
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also increases, the rate of nasal drug permeability is directly proportional to the lipophilic
nature of the drug.
3. Molecular nature: molecular weight, lipophilicity/hydrophilicity act together to
determine the drug permeation. Drugs which are having molecular weight of <300
Daltons can easily crosses the nasal membrane, diffusion of proteins and peptides with a
molecular weight >1000 Daltons are significantly affected by their molecular weight.
4. pKa and partition coefficient: unionized species are absorbed better as compared with
the ionized species it is also similar in case of nasal absorption, the amount of drug
present in an unionized form is determined by its pKa, the rate of absorption of unionized
species is four times higher than that of ionized species. It indicates that pKa and nasal
absorption are directly related, higher the pKa/lipophilicity greater is the absorption.
b) Physico-chemical properties of formulation
1. Dosage form: inspite of being simple and convenient, nasal drops do not accurately
deliver the required amount of drug resulting in overdose, as powder sprays cause
mucosal irritation, solution and suspension sprays are preferred. Recent devices include
metered-dose gel devices, which reduces anterior leakage, post nasal drip and localize the
formulation at the site of action. Several novel drug systems such as microspheres, lipid
emulsions, liposomes, proliposomes, niosomes and films have also been developed. As
this systems increases the contact time of the drug with the nasal mucosa, and increases
absorption.
2. Osmolarity: tonicity of the formulations influence the drug absorption. The hypertonicity
of the solutions cause shrinkage of the nasal epithelium and also inhibit the ciliary
activity. To get an optimum results an isotonic solutions are generally preferred.
3. Viscosity: higher the viscosity of formulation, higher is the contact time between the drug
and the nasal mucosa. Viscous formulations also reduces the mucociliary clearance of
drugs. some studies suggested that by administering highly viscous formulations the
residence time can be increased but there could be diminished drug absorption due to
decreased drug diffusion from the formulation, it has also been reported that the viscosity
of the solution provides a larger therapeutic period of the nasal formulations.
4. pH and mucosal irritancy: drug absorption or permeation depends on the pH of
formulation as well as that of nasal surface, pH of the formulation should be adjusted to
4.5-6.5 to avoid the nasal irritation and to prevent the bacterial growth. Lysozymes (also
known as suicidal bags) in nasal secreation is active at acidic pH for destroying certain
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bacteria, it gets inactivated in alkaline conditions and mucosa becomes susceptible for
microbial infection.
4) Device related factors: The particle size, droplet size and the type of surface distribution
of the formulation affects the drug absorption, factors which influence the site and pattern
of deposition include physical state of formulation, formulation composition, devices
used, design of adapters, actuators and technique of administration.
STRATEGIES TO IMPROVE NASAL DRUG ABSORPTION
Several attempts are being made to increase the nasal absorption:
1) Inhibitors of nasal enzymes
2) Permeation enhancers
3) Prodrugs
4) Structural modifications
5) Usage of bioadhesive polymers
6) Particulate drug delivery
7) In-situ gel.
1. Inhibitors of nasal enzymes: Enzymatic degradation of drugs in nasal mucosa can be
decreased by using enzyme inhibitors like peptidases, proteases, trypsin, amastatin,
bestatin, apotinin. Certain absorption enhancers like fusidic acid cerivatives also exhibit
enzyme inhibitory activities. This method is especially useful for protein and peptide
formulations, as they get degrade by nasal enzymes.
2. Permeation enhancers: Permeation enhancers helps to increase the drug absorption,
several permeation enhancers like surfactants, bile acids, cyclodextrins, phospholipids,
fatty acids etc. has been investigated top enhance the nasal absorption of the drugs.
3. Prodrug approach: Prodrug approach is mainly used to improve the physicochemical
properties of drug molecules such as taste, odour, stability, solubility. It is more beneficial
for improving the nasal delivery of peptides and proteins which are susceptible to
enzymatic degradation. Recent studies have shown that when peptides like bradykinin,
vasopressin and calcitonin were prepared as amine derivatives, they exhibited increased
absorption.
4. Structural modification: Modification of drug structure can be done without interacting
with drugs pharmacological activity, this approach has been widely used for altering the
physicochemical properties of the drugs such as molecular size, molecular weight, pKa,
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solubility.
Table 2: Nasal Drug Absorption Enhancers And Mechanism.
CLASS OF COMPOUND EXAMPLE POSSIBLE ACTION
Fatty acids
Dideconoylphosphatidyl
chloride, lysophosphotidyl
chloride
Membrane distruption
Surfactants SLS, saponins, polyoxy
ethylene-9-lauryl ether Membrane distruption
Bile salts
Sodium deoxycholate, sodium
glycocholate, sodium
taurodihydrofusidate
Open tight junction, enzyme
inhibition, mucolytic activity
Cyclodextrins and derivatives Clyclodextrins-DM-HP Open tight junctions,
membrane distruption
Enzyme inhibitors Bestatin, amastatin Enzyme inhibition
Bio-adhesive materials Carbopol, starch,
microspheres, chitosan
Reduces nasal clearance, open
tight junctions
5. Usage of bioadhesive polymers: To increase the nasal residence time of the drug in nasal
cavity and reduces the mucociliary clearance, to increase the adhesion of drug in nasal
mucosa bioadhesive polymers are used they increases the adhesion of the formulation
with nasal mucosa. Eg: cellulose derivatives, carbomers, polycarbophils, chitosan.
6. Particulate drug delivery: Several particulate drug delivery systems such as
nanoparticles, liposomes, niosomes, microspheres are being used as a carriers to
encapsulate an active drug. These carriers will prevent the active drug from the nasal
environment, thus it increases stability and decreases toxicity of the drug.
7. In-situ gel: This is a different kind of formulation that get converted into gel upon
installation into nasal cavity due to the influence of the nasal stimuli includes
temperature, pH and ionic concentration. Because of its thick consistency it makes the
formulation difficult to drain by the influence of ciliate movement.
NASAL DRUG ABSORPTION ENHANCERS AND MECHANISM: EXCIPIENTS
USED IN NASAL FORMULATION
There are various types of excipients are used in the nasal formulations they are:
1. Bio-adhesive polymers
2. Penetration enhancers
3. Buffers
4. Solubilizers
5. Preservatives
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6. Antioxidants
7. Humectants
8. Surfactants
1) Bio-adhesive polymers: The compounds capable of interacting with biological material
through interfacial forces and retained on the material for prolonged period of time is said
to be the bio- adhesive polymer also called as mucoadhesives. The bio-adhesive force of
the polymer material is dependent on the nature of the polymer, surrounding medium,
swelling and physiological properties. Eg: cellulose derivatives, poly-acrylates, starch,
chitosan.
2) Penetration enhancers: The chemical penetration enhancers are commonly used in nasal
drug delivery systems they includes solvents, alkyl methyl sulphoxides, pyrolidones, 1-
dodecyl azacycloheptan-2-ones and surfactants.
3) Buffers: Due to the administration of small volumes of nasal formulations, the nasal
secreations may alter the pH of the administered dose which can affect the concentration
of unionized drug available for absorption, therefore an adequate formulation buffer
capacity may be required to maintain the pH in-situ.
4) Solubilizers: For the formulation available for nasal drug delivery in solution form
aqueous solubility of the drug always a limitation, conventional solvents or co-solvents
are used to overcome this drawback, glycols, small quantities of alcohols, transcutol,
medium chain glycerides and labrasol can be used to enhance the drug solubility.
5) Preservatives: Most of the nasal formulations are formulated the aqueous form so it
needs preservatives to control the microbial growth. Commonly used preservatives are
parabens, phenyl ethyl alcohol, benzalconium chloride, EDTA, and benzoyl alcohol.
6) Antioxidants: A small quantity of antioxidants are required to prevent the drug from
oxidation. Commonly used antioxidants are sodium bisulfite, butylated hydroxytoulene,
sodium metabisulfite and tocopherol.
7) Humectants: Because of the allergic and chronic diseases there can be crusts and drying
of the nasal membrane. Adequate intranasal moisture is essential for preventing
dehydration. Therefore humectants can be added especially in a gel based nasal products.
Thus humectants avoids the nasal irritation and do not affect the drug absorption.
Glycerin, sorbitol and mannitol are commonly used.
8) Surfactants: To facilitate the nasal absorption of the drug surfactants are used they will
modify the permeability of the nasal membrane and enhances the drug absorption.
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Table 3: Current Formulations.
INDICATION API FORMULATION
Analgesia
Diamorphine Hcl,
fentanyl
citrate
Nasal powders, nasal
sprays,
nasal solution
Acute treatment of
migrane Sumatriptan zolmitriptan
Nasal sprays, nasal
solutions
Endometriosis ovarian
stimulation Nafarelin acetate
Nasal sprays, nasal
solution
Nasal congestion
Xylometazoline Hcl
Oxymetazoline Hcl
Azelastine Hcl
Ephedrine
Nasal spray, nasal
solution, nasal drops
Prostatic carcinoma
(hormone-dependent) Busorelin acetate Nasal spray, nasal solution
Nasal congestion Levomentol Nasal ointment
Nicotine withdrawal
symptoms Nicotine Nasal spray, nasal
Nasal infection Neomycin, sulfate
chlorhexidine Nasal cream
NASAL DRUG DELIVERY SYSTEM DOSAGE FORMULATIONS
The final dosage form of nasal drug delivery system is chosen based on the patient
compliance, formulation factors and efficiency of the drug delivery. Novel nasal drug
delivery system aims to overcome the demerits of the conventional dosage forms.
1. Nasal liquid formulations:
a) Nasal drops
b) Squeezed bottles
c) Nebulizers
d) Metered dose sprays
2. Powder dosage forms:
a) Dry powder inhalers
b) Insufflators
3. Pressurized MDIs.
4. Nasal gels
1. NASAL LIQUID FORMULATIONS
a) Nasal drops: It is the most simple and convenient dosage form amoung all
formulations, it is a simple mixture composed of therapeutically active substance dissolved in
a excipient mixture or solutions. Nasal drops are administered by a dropper. Disadvantage:
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the main disadvantage of this formulation includes the inadequate dosage volume/ the lack of
dose precision.
Fig 4: Nasal drops.
b) Squeezed bottles: The squeezed bottle is a plastic bottle with a jet outlet, usually
decongestants are administered through squeezed bottles. When the plastic bottle is pressed,
the air present in the container comes out through the small nozzle resulting in atomization of
certain volume of drug solutions.
Disadvantage: The drug delivery system suffers from the contamination by the nasal
secreations and microorganisms, dose administered is dependent on the strength with which
the bottle is pressed.
Fig 5: Squeezed bottle.
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c) Nebulizers: Nebulizers are the devices that deliver the large amount of drug in the form
of mist into the lungs. They are also called as compressed air nebulizers. It is more
advantageous for delivering the large amount of drug, drugs such as corticosteroids and
bronchodilators are given by nebulizers as they are directly targeted to the respiratory tract.
Advantages: Rapid onset of action, shows targeted effect, less side effects.
Disadvantages: Self-administration is impossible.
Fig 6: Nebulizers.
d) Metered-dose sprays: Most of the nasal formulations like solutions, suspensions or
emulsions are administered through this route. This formulation will administer the drug in
the form of mist in the nostril by a hand operated pump mechanism. This device is made up
of container, a pump with an actuator and valve. It is mainly used in the treatment of both
systemic and local infections such as cold, allergy, nasal congestion.
Fig 7: Metered-dose spray.
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2. NASAL POWDER FORMULATIONS
a) Dry powder inhalers: In these type of devices, the drug is inhaled in the form of cloud of
particles for local or systemic effect. This formulation composed of active drug dissolved or
suspended in a propellant or in a dry powder inhaler. It is mainly used in the treatment of
bronchitis, COPD, asthma and emphysema along with diabetes mellitus. These device is
activated by taking deep inhalation of the patient by holding his breath about 5-10 seconds.
Disadvantage: As larger doses may cause cough, it is used to deliver only less than a few
milligrams of drug powder in one breath.
Fig 8: Dry powder inhalers.
b) Insufflators: It is an inhalation device composed of tube or straw containing medication
and also has a syringe. It can deliver the drug having large particle size when compared to the
particle size of powders, many of the insufflators loaded with pre-dosed doses within the
capsules.
Fig 9: Insufflators.
3. PRESSURIZED MDIS
Pressurized metered dose inhalers also called as metered dose inhalers, these devices deliver
the medication in the form of fine spray to the lungs. In these device the medication is
suspended or dissolved in liquid propellants along with excipients such as surfactants.
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Advantages: Easy to carry as they are small in size, easily available, provides consistency in
doses, enables in accurate dosing.
Fig 10: pressurized MDI.
NASAL GELS: The highly viscous thick drug solutions or suspensions are termed as nasal
gels. It is administered such that it should deposited in the nasal cavity for long time, due to
its viscous nature it does not spread easily, thus it requires special application technique.
Advantage: Decreased bad after taste due to decreased swallowing, anterior leakage of the
formulation is also less, nasal irritation can be reduced by using soothing/emollient
excipients, postnasal drip is less due to high viscosity.
Fig 11: Nasal gel.
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Table 4: Marketed Nasal Drug Formulations For Systemic Delivery.
DRUG TREATMENT FORMULATION:
Protirelin Thyroid diagnosis Solution, spray
Nafarelin endometriosis Solution, spray
Desmopressin Antidiuretic hormone Solution, spray
Oxytocin Lactation induction Solution, spray
Buserelin Prostate cancer Solution, spray
Salmon calcitonin osteoporosis Solution, spray
estradiol Hormone replacement Nasal solution
Nasal spray
dihydroergotamine migrane Nasal spray
Nasal solution
sumafriptan migrane Nasal spray, nasal solution
EVALUATIONS OF NASAL DRUG DELIVERY SYSTEMS
1. IN-VITRO DIFFUSION STUDIES: These study is carried out by „ussing chamber‟, it
consists of two chambers, donor and receptor chambers, both this chambers are connected
to a U-shaped glass tube which is filled with a experimental solution. This tube can be
filled with air, nitrogen, oxygen or carbon dioxide. A semipermeable membrane is placed
between the two chambers. Nasal mucosa of rat/rabbit is used in this model because it is
similar to the human nasal mucoepithelium. Drug solution is added to the donor
compartment and temperature of the system is maintained at 37 samples are withdrawn
from the receiver compartment at regular intervals. The samples are then tested for the
drug content, which indicates the amount of drug permeated through the nasal epithelium.
2. IN-VIVO MODELS
a) Rat model
b) Rabbit model
c) Dog model
d) Sheep model
e) Monkey model
a) Rat model: Initially the rat is anaesthetized by intra-peritoneal injection of sodium
pentobarbital, an incision is made on the neck and the trachea is cannulated using a
polyethylene tube, another plastic tube is inserted through the oesophagus and directed
towards the posterior portion of the nasal cavity, the lumen of the nasopalatine track is
closed either surgically or by using an adhesive agent. This prevent drainage of drug
solution into the mouth, drug solution is administered either via the nostrils or through the
tubings, blood samples are collected through the femoral vein. Since all the pathways for
drug drainage have been closed, the drug reaches the systemic circulation by permeating
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through the nasal mucosa.
b) Rabbit model: Rabbit weighing approximately 3kg is selected, it is anaesthetized by
administering ketamine and xylazine mixture by IM route, the rabbit‟s head is held in an
upright position and the drug is administered in the form of nasal spray in each nostrils. A
catheter is positioned in the marginal ear vein from which blood is withdrawn and
analysed for drug content.
c) Dog model: This test requires male beagle dogs who are either anaesthetized or
maintained in a conscious position depending upon the purpose of the study or
characteristics of the drug, the animal is ventilated using a positive pressure tube through
the cuffed endotracheal tube. Body temperature of the animal is maintained at 37using a
heating pad, blood samples are withdrawn at regular intervals from the jugular vein and
analysed for the drug content.
d) Sheep model: The sheep rabbit and dog models are more suitable for introducing nasal
drug delivery form more sophisticated formulations, they allows the better evaluation
of parameters this model is more similar to the dog model for this male in-house breed
sheep are selected as it is free from nasal infections.
e) Monkey model: A monkey weighing about approximately 8kgs are selected and it is
anaesthetized, tranquilized by intra muscular injection of ketamine hydrochloride or
anaesthetized by intra venous injection of sodium phenobarbital, the head of monkey is
held in an upright position and the drug solution is administered into each nostrils.
Following the administration the monkey is placed in supine position on a metabolism
chair for 5-10 min, the blood samples are collected through an indwelling catheter in the
vein.
3. EX-VIVO NASAL PERFUSION MODEL: It is similar to the surgical preparation as
that is for in- vivo rat model, to minimize the loss of drug solution during perfusion
studies a funnel is placed between the nose and reservoir. The drug solution is placed in a
reservoir maintained at 37 and is circulated through the nasal cavity of the rat with a
peristaltic pump. The perfusion solution passes out from the nostrils through the funnel
and runs again into the reservoir, the drug solution in the reservoir is continuously stirred,
the drug utilized can be predicted by using residual drug concentration present in the
perfusion solution. Other animals like rabbits can also used for this study.
4. IN-VIVO BIOAVAILABILITY STUDIES: These study is preferred for healthy male
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rabbits, it is divided into 3 sections each section containing 6 rabbits which are fasted for
24hrs. One section of rabbits are treated with the conventional preparation, second section
is considered as a control, and third section is for test formulation. During fasting and
throughout the experiment water is given to the rabbits, blood samples are collected by
selecting marginal ear vein of the rabbits 2ml of blood is collected from each rabbit in a
heparinized centrifuge tube at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8hrs after the administration of
the drug. The blood samples are centrifuged at 3000 * grams for 15min to collect the
plasma and stored at -20C until analysis. Pharamacokinetic parameters can be derived
from the plasma concentration Vs time plot. AUC, Cmax, Tmax can be obtained by these
plots.
APPLICATIONS OF NASAL DRUG DELIVERY
Some of the potential applications for nasal drug delivery are given below:
1) Delivery of non-peptide pharmaceuticals
2) Delivery of peptide based pharmaceuticals
3) Delivery to brain
4) Delivery of vaccines.
1) DELIVERY OF NON-PEPTIDE PHARMACEUTICALS
Several non-peptide drugs have been administered by the nasal route which have shown
promising results, when drugs such as progesterone, hydrlazine, propranolol, cocaine,
naloxone, testosterone, nitroglycerine which experience extensive first pass effect were given
by the nasal route. They exhibited a systemic bioavailability of 100% by undergoing rapid
absorption through the nasal mucosa. Even small non-peptide lipophilic drug exhibited good
nasal bioavailability even in the absence of permeation enhancers.
2) DELIVERY OF PEPTIDE BASED PHARMACEUTICALS
Proteins and peptides are generally administered through the parenteral route, because they
are subjected to extensive first pass metabolism and are unstable. These substances are polar,
high molecular weight compounds which exhibit poor absorption across the biological
membrane. Hence attempts are being made to increase the residence time of peptides and
proteins in the nasal cavity by using viscosity enhancing agents, surfactants, enzyme
inhibitors, muco-adhesives or bio-adhesive polymers.
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3) DELIVERY TO BRAIN
Nasal drug delivery can be used to deliver the drugs to brain, which can be useful in
conditions like Alzheimer‟s diseases, parkinson‟s diseases etc. the olfactory region is capable
of delivering the drugs directly to the brain by avoiding the blood brain barrier. Hence nasal
route appears to be a promising routes for the delivery of drugs to brain. Several neurotropic
factors such as ADNF, NGF etc. were given by the intranasal route which exhibited
appreciable bioavailability in the brain tissues.
4) DELIVERY OF VACCINES
Nasal route has the potential to be used for the delivery of vaccines because:
a) Nasal mucosa is the first site of contact with the pathogens inhaled by the nasal route.
b) Nasal cavity contains nose associated lymphoid tissue which is a component of the
immune system.
c) It is associated with the stimulation of both local and systemic immune responses.
d) The route is patient friendly, safe and inexpensive.
Recently nasal vaccines for the anthrax has been prepared by using recombinant bacillus
anthracis protective antigen. Nasal vaccines can be prepared for diseases like pertussis,
meningitis, influenza etc. as the causative pathogens enters through the nose.
CONCLUSION
The nasal cavity is selected for drug delivery because of its large surface area and highly
vascularized mucosa drugs which are absorbed by rich network of blood vessels passes
directly into systemic circulation, there by avoiding first pass metabolism, not only for nasal
route a number of factor limits the intranasal absorption of drugs mostly peptide and protein
drugs, those barriers are mucous epithelial barrier, mucociliary clearance and enzymatic
activity the drug formulations that are deposited through mucociliary clearance in the nasal
cavity is an important factor causing low bioavailability of drugs administered intranasally.
Increasing residence time of the drugs in nasal cavity. Hence prolonging the contact period of
nasal mucosa, thereby improving the drug absorption the lipophilic drugs are mostly
preferred because they shows good nasal absorption, the nasal route of administration will
probably have great potential for the future development of peptide preparations and other
drugs that otherwise shouldn‟t administered parentrally.
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