PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY
COLLEGE OF PHARMACY
PHARMACEUTICSIV
(PHT 414 )
NASAL DRUG DELIVERY
SYSTEM
Dr. Shahid Jamil
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Inhalation/pulmonary drug delivery system includes
 Metered dose inhalers
 Dry powder inhalers
 Inhalation solutions & suspensions (for nebulizers)
 Inhalation nasal sprays
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Merits
Avoidance of hepatic first-pass metabolism
Rate of absorption comparable to IV
medication
Rapid onset of pharmacological action
User-friendly, painless, non-invasive,
needle-free administration mode
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Merits...
Lower dose & hence lower side effects
Useful for both local & systemic drug delivery
For CNS drugs, better site for rapid onset of
action
Eg. Inhalation anesthesia, Morphine etc.
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Limitations

Once administered, rapid removal of the
therapeutic agent from the site of absorption is
difficult

Pathologic conditions such as cold or allergies
may alter significantly the nasal bioavailability
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 The respiratory tract, which includes the


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nasal mucosa
hypopharynx
large airways &
small airways
 provides a relatively large mucosal surface area of
approx. 100 m2 (in normal adult) for drug
absorption
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Cross-sectional view
Nasal site of drug spray & absorption
Pathways for nasal absorption
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Cross-sectional view
a – nasal vestibule
d – middle turbinate
b – palate
e – superior turbinate (olfactory mucosa)
c – inferior turbinate
f – nasopharynx
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Site of drug
spray &
absorption
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Pathways for nasal absorption
 Absorption through the olfactory neurons
- transneuronal absorption. Olfactory epithelium is
considered as a portal for substances to enter CNS
 Absorption through the supporting cells & the
surrounding capillary bed
- venous drainage
 Absorption into the cerebrospinal fluid
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Transneuronal absorption
Olfactory nerve – 1st cranial sensory nerve
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Nasal enzymes
•Cytochrome P 450 dependent monooxygenases,
Lactate dehydrogenase, Oxidoreductase, Hydrolases,
Esterase, lactic dehydogenase, malic enzymes, lysosomal
proteinases, steroid hydroxylases., etc.,
•Cytochrome P450 dependent mono oxygenases has
been reported to catalyse the metabolism of xenobiotics,
nasal decongestants, nicotine, cocaine, phenacetin,
nitrosamine progesterone etc.,
•Insulin zinc free was hydrolysed slowly by leusine
aminopeptidase,
•PG of E series was inactivated 15 hydroxyprostaglandin
dehydrogenase
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Nasal enzymes – contd.,
•Progesterone and testosterone were
metabolized by several steroid
hydroxylases in the nasal mucosa of rats
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Nasal pH
•Nasal secretion of adult : 5.5-6.5
•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
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Therapeutic class of drugs
1. 2 adrenergic agonists
2. Corticosteroids
3. Antiviral
4. Antibiotics
5. Antifungal
6. More recently, vaccines
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Drugs commonly administered through pulmonary
route include
1. Terbutaline Sulphate - 2 adrenergic agonist
2. Salbutamol - 2 adrenergic agonist
3. Budesonide - corticosteroid
4. Ipratropium Bromide - anticholinergic
5. Sodium Chromoglycate – mast cell stabilizer
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Formulation
Development
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Formulation Development
Dosage form
Factors affecting drug
absorption
Formulation considerations
Physiological
Pharmaceutical
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Dosage forms
Liquid drop
Liquid spray/nebulizers
Aerosol
Suspension spray/nebulizers
Gel
Sustained release
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Drug concentration
Factors affecting
drug absorption
Vehicle of drug delivery
Mucosal contact time
Degree of drug’s ionization
pH of the absorption site
Size of the drug molecule
Relative lipid solubility
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Physiological effects
-
Drug metabolism in the respiratory tract &
reduction of systemic effect
-
Protein binding
-
Mucociliary transport causing increased or
decreased drug residence time
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Physiological effects....
-
Local toxic effects of the drug
Eg., edema, cell injury, or altered tissue defenses
-
Local or systemic effects of propellants,
preservatives, or carriers
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Pharmaceutical
-
Physico-chemical properties of a drug candidate
-
Methods to enhance drug absorption
-
Spray pump devices
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1. Effect of particle size
2. Effect of molecular size
3. Effect of solution pH
4. Effect of drug lipophilicity
5. Effect of drug concentration
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1. Effect of particle size
(aerodynamic size distribution)
- 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
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2. Effect of 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
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2. Effect of molecular size.....
- With the assistance of absorption enhancer, a good
bioavailability can be extended to a molecular
weight of at least 6000 Daltons
Absorption enhancers:
Polyacrylic acid
Sodium Glycocholate
Sodium Deoxycholate
Polysorbate 80 etc.
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3. Effect of 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
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4. Effect of drug 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
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5. Effect of drug concentration
- Absorption depends on the initial concentration of
the drug
- The absorption follows first-order kinetics
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Methods to enhance nasal absorption of drugs
Structural modification
Salt or ester formation
Formulation design
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SPRAY PUMP DEVICES
- Unidose
- Bidose
- Multidose
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Bidose
Unidose
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Multidose
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Applications
Delivery of non-peptide pharmaceuticals
Delivery of peptide-based pharmaceuticals
Delivery of diagnostic drugs
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1. Delivery of non-peptide pharmaceuticals
Drugs 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%
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2. Delivery of peptide-based pharmaceuticals
Peptides & proteins have a generally low oral
bioavailability because of their physico-chemical
instability and susceptibility to hepatogastrointestinal first-pass elimination
Eg. Insulin, Calcitonin, Pituitary hormones etc.
Nasal route is proving to be the best route for such
biotechnological products
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3. Delivery of diagnostic drugs
Diagnostic agents such as
 Phenolsulfonphthalein – kidney function
 Secretin – pancreatic disorders
 Pentagastrin – secretory function of gastric acid
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