NASAL DRUG DELIVERY SYSTEM: A REVIEW

www.wjpr.net Vol 8, Issue 13, 2019.

Reddy et al. World Journal of Pharmaceutical Research

431

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 bioadhesive 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.



450

REFERENCES

1. Parmar Harshad, Bhandari Anand, Shah Dushyant. Recent techniques in nasal drug

delivery. International journal of drug research and development, 2010.

2. M. Alagusundaram, B. Chengaiah, K. Gnanaprakash, S. Ramkanth, C. Madhusudhana

Chetty, D. Dhachinamoorthi. Nasal drug delivery system. International journal of

research pharma, 2010; 1(4): 454-465.

3. Pagar Swati Appasaheb, Shinkar Dattatraya Manohar Saudagar Ravindra Bhanudas.

Intranasal drug delivery system. Advanced pharma educational and research, 2013; 3(4):

333-340.

4. Sulaiman Alnasser. Nasal drug delivery system and its contribution in therapeutic

management. Asian journal of pharmaceutical and clinical research, 2019; 1(12): 41-43.

5. Sachin Chhajed, Sagar Sangale and S.D Barhate. Advantageous nasal drug delivery

system. International journal of pharmaceutical sciences and research, 2011.

6. Muhammad U. Ghori, Mohammed H. Mahdi, Alan M. Smith, Barbara R. Conway. Nasal

drug delivery system. American journal of pharmacological sciences, 2015; 5(3):

111-115.

7. Dharmendra Kumar, Sumedha Bansal. Nasal drug delivery system. Pharma tutor-Art-

1593.

8. D. Anish Kumar, G. Mohanranga reddy, D. Saidarao. Review article of nasal drug

delivery system. International journal of research in pharmaceutical and nano sciences.

2012; 1(1): 35-37.

9. Shivam Upadhayay, Ankit Parikh Joshi, U M Upadhaya and N P Chotai. Intra nasal drug

delivery system. Journal of applied pharmaceutical sciences, 2011; 1(3): 36-44.

10. Springer US. Nasal drug delivery devices characteristics and performance. Drug delivery

and translational research, 2013; 1(3).

11. Selcan Turker, Erten Onur and Yekta Ozer. Nasal route and drug delivery systems.

Pharma world sciences, 2004; 26: 137-138.

12. Lisheth Illum. nasal drug delivery new developments and strategies. Research Focus,

2002; 23(7): 1184-1186.

NASAL DRUG DELIVERY SYSTEM: A REVIEW

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