nasaldrugdeliverysystem-160412060720

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A SEMINAR ON
NASAL DRUG
Nasal Drug Delivery System
1
Prepared By…
Chinchole Pravin Sonu
[IIst sem M. Pharm.]
Department of Pharmaceutics
R. C. Patel Institute of Pharmaceutical
Education and Research, Shirpur
4/12/2016
DELIVERY SYSTEM
CONTENT
1.
2.
4.
5.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Nasal Drug Delivery System
6.
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3.
INTRODUCTION
ANATOMY & PHYSIOLOGY OF NOSE
MERIT & LIMITATION
MACHANISM OF ABSORPSION
BARRIARS OF NASAL ABSORPSION
FACTOR AFFECTIONING NASAL ABSORPSION
MUCOCILLARY CLEARANCE
DRUG DISTRUBUTION
STRATERGIES TO IMPROVE NASAL ABSORPSION
PENETRATION ENHANCERS
FORMULATION
DELIVERY SYSTEM
EVALUATION
APPLICATION
CONCLUSION
REFERENCE
2

In ancient times the Indian Ayurvedic system of medicines
used nasal route for administration of drug and the process
is called as “Nasya-karma”
It has been used for local effects extensively in
decongestant and local activity.
In recent times intranasal drug delivery is being considered
as a preferred route of drug delivery for systemic
bioavailability
Nasal Drug Delivery System

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
3
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Nasal Drug Delivery System
4

The nasal cavity is run from the nasal vestibule to the nasopharynx which has

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depth of approximately 12-14cm.
The nasal vestibule, the respiratory region and the olfactory region are the three

Nasal Drug Delivery System
main regions of the nasal cavity.
The submucosal zone of the nasal mucosa directly connects to the systemic
circulation, thus avoids first pass metabolism.

The lateral walls of the nasal cavity includes a folded structure which enlarges
the surface area in the nose to about 150cm2 .

This folded structure includes three turbinates: the superior, the median and the
inferior.

These turbinates increases the area of absorption.

Nasal cavity is about 60mm in length.
5

The nasal cavity is covered with a mucous membrane which can be divided
into nonolfactory and olfactory epithelium areas. The nonolfactory area
Nasal blood flow external & internal carotid arteries.

Nasal secretions (1500-2000ml/day):- Goblet cell, nasal glands, lacrimal
Nasal Drug Delivery System

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includes the nasal vestibule and respiratory region.
glands

Composition:- 95% water, 1-2% salt, 2-3% mucin. in trace amount Na, K,
Ca, Albumin also present.

Nasal enzymes:- Monooxygenase, lactate dehydrogenase, oxidoreductase,
phosphates , hydrolases, esterases, etc.

Nasal pH:- 5.5-6.5(adults)
5.0-6.7(infants & child)
6
MERITS

Hepatic first – pass metabolism is absent.

Rapid drug absorption.

Quick onset of action.

The bioavailability of larger drug molecules can be improved by means of
Nasal Drug Delivery System
Drug degradation is absent.
4/12/2016

absorption enhancer or other approach.

Better nasal bioavailability for smaller drug molecules.

Drugs which can not be absorbed orally may be delivered to the systemic
circulation through nasal drug delivery system.

Convenient route when Compared with parenteral route for long term
therapy.
7
LIMITATIONS
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The absorption enhancers used to improve nasal drug delivery system may have
Nasal Drug Delivery System

histological toxicity which is not yet clearly established.

Absorption surface area is less when compared to GIT.

Once the drug administered can not be removed.

Nasal irritation.
8
MECHANISM OF ABSORPTION
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
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
Nasal Drug Delivery System
penetration enhancers.


Two mechanisms are found:
Transcellular process: Transport of lipophillic drugs through cell membrane
by active transport or transport through opening of tight junction.
Example: Levodopa,Carbidopa

Paracellular process: It involves aqueous route of transport. it is slow and
passive.Water soluble drugs which have moleculer weight greater than 1000
daltons shows poor bioavailability.
Example: Insulin,MSH,ACTH
9
PATHWAY OF ABSORPTION
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Nasal Drug Delivery System
10
BARRIERS TO NASAL ABSORPTION
It is due to Low membrane permeability (limiting factor for high
mol.weight polar drugs like protein and peptides )
Low Membrane Transport:

Rapid clearance of administered formulation due to MCC.

Ex: Liquid and powder formulation shows rapid clearance
Nasal Drug Delivery System
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Low Bioavailability:
Enzymatic Degradation:

Degradation of protein and peptides by Exopeptidase and Endopeptidase.
11
FACTORS AFFECTING ABSORPTION

Chemical form:
Example : Nasal absorption of carboxylic acid esters of L-Tyrosine significantly

Polymorphism:
Polymorphism is known to affect the dissolution rate, solubility of drug and thus
their absorption through biological membranes.

Nasal Drug Delivery System
greater than that of L-Tyrosine.
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The form of a drug can be important in determining absorption.
Molecular Weight:
A linear
molecular
correlation has been reported between the absorption of drugs and
Weight
up
to
300
Daltons.
Absorptions decreases significantly if the molecular weight is greater than12
1000 Daltons (except with the use of absorption enhancers).

Particle Size:
It has been reported that particle sizes 10 -20 μm are deposited in the nasal
of greater than 20 um size exhaled with air.
Solubility and Dissolution Rate:
Drug solubility and dissolution rates are important factors in determining nasal
absorption from powders and suspensions. The particles deposited in the nasal
cavity need to be dissolved prior to absorption.

Nasal Drug Delivery System
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cavity. Particles Which are less than 2 μm can be retained in the lungs, and particles
Nasal pH:
5.5-6.5(adult)
5.0-6.7(infants)
13
MUCOCILIARY CLEARANCE
It is a preventive function.

Prevents the entry of hazardous particles

When the drugs adhere to the nasal mucosa, they eventually goes into nasopharynx

This clearance of mucus & the adsorbed/dissolved substances into GIT called as
Mucocilliary clearance.
A-Ciliated cells
B-Nonciliated cells
C-Goblet cells
D-Mucus layer
E-Sol layer
F-Basal cells
G-Basement membrane
Fig- Cell types of the nasal epithelium
Nasal Drug Delivery System
and lead towards GIT.
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
14
Strategies To Improve Nasal Absorption
1.Nasal Enzymes Inhibitors:
boroleucin inhibitors.
3. 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.
4.Prodrug approach:
Nasal Drug Delivery System
2.Formulation Design:
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eg- peptidases, proteases, tripsin, aprotinin, borovaline, amas-tatin, bestatin and
eg- peptides like angiotensin II, bradykinin, caulein, carnosine, enkepha-lin,
vasopressin and calcitonin.
5.Particulate drug delivery:
6.Absorption Enhancers:
15
Mechanism of Penetration Enhancers:

Reduce mucus viscosity

Reduce MCC

Open tight junctions

Solubilize the drug
Ideal Properties:
1.It should increase in the absorption of the drug
2. It should not cause permanent damage or alteration to the tissue
Nasal Drug Delivery System
Inhibit enzymetic activity
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
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.
16
Classification of penetration enhancer
Surfactants
Sodium dodecyl sulphate,
Polyoxyethylene-9-lauryl ether,
Saponin
Complexing and chelating agents
EDTA, Salicylates
Cyclodextrins and derivatives
α-, β-, γ-cyclodextrin, DMβcyclodextrin, HPβ-cyclodextrin
Bile salts
Sodium taurocholate
Sodium glycocholate
Sodium deoxycholat
Fusidic acid derivatives
Fatty acid salts
Oleic acid, Caprylate (C8),
Caprate (C10), Laurate (C12)
Dry microspheres
Degradable starch microsphere
Dextran microsphere
Nasal Drug Delivery System
Examples
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Type
17
FORMULATION CONSIDERATION

To avoid irritation of nasal mucosa.

To allow drug to be available in unionised form for absorption.

To prevent growth of the bacteria in nasal passage.

To sustain normal physiological ciliary moments.

HUMECTANTS

To prevent dehydration adequate intranasal moisture is required
humectants are added.

Prevent nasal irritation.

The commonly used humectants are
Nasal Drug Delivery System
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pH of the formulation
It is important as..
and therefore
- Glycerine
- Sorbitol
- Manitol
18
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

SOLUBILISERS

Aqueous solubility of drug is always a limitation for nasal drug delivery of dosage
form.
Commonly used solubilisers are
Glycols
Small quantities of alcohol
Transcutol(diethylene glycol monoethyl ether)
Medium chain glycerides
Labrasol(saturated polyglycolysed C8-C10 glycerides)
19
Surfactant
Cyclodextrin (B-cyclodextrin)

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
Nasal Drug Delivery System
GELLING/VISCOSIFYING AGENTS/GEL FORMING CARRIER

Increasing solution viscosity may provide means of prolonging the therapeutic effect of
nasal preparations.

Highly viscous formulations interfere with the normal functions like ciliary beating or
mucociliary clearance and thus alter the permeability of drug.

Commonly used gelling agents are…
Nasal Drug Delivery System
Carbopol, Cellulose agents, Starch, Dextran, Chitosan, etc.
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

ABSORPTION ENHANCERS

Unlike the most small drug molecules, some drugs and peptides do no cross the nasal
membrane efficiently.

The nasal mucosa is almost impermeable to molecular size greater than 1000 Dalton.

The low nasal membrane permeability is due to
Molecular Size
Lack Of Lipophilicity
Enzymatic Degradation
20








PRESERVATTVE
Commonly Used Preservatives
Parabens
Benzolkonium Choride
Phenyl Ethyl Alcohol
Benzoyl alcohol
Mercury containing preservatives are not used.
Nasal Drug Delivery System

Usually antioxidants do not affect drug absorption or cause nasal irritation.
Chemical / Physical interaction of antioxidant with drug and excipients should be
considered during formulation development.
Commonly used antioxidants are
- Sodium Metabisulfite
- Sodium Bisulfite
- Butylated Hydroxytoluene
- Tocopherol.
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
ANTIOXIDANT
21
DELIVERY SYSTEM
Nasal Drops
Nasal drops are one of the most simple and
convenient
systems
developed
for
nasal
delivery.

Nasal drops delivered the drug to a larger area
back in the nasal cavity.

Nasal Drug Delivery System
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
The main disadvantage of this system is the
lack of the dose precision.
22
4/12/2016
Nasal Drug Delivery System
23

Nasal spray
Both
solution
and
suspension
sprays.

Due to the availability of metered dose
pumps and actuators, a nasal spray can
deliver an exact dose from 25 to 200 μm.


Nasal Drug Delivery System
formulations can be formulated into nasal
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
Choice of pumps and actuators:The particles size and morphology of the
drug

viscosity of the formulation .
24

Nasal gels are high-viscosity thickened
solutions or suspension .
•
Advantages :
The reduction of post-nasal drip due to
high viscosity .
•
Reduction of taste impact due to reduced
swallowing.
•
Reduction of leakage of the formulation.
•
Reduction of irritation by using emollient.
Nasal Drug Delivery System
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Nasal Gels
25

This dosage form may be developed if
can not be developed , such as lack of
drug stability.




Advantages:
Nasal Drug Delivery System
solution and suspension dosage forms
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Nasal Powder
Absence of preservatives
Local application of drug
stability of formulation
26
Nasal Drug Delivery System
FORMULATION
• Active Drug
• Surfactant
• Co-solvent
• Propellant
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Nasal Aerosols
Eg:-BUDESONIDE NASAL AEROSOL
INHALER.
27
EVALUATION
Nasal Drug Delivery System
 Chamber consist of U-shaped tubing system,
usually made of glass, filled with
experimental solution.
 Barrier used are excised nasal mucosa from
rats or rabbits.
 Drug solution is introduced into the mucosal
side of the chamber and samples were
collected from receiver chamber.
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IN VITRO NASAL
PERMEATION STUDIES
 USSING CHAMBER :(Hans Ussing)

28
EX VIVO NASAL PERFUSION MODEL
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Nasal Drug Delivery System
29
Fig- Experimental setup for ex-vivo nasal perfusion studies
IN VIVO NASAL ABSORPTION STUDIES

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.

The passage of the nasopalatine tract is
sealed so that the drug solution is not
drained from the nasal cavity through
the mouth.

The blood samples are collected from
the femoral vein.
Nasal Drug Delivery System
RAT MODEL
4/12/2016
1.
30

Rabbits anaesthetized by intramuscular
injection of a combination of ketamine
and xylazine.

The rabbit's head is held in an upright
position and the drug solution is
administered by nasal spray into each
nostril.

The blood samples are collected by an
indwelling catheter in the marginal ear
vein or artery.
Nasal Drug Delivery System
RABBIT MODEL
4/12/2016
2.
31

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.
Nasal Drug Delivery System
DOG MODEL
4/12/2016
3.
32

Practical
and
suitable
for
investigating
nasal
delivery
formulations.

Male in-house bred sheep are
employed since they are free from
nasal infections.
5.
•
•
•
MONKEY MODEL
The monkey is tranquillized 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.
Nasal Drug Delivery System
SHEEP MODEL
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4.
33
APPLICATION OF NASAL DRUG DELIVERY
SYSTEMS
EX.. Progesterone, estradiol, propranolol, nitroglycerin, sodium chromoglyate, etc.
Eg. Insulin, Calcitonin, Pituitary hormones etc.
3. Delivery of Diagnostic Drugs

Phenolsulfonphthaline-For diagnosis of kidney functions

Secretin-For diagnosis of pancreatic disorders

Pentagastrin-For diagnosis of secretory functions of gastric acid.

Cerulin-For diagnosis of Gallbladder function

Vital dyes-Trypan blue and Evans blue (it can not enter in cranium because they
can not pass through sheath)
Nasal Drug Delivery System
2. Delivery of peptide-based pharmaceuticals
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1. Delivery of non-peptide pharmaceuticals
34
4. Delivery of drugs to Brain:
For Treatment of Parkinson’sdisease,Alzheimer disease.

For Delivery of MSH,ACTH,Insulin to brain
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

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
Nasal Drug Delivery System
5. Delivery of Vaccines :
Examples:
Nasal Vaccines are Prepared for Measels,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.
35
Marketed Preparations
Delivery
Action
Indications
Azelastine
Astelin
(Meda)
Duonase
(Cipla)
Nasal spray
Local
Allergic rhinitis
Beclometasone Beconase
Nasal spray
Local
Hay fever
Nasal Drug Delivery System
Brands
4/12/2016
Drug
(Glaxo)
Ciclesonide
Zetonna
(Sunovion
pharma)
Nasal aerosol
Local
Allergies
Xylomethazolin
e
Otrivin
(novartis)
Nasal spray
Nasal gel
Local
Congestion
Sinusitis
Oxytocin
Syntocinon
(novartis)
Nasal spray
Systemic
Labor pain
Nasal gel
Nasal spray
Systemic
Pernicious
Anaemia (B12
def)
Cynocobalamin Nascobal
e
(par.
pharma)
,
36
CONCLUSION

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 of site-specific delivery with improved therapeutic effects.

Allowing systemic administration without significant degradation.

Nasal Drug Delivery System
Nasal route is attractive for the delivery of the many drugs and vaccines.
4/12/2016

Nasal drug delivery system offers flexibility for multiple formulations ranging
from nasal drop to suspension spray
37
REFERENCES




Nasal Drug Delivery System

4/12/2016

Y.W.Chein, K.S.E. Su and S.F.Chang. “Nasal systemic drug delivery” Dekker, 1989,
27-34,89,199.
Anya M.Hillery, Andrew W.Lloyd, James Swarbrick. “Drug Delivery and Targeting
for Pharmacists and Pharmaceutical Scientists” published by Taylor & Francis,
2001, 215-243.
M.E. Aulton “ Pharmaceutics – The science of dosage form design” Churchill
Livingston., 2002, 494.
Y.W.Chein, “ Novel drug delivery systems”, Marcel Dekker Inc.50 (2), 1982, 229260.
Latika Nasare* , Kamlesh Niranjane, Anuradha Nagdevte, Sumedh Mohril “Nasal
drug delivery system : An Emerging Approach For Brain Targeting’’ Review Article
of WJPPS.
M.Alagusundaram*, B.Chengaiah, K.Gnanaprakash, S.Ramkanth, C.Madhusudhana
Chetty, D.Dhachinamoorthi “Nasal drug delivery system - an overview” Review
Article of IJIPRS.

RAHISUDDIN*, PRAMOD K SHARMA, GARIMA GARG, AND MOHD SALIM
“REVIEW ON NASAL DRUG DELIVERY SYSTEM WITH RECENT ADVANCEMNT”
Review Article of IJPPS.

Shivam Upadhyay, Ankit Parikh, Pratik Joshi, U M Upadhyay and N P Chotai
“Intranasal drug delivery system- A glimpse to become maestro” Review Article of38
JAPS.
4/12/2016
Nasal Drug Delivery System
39
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