INTRA NASAL DRUG
DELIVERY SYSTEM
Molecular Pharmaceutics
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CONTENTS
■ Introduction
■ Advantages & Limitation
■ Nasal anatomy and physiology
■ Mechanism of nasal absorption
■ Factor influencing the nasal drug absorption
■ Strategies to improve nasal absorption
■ Types & preparation
■ Evaluation
■ Application
■ References
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INTRODUCTION
■ Administration of drug through nasal route is referred
as nasal drug delivery system.
■ The nasal route is an attractive alternative to invasive
administrations and provides a direct access to the
systemic circulation.
■ The systemic bioavailability by nasal delivery of some
peptide and protein drugs with low nasal absorption
has been improved by coadministering them with
absorption promotors, enzyme inhibitors
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ADVANTAGES
■ Rapid drug absorption, higher bioavailability therefore
lower dose.
■ Fast onset of action.
■ Easily administered to unconscious patients.
■ Lower dose reduced side effects.
■ Self-administration.
■ Avoidance of liver first pass effect.
■ Avoidance of gut wall metabolism.
■ Avoidance of destruction drug in the GIT
■ Patient convenience and compliance is improved
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■ Better nasal bioavailability for smaller drug molecules.
■ The bioavailability of larger drug molecules improved
by means of absorption enhancer.
■ Direct transport into systemic circulation and CNS is
possible.
LIMITATION
■ Very specific amount i.e. 25-200µl can be delivered
through intra nasal route. Once the drug administered
cannot be removed.
■ Irritation of nasal mucosa by drug eg: Budesonide,
Azilactine
■ Local side effects and irreversible damage of the cilia of
nasal mucosa.
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■ Mechanical loss of the dosage form into the other parts of
the respiratory tract.
■ Absorption surface area is less when compared to GIT.
■ Difficult to administered drug in pathological condition
such as nasal congestion due to cold or allergic reaction.
■ Enzymatic barrier to permeability of drug
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NASAL ANATOMY AND PHYSIOLOGY
■ The nasal passage – nasal vestibule to the nasopharynx,
depth approximately 12-14 cm2.
■ The human nasal cavity has a total volume about – 16-
19ml.
■ Total surface area – about 180 cm2.
■ Nasal cavity is covered with mucous membrane which
contains – goblet cells, basal cell & non ciliated & ciliated
columnar cell.
■ Nasal pH : 5.5-6.5 (Adults)
5.0-6.7 (Infants)
Nasal Enzymes – Cytochrome P-450, Carboxyl esterase and
Glutathione S- tranferase, lactate dehydrogenase, oxido
reductase, phosphates , hydrolases.
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Fig1: Nasal Cavity
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■ It contains 3 region:
a) Vestibule region
b) Respiratory region
c) Olfactory region
1)Vestibular Region:
■ Located at the opening of nasal passage.
■ Responsible for filtering out the air borne particles.
2)Respiratory Region:
■ It having the highest degree of vascularity.
■ Mainly responsible for systemic drug absorption.
3)Olfactory Region:
■ Located roof of the nasal cavity .
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MECHANISM OF NASAL ABSORPTION
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Mechanism of drug absorption
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FACTOR INFLUENCING THE NASAL DRUG
ABSORPTION
Factors Related To Drug:
■ Molecular weight and size
■ Chemical form
■ Polymorphism
■ Lipophilicity, Partition coefficient and pKa.
■ Solubility & dissolution.
Factor Related To Formulation
1.Physicochemical properties of formulation
■ pH
■ Viscosity
■ Osmolarity
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2.Dosage form used for developing the formulation
■ Nasal drops
o Most simple, convenient
o Disadvantage :lack of dose precision
■ Nasal sprays
o Both solution and suspension – formulated in this form
o Metered dose pumps – exact dose
o Preferred over powder spray
■ Nasal gels –precise dosing
■ Nasal powders
o This form may be developed due to lack of stability
o Advantage :absence of preservatives, superior stability
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STRATEGIES TO IMPROVE NASAL ABSORPTION
■ Prodrugs:
o Improve taste, odor, solubility eg. L-Dopa
■ Nasal enzymatic inhibitors:
o Minimize metabolism of drug
o Minimizing activity of enzyme in cavity
o Eg:bestatine & comostate amylase – amino peptidase
inhibitors.
o Protease and peptidase used as inhibitors for peptide and
protein molecule
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■ Structural modification:
o Eg, Calcitonin to Ecatonin
■ Mucoadhesive polymer :
o To improve the nasal residence and absorption
o Eg: Chitosan, alginate, cellulose & its derivative,
■ Novel formulation / particulate drug delivery
o Eg: Microspheres, liposomes, nanoparticles
■ Absorption or permeation enhancers
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PERMEATION ENHANCER
Type of Examples Mechanisms of action
compound
Bile salts(and Sodium deoxycholate Disrupt membrane,
derivatives) Sodium glycocholate open tight junctions, enzyme
inhibition, mucolytic activity
Surfactants SLS, Saponin Disrupt membranes
Chelating agents EDTA, Salicylates Open tight junction
Fatty acids Sodium laurate Disrupt membranes
Phospholipids
Bioadhesive Open tight junctions, reduce
materials Carbopol, Chitosan nasal clearance
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FORMULATION
■ Drugs
■ Viscosifying agents
■ Solubilizers
■ Surfactants
■ Preservative
■ Antioxidants
■ Humectants
■ Osmotic agent
■ Bioadhesive polymers
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1.Drug
■ Appropriate nasal absorption properties.
■ No nasal irritation from the drug .
■ Rapid onset of action.
■ Low dose generally 25 mg per dose.
■ No toxic metabolites.
■ No offensive odors associated with the drug.
■ Suitable stability characteristics.
■ Eg: anticholinergic(ipratropium bromide)
Mast cell stabilizer(sodium cromogylate),
corticosteroids(budesonide)
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2.Viscosifying /Gelling agents:
■ Increasing solution viscosity may provide prolong
therapeutic effect of nasal preparations.
■ Highly viscous formulations interfere with mucociliary
clearance and alter the permeability of drug.Eg: Methyl
cellulose, Hydroxy propyl cellulose, Carbopol.
3.pH of the formulation:
■ It is important to avoid irritation of nasal mucosa.
■ Use phosphate buffer pH 6.8 as a vehicle.
4.Solubilizers:
■ Aqueous solubility of drug always a limitation for nasal
drug delivery.
■ Eg: Alcohol, Labrasol, Surfactants, Transcutol
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5.Preservatives:
■ These are used to prevent the growth of micro organisms.
■ Mercury containing preservatives are not used.
■ Eg: Paraben, Benzalkonium chloride, Phenyl ethyl alcohol,
EDTA etc.
6.Antioxidants:
■ These are used to prevent drug oxidation.
■ Eg: Sodium Metabisulphite, Sodium Bisulfite, Butylated
hydroxy toluene, Tocopherol etc.
7.Humectants :
■ To prevent dehydration, adequate intranasal moisture is
required to prevent nasal irritation.
■ Eg: Glycerine, Sorbitol, Mannitol.
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8.Osmotic agent :
■ It affect the nasal absorption of the drug.
■ The higher concentration of drug not only causes increased
bioavailability but also leads to the toxicity to the nasal
epithelium.
■ Eg: Sodium Chloride, Sodium Sulfite, Sodium Acid
Phosphate.
9.Bioadhesive polymers:
■ Compounds capable of interacting with biological material
through interfacial forces and retained on such material for
prolonged periods
■ Eg: cellulose derivatives
Polyacrylates, starch
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NASAL DROPS
■ Most simple and convenient systems developed
for nasal delivery.
■ These are solution emulsion suspensions
intended for instillation into the nostrils with
dropper.
■ Nasal drops deposit human serum albumin in the
nostrils more efficiently than nasal sprays.
■ Disadvantage: Lack of the dose precision.
■ Eg: Xylometazoline, Phenylephrine, Sodium
chloride.
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www.DuloFMixi.cgom 4 : Ephedrine Nasal Drops 23
NASAL SPRAY
■ These are solution emulsion suspensions
intended for spraying into the nostrils.
■ Aim – To retain the nasal solution in the
droplet form in the nasal cavity.
■ Availability of metered dose pumps and
actuators, a nasal spray can deliver an
exact dose from 25 to 200 μg.
■ Advantage : Simple & convenient system.
■ Disadvantage: Lack of dose precision.
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■ Eg: Xylometazolin, Beclomethasone, Normal
Fig 5 : Otrivine Nasal Spray (0.1 % w/v)
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■ Nasal spray products contain – therapeutically active
ingredients (drug substances) dissolved or
suspended in solutions or mixtures of excipients
(e.g. preservatives, viscosity modifiers and buffering
agents).
■ Used for local therapy & systemic therapy.
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SPRAY PUMP DEVICES
Unidose Multidose
Bidose
Fig 6 : Spray Pump Devices
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NASAL POWDER
■ This dosage form may be developed if solution and
suspension dosage forms cannot be developed.
■ These are powders intended for insufflation into
the nostrils by means of suitable device.
■ Nasal powder formulation depends on the
solubility, particles size and nasal irritancy of the
active drug and excipients.
Advantages :
■ The absence of preservative.
■ Superior stability of the formulation.
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■ Eg: Normal Saline , Sumatriptan.
Fig 7 : Normal saline powder (0.9 % w/v)
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NASAL GEL
■ Nasal gels are high-viscose thickened solutions or
suspensions.
Advantages :
■ Reduction of post-nasal drip.
■ Reduction of taste impact due to reduced
swallowing.
■ Reduction of anterior leakage of the formulation.
■ Reduction of irritation by using emollient excipients.
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■ Eg: Oxytocin, Metoclopramide Hydrocloride.
Fig 8 : Chlorpheniramine Nasal Gel
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NASAL INSERTS
■ Nasal inserts are bioadhesive, solid dosage forms for
prolonged systemic drug delivery via the nasal route.
■ Nasal fluid from the mucosa after administration and to form
a gel in the nasal cavity to avoid foreign body sensation.
■ Eg: Chlorpromazine, Albuterol .
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Fig 9 : Nasal Inserts
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LIPOSOMES
■ Liposomes are phospholipids vesicles composed
by lipid bilayers enclosing one or more aqueous
compartments and wherein drugs and other
substances can be included.
Advantages :
■ Effective encapsulation of small and large
molecules with a wide range of hydrophilicity and
pKa values
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www.DuloMFix.ciogm 10 : Liposome 35
■ Administered to the respiratory tract as an
aerosol or solution for a nebulizer & micro fine
powder for insufflations, alone or in
combination with an inert carrier such as
lactose.
■ The particles of the formulation have diameters
of less than 50 microns.
■ Eg: Insulin, Calcitonin, Influenza vaccine,
Levonorgestrol, Acyclovir, non-peptide drug
(Nifedipine)
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NANOPARTICLES
■ Nanoparticles are sub-nanosized colloidal structures
composed of synthetic or semi-synthetic polymers.
■ The drug is dissolved, entrapped, encapsulated or
attached to polymer matrix.
■ Size range : 10–1000 nm.
■ Nano drug delivery system used for treatment of CNS
disorders.
■ Types:
■ Nanospheres
■ Nanocapsules
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■ Solid Lipid Nanoparticles
■ Polymeric Nanoparticles
■ Ceramic Nanoparticles
■ Hydrogel Nanoparticles
■ Copolymerized Peptide Nanoparticles
■ Nanocrystals and Nanosuspensions
■ Nanotubes and Nanowires
■ Functionalized Nanocarriers
■ Eg: Vaccines
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www.DuloMix.com Fig 11 : Nanoparticles 39
MICROSPHERES
■ It provides prolonged contact with nasal mucosa.
■ Microspheres swell in contact with nasal mucosa to
form a gel and control the rate of clearance from the
nasal cavity.
■ The ideal microsphere particle size requirement for
nasal delivery – range from 10 to 50 µm as smaller
particles.
■ The materials used in formulation : Starch, Dextran,
Albumin and Hyaluronic acid, Mucoadhesive polymer
(chitosan, alginate).
■ Eg. Carbamazepine Chitosan Microspheres, Dextran
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Gentamicin, Insulin.
Fig 12 :Microcapsules & Microspheres
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NASAL IN-SITU GEL
■ In-situ gel formulations are drug delivery systems that are in
solution form before administration in the nasal cavity, but
after administration it undergoes gelation to form gel.
■ This can be achieved by using different polymers such as
Chitosan, PVA, Poloxamers, Carbopol.
■ Eg: Midazolam, Insulin, Diltiazem.
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MICROEMUSION & NANOEMULSION
■ It composed of oil, surfactant & co-surfactant was developed
for intranasal delivery.
■ Oil phase : Lauroglycol 90.
■ Surfactant : Labrasol.
■ Co-surfactant : Plurol oleique or its mixture with PEG 400
(1:1).
■ Eg: Fexofenadine, Resperidone.
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NASAL DELIVERY DEVICES
Common devices
■ Droppers
■ Squeeze bottle
■ Spray pump/Atomizers (MAD- Mucosal
Atomization Device)
■ Gel applicators
■ Nasal nebulizers ( Sinus Nebulizer Rhino Clear)
■ Pressurized Meter Dose Nasal Inhaler
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MUCOSAL ATOMIZATION DEVICE (MAD)
■ Device designed to allow emergency personnel to
delivery nasal medications as an atomized spray.
■ Broad 30-micron spray ensure excellent mucosal
coverage.
■ It is disposable and single use only.
■ Eg: Naloxone.
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Fig 13 : Mucosal Atomization Device
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METERED DOSE NEBULIZER
■ Operates by mechanical actuation.
■ Delivers a predetermined volume with precision.
■ Atomization results in higher bioavailability than
either spray or drops.
■ Eg : Corticosteroids.
www.DuloMix.com Fig 14 : Nasal Nebulizer47
NASAL AEROSOLS INHALER
■ Aerosol inhalations are solutions suspensions or
emulsions of drug in a mixture of propellant held
under pressure in aerosol container.
■ Form droplet – 50 µm or less using metered valve.
■ Eg:-Budesonide & Beclomethasone .
www.DuloMFix.ciogm 15: Nasal Aerosol Inhaler 48
EXAMPLES OF MARKETED PREODUCT
LOCAL DELIVERY
DRUG BRAND MAIN EXCIPIENTS MAIN
INDICATION
Beclomethason Beconase Microcrystalline cellulose, Management/
e Carboxy methyl cellulose treatment of
sodium. symptoms of
seasonal and
Rhinocort Microcrystalline cellulose, perennial
Budesonide Carboxy methyl cellulose . rhinosinusitis
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SYSTEMIC DELIVERY
DRUG BRAND MAIN EXCIPIENTS MAIN
INDICATION
Estradiol Aerodiol Methyl beta dextrin, Hormone
Sodium chloride. replacement
therapy
Cyanocobalam Nascobal Sodium citrate, Vitamin B12
in Citric acid, deficiency
Benzalkonium
chloride
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EVALUATION OF NASAL DRUG
FORMULATION
A.IN VIVO NASAL ABSORPTION STUDIES
1.RAT MODEL
■ The rat is anaesthetized-intraperitoneal injection (sodium
pentobarbital) .After incision is made in the neck, the
trachea is cannulated with a polyethylene tube.
■ Another tube is inserted through the esophagus towards
the posterior region of the nasal cavity.
■ The drug solution is delivered to the nasal cavity through
the nostril or esophageal tubing.
■ The blood samples are collected from the femoral vein.
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2.RABBIT MODEL
■ The rabbit weighing approximately-3kg is
anaesthetized by an intramuscular
injection(combination of ketamine and xylazine)
■ The rabbit head is held in an upright position.
■ The drug solution is administered by nasal spray into
each nostrils.
■ During the experiment the body temperature of the
rabbit is maintained at 37°C with the help of a heating
pad.
■ The blood samples are collected by an catheter in the
marginal ear vein or artery.
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3.DOG MODEL
■ Anaesthetized by intravenous injection of Sodium
Thiopental and maintained in an anaesthetized state with
Sodium Phenobarbital.
■ A positive pressure pump provides ventilation through a
cuffed endotracheal tube.
■ Using heating pad keeps the body temperature at 37°C.
■ Blood samples are collected from the jugular vein.
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B.EX VIVO NASAL PERFUSION MODEL
■ During perfusion studies, to minimize the loss of drug
solution a funnel is placed between the nose and
reservoir(drug).
■ Maintained at 37°C and circulated through the nasal
cavity of the rat by means of a peristaltic pump.
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■ The perfusion solution passes out from the nostril and
through the funnel and flows in to the drug reservoir
solution again.
■ Drug solutions of 3–20 ml are continuously circulated
through the nasal cavity of anaesthesized rats.
■ The reservoir is stirred constantly.
■ The amount of drug absorbed is determined by measuring
the drug concentration remaining in the solution after a
period of perfusion.
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3.IN VITRO DRUG DIFFUSION STUDY
■ Nasal diffusion cell is fabricated in glass.
■ The water jacketed recipient chamber having total
capacity-60ml.
■ Three openings-sampling,thermometer and donor tube
chamber.
■ Nasal mucosa of sheep was separated from sub layer bony
tissues and stoned in distilled water.
■ The donor chamber tube is placed just touches the diffusion
medium in recipient chamber.
■ Sample (0.5ml) from recipient chamber are withdraw-
transferred to amber coloured ampoules.
■ Estimated by analytical techniques.
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IN-VITRO STUDIES
In the case of nasal powders:
■ Uniformity of content, Uniformity of weight, Particle size,
Melting point, Angle of Repose, Carr’s index etc.
In the case of nasal in-situ gelling system:
■ Viscosity of solution, PH, Gelling Temperature & Gelling
time, Spreadability, in vitro drug release, Mucoadhesive
strength etc.
In the case of nasal drops:
■ Uniformity of content, Uniformity of weight, Clarity test,
Sterility test, Closure system etc.
In the case of nasal sprays:
■ Clarity of liquid, sterilization, net content, pump delivery,
spray content uniformity, spray pattern, particle size
distribution(suspension), droplet size distribution etc.
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APPLICATION
1.Delivery of vaccines through nasal route:
■ Nasal mucosa is the first site of contacts with inhaled
pathogens.
■ Nasal passages are rich in lymphoid tissue
■ Creation of both mucosal and systemic immune response
■ Low cost ,non injectable
■ Eg: For measeles, pertussis, meningitis
2.Delivery of drugs to Brain:
■ For Treatment of Parkinson’s disease, Alzheimer disease.
■ For Delivery of Melanocyte Stimulating Hormone,
ACTH, Insulin to brain.
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3.Delivery of non-peptide pharmaceuticals:
■ Eg. Propranolol, Nitroglycerin, vitamin B, sex hormone
4.Delivery of peptide based pharmaceuticals:
■ Peptides – low BA because of physicochemical
instability and susceptibility to hepato gastrointestinal
first pass elimination
■ Eg. Insulin, Calcitonin, Pituitary hormones etc.
5.Delivery of Diagnostic Drugs:
■ Secretory function of gastric acid – Pentagastrin
■ Secretin – For diagnosis of pancreatic disorders in
diabetic patient
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Drug substance Indication Dosage form
1.Proteins & Antidiuretic Solution (spray)
peptides: hormone
Desmopressin
Oxytocin Lactation induction Solution (spray)
2.Non-peptide: Migraine Solution (spray)
Zolmitriptan
3.Vaccine spray
Human influenza
vaccine
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REFERENCE
■ Y W. Chien, Novel Drug Delivery System, 2nd
edition, revised and expanded, Marcel Dekker,
lnc., New York, 1992. Page no 230- 262.
■ Jeyesh K. Kakad, et al World Journals Of
Pharmaceutical Research: A Resent Review On
Nasal Drug Delivery System.
■ Kapil Kulkarni, et al Brain Targeting Through
Intranasal Route.
■ Anaisa Pires, et al Intra Nasal Drug Delivery.
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THANK YOU
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