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INTRA NASAL ROUTE DELIVERY
SYSTEMS
TYPES, PREPARATION & EVALUATION
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INTRODUCTION
• Administration of drug through nasal route is referred as Nasal drug
delivery system.
• Nasal route is an alternative to invasive administrations and provides a
direct access to the systemic circulation.
• Intranasal Medication administration offers a truly “Needleless ” solution
to drug delivery.
• In recent years many drugs have been shown to achieve better systemic
bioavailability through nasal route than by oral administration
ADVANTAGES OF NASAL DRUG DELIVERY SYSTEM
1. A non invasive route.
2. Hepatic first –pass metabolism is absent.
3. Rapid drug absorption.
4. Quick onset of action.
5. The bioavailability of larger drug molecules can be improved by means of
absorption enhancer or other approach.
6. Better nasal bioavailability for smaller drug molecules.
7. Drugs which can not be absorbed orally may be delivered to the systemic
circulation through nasal drug delivery system.
8. Convenient route when compared with parenteral route for long term
therapy.
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LIMITATIONS
1. The absorption enhancers used to improve nasal drug delivery system
may have histological toxicity which is not yet clearly established
2. Absorption surface area is less when compared to GIT.
3. Once the drug administered can not be removed.
4. Nasal irritation.
5. There is a risk of local side effects and irreversible damage of the cilia on
the nasal mucosa
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ANATOMY OF NASAL CAVITY
The nasal cavity is divided into two halves by
the nasal septum and extends posterior to the
nasopharynx, while the most anterior part of
the nasal cavity, the nasal vestibule, opens to
the face through the nostril.
It contains 3 regions
a)Nasal vestibule a – nasal vestibule d – middle turbinate
b)Olfactory region b – palate e – superior turbinate
c – inferior turbinate f – nasopharynx
c)Respiratory region
Nasal cavity is covered with mucous membrane
which contains goblet cells and secrets mucous
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➢ The nasal cavity can be divided into two areas;
1. Non-olfactory and
2. Olfactory epithelium,
▪ In non-olfactory area includes- the nasal vestibule, covered with skin-like
stratified squamous epithelium cells.
▪ The respiratory region contain three nasal turbinates – the superior,
middle and the inferior, which project from the lateral wall of each half of
the nasal cavity
▪ In respiratory region – it has typical airways in the epithelium covered
with numerous microvilli, resulting in a large surface area available for
drug absorption and transport.
Nose brain pathway
➢ The olfactory mucosa (smelling area in nose) is in direct contact with the
brain and CSF.
➢ Medications absorbed across the olfactory mucosa directly enter the
brain.
➢ This area is termed the nose brain pathway and offers a rapid, direct
route for drug delivery to the brain.
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NASAL ENZYMES:
• Cytochrome p-450 dependent oxygenase , lactase dehydrogenase, Oxido-
reductase, acid hydrolases, esterase’s, lactic dehydrogenases, malic
enzymes, liposomal proteinases, steroid hydroxylases etc.
NASAL pH:
• Adult nasal secretion pH:5.5-6.5
• Infants and children: 5-6.7
• It become alkaline in conditions such as acute rhinitis, acute sinusitis
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MECHANISM OF ABSORPTION
• Drug passes through the mucous membrane of nasal cavity
• Majority of Drugs are absorbed by passive diffusion.
• Some may be by active transport, such as amino acids.
• Literature shows that upto 1000dalton drug get easily absorbed without
help of penetration enhancers.
• Two mechanisms involved in the transportation of the drug which are;
a) Para-cellular transport
b) Transcellular transport
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Para-cellular •Aqueous route of transport.
•Slow and passive.
transport
•Transport through lipoidal membrane
Transcellular •Active transport occurs via carrier mediated
transport transport.
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BARRIERS TO NASAL ABSORPTION
Low Bioavailability Low Membrane Enzymatic Degradation
Transport
It is due to Low membrane Rapid clearance of Degradation of protein
permeability (limiting factor administered formulation and peptides by
for high molecular weight due to MCC. Exopeptidase and
polar drugs like protein Ex: Liquid and powder Endopeptidase
and peptides ) Formulation shows rapid
clearance
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FACTORS AFFECTING NASAL ABSORPTION
The various factors affecting nasal absorption are
➢ Effect of particle size
➢ Effect of molecular size
➢ Effect of solution pH
➢ Effect of drug lipophilicity
➢ Effect of drug concentration
➢ Effect of Mucosal contact time
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Effect of particle size
o Access to distal airways is a function of particle size
o Large particles(>7μ)will be lost in the GI tract
o Small particles(<3μ)will be lost in exhaled breathe
o Intermediate particles (3 to 7μ) reaches the actual site
Effect of molecular size
o Higher the molecular size, lower the nasal absorption
o A good systemic bioavailability can be achieved for molecules with a
molecular weight of up to 1000 Daltons when no absorption enhancer is
used.
Effect of solution pH
o Nasal absorption is pH dependent
o Absorption is higher at pH lower than the dissociation constant (pKa) of
the molecule
o Absorption is lower as the pH increases beyond the dissociation constant.
➢ pH of the nasal formulation is important because:
1. To avoid the nasal irritation
2. To allow drug to be available in unionized form for absorption
3. To prevent the growth of pathogenic bacteria in nasal passage
4. To maintain functionality of excipients such as preservatives etc.
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Effect of drug lipophilicity
o Polar(water soluble) drugs tend to remain on the tissues of the upper
airway
o Non-polar(lipid soluble)drugs are more likely to reach distal airways
o Lipid soluble drugs are absorbed more rapidly than water soluble drugs
Effect of drug concentration
o Absorption depends on the initial concentration of the drug
o Absorption follows first order kinetics
Effect of Mucosal contact time
o Viscosity of formulations increases the contact time which increases the
permeation of the drug
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Strategies To Improve Nasal Absorption
1.Nasal Enzymes Inhibitors:
Eg- peptidases, proteases, tripsin, aprotinin, borovaline, amastatin, bestatin
and boroleucin inhibitors.
2. Modifying drug structure:
Eg- chemical modification of salmon calcitonin to ecatonin (C-N bond replaces
the S-S bond) showed better bioavailability than salmon calcitonin.
3.Prodrug approach:
Eg- peptides like angiotensin II, bradykinin, caulein, carnosine, vasopressin and
calcitonin.
4.Particulate drug delivery: Particle design is an increasingly important role in
absorption enhancement. Microspheres, nanoparticles and liposomes are all
systems which can be used as carriers to encapsulate an active drug.
5.Absorption Enhancers
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FORMULATION CONSIDERATION
✓ Nasal formulation are generally administered in small volumes in the
range 25-200μ L with 100μL, the most common dose volume.
✓ The excipients should be carefully selected so as to avoid damage to the
muco-epithelial layers and to sustain normal physiological ciliary
movement.
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FORMULATION OF NASAL DRUG DELIVERY SYSTEMS
1) Drugs commonly used in nasal drug delivery are:
• β2-adrenergic agonist: Terbutaline sulphate
• Corticosteroids: Budesonide
• Anti-cholinergic: Ipratropium bromide
• Mast cell stabilizer: sodium chromogylate
2)Humectants
To prevent dehydration adequate intranasal moisture is required and
therefore humectants are added.
To Prevent nasal irritation.
The commonly used humectants are
– Glycerine
– Sorbitol
– Mannitol www.DuloMix.com
3) Viscosifying agents
• These agents increase the viscosity of the solution, there by prolonging
the therapeutic activity of preparation. e.g.: hydroxypropyl cellulose.
4) Osmotic agent
• The osmolarity of the dosage form 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.
• The commonly used osmotic agents are
Sodium Chloride
Sodium sulfite
Sodium acid phosphate
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5) Solubilizers
Aqueous solubility of drug always a limitation for nasal drug delivery.
e.g.: glycol, alcohol, labrasol, transcutol.
In such cases surfactants or cyclodextrins (HP-β -cyclodextrin) are used ,
these serve as a biocompatible solubilizer & stabilizer in combination with
lipophilic absorption enhancers.
6) Surfactants
Modify the permeability of nasal mucosa & facilitate the nasal absorption
of drugs. E.g. SLS, Poly acrylic acid, sodium glycol-cholate.
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7) Bio-adhesive polymers
Increases the residence time of drug in nasal cavity and a higher local drug
concentration in the mucus lining on the nasal mucosal surface
E.g.: Methylcellulose, Carboxymethylcellulose, Hydroxyl propyl cellulose
8) preservatives
These are used to prevent the growth of micro organisms. e.g.: parabens,
benzalkonium chloride, phenyl ethyl alcohol, EDTA etc.
9) antioxidants
These are used to prevent drug oxidation. E.g.: sodium meta bisulphite ,
sodium bisulfite, butylated hydroxy toluene& tocopherol etc.
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10) Penetration Enhancers
Mechanism:
✓ Inhibit enzymatic activity
✓ Reduce mucus viscosity
✓ Reduce MCC
✓ Open tight junctions
✓ Solubilize the drug www.DuloMix.com
Ideal Properties:
1.It should increase in the absorption of the drug
2. It should not cause permanent damage or alteration to the tissue
3. It should be non irritant and nontoxic.
4. It should be effective in small quantity.
5. The enhancing effect should occur when absorption is required .
6. The effect should be temporary and reversible .
7. It should be compatible with other excipients.
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NASAL DRUG DELIVERY SYSTEM DOSAGE FORMS
Four basic formulations must be considered, i.e. solution, suspension,
emulsion and dry powder systems.
A.LIQUID NASAL FORMULATIONS
1. Instillation and rhinyle catheter
2. Compressed air nebulizers
3. Squeezed bottle
4. Metered-dose pump sprays
B. POWDER DOSAGE FORMS
1. Insufflators
2. Dry powder inhaler
C. PRESSURIZED MDIs
D. NASAL GELS
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A. LIQUID NASAL FORMULATIONS
• Liquid preparations are the most widely used dosage forms for nasal
administration of drugs.
• They are mainly based on aqueous state formulations.
• Their humidifying effect is convenient and useful.
Disadvantages:
o Microbiological stability, irritation and allergic rhinitis are the major
drawbacks associated with the water-based dosage forms.
o The reduced chemical stability of the dissolved drug substance and the
short residence time of the formulation in the nasal cavity are major
disadvantages of liquid formulations
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1. Instillation and rhinyle catheter :
➢ Catheters are used to deliver the drops to a specified region of nasal cavity
easily.
➢ Place the formulation in the tube and kept tube one end was positioned in
the nose, and the solution was delivered into the nasal cavity by blowing
through the other end by mouth.
➢ Dosing of catheters is determined by the filling prior to administration and
accuracy of the system and this is mainly used for experimental studies
only.
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2. Compressed air nebulizers:
➢ Nebulizer is a device used to administer medication in the form of a mist
inhaled into the lungs.
➢ The common technical principal for all nebulizers, is to either use oxygen,
compressed air or ultrasonic power, as means to break up medical
solutions or suspensions into small aerosol droplets, for direct inhalation
from the mouthpiece of the device.
➢ Nebulizers accept their medicine in the form of a liquid solution, which is
often loaded into the device upon use. Corticosteroids and
Bronchodilators such as salbutamol (Albuterol USAN) are often used, and
sometimes in combination with ipratropium.
➢ These target their effect to the respiratory tract, speeds onset of action of
the medicine and reduces side effects.
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3. Squeezed bottle
➢ Squeezed nasal bottles are mainly used as delivery device for
decongestants.
➢ They include a smooth plastic bottle with a simple jet outlet. While pressing
the plastic bottle the air inside the container is pressed out of the small
nozzle, thereby atomizing a certain volume.
➢ Dose accuracy and deposition of liquids delivered via squeezed nasal bottles
are strongly de-pendent on the mode of administration.
Disadvantages:
• Dose is hard to control, it differences between
vigorously and smoothly pressed application.
• Contamination of the liquid by microorganisms
and nasal secretion
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4. Metered-dose pump sprays :
➢ Nasal sprays, or nasal mists, are used for the nasal delivery of a drug or
drugs (antihistamines, corticosteroids, and topical decongestants), either
locally to generally alleviate cold or allergy symptoms.
➢ Metered- dose pump sprays include the container, the pump with the
valve and the actuator.
➢ The dose accuracy of metered-dose pump sprays
is dependent on the surface tension and viscosity
of the formulation.
➢ Nasal sprays function by instilling a fine mist into
the nostril by the action of hand-operated pump
mechanism.
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B. POWDER DOSAGE FORMS
Dry powders are less frequently used in nasal drug delivery.
Advantages:
o The lack of preservatives,
o The improved stability of the formulation,
o A pro-longed contact with the nasal mucosa.
1. Insufflators
• Insufflators are the devices to deliver the drug substance for inhalation;
• It can be constructed by using a straw or tube which contains the drug
substance and sometimes it contains syringe also.
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• The achieved particle size of these systems is often increased compared to
the particle size of the powder particles due to insufficient deaggregation
of the particles and results in a high coefficient of variation for initial
deposition areas.
• Many insufflator systems work with pre-dosed powder doses in capsules
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2. Dry powder inhaler
• Dry powder inhalers (DPIs) are devices through which a dry powder
formulation of an active drug is delivered for local or systemic effect via
the pulmonary route.
• Dry powder inhalers are bolus drug delivery devices that contain solid
drug, suspended or dissolved in a non polar volatile propellant (or) in dry
powder inhaler that is fluidized when the patient inhales.
• These are commonly used to treat respiratory diseases such as asthma,
bronchitis, emphysema and COPD and have also been used in the
treatment of diabetes mellitus.
• The medication is commonly held either in a capsule for manual loading
or a proprietary form from inside the inhaler.
• Once loaded or actuated, the operator puts the mouthpiece of the
inhaler into their mouth and takes a deep inhalation, holding their breath
for 5-10 seconds.
• The dose that can be delivered is typically less than a few tens of
milligrams in a single breath since larger powder doses may lead to
provocation of cough.
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C. PRESSURIZED MDIs
• A metered-dose inhaler (MDI) is a device that delivers a specific amount
of medication to the lungs, in the form of a short burst of aerosolized
medicine that is inhaled by the patient.
• It is the most commonly used delivery system for treating asthma, chronic
obstructive pulmonary disease (COPD) and other respiratory diseases.
• The medication in a metered dose inhaler is most commonly a
bronchodilator, corticosteroid or a combination of both.
• Other medications less commonly used but also administered by MDI are
mast cell stabilizers, such as (cromoglicate or nedocromil).
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Advantages :
✓ Portability and small size,
✓ Availability over a wide do-sage range per actuation,
✓ Dose consistency,
✓ Dose accuracy,
✓ Protection of the contents and
✓ Quickly ready for use.
• To use the inhaler the patient presses down on the top of the canister,
with their thumb supporting the lower portion of the actuator.
• The propellant provides the force to generate the aerosol cloud and is also
the medium in which the active component must be suspended or
dissolved.
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• Actuation of the device releases a single metered dose of the formulation
which contains the medication either dissolved or suspended in the
propellant.
• Breakup of the volatile propellant into droplets, followed by rapid
evaporation of these droplets, results in the generation of an aerosol
consisting of micrometer-sized medication particles that are then
inhaled. www.DuloMix.com
D. NASAL GELS
Nasal gels are high – viscosity thickened solutions or
suspensions.
Advantages:
✓ The reduction of post-nasal drip due to high viscosity,
✓ Reduction of taste impact due to reduced swallowing,
✓ Reduction of anterior leakage of the formulation,
✓ Reduction of irritation by using soothing/emollient
excipients and
✓ Target delivery to mucosa for better absorption.
❑ The deposition of the gel in the nasal cavity depends on the mode of
administration, because, due to its high viscosity the formulation has
poor spreading abilities.
❑ Without special application techniques it only occupies a narrow
distribution area in the nasal cavity, where it is placed directly.
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Evaluation of nasal formulations:
Various approaches used to determine the drug passes through mucosa from
the formulation
1. In vitro diffusion studies:
➢ Nasal diffusion cell is fabricated in glass.
➢ Water jacketed recipient chamber has total capacity of 60ml and a flanged
top of about 3mm, the lid has 3 openings; each for sampling,
thermometer, and a donor tube which has internal diameter of 1.13cm.
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➢ Nasal mucosa of sheep was separated from sub layer bony tissues and
stoned into distilled water containing few drops at gentamycin injection.
➢ After complete removal of blood mucosal surface is attached to donor
chamber tube.
➢ The donor cell should be placed in such a way that it just touches the
diffusion medium in recipient chamber. At predetermined intervals,
samples (0.5ml) are withdrawn and transferred into amber colored
ampoules and replaced with suitable solution.
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➢ Samples are estimated for drug content by suitable analytical techniques
2. In vivo nasal absorption studies:
Whole animal or in vivo model:
• Several animal models have been described for studying drug absorption
through the nasal mucosa.
• The most convenient model is the anesthesized rat model developed by
Hirai et al.
• For most non-peptide drugs, the results obtained in rats can accurately
reflect the absorption profiles in humans.
• Some experimental modifications are possible, with a similar surgical
operation, and can be chosen for special purposes.
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Rat model:
It has the following steps
➢ Rat is anesthetized by Intraperitoneal injection of sodium pentobarbital.
➢ Then an incision is made in the neck, the trachea is cannulated with a poly
ethylene tube. Another tube is inserted through oesophagus towards the
posterior part of the nasal cavity.
➢ The passage of the nasopalatine tract is sealed surgically to prevent the
drainage of drug solution from the nasal cavity in to the mouth.
➢ The drug solution is delivered to the nasal cavity through either nostril or
the oesophageal tubing.
➢ The blood samples are then collected from the femoral vein and analyzed
for absorbed drug.
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Rabbit model
It has the following steps
➢ A rabbit weighing 3 kg is anaesthetized by an Intramuscular injection of a
combination of ketamine and xylazine.
➢ The drug solution is delivered by nasal spray into each nostril while the
rabbits head is held in an upright position.
➢ The rabbit is permitted to breath normally through nostrils and body
temperature maintained at 37°C by a heating pad.
➢ The blood samples are collected in the marginal ear vein.
➢ The blood volume of the rabbit is sufficiently large (approximately 300 ml)
to permit multiple blood samplings (1-2 ml each) at a frequency that
permits full characterization of the pharmacokinetic profile of a drug
candidate following nasal delivery.
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Dog model
➢ The dog is anaesthetized by intravenous injection of sodium-thiopental
and the anesthesia is maintained with sodium-phenobarbital.
➢ A positive pressure pump through a cuffed endotracheal tube gives the
ventilation.
➢ The blood sampling is carried out from the jugular vein.
Sheep model
➢ A male inhouse-bred sheep is used because it lacks nasal infectious
diseases.
➢ Because of their larger nostril and body size compared to the rat model,
rabbit, and dog, sheep are suitable and practical animal models for the
evaluation of pharmacokinetic and pharmaceutical parameters involved
in the nasal delivery of drugs
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Monkey model
➢ The monkey is tranquillized by intramuscular injection of ketamine HCl or
anaesthetized by intravenous injection of sodium-phenobarbital.
➢ The head of the monkey is held in an upright position and the drug solution
is administered into each nostril.
➢ The blood samples are collected through an indwelling catheter in the vein.
3. Ex vivo nasal perfusion model
➢ During perfusion studies, a funnel is provided underneath the nose to lead
the drug solution, which is flowing out of nasal cavity in the drug reservoir
(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 3–20mL are
continuously circulated through the
nasal cavity of anesthetized rats.
➢ The reservoir is stirred constantly
and the amount of drug absorbed is
determined by measuring the drug
concentration remaining in the
solution after a period of perfusion.
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APPLICATIONS
1. Delivery of non-peptide pharmaceuticals:
✓ Low molecular weight (below 1000 Daltons) small non- peptide lipophilic
drugs are well absorbed through the nasal mucosa even though absence
of permeation enhancer.
✓ Drugs with extensive pre-systemic metabolism, such as progesterone,
estradiol, propranolol, nitroglycerin, sodium chromoglyate can be rapidly
absorbed through the nasal mucosa with a systemic bioavailability of
approximately 100% .
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2. Delivery of peptide-based pharmaceuticals:
✓ Peptides & proteins have low oral bioavailability (1–2%) because of their
physico-chemical instability and susceptibility to hepato-gastrointestinal
first-pass elimination.
✓ Examples are insulin, calcitonin, pituitary hormones etc.,
✓ Absorption enhancers like surfactants, glycosides, cyclodextrin and
glycols increases the bioavailability.
✓ Nasal route is proving to be the best route for such biotechnological
products.
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3. Delivery of drug to brain through nasal cavity:
✓ It is beneficial in conditions like Parkinson’s disease, Alzheimer’s disease or
pain because it requires specific targeting of drugs to brain.
✓ It will increase the fraction of drug that reaches the C.N.S. after the nasal
delivery.
✓ The olfactory region located at the upper remote areas of the nasal
passages offer the potential for the compound to circumvent the B.B.B. &
enter in to the brain.
4. Delivery of vaccines through nasal route
Reason for exploiting the nasal route for vaccine delivery are,
• Nasal mucosa is the first site of contacts with the inhaled pathogen.
• Nasal passages are rich in lymphoid tissues.
• Creation of both mucosal and systemic immune response.
• Low cost , patient friendly, non-injectable, safe.
✓ Nasal delivery of vaccines has been reported to not only produce
systemic but also local immune response.
✓ Delivering the vaccine to the nasal cavity stimulates the production of
local secretory Ig-A & Ig-G antibodies, providing an additional first line of
defense, which helps to eliminate the pathogens.
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5. Delivery of diagnostic agents
✓ Nasal drug delivery system can be used for the diagnosis of various
diseases and disorders in the body.
✓ Pancreatic disorders of the diabetic patients were diagnosed by using the
‘Secretin’.
✓ The secretory function of gastric acid was determined by Pentagastrin.
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QUESTIONS:
1) Give a note on the development and evaluation of nasal drug
delivery systems with their applications. (10M)
2) Write a short note on Nasal drug absorption. (5M)
3) Write the merits and limitations of nasal drug delivery system.
(10M)
4) Discuss the formulation of nasal drug delivery system. (10M)
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REFERENCES:
• Y.W.Chein, “ Novel drug delivery systems”, Marcel Dekker
Inc.50 (2), 1982, 229-260.
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