NASAL DRUG DELIVERY AN INTRODUCTION

1. NASAL DRUG DELIVERY
SYSTEM
A SEMINAR ON
BILAL H MERCHANT
M-PHARM (2016-2018)
DEPARTMENT OF PHARMACEUTICS
S.S.D.J. COLLEGE OF PHARMACY,
CHANDWAD.

2. CONTENTS
 History
 Introduction
 Adavantages and Limitations
 Nasal cavity: Anatomy, Physiology
 Transport of drugs across nasal epithelium
 Factors affecting nasal absorption
 Mechanism and Pathways
 Delivery systems
 Strategies to increase nasal absorption and Applications
 Evaluation and Marketed preparations
 References

3. History
 Oral route is most convenient method due to their ease of
manufacturing and administration.
 Now a days researcher have selected nasal mucosa as an
alternate route because of the low metabolic environment of
nose that overcomes the limitation of oral route such as
minimises the lag time associated with oral drug delivery.
 In ancient times the Indian Ayurvedic system of medicines used
nasal route for administration of drug and the process is called
as “Nasya Karma”.
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4. Introduction
 Intranasal administration of local drugs is much older. Improving
irrigation of nasal sinuses was described in scientific publication
in 1926 about intranasal drug administration for local treatment.
Intranasal steroid treatment followed in the 1950’s.
 The early 1980’s introduce nasal route as a promising systemic
delivery of drug.
 In recent years many drugs have been shown to achieve better
systemic bioavailability through nasal route due to the large
surface area, porous endothelial membrane, the avoidance of first
pass metabolism.
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5. Advantages
 Its easy and convenient
 Can be easily administered to the unconscious patients
 Compared to oral medications, intranasal medication
delivery results in:
 Faster delivery to the blood stream and higher blood levels
 No destruction by stomach acid and intestinal enzymes
 No destruction by hepatic first pass metabolism
 Compared to IV medications, intranasal medication
delivery results in:
 Comparable blood levels depending on the drug and dose.
3

6. Disadvantages
 Adversely affected by pathological conditions(cold or
allergies may alter significantly the nasal bioavailability)
 Irritation of nasal mucosa by drugs.
 Volume that can be delivered into nasal cavity is restricted
to 25-200 μl.
 Normal defence mechanism like mucociliary clearance
affects the permeability of drugs. Enzymatic barrier to the
permeability of drugs.
 Absorption enhancers causes irritation.
 Once administered, rapid removal of the therapeutic agent
from the site of absorption is difficult. 4

7. Nasal Cavity:Anatomy,
Physiology
 Major functions of the nasal cavity are breathing and olfaction.
 Nasal passage which runs from nasal vestibule to nasopharnyx
has a depth of 12-14 cm.
 Nasal cavity has mucus layer and hairs.
 Relatively large surface area (~150 cm2) because of the presence
of ~400 microvilli per cell.
 It is divided by middle (or nasal) septum into two symmetrical
halves, each one opening at the face through nostrils and
extending posterior to the nasopharynx.
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8. Anatomy and Histology
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9. Cross-Sectional View
a – nasal vestibule
b – palate
c – inferior turbinate
d – middle turbinate
e – superior turbinate
f – nasopharynx
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10. Human Nasal Epitheliuum
Characteristics
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11. Continue…
 Nasal secretions-Nasal secretion contains sodium, potassium,
calcium, mucus glycoproteins, albumins, immunoglobulins IgA,
IgG, lysozymes, cytochrome P450 dependent monooxygenases,
lactate dehydrogenase, oxidoreductases, hydrolases like steroid
hydrolases.
 Nasal pH-It varies between 5.5–6.5 in adults and 5.0–7.0 in
infants. Nasal epithelium is covered with a thin mucus layer and
organized in two distinct layers: an external, viscous and
dense(gel), and an internal, fluid and serous(watery). Nasal mucus
layer consists of 95% of water, 2.5-3% of mucin, and 2% of
electrolytes, proteins, lipids, enzymes, antibodies, epithelial cells
and bacterial products.
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12. Transport Of Drugs Across
Nasal Epithelium
A- Transcellular passive diffusion
B- Paracellular passive diffusion
C-Carrier mediated
D- Transcytosis
E- Efflux transport
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13. Factors Affecting Nasal
Absorption
 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 weight and molecular size: Mc Martin et al
reported a sharp decline in drug absorption having molecular
weight greater than 1000Dalton except with the use of
penetration enhancers. Eg. Polyacrylic acid, Polysorbate 80
etc.
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14. Factors Affecting Nasal
Absorption
 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.
 Lipophilicity: 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.
 Drug concentration: Absorption increases as
concentration of drug increases. 1-tyrosine shows increased
absorption at high concentration.
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15. Mechanisms
 The absorbed drugs from the nasal cavity must pass through
the mucus layer. It is the first step in absorption. The principle
protein of the mucus is mucin which has the tendency to bind
to the solutes, hindering diffusion.
 Two mechanisms are found to be involved:
 Slow rate mechanism: It involves an aqueous route of
transport, which is also known as paracellular route but slow
and passive. It is dependent on molecular weight.
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16. Mechanisms
 Fast rate mechanism: It involves transport through a lipoidal
route known as the transcellular process. It is responsible for the
transport of lipophilic drugs that show a rate dependency on their
lipophilicity. Drugs can also cross cell membranes by an active
transport route via carrier-mediated.
 For example chitosan, a natural biopolymer from shell fish
permeates through opening of tight junctions between epithelial
cells to facilitate drug transport.
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17. Pathways
Possible drug absorption pathways
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18. Delivery Systems
 Various delivery systems are used like
 Nasal drops
 Nasal spray
 Nasal gels
 Nasal powders
 Nasal inserts
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19. New and developing approach to deliver drugs to the brain. Improved delivery
to the brain via the IN route has been reported for some low-mol.wt drugs as well
as therapeutic peptides and proteins.
Nose to brain delivery has been reported either in humans or animal models of
Alzheimer’s disease, brain tumours, epilepsy, pain and sleep disorders .
Nose to the CNS may occur via olfactory neuroepithelium.
Since central nervous bioavailability of drugs, transported by the olfactory-
pathway is estimated to be 0.01% to 0.1%, only very potent drugs may reach
therapeutic levels.
Nose To Brain Delivery
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20. Stratagies to Increase Nasal
Absorption
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21. Continue…
1. Prodrugs: Ex. Yang et al. stated that L-aspartate- β-ester prodrug of
acyclovir was more permeable and less labile to enzymatic hydrolysis
than its parent drug.
2. Enzymatic inhibitors: Trypsine inhibitors – leupeptine and
aprotinin (against degradation of calcitonin).
3. Absorption enhancers: They improve the absorption of poorly
permeable molecues across nasal epithelium. Ex. bile salts-fusidic
acid.
4. Cyclodextrin: They interact with the lipophilic components of
membranes changing their permeability. Ex. A nasal product (Aerodiol)
containing 17-estradiol solubilized in dimethyl-cyclodextrin is
marketed for menopausal symptoms. 20

22. Applications of Nasal Drug
Delivery
 Nasal Delivery of Organic based Pharmaceuticals
e.g.: Progesterone, Estradiol, Testosterone, Hydralzine,
Propranolal, Cocain, Naloxon & Nitrogylcerine. These have
shown good Bioavailability by this route.
Water-soluble organic based compounds such as Sodium
cromoglycate were also found to be well absorbed.
 Nasal Delivery of Peptide-Based Drugs
 As peptide based drugs are susceptible to hepatogastrointestinal
first pass elimination & instability, they show very low oral
bioavailability thus administered through nasal route. Eg.
Insulin, Calcitonin, Pituitary hormones etc.
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23. Applications of Nasal Drug
Delivery
 Delivery of diagnostic drugs: Diagnostic agents such as
 Phenolsulfonphthalein – kidney function
 Secretin – pancreatic disorders
 Pentagastrin – secretory function of gastric acid
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24. Evaluation parameters
1. Evaluation of general physical properties:
1.1. Physical appearance
1.2. Identification of drug in the formulation
1.3. Assay of drug substance in the container
1.4. Determination of impurities and degradation products
1.5. Assay of preservatives and other excipients
1.6. pH of the formulation
1.7. Osmolality of the formulation
1.8. Viscosity of the formulation
1.9. Microbial limit
1.10. Weight loss(Stability) 23

25. Continue…
1.11. Leachability
2. In vitro nasal permeation study: These studies are generally
carried out by the help of diffusion cell. Diffusion cells are available
in different capacities from 10 to 100 ml. we can choose any one of
them as per our requirements. An in vitro permeation study gives us
idea about amount of drug released from the formulation.
3. In vivo nasal absorption study: 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.
3.1. Ex vivo Nasal Perfusion Models: Surgical preparation is the
same as that is for in vivo rat model.
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26. Continue…
3.2. In-vivo bioavailability studies: In-vivo bioavailability study is
conducted on healthy male rabbits.
4. Evaluation of spray related properties
4.1. Net content
4.2. Pump delivery
4.3. Spray content uniformity(SCU)
4.4. Spray pattern
4.5. Droplet size distribution
4.6. Particle size distribution(suspensions)
4.7. Particulate matter
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27. Marketed Preparations
Sr
.
no
Drug substance (Product
name)
Indication Dosage form Manufacturer
A) Proteins and peptide products
1. Salmon Calcitonin (Karil 200
I.E.)
Osteoporosis Solution (spray) Novartis
Pharma
2. Protirelin (Antipan*nasal) Thyroid
diagnostics
Solution (sray) Aventis Pharma
B) Nonpeptide products
1. Sumatriptan Imigran Migraine Solution (spray) GSK
2. Estradiol (Aerodiol) Harmone
replacement
Solution (spray) Servier
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28. References
1. More. PK, Saudagar. RB, Gondkar. SB 2015,“Nasal In-Situ Gel: A
Novel Approach for Nasal Drug Delivery System”,World Journal
of Pharmaceutical Research, Vol.4, Issue 02, pp.686-708.
2. Chein. YW,”Novel Drug Delivery System”,2nd edition, Informa
healthcare, New York, pp.229-268.
3. Robinson. JR, Lee. VHL,”Controlled Drug Delivery Fundamentals
and Aplications”,2nd edition, Marcel Dekker, New York, pp.44.
4. Dave. K, et.al 2012,”Intranasal Drug Delivery System: A Review
on formulation consideration and evaluation parameters” Journal of
Global Pharma Technology, Vol.4, Issue 09, pp.1-17.
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29. References
5. Pagar. SA, et.al 2013,”A Review on Intranasal Drug Delivery
System”,Journal of Advanced Pharmacy Education and
Research, Vol.3, Issue 04, pp.333-346.
6. Kushwaha. SKS, Keshari. RK, Rai. AK 2011,”Nasal Trans-
mucosal Drug Delivery”,Journal of Applied Pharmaceutical
Science”, Vol.1, Issue 07, pp.21-28.
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