INTRA NASAL DRUG DELIVERY SYSTEM PDF

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1

INTRA NASAL DRUG
DELIVERY SYSTEM

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CONTENTS

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 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 www.DuloMix.com

 

INTRODUCTION

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 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.

 In nasal mucosa high permeability, high vascularity
and low enzymatic environment of nasal cavity –
suitable for systemic delivery of drug molecules.

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ADVANTAGES

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 Rapid drug absorption, higher bioavailability therefore
lower dose.

 Fast onset of action.

 Avoidance of liver first pass effect.

 Avoidance of gut wall metabolism.

 Avoidance of destruction drug in the GIT

 Non-invasive therefore reduced risk of infectious
disease transmission.

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 Easily administered to unconscious patients.

 Lower dose reduced side effects.

 Self-administration.

 Better nasal bioavailability for smaller drug
molecules.

 The bioavailability of larger drug molecules
improved by means of absorption enhancer.

 Improved patient compliances.

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LIMITATION

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 Local side effects and irreversible damage of the
cilia of nasal mucosa.

 Certain surfactants used as chemical enhancer may
disrupt and dissolve membrane in high
concentration.

 Mechanical loss of the dosage form into the other
parts of the respiratory tract.

 Absorption surface area is less when compared to
GIT.

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 Once the drug administered cannot be removed.

 Very specific amount i.e. 25-200µg can be
delivered through intra nasal route.

 Difficult to administered drug in pathological
condition such as nasal congestion due to cold or
allergic reaction.

 Some drug cannot administered through this route
because they causes nasal irritation.

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NASAL ANATOMY AND PHYSIOLOGY

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 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 (Infantsww)w.DuloMix.com

 

Nasal Cavity

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Fig1: Nasal Cavity
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 Nasal Enzymes – Cytochrome P-450, Carboxyl esterase
and Glutathione S- tranferase, lactate dehydrogenase,
oxido reductase, phosphates , hydrolases.

 It is divided in to two halves by nasal septum.

 It contains 3 region:

a) Vestibule region

b) Respiratory region

c) Olfactory region

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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 nasalwcwaw.vDuiltoyMix..com

 

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 Surface area about – 10 cm2

 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.

 It comprises :1.Thick connective tissue lamina propria.

2.Olfactory epithelium.

 Lamina propria – axons, bowmen’s gland and blood
vessels .

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 Olfactory epithelium consist of three different cells :

1.Basal cells

2.Supporting cells

3.Olfactory receptor cells

 Nasal blood flow – external & internal carotid arteries.

 The mucus layer is cleared from the nasal cavity by cilia and
is renewed every 10-15 minutes.

 Mucus secretion composition: 95%-water, 2%-mucin,1%-
salts,1%-of other proteins such as albumin, lysozyme and
lactoferrin and 1%-lipid.

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MECHANISM OF NASAL
ABSORPTION

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1.Paracellular transport(intercellular):

 Aqueous route of transport.

 Slow and passive route.

2.Transcellular transport(intracellular):

 Transport through lipoidal membrane.

 Drug also cross membrane by active transport via
carrier mediated mean or transport through opening of
junctions.

3.Transcytosis:

 Particle is taken into a vesicle and transferred to the
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cell.

 

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Fig 2: Mechanism of wdwrwu.Dgul oaMbix.scoomrption

 

POSSIBLE DRUG ABSORPTION PATHWAYS

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OLFACTORY
TISSUE BRAIN TISSUE

NASAL
CAVITY BLOOD

CSF

LYMPHATICS TISSUE &
ORGANS

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Fig 3: Nasal Absorption

 

FACTOR INFLUENCING THE NASAL
DRUG ABSORPTION

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Factors Related To Drug:

 Molecular weight

 Chemical form

 Polymorphism

 Lipophilicity, Partition coefficient and pKa.

 Solubility & dissolution.

Factor Related To Formulation

 pH

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 Viscosity

 Osmolarity

 Buffer capacity

 Drug Concentration & Dose Volume.

Physiological Factors:

 Nasal Blood Flow

 Effect of Enzyme Activity

 Effect of Mucociliary Clearance

 Effect Of Physical Condition
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STRATEGIES TO IMPROVE NASAL
ABSORPTION

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 Prodrugs: eg. L-Dopa

 Enzymatic inhibitors:

Eg: bestatine & comostate amylase – amino peptidase
inhibitors.

Leupeptine, aprotinin – trypsine inhibitors (calcitonin)

 Mucoadhesive polymer : Chitosan, alginate, cellulose &
its derivative, polycarbophil.

 Novel formulation.

 Absorption enhancers.

 Structural modification: Eg, Calcitonin to Ecatonin
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PERMEATION ENHANCER

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Type of compound Examples Mechanisms of action

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 nasal
materials Carbopol, Chitosan clearance

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APPROPRIATE DRUG CANDIDATE
FOR NASAL DELIVERY

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 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.

 Appropriate aqueous solubility to provide the desired
dose in a 25-150µL volume of formulation
administered per nostrils.www.DuloMix.com

 

TYPES OF INTRA NASAL ROUTE
DRUG DELIVERY SYSTEM

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 Nasal Drops

 Nasal Spray

 Nasal Powders

 Nasal Gel

 Nasal Inserts

NOVEL INTRANASAL
DRUG DELIVERY
SYSTEM

 Nasal In-situ Gels
 Liposomes

 Microemusion
 Nanoparticles &Nanoemulsion

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 Microspheres

 

FORMULATION CONSIDERSTION

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1.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.

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2.pH of the formulation:

 It is important to avoid irritation of nasal mucosa.

 Use phosphate buffer pH 6.8 as a vehicle.

3.Solubilizers:

 Aqueous solubility of drug always a limitation for nasal
drug delivery.

 Eg: Alcohol, Labrasol, Surfactants, Transcutol,

β-cyclodextrin.

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4.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.

5.Antioxidants:

 These are used to prevent drug oxidation.

 Eg: Sodium Metabisulphite, Sodium Bisulfite,
Butylated hydroxy toluene, Tocopherol etc.

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6.Humectants :

 To prevent dehydration, adequate intranasal moisture is
required to prevent nasal irritation.

 Eg: Glycerine, Sorbitol, Mannitol.

7.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. www.DuloMix.com

 

NASAL DROPS

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 Most simple and convenient systems developed for
nasal delivery.

 These are solution, emulsion or 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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Fig 4 : Ephedrine Nasal Drops

 

NASAL SPRAY

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 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.

 Eg: Xylometazolin, Beclomethasone, Normal saline.
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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 Pumwwpw .DuleoMvixi.coems

 

NASAL POWDER

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 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

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 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

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 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

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 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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Fig 10 : Liposome

 

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 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

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 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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Fig 11 : Nanoparticles

 

MICROSPHERES

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 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
Gentamicin, Insulin. www.DuloMix.com

 

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Fig 12 :Microcapsules & Microspheres
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NASAL IN-SITU GEL

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 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

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 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

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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)
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 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 Awwtow.DmuloiMziax.tcoimon Device

 

METERED DOSE NEBULIZER

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 Operates by mechanical actuation.

 Delivers a predetermined volume with precision.

 Atomization results in higher bioavailability than
either spray or drops.

 Eg : Corticosteroids.

Fwwiwg.D u1lo4M ix:. cNomasal Nebulizer

 

NASAL AEROSOLS INHALER
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 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 .

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Fig 15: Nasal Aerosol Inhaler

 

EXAMPLES OF MARKETED
PREODUCT

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LOCAL DELIVERY

DRUG BRAND MAIN EXCIPIENTS MAIN
INDICATION

Beclomethasone Beconase Microcrystalline cellulose, Management/
Carboxy methyl cellulose treatment of
sodium. symptoms of

seasonal and
Budesonide Rhinocort Microcrystalline cellulose, perennial

Carboxy methyl cellulose . rhinosinusitis

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SYSTEMIC DELIVERY

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DRUG BRAND MAIN EXCIPIENTS MAIN
INDICATION

Estradiol Aerodiol Methyl beta dextrin, Hormone
Sodium chloride. replacement

therapy

Cyanocobalamin Nascobal Sodium citrate, Vitamin B12
Citric acid, deficiency
Benzalkonium
chloride

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EVALUATION

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1.IN VIVO NASAL ABSORPTION STUDIES

RAT MODEL

 The rat is anaesthetized. 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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RABBIT MODEL

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 The rabbit is anaesthetized by an intramuscular
injection.

 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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DOG MODEL

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 The dog is 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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MONKEY MODEL

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 The monkey anaesthetized by intravenous injection of
Sodium Phenobarbital.

 Holding the head in an upright position.

 The drug solution is delivered into each nostrils.

 The monkey is then placed in a supine position in for
5-10 min following intranasal administration.

 During the entire course of the study, the monkey
breathes normally through the nostrils.

 Blood samples are collected via indwelling catheter in
the vein.

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SHEEP MODEL

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 A male inhouse-bred sheep is used because it lacks

nasal infectious diseases.

2. 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 into drug reservoir at 37°C

and circulated through the nasal cavity of the rat by

means of a peristaltic pumwpw.w.DuloMix.com

 

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Fig 16 :Ex Vivoww Nw.DaulsoMailx .cPomerfusion Model

 

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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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 The obtained disappearance kinetics can be used for
predicting the in vivo rate of drug absorption.

 The method is also applicable to the assessment of the
damaging effects of absorption enhancers on the nasal
mucosa.

3.IN VITRO DRUG DIFFUSION STUDY

 Using treated cellophane membrane in Franz diffusion
cell.

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IN-VITRO STUDIES

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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.

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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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Evaluation of general physical properties:

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 Physical appearance,

 Identification of drug in formulation.

 Assay of drug substance in container.

 Determination of impurities and degradation
products.

 Assay of preservative & other excipients.

 pH, Osmolarity, Viscosity of the formulation.

 Microbial limit.

 Stability.
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APPLICATIONS OF NASAL DRUG
DELIVERY SYSTEM

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1.Delivery of non-peptide pharmaceuticals:

 Eg. Propranolol, Nitroglycerin, Sodium
Chromoglyate, etc.

2.Delivery of peptide based pharmaceuticals:

 Eg. Insulin, Calcitonin, Pituitary hormones etc.

3.Delivery of Diagnostic Drugs:

 Phenol Sulfo Naphthalene – For diagnosis of kidney
functions.

 Secretin – For diagnosis of pancreatic disorders.
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 Pentagastrin – For diagnosis of secretary functions
of gastric acid.

 Cerulin – For diagnosis of Gallbladder function.

4.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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REFERENCE

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 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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