info on Nasal Drug Delivery systems

2. CONCEPTS UNDER DISCUSSION
• INTRODUCTION.
• ADVANTAGES.
• DISADVANTAGES.
• FACTORS INFLUENCING NASAL DRUG ABSORPTION.
• GENERAL FORMULATIONS.
• PHYSIOLOGICAL EFFECTS.
• PHARMACEUTICAL EFFECTS.
• DOSAGE FORMS.
• APPLICATIONS.
• EVALUATION OF NASAL FORMULATION.
• MARKETED PRODUCTS. 2DEPARTMENT OF PHARMACEUTICS, NIPS

3. Introduction
• Administration of drug through nasal route is referred
as Nasal drug delivery system.
• Nasal route is an alternative to invasive
administrations and provides a direct access to the
systemic circulation.
• Intranasal Medication administration offers a truly
“Needleless ” solution to drug delivery.
• In recent years many drugs have been shown to
achieve better systemic bioavailability through nasal
route than by oral administration.
• Nasal therapy, has been recognized form of treatment
in the Ayurvedic systems of Indian medicine, it is also
called “NASAYA KARMA”.
• For many years drugs have been administered nasally
for both topical and systemic action. 3DEPARTMENT OF PHARMACEUTICS, NIPS

4. 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 Studied so far
carried out indicate that the nasal route is an alternate to
parenteral route, especially, for protein and peptide drugs.
• Convenient for the patients, especially for those on long
term therapy, when compared with parenteral medication.
• Drugs possessing poor stability in G.I.T. fluids are given
by nasal route.
• Polar compounds exhibiting poor oral absorption may be4DEPARTMENT OF PHARMACEUTICS, NIPS

5. DISADVANTAGES
• 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.
• There is a risk of local side effects and irreversible damage of
the cilia on the nasal mucosa, both from the substance and
from constituents added to the dosage form.
• Certain surfactants used as chemical enhancers may disrupt
and even dissolve membrane in high concentration.
• There could be a mechanical loss of the dosage form into the
other parts of the respiratory tract like lungs because of the
improper technique of administration.
5DEPARTMENT OF PHARMACEUTICS, NIPS

6. FACTORS INFLUENCING
NASAL DRUG ABSORPTION
The factors influencing nasal drug absorption are described as follows.
Drug concentration:
Absorption depends on the initial concentration of the drug The absorption
follows first-order kinetics.
perfusion rate:
According to the Ex- vivo nasal perfusion technique of Phenobarbital, with the
increase in the perfusion rate the nasal absorption is first increased & then
reaches to a plateau level that is independent of the rate of perfusion.
Degree of drug ionization:
Polar (water soluble) drugs tend to remain on the tissues of the upper airway
.Non-polar (lipid soluble) drugs are more likely to reach distal airways .Lipid
soluble drugs are absorbed more rapidly than water soluble drugs.
pH at absorption site:
Nasal absorption is pH dependent .Nasal pH in nasal secretion of adult : 5.5-
6.5.In infants and children: 5-6.7. It becomes alkaline in conditions such as
acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as
antibacterial and its activity is diminished in alkaline pH.
6DEPARTMENT OF PHARMACEUTICS, NIPS

7. GENERAL FORMULATIONS
DRUG
VISCOSIFYING AGENT
SOLUBILIZERS
PRESERVATIVES
ANTIOXIDANTS
7DEPARTMENT OF PHARMACEUTICS, NIPS

8. DRUGS
• Drugs commonly used are
• β2-adrenergic agonist: terbutaline
sulphate.
• Corticosteroids : budesonide.
• Anti cholinergic: ipratropium bromide .
• Mast cell stabilizer : sodium
chromogylate.
8DEPARTMENT OF PHARMACEUTICS, NIPS

9. VISCOSIFYING AGENTS
These agents increase the viscosity of the solution
prolonging the therapeutic activity of preparation.
e.g.: hydroxypropyl cellulose.
SOLUBILIZERS
Aqueous solubility of drug always a limitation for
nasal drug delivery. e.g.: glycol, alcohol, labrasol,
transcutol.
In such cases surfactants or cyclodextrines (HP- β -
cyclodextrine) are used , these serve as a
biocompatible solubilizer & stabilizer in combination
with lipophilic absorption enhancers.
9DEPARTMENT OF PHARMACEUTICS, NIPS

10. 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 10DEPARTMENT OF PHARMACEUTICS, NIPS

11. 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.
11DEPARTMENT OF PHARMACEUTICS, NIPS

12. PHYSIOLOGICAL EFFECTS
• Drug metabolism in respiratory tract
and reduction of systemic effect.
• Protein binding.
• Mucociliary transport causing
increased or decreased drug
residence time.
• Local toxic effects of the drug.
12DEPARTMENT OF PHARMACEUTICS, NIPS

13. PHARMACEUTICAL EFFECTS
Particle size.
• Access to distal airways is a function of particle size.
Large particles (> 7 microns) will be lost in the
gastrointestinal tract. Small particles (< 3 microns) will
be lost in exhaled breathe. Intermediate particles (3 to
7 microns) reach the actual site of action.
Molecular size.
• Higher the molecular size, lower the nasal absorption.
A good systemic bioavailability can be achieved for
molecules with a molecular weight of up to 1000
Daltons when no absorption enhancer is used. 13DEPARTMENT OF PHARMACEUTICS, NIPS

14. Solution pH
Nasal absorption is pH dependent . Absorption is
higher at a pH lower than the dissociation constant
(pKa) of the molecule. Absorption is lower as the pH
increases beyond the dissociation constant. The pH of
the nasal formulation is important for following
reasons: To avoid nasal irritation. To allow drug to be
available in unionized form for absorption. To prevent
the growth of pathogenic bacteria in the nasal passage.
To maintain functionality of excipients such as
preservatives etc. Effect of Solution pH With the help
of water- soluble ionizable compound viz. Benzoic acid
in the pH range 2.0- 7.1, we will see that the rate of
nasal absorption decreased as the pH increased. 14DEPARTMENT OF PHARMACEUTICS, NIPS

15. Drug lipophilicity
• If we use a series of Barbiturates at pH 6.0 the
Barbiturates will exist completely in a undissociated
form. Very little change is noticed between
phenobarbital & barbital. The total observation
indicates that the transnasal permeation behavior
can not be predicted with the help of drug
lipophilicity measured.
Drug concentration
• By studying the Ex vivo nasal perfusion technique in
the rat one can monitor the disappearance of
1-tyrosile-1-tyrosine and the formation of 1-tyrosine.
It was actually found that the nasal absorption of
1-tyrosine depends upon the initial concentration.
15DEPARTMENT OF PHARMACEUTICS, NIPS

16. 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.:- ephedrine nasal drops B.P.C, otrivine nasal drops.
16DEPARTMENT OF PHARMACEUTICS, NIPS

17. 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.:- adrenaline & atropine spray B.P.C.
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 17DEPARTMENT OF PHARMACEUTICS, NIPS

18. 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.
18DEPARTMENT OF PHARMACEUTICS, NIPS

19. 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
100% 19DEPARTMENT OF PHARMACEUTICS, NIPS

20. 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, Calcitonin , Pituitary hormones
etc. Nasal route is proving to be the best route
for such biotechnological products.
20DEPARTMENT OF PHARMACEUTICS, NIPS

21. Delivery of diagnostic drugs.
• Delivery of diagnostic drugs Diagnostic agents
such as
• Phenolsulfonphthalein – kidney function.
• Secretin – pancreatic disorders.
• Pentagastrin – secretory function of gastric
acid
21DEPARTMENT OF PHARMACEUTICS, NIPS

22. 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.
22DEPARTMENT OF PHARMACEUTICS, NIPS

23. EVALUATION OF NASAL FORMULATION
In vitro nasal permeation studies ( diffusion ):
• The nasal diffusion cell is fabricated in glass. The water-jacketed
recipient chamber has 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 nasal mucosa of
sheep was separated from sub layer bony tissues and stoned in
distilled water containing few drops at gentamycin injection.
After the complete removal of blood from mucosal surface, 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. At predetermined
intervals, samples (0.5 ml) from recipient chamber are with draw
and transferred to amber colored ampoules. The sample
withdrawn is suitably replaced. The samples are estimated for
drug content by suitable analytical technique. Throughout the
experiment the temperature is maintained at 37 o C. 23DEPARTMENT OF PHARMACEUTICS, NIPS

24. 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,
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. 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. The blood samples are collected
from the femoral vein. 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
24DEPARTMENT OF PHARMACEUTICS, NIPS

25. Rabbit Model:
• The rabbit offers several advantages as an animal model for
nasal absorption studies. It is relatively cheap, readily available
and easily maintained in laboratory settings. It permits
pharmacokinetic studies as with large animals (like monkey).
The blood volume is large enough (approx. 300ml). To allow
frequent blood sampling (l-2ml). Rabbits (approx. 3 kg) are
either anaesthetized or maintained in the conscious state
depending on the purpose of study.
• In the anaesthetized model, the rabbit is anaesthetized by an
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.
25DEPARTMENT OF PHARMACEUTICS, NIPS

26. 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.
Sheep Model:-
• The sheep model prepared as same as dog model. A make 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.
26DEPARTMENT OF PHARMACEUTICS, NIPS

27. MARKETED PRODUCTS
• Otrivin spray (xylometazoline).
• Miacalcin spray (calcitonin).
• Vibrocil gel
( phenylephrine,dimethindene maleate).
• Naset-p (xylometazoline HCL)-nasal
drops.
• Nasovac H1N1 vaccine.
27DEPARTMENT OF PHARMACEUTICS, NIPS

28. THANK YOU