Intranasal drug delivery system - Introduction, Nasal enzymes and nasal ph, cross sectional view of nose, factors affecting nasal absorption, general formulations of intranasal drugs, Intranasal dosage forms, nasal sprays, spray pump devices, nasal aerosols, compressed air nebulizers, nasal powder, nasal gels, applications of intranasal drug delivery system, delivery of intranasal vaccines, intranasal anaesthesia, Evaluation of intranasal formulation, ussing chamber, Advantages and disadvantages of intranasal drug delivery system

1. PRESENTED TO:
PROF. DR. DINESH KAUSHIK
DEPARTMENT OF PHARMACEUTICS

2. INTRODUCTION
 In this drugs are administered through nasal cavity by
different dosage forms like solutions, emulsions, gels, etc
 In ancient times the Indian Ayurvedic system of
medicines used nasal route for administration of drug and
the process is called as “Nasya”
 It has been used for local effects extensively in
decongestant and local activity. But, in recent times
intranasal drug delivery is being considered as a preferred
route of drug delivery for systemic bioavailability
 Various proteins & peptides have shown a good
bioavailability

3. NASAL ENZYMES AND
NASAL pH
Nasal Enzymes:-
Cytochrome p-450 dependent oxygenase, lactate
dehydrogenase, oxydoreductase, acid hydrolases, esterases,
lactic dehydrogenases, malic enzymes, lysosomal proteinases,
steroid hydroxylases etc.
Nasal pH:-
• Adult nasal secretion pH: 5.5 - 6.5
• Infants and children: 5 - 6.7
• It becomes alkaline in conditions such as acute rhinitis, acute
sinusitis
• Lysosome in the nasal secretion helps as antibacterial and its
activity is diminished in alkaline pH.

4. Cross-sectional view
a – nasal vestibule d – middle turbinate
b – palate e – superior turbinate
(olfactory mucosa)
c – inferior turbinate f – nasopharynx

5. Site of drug
spray &
absorption

6. PATHWAYOFABSORPTION

7. FACTORS AFFECTING NASAL
ABSORPTION
 Molecular weight: Absorption of drugs decreases as the
molecular weight of drug molecules increases. A sharp
decline in drug absorption having molecular weight greater
than 1000 Dalton
 Lipophilicity : On increasing
lipophilicity the permeation of the compound
normally increases through nasal mucosa.
These mucosa have some hydrophilic
character but their primary lipophilic nature
and lipid domain plays important role in
barrier function.

8.  Chemical Form: Chemical form of a drug can be
important in determining absorption. Eg.- Conversion of
drug into a salt or ester form can alter its absorption. Nasal
absorption of carboxylic acid esters of L-Tyrosine is
greater than L-Tyrosine.
 Drug concentration: Absorption increases as
concentration of drug increases. Tyrosine shows
increased absorption at high concentration in rate..
 Particle size: Particle size 10-20 microns adheres best to
the nasal mucosa. Particles Which are less than 2 μm can
be retained in the lungs, and particles of greater than 20
um size exhaled with air.
(Contd...)

9. (Contd…)
 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.
 Polymorphism: Polymorphism is known to affect the
dissolution rate, solubility of drug and thus their
absorption through biological membranes.

10. GENERAL
FORMULATIONS
DRUG
VISCOSIFYING AGENT
SOLUBILIZERS
SURFACTANTS
BIOADHESIVE POLYMERS
PRESERVATIVES
ANTIOXIDANTS

11. DRUGS
Drugs commonly used are :
 β2-adrenergic agonist: terbutaline sulphate
 Corticosteroids : budesonide
 Anti cholinergic: ipratropium bromide
 Mast cell stabilizer : sodium chromogylate
 Antiviral : Viraleze (Astodimer Sodium)
 Antifungal :Voriconazole

12. VISCOSIFYING AGENTS
 These agents increase the viscosity of the
solution prolonging the therapeutic activity
of preparation. e.g.: hydroxypropyl cellulose.

13. SOLUBILIZERS
Aqueous solubility of drug always a limitation
for nasal drug delivery. e.g.: glycol, alcohol,
labrasol, transcutol.
In such cases surfactants or cyclodextrines
(β -cyclodextrine) are used , these serve as a
biocompatible solubilizer & stabilizer in
combination with lipophilic absorption
enhancers.

14. SURFACTANTS
Modify the permeability of nasal mucosa &
facilitate the nasal absorption of drugs. E.g. SLS,
Poly acrylic acid, sod.glycocholate.
BIOADHESIVE POLYMERS
Increases the residence time of drug in nasal
cavity and a higher local drug concentration in the
mucus lining on the nasal mucosal surface E.g.:
Methylcellulose, Carboxymethylcellulose Hydroxyl
propyl cellulose

15. HUMECTANTS
 To prevent dehydration adequate intranasal
moisture is required so humectants are added.
 Prevent nasal irritation.
 The commonly used humectants are
-Glycerine
-Sorbitol
-Manitol

16. PRESERVATIVES
• These are used to prevent the growth of micro
organisms. e.g.: parabens, benzalkonium chloride,
phenyl ethyl alcohol, EDTA etc.
ANTIOXIDANTS
• These are used to prevent drug oxidation. E.g.:
sodium meta bisulphite , sodium bisulfite,
butylated hydroxy toluene& tocopherol etc.

17. DOSAGE FORMS
Nasal drops:
 Nasal drops are one of the most convenient & simple
systems for nasal delivery. These are instilled into the
nose by dropper. Aqueous or oily solutions, since the
latter inhibit the movement of cilia in the nasal mucosa.
 If used for longer periods , may reach the lungs & cause
lipoid pneumonia. nasal drops should be isotonic
having neutral pH & viscosity similar to nasal
secretions by using methyl cellulose.
 E.g.:- Otrivin nasal drops, Sodium Chloride Nasal
Drops

19. Nasal sprays
• These are aqueous or alcoholic preparations. Applied to
the mucous membrane of nose by atomizer. Only fine
droplets are required so they may reach the lungs. By
using metered pumps & actuators a nasal spray can
deliver an exact 25-200µm.
• e.g.:- Fluticasone Nasal Spray and Oxymetazoline nasal
spray

20. SPRAY PUMP DEVICES
- Unidose
- Multidose
- Bidose

21. 03/10/2009
Bidose
Unidose

22. HINDU COLLEGE OF PHARMACY, SONIPAT
Multidose

23. Nasal Aerosols
FORMULATION
• Active Drug
• Surfactant
• Co-solvent
• Propellant
Eg:-BUDESONIDE NASALAEROSOL
INHALER.

24. COMPRESSED AIRNEBULIZERS
• Nebulizer isadeviceusedto administermedicationintheform
of amist inhaledinto thelungs.
• Thecompressedairisfillingintothedevice,soitiscalled
compressed air nebulizers.
• Eg–ForacortRespules

25. Nasal Powder
This dosage form may be
developed if solution &
suspension dosage forms
cannot be developed e.g. due to
lack of drug stability. The
powder formulation is
dependent on the solubility,
particle size, aerodynamic
properties & nasal irritancy of
the active drug & or excipients.
E.g:- Sinu Air Nasal Powder

26. Nasal Gels
• These are high viscosity thickened solutions or
suspensions. Nasal gels include the reduction of post-
nasal drip due to high viscosity , reduction of taste impact
due to reduced swallowing, reduction of anterior leakage
of formulation, reduction of irritation by using soothing
/emollient excipients & target to mucosa for better
absorption.

27. APPLICATIONS
Delivery of non peptide pharmaceuticals
• Delivery of non-peptide pharmaceuticals with
extensive pre-systemic metabolism, such as
• - progesterone
• - estradiol
• - propranolol
• - nitroglycerin
• - sodium chromoglyate
• can be rapidly absorbed through the nasal mucosa
with a systemic bioavailability of approximately
98%

28. Delivery of peptide based
pharmaceuticals
• Peptides & proteins have a generally low oral
bioavailability because of their physico -
chemical instability and susceptibility to
hepato -gastrointestinal first-pass elimination.
E.g. . Insulin (Nasulin) , Calcitonin , Pituitary
hormones etc.

29. Delivery of diagnostic drugs
• Delivery of diagnostic drugs Diagnostic agents
such as
• Phenolsulfonphthalein – kidney function.
• Secretin – pancreatic disorders.
• Pentagastrin – secretory function of gastric
acid

30. Delivery of Vaccines
• The nasal mucosa is the first site of contacts with inhaled pathogens.
The nasal passages are rich in lymphoid tissue. Creation of both
mucosal and systemic immune responses. Low cost, patient friendly,
non- injectable , safe .Many diseases, such as measles, pertussis ,
meningitis and influenza are associated with the entry of pathogenic
microorganisms across the respiratory mucosal surfaces and are hence
good candidates for nasal vaccines.
• Eg:- Nasovac H1N1 Vaccine
Eg:- Intranasal Covaxin – BBV154 (under development)

31. Intranasal Vaccine administration

32. Inhalation Anesthesia
Intranasal route is used to give anesthesia for surgeries.
Eg:- Isoflurane, Desflurane, Sevoflurane, Nitrous Oxide

33. Nitrous Oxide Administration

34. EVALUATION OF NASAL FORMULATION
In vitro nasal permeation studies :
USSING CHAMBER :- (Hans Ussing)
usually made of glass, filled
experimental solution.
 Barrier used are excised nasal mucosa
rats or rabbits.
with
from
 Drug solution is introduced into the mucosal
side of the chamber and samples were
collected from receiver chamber.
 Chamber consist of U-shaped tubing system,

35. In Vivo Nasal Absorption
studies
 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 drug solution is delivered to the nasal cavity through the
nostril or through the cannulation tubing.
• 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
• The blood samples are collected from the femoral vein.

36. 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.
 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
indwelling catheter in the marginal ear
vein or artery.

37. Dog Model :-
• Either anesthetized or maintained
conscious state depending upon the
purpose of the study &
characteristics of the drug.
Anesthetized by intravenous inj. of
sod. thiopental & maintained in the
an anesthetize state with sod.
Phenobarbital. Positive pressure
pumps provides ventilation through
a cuffed endotracheal tube & a
heating pad keeps the body temp.
at 37ᴼC. Blood sampled collected
from the jugular vein.

38. Sheep Model:-
• The sheep model prepared as same
as dog model. In-house bred sheep
is use because it lacks nasal
infectious nose.
• In summary rat & rabbit are small,
easy to handle & low in cost &
inexpensive to maintain. In rat
limitation application because of
small body & size hence only useful
for preliminary studies of nasal
drug absorption.

39. Monkey Model :-
HINDU COLLEGE OF PHARMACY, SONIPAT
• 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 inserted catheter in the
vein. 33

40. ADVANTAGES
• Drug degradation that is observed in the gastrointestinal tract is
absent.
• Hepatic first pass metabolism is avoided.
• Rapid drug absorption and quick onset of action can be achieved.
• The bioavailability of larger drug molecules can be improved
by means of absorption enhancer or other approach.
• The nasal bioavailability for smaller drug molecules is good.
• Drugs that are orally not absorbed can be delivered to the systemic
circulation by nasal drug delivery.

41. DISADVANTAGES
• Nasal administration is primarily suitable only for potent drugs.
• Drugs for continuous & frequent administration may be less
suitable because of harmful long term effects.
• Nasal administration has also been associated with a high
variability in the amount of drug absorbed.
• The histological toxicity of absorption enhancers used in nasal drug
delivery system is not yet clearly established.
• Relatively inconvenient to patients when compared to oral delivery
systems since there is a possibility of nasal irritation & nasal cavity
provides smaller absorption surface area when compared to GIT.

42. REFERENCES
 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.
 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 o3f8
JAPS.