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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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 Historically, nasal drug delivery system has
received interest since ancient times

Therapy through intranasal administration has been

an accepted form of treatment in the Ayurvedic
system of Indian medicine

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 Nasal Drug Delivery System
&
Opportunity
Annual market growth

Development time vis-a-vis new chemical entity

Development cost vis-a-vis new chemical entity

Merits

Limitations

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 30%

11%

Annual growth of Annual growth of

locally acting systemically acting
products products

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 Drug development time

10 – 14 years New Chemical Entity

2 – 5 years Nasal Drug Delivery

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 Drug development cost

$300-600 mio New Chemical Entity

$50 mio
Nasal Drug Delivery

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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

 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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 Venous drainage

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 Nasal enzymes
•Cytochrome P 450 dependent onooxygenases, 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, nocotine, 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

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
Vehicle of drug delivery
drug absorption
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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 LEADING PUMP SUPPLIERS

Pfeiffer, Germany

Valois, France

Becton Dickinson, France

Nemo, Spain

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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 hepato-
gastrointestinal 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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 Nasal route is a part of drug delivery
strategy that is emerging to be a fastest
growing drug delivery system with an
annual growth of
11% for locally acting drugs
&
30% for systemically acting drugs

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 Nasal drug delivery offers such benefits as

Rapid onset of action with lower dose &

minimal side effects

Has an advantage of site-specific delivery

with improved therapeutic effects

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 Attractive for delicate molecules
allowing systemic administration
without significant degradation

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 Nasal drug delivery system offers
flexibility for multiple formulations
ranging from nasal drop to
suspension spray

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 51

 Recent activities indicate a bright
prospect for site-specific delivery of
biotechnological products such as
Insulin & other hormones

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