1. NASAL DRUG
DELIVERY SYSTEM
Prepared By…
Chinchole Pravin Sonu
[IIst sem M. Pharm.]
Department of Pharmaceutics
R. C. Patel Institute of Pharmaceutical
Education and Research, Shirpur
A SEMINAR ON
4/12/2016NasalDrugDeliverySystem
1

2. CONTENT
1. INTRODUCTION
2. ANATOMY & PHYSIOLOGY OF NOSE
3. MERIT & LIMITATION
4. MACHANISM OF ABSORPSION
5. BARRIARS OF NASALABSORPSION
6. FACTOR AFFECTIONING NASALABSORPSION
7. MUCOCILLARY CLEARANCE
8. DRUG DISTRUBUTION
9. STRATERGIES TO IMPROVE NASALABSORPSION
10. PENETRATION ENHANCERS
11. FORMULATION
12. DELIVERY SYSTEM
13. EVALUATION
14. APPLICATION
15. CONCLUSION
16. REFERENCE
4/12/2016NasalDrugDeliverySystem
2

3.  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
4/12/2016NasalDrugDeliverySystem
3

4. 4/12/2016NasalDrugDeliverySystem
4

5.  The nasal cavity is run from the nasal vestibule to the nasopharynx which has
depth of approximately 12-14cm.
 The nasal vestibule, the respiratory region and the olfactory region are the three
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.
4/12/2016NasalDrugDeliverySystem
5

6.  The nasal cavity is covered with a mucous membrane which can be divided
into nonolfactory and olfactory epithelium areas. The nonolfactory area
includes the nasal vestibule and respiratory region.
 Nasal blood flow external & internal carotid arteries.
 Nasal secretions (1500-2000ml/day):- Goblet cell, nasal glands, lacrimal
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)
4/12/2016NasalDrugDeliverySystem
6

7. MERITS
 Drug degradation is absent.
 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
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.
4/12/2016NasalDrugDeliverySystem
7

8. LIMITATIONS
 The absorption enhancers used to improve nasal drug delivery system may have
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.
4/12/2016NasalDrugDeliverySystem
8

9. 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
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
4/12/2016NasalDrugDeliverySystem
9

10. PATHWAY OF ABSORPTION
4/12/2016
10
NasalDrugDeliverySystem

11. BARRIERS TO NASAL ABSORPTION
Low Bioavailability:
 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
Enzymatic Degradation:
 Degradation of protein and peptides by Exopeptidase and Endopeptidase.
4/12/2016NasalDrugDeliverySystem
11

12. FACTORS AFFECTING ABSORPTION
 Chemical form:
The form of a drug can be important in determining absorption.
Example : Nasal absorption of carboxylic acid esters of L-Tyrosine significantly
greater than that of L-Tyrosine.
 Polymorphism:
Polymorphism is known to affect the dissolution rate, solubility of drug and thus
their absorption through biological membranes.
 Molecular Weight:
A linear correlation has been reported between the absorption of drugs and
molecular Weight up to 300 Daltons.
Absorptions decreases significantly if the molecular weight is greater than
1000 Daltons (except with the use of absorption enhancers).
4/12/2016NasalDrugDeliverySystem
12

13.  Particle Size:
It has been reported that particle sizes 10 -20 μm are deposited in the nasal
cavity. Particles Which are less than 2 μm can be retained in the lungs, and particles
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 pH:
5.5-6.5(adult)
5.0-6.7(infants)
4/12/2016NasalDrugDeliverySystem
13

14. 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
and lead towards GIT.
 This clearance of mucus & the adsorbed/dissolved substances into GIT called as
Mucocilliary clearance.
4/12/2016NasalDrugDeliverySystem
14
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

15. Strategies To Improve Nasal Absorption
1.Nasal Enzymes Inhibitors:
eg- peptidases, proteases, tripsin, aprotinin, borovaline, amas-tatin, bestatin and
boroleucin inhibitors.
2.Formulation Design:
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:
eg- peptides like angiotensin II, bradykinin, caulein, carnosine, enkepha-lin,
vasopressin and calcitonin.
5.Particulate drug delivery:
6.Absorption Enhancers:
4/12/2016NasalDrugDeliverySystem
15

16. Mechanism of Penetration Enhancers:
 Inhibit enzymetic activity
 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
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.
4/12/2016NasalDrugDeliverySystem
16

17. Classification of penetration enhancer
4/12/2016NasalDrugDeliverySystem
17
Type Examples
Surfactants Sodium dodecyl sulphate,
Polyoxyethylene-9-lauryl ether,
Saponin
Complexing and chelating agents EDTA, Salicylates
Cyclodextrins and derivatives α-, β-, γ-cyclodextrin, DMβ-
cyclodextrin, 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

18. FORMULATION CONSIDERATION
 pH of the formulation
It is important as..
 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 and therefore
humectants are added.
 Prevent nasal irritation.
 The commonly used humectants are
- Glycerine
- Sorbitol
- Manitol
4/12/2016NasalDrugDeliverySystem
18

19.  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
4/12/2016NasalDrugDeliverySystem
19
 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)
Surfactant
Cyclodextrin (B-cyclodextrin)

20.  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…
Carbopol, Cellulose agents, Starch, Dextran, Chitosan, etc.
 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
4/12/2016NasalDrugDeliverySystem
20

21.  ANTIOXIDANT
 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.
 PRESERVATTVE
Commonly Used Preservatives
 Parabens
 Benzolkonium Choride
 Phenyl Ethyl Alcohol
 Benzoyl alcohol
 Mercury containing preservatives are not used.
4/12/2016NasalDrugDeliverySystem
21

22. 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.
 The main disadvantage of this system is the
lack of the dose precision.
4/12/2016NasalDrugDeliverySystem
22

23. 4/12/2016NasalDrugDeliverySystem
23

24.  Nasal spray
 Both solution and suspension
formulations can be formulated into nasal
sprays.
 Due to the availability of metered dose
pumps and actuators, a nasal spray can
deliver an exact dose from 25 to 200 μm.
 Choice of pumps and actuators:-
 The particles size and morphology of the
drug
 viscosity of the formulation .
4/12/2016NasalDrugDeliverySystem
24

25. Nasal Gels
 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.
4/12/2016NasalDrugDeliverySystem
25

26. Nasal Powder
 This dosage form may be developed if
solution and suspension dosage forms
can not be developed , such as lack of
drug stability.
 Advantages:
 Absence of preservatives
 Local application of drug
 stability of formulation
4/12/2016NasalDrugDeliverySystem
26

27. Nasal Aerosols
FORMULATION
• Active Drug
• Surfactant
• Co-solvent
• Propellant
Eg:-BUDESONIDE NASAL AEROSOL
INHALER.
4/12/2016NasalDrugDeliverySystem
27

28. EVALUATION
 IN VITRO NASAL
PERMEATION STUDIES
 USSING CHAMBER :-
(Hans Ussing)
 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.
4/12/2016NasalDrugDeliverySystem
28

29. EX VIVO NASAL PERFUSION MODEL
Fig- Experimental setup for ex-vivo nasal perfusion studies
4/12/2016NasalDrugDeliverySystem
29

30. IN VIVO NASAL ABSORPTION STUDIES
1. RAT MODEL
 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.
4/12/2016NasalDrugDeliverySystem
30

31. 2. RABBIT MODEL
 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.
4/12/2016NasalDrugDeliverySystem
31

32. 3. DOG MODEL
 The dog is anaesthetized by
intravenous injection of sodium
thiopental and the anesthesia is
maintained with sodium
Phenobarbital.
 A positive pressure pump through a
cuffed endotracheal tube gives the
ventilation.
 The blood sampling is carried out
from the jugular vein.
4/12/2016NasalDrugDeliverySystem
32

33. 4. SHEEP MODEL
 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.
4/12/2016NasalDrugDeliverySystem
33

34. APPLICATION OF NASAL DRUG DELIVERY
SYSTEMS
1. Delivery of non-peptide pharmaceuticals
EX.. Progesterone, estradiol, propranolol, nitroglycerin, sodium chromoglyate, etc.
2. Delivery of peptide-based pharmaceuticals
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)
4/12/2016NasalDrugDeliverySystem
34

35. 4. Delivery of drugs to Brain:
 For Treatment of Parkinson’sdisease,Alzheimer disease.
 For Delivery of MSH,ACTH,Insulin to brain
5. 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 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.
4/12/2016NasalDrugDeliverySystem
35

36. 4/12/2016
36
NasalDrugDeliverySystem
Drug Brands Delivery Action Indications
Azelastine Astelin
(Meda)
Duonase
(Cipla)
Nasal spray Local Allergic rhinitis
Beclometasone Beconase
(Glaxo)
Nasal spray Local Hay fever
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
Cynocobalamin
e
Nascobal
(par.
pharma)
Nasal gel
Nasal spray
Systemic Pernicious
Anaemia (B12
def)
Marketed Preparations

37. CONCLUSION
 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 of 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
4/12/2016NasalDrugDeliverySystem
37

38. REFERENCES
 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, 229-
260.
 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 of
JAPS.
4/12/2016NasalDrugDeliverySystem
38

39. 4/12/2016NasalDrugDeliverySystem
39