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INTRA NASAL ROUTE
DELIVERY SYSTEMS
SUBMITTED BY,
FEBA ELSA MATHEW
2ND SEMESTER M.PHARM
SUBMITTED TO,
MRS. CHRISTEENA DAS
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
1
CONTENTS
 Introduction
 Merits
 Limitations
 Anatomy and physiology of Nasal cavity
 Mechanism of Nasal Absorption
 Factors influencing nasal drug absorption
 Barriers of Nasal Absorption
 Strategies to improve Nasal Absorption
 Excipients used with nasal formulation
 Nasal Drug Delivery System Dosage Forms
 Evaluation
2
INTRODUCTION
(DEFINITION)
 Nasal administration is a route of administration in which
the drugs are insufflated through the nose for either local
or systemic effect.
 Nasal mucosa has been considered as a potential ad-
ministration route to achieve faster and higher level of
drug absorption because it is permeable to more com-
pounds than the gastrointestinal tract due to lack of
pancreatic and gastric enzymatic activity, neutral pH of
the nasal mucus and less dilution by gastrointestinal
contents.
 Nasal therapy recognized form of treatment in the
Ayurvedic systems of Indian medicine, it is also called
“NASAYA KARMA”
 Intranasal medication administration offers a truly
“Needleless” solution to drug delivery
3
MERITS
Avoid “first pass” metabolism
Avoid parenteral
administration
Rapid absorption, peaking
generally within 15-30
minutes
Apparent permeability to
some peptides
Ease of self-administration &
good patient compliance
Lower doses and less sides
effects
Quicker onset of
pharmacological activity
Rate of absorption
comparable to IV medication
User-friendly, painless,
needle-free administration
mode
Useful for both local &
systemic drug delivery
For CNS drugs, better site for
rapid onset of action Ex.
Inhalation anaesthesia,
Morphine etc.
The nose is a very easy access
point for medication delivery,
even easier to access than IM
or iv sites
4
LIMITATIONS
Delivery volume in nasal
cavity is restricted to 25–200
μL.
High molecular weight
compounds cannot be
delivered through this route
(mass cut off ~1 Kd
Adversely affected by
pathological conditions.
Large interspecies variability
is observed in this route.
Normal defense mechanisms
like Mucociliary Clearance
and ciliary beating affects the
permeability of drug.
Irritation of nasal mucosa by
drugs like Budesonide,
Azilactine.
Limited understanding of
mechanisms and less
developed models at this
stage.
Systemic toxicity occurring
due to absorption enhancers
is yet not established.
Smaller absorption surface
compared with GIT.
Possibility of nasal irritation
hence inconvenient
compared with oral route.
Enzymatic barrier to
permeability of drug.
5
ANATOMY AND PHYSIOLOGY OF NASAL CAVITY
Parts of nasal cavity consists of:
a) Nasal vestibule
b) Palate
c) Interior turbinate
d) Middle turbinate
e) Superior turbinate (olfactory mucosa)
f) Nasopharynx
6
The nasal cavity consists three main regions
 Nasal vestibule,
 Olfactory region and
 Respiratory region.
The main nasal airway have the narrow passages about 1-3mm wide.
The nasal cavity is covered with a mucous membrane which can be divided into two
areas;
 Non olfactory and
 Olfactory epithelium,
The nasal vestibule is covered with skin-like stratified squamous epithelium cells.
Respiratory region, which has a typical airways epithelium covered with numerous
microvilli, resulting in a large surface area available for drug absorption and transport
7
 The mucus layer present in the nasal cavity.
 The goblet cells are present in the mucus membrane, it secretes the mucus as mucus granules
which are swelling in the nasal fluid to contribute to the mucus layer.
 The mucus secretion is composed of about 95% water, 2 % mucin, 1% salts, 1% of other
proteins such as albumin, immunoglobulin s, lysozyme and lactoferrin, and b 1% lipids.
 The mucus secretion gives immune protection against inhaled bacteria and viruses. It also
performs a number of physiological functions:
 It covers the mucosa physically and enzymatically protects it.
 The mucus has water holding capacity.
 It exhibits surface electrical activity.
 It permits efficient heat transfer.
 It acts as adhesive and transports particulate matter towards the nasopharynx
8
MECHANISM OF DRUG ABSORPTION FROM NOSE
 First step in the absorption of drug from the nasal cavity is passage through the
mucosa,
 Mechanisms for absorption through the nasal mucosa include paracellular
transport via movement between cell and transcellular or simple diffusion
the membrane.
 Paracellular transport
o slow and passive route
o Poor bioavailability for drugs with a molecular weight greater than 1000 Daltons, because
inverse log-log relationship exists between molecular weight and absorption
 Transcellular process
o transport through a lipoidal route
o for the transport of lipophilic drugs that show a rate dependency on their lipophilicity.
9
Drugs also cross cell membranes by an active transport route via carrier-
mediated means or transport through the opening of tight junctions.
Drug transport pathways across the epithelium. (A), paracellular transport (B), transcytosis
(C), Carrier mediated transport (D), and intercellular tight junction (E). 10
PATHWAYS FOR NASAL ABSORPTION
11
DIFFERENT FACTORS AFFECTING NASAL DRUG ABSORPTION
A, Biological Factors
 Structural features
 Biochemical changes
B. Physiological factors
 Blood supply and
neuronal regulation
 Nasal secretions
 Mucociliary clearance
and ciliary beat
frequency
 Pathological conditions
 Environmental
conditions.
 Membrane permeability.
C. Physicochemical Properties of Drugs
 Molecular weight
 Size
 Solubility
 Lipophilicity
 pka and Partition coefficient
 Chemical form of drug.
 Polymorphism.
 Chemical state.
 Physical state.
12
D. Physicochemical Properties of Formulation
 Physical form of formulation
 pH
 Osmolarity
 Volume of solution applied and drug concentration
 Viscosity.
13
IDEAL CHARACTERISTICS OF DRUG IN NASAL DELIVERY
1
Appropriate
aqueous
solubility to
provide the
desired dose in
a 25–150 ml
volume of
formulation
administration
per nostril.
2
Appropriate
nasal absorption
properties.
3
No nasal
irritation from
the drug.
4
A suitable
clinical rationale
for nasal dosage
forms, e.g. rapid
onset of action.
5
Low dose.
Generally, below
25 mg per dose.
6
No toxic nasal
metabolites.
7
No offensive
odours/aroma
associated with
the drug.
8
Suitable stability
characteristics.
14
BARRIERS TO NASAL ABSORPTION
15
• It is due to Low membrane permeability (limiting factor for high molecular
polar drugs like protein and peptide
Low Bioavailability
• Rapid clearance of administered formulation due to MCC. Ex: Liquid and
powder formulation shows rapid clearance
Low Membrane Transport
• Degradation of protein and peptides by Exopeptidase and Endopeptidase
Enzymatic Degradation
STRATEGIES TO IMPROVE NASAL ABSORPTION
 Nasal enzymes inhibitors
 Structural modification
 Permeation enhancer
 Particulate drug delivery
 Prodrug approach
 Bio adhesive polymer
 In situ gel
16
EXCIPIENTS USED ON NASAL FORMULATION
1) Buffers
Isotonic potassium phosphate buffer
citrate buffer
Acetate buffer
2) Osmotic agents
sodium chloride
Sodium sulphite
Sodium acid phosphate
3) gelling/viscosifying agents
Carbopol
Cellulose agent
starch
dextran
chitosan
4) Solubilizers
glycols
small quantities of alcohol
Transcutol (Diethylene glycol monoethyl ether)
Medium chain Glycerides
Surfactants
5) Preservatives
parabens
benzalkonium chloride
phenyl ethyl alcohol
benzoyl alcohol
6) Anti-oxidants
Sodium metabisulphite
Sodium bisulphote
Butylated Hydroxytoluene
Tocopherol
17
7) Humectants:
Glycerine
Sorbitol
Mannitol
8) Absorption Enhancers
(a) Surfactants
SodiumGlychocholate
Sodium deoxycholate
(b) Chitosan
(c) Cyclodextrins
Hydroxypropyl-8-cyclodxtran
(d) Complexing agents
EDTA
Citric acid
(e) Fatty acids salts
Oleic Acid
Caprylic acid
Lauric acid
(f) Fusidates
Sodium taurohydrofusidate
(g) Phospholipids
L- α-lsophosphatidyl choline
(9) Enzyme Inhibitors
Bestatin
Amastatin
Boroleucine
Fusidic acid
Bile Acid
18
19
PERMEATION
ENHANCERS
:Improve the
bioavailability of
drugs particularly
molecular weight
above 1000Da causes
nasal epithelial
toxicity. Used in
powder, gels,
solutions
SOLVENTS: To
increase the
concentration of
drug in vehicle and
reduce the dose
volume. May act as a
permeation
enhancer. Used in
Gels and solutions.
VOSCOSITY
MODIFIERS: To
improve Nasal
residential time.
Used in Gels
and solutions
MUCOADHESIVE
POLYMERS: To
improve the nasal
residential time.
Used in Powders,
gels , Solutions
PRESERVATIVE
: To maintain
sterility of
dosage form
may alter the
nasal residential
time.
ENZYME
INHIBITORS:
To improve the
bioavailability
of protein and
peptides
TOXICITY
MODIFIERS: To
avoid the nasal
epithelial toxicity
NASAL DRUG DELIVERY SYSTEM DOSAGE
FORMULATION
LIQUID NASAL FORMULATION
INSTILLLATION AND RHINYLE CATHETER
COMPRESSED AIR NEBULIZER
SQUEEZED BOTTLE
METERED-DOSE PUM SPRAS
SOLID / POWDER NASAL FORMULATION
INSUFFLATORSS
DRY POWDER INHALER
SEMI-SOLID NASAL FORMULATION
NASAL GEL
PRESSURIZED MDIs
NASAL VACCINES
NOVEL DRUG FORMULATION
LIPOSOMES
MICROSPHERES
NANOPARTICLES
20
LIQUID DOSAGE FORM
 Liquid preparation are the most widely used dosage forms for
nasal administration of drugs.
 They mainly based on aqueous state formulation
 Their humidifying effect is convenient and useful, since many
allergic and chronic diseases are often connected with crusta and
drying of mucous membranes
21
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.
22
COMPRESSED AIR NEBULIZERS
 Nebulizer is a device used to administer
medication in the form of a mist inhaled into the
lungs.
 The compressed air is filling into the device, so it
is called compressed air nebulizers.
 The common technical principal for all nebulizers,
is to either use oxygen, compressed air or
ultrasonic power, as means to break up medical
solutions/ suspensions into small aerosol
droplets, for direct inhalation from the
mouthpiece of the device.
23
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.
 By releasing the pressure again air is drawn inside the
bottle.
 This procedure often results in contamination of the
liquid by microorganisms and nasal secretion sucked
inside.
24
METERED – DOSE PUMP SPRAYS
 Most of the pharmaceutical nasal preparations on the market
containing solutions, emulsions or suspensions are delivered
by metered-dose pump sprays.
 Nasal sprays, or nasal mists, are used for the nasal delivery
of a drug or drugs, either locally to generally alleviate cold or
allergy symptoms such as nasal congestion or systemically.
 Most nasal sprays function by instilling a fine mist into the
nostril by action of a hand-operated pump mechanism.
 The three main types available for local effect are:
antihistamines, corticosteroids, and topical decongestants
 Metered- dose pump sprays include the container, the pump
with the valve and the actuator.
25
SOLID/ POWDER DOSAGE FORM
 Dry powders are less frequently used in nasal drug delivery.
 Powder dosage form may be developed if solution & suspension dosage form cannot be developed. E.g.
due to lack of drug stability.
 Major advantage of the dosage form are the lack of preservatives and the improved stability of the
formulation.
26
INSUFFLATOR
 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.
 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
27
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.
28
PRESSURIZED METERED-DOSE INHALERS (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 for the treatment of asthma and COPD.
Other medications less commonly used but also administered by MDI are mast cell
stabilizers, such as (cromoglicate or nedocromil).
 The advantages of MDIs are their portability and small size, availability over a wide
do-sage range per actuation, dose consistency, dose accuracy, protection of the
contents and that they are quickly ready for use. 29
 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.
 Propellants in MDIs typically make up more than 99
% of the delivered dose. 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.
30
SEMI-SOLID DOSAGE FORM (NASAL GEL)
 Nasal gels are high-viscosity thickened solutions or suspensions.
 The advantages of a nasal gel include 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 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.
 Recently, the first nasal gel containing Vitamin B12 for systemic
medication has entered the market
31
NASAL VACCINES
 Nasal mucosa is the first site of contact with inhaled antigens and therefore, it is used for
respiratory infections.
 Nasal vaccination is promising alternative to the parenteral route, because it is to able
enhance the systemic levels of specific immunoglobulin G & nasal secretary immunoglobin A.
 E.g. Nasal vaccine against influenza A & B virus
32
 It include nasal formulations containing liposomes, microspheres and nanoparticles for intranasal drug
delivery.
 These systems can include, besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and
mucoadhesive polymers in order to improve the stability, membrane penetration and retention time in nasal
cavity.
33
NOVEL DRUG FORMULATION
Liposomes
Liposomes are phospholipids vesicles composed by lipid bilayers enclosing one or more aqueous
compartments where drugs and other substances can be included.
Liposomal drug delivery systems present various advantages such as the effective encapsulation of
and large molecules with a wide range of hydrophilicity and pKa values .
They enhance nasal absorption of peptides such as insulin and calcitonin by increasing their
penetration. Therefore increasing nasal retention of peptides.
Protection of the entrapped peptides from enzymatic degradation and mucosal membrane disruption
Microspheres
Microsphere technology has been widely applied in designing formulations for nasal drug delivery.
Microspheres are usually based on mucoadhesive polymers (chitosan, alginate).
Microspheres may also protect the drug from enzymatic metabolism and sustain drug release,
prolonging its effect.
34
Nanoparticles
Nanoparticles are solid colloidal particles with diameters raging from 1-1000 nm.
They consist of macromolecular materials and can be therapeutically used as adjuvant in
vaccines or as drug carriers, in which the active substance is dissolved, entrapped,
adsorbed or chemically attached.
Nanoparticles may offer several advantages due to their small size, but only the smallest
nanoparticles penetrate the mucosal membrane by paracellular route and in a limited quantity
because the tight junctions are in the order of 3.9-8.4 Å.
35
EVALUATION OF NASAL DRUG FORMULATIONS
 In-vitro nasal permeation studies
In vitro diffusion studies
In Vivo Nasal Absorption studies
 Ex-vivo Nasal Perfusion Models
 In-vivo bioavailability studies
36
In-vitro
NASAL
PERMEATIO
N STUDIES
1. In-vitro DIFFUSION
STUDIES
 The nasal diffusion cell is fabricated in glass.
 The water-jacketed recipient chamber having total capacity of 60 ml and a flanged top of about 3mm;
the lid has 3 opening, each for sampling, thermometer, and a donor tube chamber.
 The donor chamber is 10 cm long with internal diameter of 1.13 cm, and a donor tube chamber has total
capacity of 60 ml and a flanged top of about 3mm; the lid has 3 openings, each for sampling,
thermometer.
 The nasal mucosa of sheep was separated from sub layer bony tissues and stoned in distilled water
containing few drops at genatamycin injection. After the complete removal of blood from muscosal
surface, it is attached to donor chamber tube.
 The donor chamber tube is placed such a way that it just touches the diffusion medium in recipient
chamber.
 Samples (0.5 ml) from recipient chamber are with draw at predetermined intervals, and transferred to
amber colored ampoules. The samples withdrawn are suitably replaced.
 The samples are estimated for drug content by suitable analytical technique.
 The temperature is maintained at 37oC throughout the experiment.
37
2. In-vivo NASAL ABSORPTION STUDIES
Animal models for nasal absorption studies
 The animal models employed for nasal absorption studies can be of two types, viz., whole animal or in vivo
model and an isolated organ perfusion or ex vivo model.
38
RAT MODEL The surgical preparation of rat for in vivo nasal
absorption study is carried out as follows:
 The rat is anaesthetized by intraperitoneal injection
of sodium pentobarbital.
 An incision is made in the neck and the trachea is
cannulated with a polyethylene tube.
 Another tube is inserted through the oesophagus
towards the posterior region of the nasal cavity.
 The passage of the nasopalatine tract is sealed so
that the drug solution is not drained from the nasal
cavity through the mouth.
 The drug solution is delivered to the nasal cavity
through the nostril or through the cannulation
tubing. Femoral vein is used to collect the blood
samples.
 As all the probable outlets of drainage are blocked,
the drug can be only absorbed and transported into
the systemic circulation by penetration and/or
diffusion through nasal mucosa.
39
RABBIT MODEL
40
The rabbit offers several advantages as an animal model for nasal absorption studies:
•1. It permits pharmacokinetic studies as with large animals (like monkey)
•2. It is relatively cheap, readily available and easily maintained in laboratory settings
•3. The blood volume is large enough (approx. 300ml)
•4. To allow frequent blood sampling (l-2ml).
Thus, it permits full characterization of the absorption and determination of the pharmacokinetic profile of a drug.
Rabbits (approx. 3 kg) are either anaesthetized or maintained in the conscious state depending on the purpose of study. In the anaesthetized model, intramuscular injection
of a combination of ketamine and xylazine is given to anesthetized rabbit.
The rabbit's head is held in an upright position and nasal spray of drug solution is administered into each nostril.
The body temperature of the rabbit is maintained at 37°C during experiment with the help of a heating pad.
The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.
DOG MODEL
 The dog is anaesthetized by intravenous injection of Sodium Thiopental and
the anaesthesia 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
41
SHEEP MODEL
 Sheep model for studying nasal drug delivery is prepared using basically the
same procedure as that described for dog model.
 Male in-house bred sheep are employed since they are free from nasal
infections.
 Practical and suitable for investigating nasal delivery formulations.
42
MONKEY MODEL
 The monkey is tranquilized by intramuscular injection of ketamine hydrochloride 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.
43
EX-VIVO NASAL PERFUSION MODELS
Surgical preparation is the same as that for in vivo rat model.
During the perfusion studies, to minimize the loss of drug solution a funnel is placed between the nose and reservoir.
 The drug solution is placed in a reservoir maintained at 37°C 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 amount of drug absorbed is estimated by measuring the
residual drug concentration in the perfusing solution.
 Rabbit can also be used as the animal model for ex vivo nasal perfusion studies.
 The rabbit is anaesthetized with parenteral uretliane-acepromazine.
 A midline incision is made in the neck and the trachea is cannulated with a polyethylene neonatal endotracheal tube.
The oesophagus is isolated and ligated.
 The distal end of the oesophagus is closed with suture and flexible tygon tubing is inserted into the proximal end and
advanced to the posterior part of the nasal cavity.
 To avoid drainage of drug solution from the nasal cavity the nasopalatine tract (that connects nasal cavity to the
mouth) is closed with an adhesive.
 The drug in isotonic buffer solution is recirculated using a peristaltic pump.
44
45
Ex-vivo Nasal perfusion models
IN-VIVO BIOAVAILABILITY STUDIES
 In-vivo bioavailability study is conducted on healthy male rabbits.
 Study consists of three groups each containing six rabbits and fasted for 24 h.
 One group treated with conventional preparation, second group kept as control (i.e. not received
any test substances) and third group of test formulation.
 Water is given ad libitum during fasting and throughout the experiment.
 For the collection of blood samples the marginal ear vein of the rabbits used and sample of about 2
ml collected in heparinized centrifuge tubes at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 h after the drug
administration.
 The blood samples are centrifuged at 3000 × g for 15 min to obtain the plasma and stored at -20°C
until analysis.
 The extraction of drug from plasma can be carried out as reported previously and then analyze
using the HPLC system.
46
APPLICATION
 Delivery of non-peptide pharmaceuticals
E.g. Progesterone, estradiol, propranolol, nitro-glycerine, sodium chromoglyate
 Delivery of peptide-based pharmaceuticals
E.g. Insulin, Calcitonin, Pituitary hormone
 Delivery of Diagnostic drugs
 Phenolsulfonpthaline – For diagnosis of kidney functions
 Secretion – For diagnosis of pancreatic disorder
 Pentagastrin – For diagnosis of secretory functions of gastric acid
 Cerulin – For diagnosis of gallbladder Function
 Vital dyes – Tryan blue and Evans blue (it cannot enter in cranium because they can not pass through sheath)
47
 Delivery of drugs to brain:
For treatment of Parkinson’s disease, Alzheimer disease.
For delivery of MSH, ACTH, Insulin to brain
 Delivery of Vaccines:
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 responses
Non injectable
Examples:
Nasal vaccines are prepared for Measles, Pertussis, Meningitis and Influenza Virus because these Pathogens enter into the body
through nasal mucosa.
 Nasal delivery of vaccines produces both local and systemic immune response.
48
CONCLUSIO
N
49
Nasal route is attractive for
the delivery of the many drugs
and vaccines
Studies are going on
improving the efficiency of
the nasal route
Outcome of these studies is
that we can utilise it for
treatment of diabetes,
osteoporosis, infertility
Nasal drug delivery offers such
benefits as rapid onset of
action with lower dose &
minimal side effects
It has an advantage on site-
specific delivery with improved
therapeutic effects
Allowing systemic
administration without
significant degradation
Nasal drug delivery system
offers flexibility for multiple
formulations ranging from
nasal drop to suspension spray
REFERENCE
 https://www.slideshare.net/AlexaJacob1/intranasal-drug-delivery-system
 https://www.japsonline.com/admin/php/uploads/32_pdf.pdf
 http://japer.sperpublications.com/oldjaper/Issue/issues%204oct-
des%202013/148.pdf
 https://www.researchgate.net/publication/49601002_Nasal_drug_delivery_syst
em_-_an_overview
50
THANK YOU
51

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Intra nasal route delivery systems molecular pharmaceutics 2

  • 1. INTRA NASAL ROUTE DELIVERY SYSTEMS SUBMITTED BY, FEBA ELSA MATHEW 2ND SEMESTER M.PHARM SUBMITTED TO, MRS. CHRISTEENA DAS ASSISTANT PROFESSOR DEPARTMENT OF PHARMACEUTICS 1
  • 2. CONTENTS  Introduction  Merits  Limitations  Anatomy and physiology of Nasal cavity  Mechanism of Nasal Absorption  Factors influencing nasal drug absorption  Barriers of Nasal Absorption  Strategies to improve Nasal Absorption  Excipients used with nasal formulation  Nasal Drug Delivery System Dosage Forms  Evaluation 2
  • 3. INTRODUCTION (DEFINITION)  Nasal administration is a route of administration in which the drugs are insufflated through the nose for either local or systemic effect.  Nasal mucosa has been considered as a potential ad- ministration route to achieve faster and higher level of drug absorption because it is permeable to more com- pounds than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH of the nasal mucus and less dilution by gastrointestinal contents.  Nasal therapy recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called “NASAYA KARMA”  Intranasal medication administration offers a truly “Needleless” solution to drug delivery 3
  • 4. MERITS Avoid “first pass” metabolism Avoid parenteral administration Rapid absorption, peaking generally within 15-30 minutes Apparent permeability to some peptides Ease of self-administration & good patient compliance Lower doses and less sides effects Quicker onset of pharmacological activity Rate of absorption comparable to IV medication User-friendly, painless, needle-free administration mode Useful for both local & systemic drug delivery For CNS drugs, better site for rapid onset of action Ex. Inhalation anaesthesia, Morphine etc. The nose is a very easy access point for medication delivery, even easier to access than IM or iv sites 4
  • 5. LIMITATIONS Delivery volume in nasal cavity is restricted to 25–200 μL. High molecular weight compounds cannot be delivered through this route (mass cut off ~1 Kd Adversely affected by pathological conditions. Large interspecies variability is observed in this route. Normal defense mechanisms like Mucociliary Clearance and ciliary beating affects the permeability of drug. Irritation of nasal mucosa by drugs like Budesonide, Azilactine. Limited understanding of mechanisms and less developed models at this stage. Systemic toxicity occurring due to absorption enhancers is yet not established. Smaller absorption surface compared with GIT. Possibility of nasal irritation hence inconvenient compared with oral route. Enzymatic barrier to permeability of drug. 5
  • 6. ANATOMY AND PHYSIOLOGY OF NASAL CAVITY Parts of nasal cavity consists of: a) Nasal vestibule b) Palate c) Interior turbinate d) Middle turbinate e) Superior turbinate (olfactory mucosa) f) Nasopharynx 6
  • 7. The nasal cavity consists three main regions  Nasal vestibule,  Olfactory region and  Respiratory region. The main nasal airway have the narrow passages about 1-3mm wide. The nasal cavity is covered with a mucous membrane which can be divided into two areas;  Non olfactory and  Olfactory epithelium, The nasal vestibule is covered with skin-like stratified squamous epithelium cells. Respiratory region, which has a typical airways epithelium covered with numerous microvilli, resulting in a large surface area available for drug absorption and transport 7
  • 8.  The mucus layer present in the nasal cavity.  The goblet cells are present in the mucus membrane, it secretes the mucus as mucus granules which are swelling in the nasal fluid to contribute to the mucus layer.  The mucus secretion is composed of about 95% water, 2 % mucin, 1% salts, 1% of other proteins such as albumin, immunoglobulin s, lysozyme and lactoferrin, and b 1% lipids.  The mucus secretion gives immune protection against inhaled bacteria and viruses. It also performs a number of physiological functions:  It covers the mucosa physically and enzymatically protects it.  The mucus has water holding capacity.  It exhibits surface electrical activity.  It permits efficient heat transfer.  It acts as adhesive and transports particulate matter towards the nasopharynx 8
  • 9. MECHANISM OF DRUG ABSORPTION FROM NOSE  First step in the absorption of drug from the nasal cavity is passage through the mucosa,  Mechanisms for absorption through the nasal mucosa include paracellular transport via movement between cell and transcellular or simple diffusion the membrane.  Paracellular transport o slow and passive route o Poor bioavailability for drugs with a molecular weight greater than 1000 Daltons, because inverse log-log relationship exists between molecular weight and absorption  Transcellular process o transport through a lipoidal route o for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. 9
  • 10. Drugs also cross cell membranes by an active transport route via carrier- mediated means or transport through the opening of tight junctions. Drug transport pathways across the epithelium. (A), paracellular transport (B), transcytosis (C), Carrier mediated transport (D), and intercellular tight junction (E). 10
  • 11. PATHWAYS FOR NASAL ABSORPTION 11
  • 12. DIFFERENT FACTORS AFFECTING NASAL DRUG ABSORPTION A, Biological Factors  Structural features  Biochemical changes B. Physiological factors  Blood supply and neuronal regulation  Nasal secretions  Mucociliary clearance and ciliary beat frequency  Pathological conditions  Environmental conditions.  Membrane permeability. C. Physicochemical Properties of Drugs  Molecular weight  Size  Solubility  Lipophilicity  pka and Partition coefficient  Chemical form of drug.  Polymorphism.  Chemical state.  Physical state. 12
  • 13. D. Physicochemical Properties of Formulation  Physical form of formulation  pH  Osmolarity  Volume of solution applied and drug concentration  Viscosity. 13
  • 14. IDEAL CHARACTERISTICS OF DRUG IN NASAL DELIVERY 1 Appropriate aqueous solubility to provide the desired dose in a 25–150 ml volume of formulation administration per nostril. 2 Appropriate nasal absorption properties. 3 No nasal irritation from the drug. 4 A suitable clinical rationale for nasal dosage forms, e.g. rapid onset of action. 5 Low dose. Generally, below 25 mg per dose. 6 No toxic nasal metabolites. 7 No offensive odours/aroma associated with the drug. 8 Suitable stability characteristics. 14
  • 15. BARRIERS TO NASAL ABSORPTION 15 • It is due to Low membrane permeability (limiting factor for high molecular polar drugs like protein and peptide Low Bioavailability • Rapid clearance of administered formulation due to MCC. Ex: Liquid and powder formulation shows rapid clearance Low Membrane Transport • Degradation of protein and peptides by Exopeptidase and Endopeptidase Enzymatic Degradation
  • 16. STRATEGIES TO IMPROVE NASAL ABSORPTION  Nasal enzymes inhibitors  Structural modification  Permeation enhancer  Particulate drug delivery  Prodrug approach  Bio adhesive polymer  In situ gel 16
  • 17. EXCIPIENTS USED ON NASAL FORMULATION 1) Buffers Isotonic potassium phosphate buffer citrate buffer Acetate buffer 2) Osmotic agents sodium chloride Sodium sulphite Sodium acid phosphate 3) gelling/viscosifying agents Carbopol Cellulose agent starch dextran chitosan 4) Solubilizers glycols small quantities of alcohol Transcutol (Diethylene glycol monoethyl ether) Medium chain Glycerides Surfactants 5) Preservatives parabens benzalkonium chloride phenyl ethyl alcohol benzoyl alcohol 6) Anti-oxidants Sodium metabisulphite Sodium bisulphote Butylated Hydroxytoluene Tocopherol 17
  • 18. 7) Humectants: Glycerine Sorbitol Mannitol 8) Absorption Enhancers (a) Surfactants SodiumGlychocholate Sodium deoxycholate (b) Chitosan (c) Cyclodextrins Hydroxypropyl-8-cyclodxtran (d) Complexing agents EDTA Citric acid (e) Fatty acids salts Oleic Acid Caprylic acid Lauric acid (f) Fusidates Sodium taurohydrofusidate (g) Phospholipids L- α-lsophosphatidyl choline (9) Enzyme Inhibitors Bestatin Amastatin Boroleucine Fusidic acid Bile Acid 18
  • 19. 19 PERMEATION ENHANCERS :Improve the bioavailability of drugs particularly molecular weight above 1000Da causes nasal epithelial toxicity. Used in powder, gels, solutions SOLVENTS: To increase the concentration of drug in vehicle and reduce the dose volume. May act as a permeation enhancer. Used in Gels and solutions. VOSCOSITY MODIFIERS: To improve Nasal residential time. Used in Gels and solutions MUCOADHESIVE POLYMERS: To improve the nasal residential time. Used in Powders, gels , Solutions PRESERVATIVE : To maintain sterility of dosage form may alter the nasal residential time. ENZYME INHIBITORS: To improve the bioavailability of protein and peptides TOXICITY MODIFIERS: To avoid the nasal epithelial toxicity
  • 20. NASAL DRUG DELIVERY SYSTEM DOSAGE FORMULATION LIQUID NASAL FORMULATION INSTILLLATION AND RHINYLE CATHETER COMPRESSED AIR NEBULIZER SQUEEZED BOTTLE METERED-DOSE PUM SPRAS SOLID / POWDER NASAL FORMULATION INSUFFLATORSS DRY POWDER INHALER SEMI-SOLID NASAL FORMULATION NASAL GEL PRESSURIZED MDIs NASAL VACCINES NOVEL DRUG FORMULATION LIPOSOMES MICROSPHERES NANOPARTICLES 20
  • 21. LIQUID DOSAGE FORM  Liquid preparation are the most widely used dosage forms for nasal administration of drugs.  They mainly based on aqueous state formulation  Their humidifying effect is convenient and useful, since many allergic and chronic diseases are often connected with crusta and drying of mucous membranes 21
  • 22. 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. 22
  • 23. COMPRESSED AIR NEBULIZERS  Nebulizer is a device used to administer medication in the form of a mist inhaled into the lungs.  The compressed air is filling into the device, so it is called compressed air nebulizers.  The common technical principal for all nebulizers, is to either use oxygen, compressed air or ultrasonic power, as means to break up medical solutions/ suspensions into small aerosol droplets, for direct inhalation from the mouthpiece of the device. 23
  • 24. 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.  By releasing the pressure again air is drawn inside the bottle.  This procedure often results in contamination of the liquid by microorganisms and nasal secretion sucked inside. 24
  • 25. METERED – DOSE PUMP SPRAYS  Most of the pharmaceutical nasal preparations on the market containing solutions, emulsions or suspensions are delivered by metered-dose pump sprays.  Nasal sprays, or nasal mists, are used for the nasal delivery of a drug or drugs, either locally to generally alleviate cold or allergy symptoms such as nasal congestion or systemically.  Most nasal sprays function by instilling a fine mist into the nostril by action of a hand-operated pump mechanism.  The three main types available for local effect are: antihistamines, corticosteroids, and topical decongestants  Metered- dose pump sprays include the container, the pump with the valve and the actuator. 25
  • 26. SOLID/ POWDER DOSAGE FORM  Dry powders are less frequently used in nasal drug delivery.  Powder dosage form may be developed if solution & suspension dosage form cannot be developed. E.g. due to lack of drug stability.  Major advantage of the dosage form are the lack of preservatives and the improved stability of the formulation. 26
  • 27. INSUFFLATOR  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.  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 27
  • 28. 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. 28
  • 29. PRESSURIZED METERED-DOSE INHALERS (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 for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as (cromoglicate or nedocromil).  The advantages of MDIs are their portability and small size, availability over a wide do-sage range per actuation, dose consistency, dose accuracy, protection of the contents and that they are quickly ready for use. 29
  • 30.  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.  Propellants in MDIs typically make up more than 99 % of the delivered dose. 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. 30
  • 31. SEMI-SOLID DOSAGE FORM (NASAL GEL)  Nasal gels are high-viscosity thickened solutions or suspensions.  The advantages of a nasal gel include 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 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.  Recently, the first nasal gel containing Vitamin B12 for systemic medication has entered the market 31
  • 32. NASAL VACCINES  Nasal mucosa is the first site of contact with inhaled antigens and therefore, it is used for respiratory infections.  Nasal vaccination is promising alternative to the parenteral route, because it is to able enhance the systemic levels of specific immunoglobulin G & nasal secretary immunoglobin A.  E.g. Nasal vaccine against influenza A & B virus 32
  • 33.  It include nasal formulations containing liposomes, microspheres and nanoparticles for intranasal drug delivery.  These systems can include, besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and mucoadhesive polymers in order to improve the stability, membrane penetration and retention time in nasal cavity. 33 NOVEL DRUG FORMULATION
  • 34. Liposomes Liposomes are phospholipids vesicles composed by lipid bilayers enclosing one or more aqueous compartments where drugs and other substances can be included. Liposomal drug delivery systems present various advantages such as the effective encapsulation of and large molecules with a wide range of hydrophilicity and pKa values . They enhance nasal absorption of peptides such as insulin and calcitonin by increasing their penetration. Therefore increasing nasal retention of peptides. Protection of the entrapped peptides from enzymatic degradation and mucosal membrane disruption Microspheres Microsphere technology has been widely applied in designing formulations for nasal drug delivery. Microspheres are usually based on mucoadhesive polymers (chitosan, alginate). Microspheres may also protect the drug from enzymatic metabolism and sustain drug release, prolonging its effect. 34
  • 35. Nanoparticles Nanoparticles are solid colloidal particles with diameters raging from 1-1000 nm. They consist of macromolecular materials and can be therapeutically used as adjuvant in vaccines or as drug carriers, in which the active substance is dissolved, entrapped, adsorbed or chemically attached. Nanoparticles may offer several advantages due to their small size, but only the smallest nanoparticles penetrate the mucosal membrane by paracellular route and in a limited quantity because the tight junctions are in the order of 3.9-8.4 Å. 35
  • 36. EVALUATION OF NASAL DRUG FORMULATIONS  In-vitro nasal permeation studies In vitro diffusion studies In Vivo Nasal Absorption studies  Ex-vivo Nasal Perfusion Models  In-vivo bioavailability studies 36
  • 37. In-vitro NASAL PERMEATIO N STUDIES 1. In-vitro DIFFUSION STUDIES  The nasal diffusion cell is fabricated in glass.  The water-jacketed recipient chamber having total capacity of 60 ml and a flanged top of about 3mm; the lid has 3 opening, each for sampling, thermometer, and a donor tube chamber.  The donor chamber is 10 cm long with internal diameter of 1.13 cm, and a donor tube chamber has total capacity of 60 ml and a flanged top of about 3mm; the lid has 3 openings, each for sampling, thermometer.  The nasal mucosa of sheep was separated from sub layer bony tissues and stoned in distilled water containing few drops at genatamycin injection. After the complete removal of blood from muscosal surface, it is attached to donor chamber tube.  The donor chamber tube is placed such a way that it just touches the diffusion medium in recipient chamber.  Samples (0.5 ml) from recipient chamber are with draw at predetermined intervals, and transferred to amber colored ampoules. The samples withdrawn are suitably replaced.  The samples are estimated for drug content by suitable analytical technique.  The temperature is maintained at 37oC throughout the experiment. 37
  • 38. 2. In-vivo NASAL ABSORPTION STUDIES Animal models for nasal absorption studies  The animal models employed for nasal absorption studies can be of two types, viz., whole animal or in vivo model and an isolated organ perfusion or ex vivo model. 38
  • 39. RAT MODEL The surgical preparation of rat for in vivo nasal absorption study is carried out as follows:  The rat is anaesthetized by intraperitoneal injection of sodium pentobarbital.  An incision is made in the neck and the trachea is cannulated with a polyethylene tube.  Another tube is inserted through the oesophagus towards the posterior region of the nasal cavity.  The passage of the nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth.  The drug solution is delivered to the nasal cavity through the nostril or through the cannulation tubing. Femoral vein is used to collect the blood samples.  As all the probable outlets of drainage are blocked, the drug can be only absorbed and transported into the systemic circulation by penetration and/or diffusion through nasal mucosa. 39
  • 40. RABBIT MODEL 40 The rabbit offers several advantages as an animal model for nasal absorption studies: •1. It permits pharmacokinetic studies as with large animals (like monkey) •2. It is relatively cheap, readily available and easily maintained in laboratory settings •3. The blood volume is large enough (approx. 300ml) •4. To allow frequent blood sampling (l-2ml). Thus, it permits full characterization of the absorption and determination of the pharmacokinetic profile of a drug. Rabbits (approx. 3 kg) are either anaesthetized or maintained in the conscious state depending on the purpose of study. In the anaesthetized model, intramuscular injection of a combination of ketamine and xylazine is given to anesthetized rabbit. The rabbit's head is held in an upright position and nasal spray of drug solution is administered into each nostril. The body temperature of the rabbit is maintained at 37°C during experiment with the help of a heating pad. The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.
  • 41. DOG MODEL  The dog is anaesthetized by intravenous injection of Sodium Thiopental and the anaesthesia 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 41
  • 42. SHEEP MODEL  Sheep model for studying nasal drug delivery is prepared using basically the same procedure as that described for dog model.  Male in-house bred sheep are employed since they are free from nasal infections.  Practical and suitable for investigating nasal delivery formulations. 42
  • 43. MONKEY MODEL  The monkey is tranquilized by intramuscular injection of ketamine hydrochloride 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. 43
  • 44. EX-VIVO NASAL PERFUSION MODELS Surgical preparation is the same as that for in vivo rat model. During the perfusion studies, to minimize the loss of drug solution a funnel is placed between the nose and reservoir.  The drug solution is placed in a reservoir maintained at 37°C 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 amount of drug absorbed is estimated by measuring the residual drug concentration in the perfusing solution.  Rabbit can also be used as the animal model for ex vivo nasal perfusion studies.  The rabbit is anaesthetized with parenteral uretliane-acepromazine.  A midline incision is made in the neck and the trachea is cannulated with a polyethylene neonatal endotracheal tube. The oesophagus is isolated and ligated.  The distal end of the oesophagus is closed with suture and flexible tygon tubing is inserted into the proximal end and advanced to the posterior part of the nasal cavity.  To avoid drainage of drug solution from the nasal cavity the nasopalatine tract (that connects nasal cavity to the mouth) is closed with an adhesive.  The drug in isotonic buffer solution is recirculated using a peristaltic pump. 44
  • 46. IN-VIVO BIOAVAILABILITY STUDIES  In-vivo bioavailability study is conducted on healthy male rabbits.  Study consists of three groups each containing six rabbits and fasted for 24 h.  One group treated with conventional preparation, second group kept as control (i.e. not received any test substances) and third group of test formulation.  Water is given ad libitum during fasting and throughout the experiment.  For the collection of blood samples the marginal ear vein of the rabbits used and sample of about 2 ml collected in heparinized centrifuge tubes at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 h after the drug administration.  The blood samples are centrifuged at 3000 × g for 15 min to obtain the plasma and stored at -20°C until analysis.  The extraction of drug from plasma can be carried out as reported previously and then analyze using the HPLC system. 46
  • 47. APPLICATION  Delivery of non-peptide pharmaceuticals E.g. Progesterone, estradiol, propranolol, nitro-glycerine, sodium chromoglyate  Delivery of peptide-based pharmaceuticals E.g. Insulin, Calcitonin, Pituitary hormone  Delivery of Diagnostic drugs  Phenolsulfonpthaline – For diagnosis of kidney functions  Secretion – For diagnosis of pancreatic disorder  Pentagastrin – For diagnosis of secretory functions of gastric acid  Cerulin – For diagnosis of gallbladder Function  Vital dyes – Tryan blue and Evans blue (it cannot enter in cranium because they can not pass through sheath) 47
  • 48.  Delivery of drugs to brain: For treatment of Parkinson’s disease, Alzheimer disease. For delivery of MSH, ACTH, Insulin to brain  Delivery of Vaccines: 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 responses Non injectable Examples: Nasal vaccines are prepared for Measles, Pertussis, Meningitis and Influenza Virus because these Pathogens enter into the body through nasal mucosa.  Nasal delivery of vaccines produces both local and systemic immune response. 48
  • 49. CONCLUSIO N 49 Nasal route is attractive for the delivery of the many drugs and vaccines Studies are going on improving the efficiency of the nasal route Outcome of these studies is that we can utilise it for treatment of diabetes, osteoporosis, infertility Nasal drug delivery offers such benefits as rapid onset of action with lower dose & minimal side effects It has an advantage on site- specific delivery with improved therapeutic effects Allowing systemic administration without significant degradation Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray
  • 50. REFERENCE  https://www.slideshare.net/AlexaJacob1/intranasal-drug-delivery-system  https://www.japsonline.com/admin/php/uploads/32_pdf.pdf  http://japer.sperpublications.com/oldjaper/Issue/issues%204oct- des%202013/148.pdf  https://www.researchgate.net/publication/49601002_Nasal_drug_delivery_syst em_-_an_overview 50