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Welcome!

NASAL

DRUG DELIVERY

SYSTEM

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Nasal Drug Delivery System

Medical aspects

Formulation Development

Applications

Conclusion

CONTENTS

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Avoidance of hepatic first-pass metabolism

Merits

Rapid onset of pharmacological action

User-friendly, painless, non-invasive,

needle-free administration mode

Rate of absorption comparable to IV

medication

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Lower dose & hence lower side effects

Merits...

For CNS drugs, better site for rapid onset of

action

Eg. Inhalation anesthesia, Morphine etc.

Useful for both local & systemic drug delivery

Continue…

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Highly vascularized sub-epithelial layer allowing rapid and direct absorption into systemic circulation

Less hostile biochemical environment in comparison to GIT

Improved patient compliance and comfort in compared to IV route

Avoiding First-pass metabolism

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Limitations

Pathologic conditions such as cold or allergies

may alter significantly the nasal

bioavailability

Once administered, rapid removal of the

therapeutic agent from the site of absorption

is difficult

Anatomy7

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

Cross-sectional view8

a – nasal vestibule c – inferior turbinate

d – middle turbinate

b – palate e – superior turbinate (olfactory mucosa)f – nasopharynx

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Three major mechanisms of drug absorption:-First mechanism involves an aqueous route of transport,

• Also known as the paracellular route• Slow and passive• Absorption is inversely proportional to the molecular weight

of water-soluble compounds. • Poor bioavailability - for drug with a molecular weight

>1000 Daltons.

The second mechanism involves • Transport through a lipoidal route is also known as the

transcellular process • Responsible for the transport of lipophillic drugs • Rate of absorption is dependent on lipophilicity of drug

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Third mechanism • An active transport route via carrier-mediated means or

transport through the opening of tight junctions. • For examples, chitosan, a natural biopolymer from

shellfish, opens tight junctions between epithelialcells to facilitate drug transport.

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• Cytochrome P 450 dependent monooxygenases, Lactate dehydrogenase, Oxidoreductase, Hydrolases, Esterase, 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

Nasal enzymes

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•Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats

Nasal enzymes – contd.

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• 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

Nasal pH

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Therapeutic class of drugs for nasal route

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Therapeutic class of drugs

1. 2 adrenergic agonists

2. Corticosteroids

3. Antiviral

4. Antibiotics

6. More recently, vaccines

5. Antifungal

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Drugs commonly administered

through pulmonary route include

1. Terbutaline Sulphate - 2 adrenergic agonist

2. Salbutamol - 2 adrenergic agonist

4. Ipratropium Bromide - anticholinergic

5. Sodium Chromoglycate – mast cell stabilizer

3. Budesonide - corticosteroid

Treatment of….17

Acute pain-reliefSmoke cessationMigraineOsteoporosisVit-B12 deficiencyPotential to deal with insulin

dependent diabetes, rheumatoid arthritis, emetics, cancer therapy, CNS drug delivery etc.

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Formulation

Developme

nt

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Formulation

Development

Dosage formDosage form

Formulation considerationsFormulation

considerations

Factors affecting drug absorption

Factors affecting drug absorption

Physiological

Pharmaceutical

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Dosage

forms

Liquid drop

Liquid spray/nebulizers

Suspension

spray/nebulizersGel

Sustained release

Aerosol

The factors influencing nasal drug absorption

21A) Physiochemical properties of drug.

· Molecular size.· Lipophilic-hydrophilic balance.

B) Nasal Effect· Membrane permeability.· Environmental pH

· Mucociliary clearance· Cold, rhinitis.· Enzymatic degradation in nasal cavity.

C) Delivery Effect· Formulation (Concentration, pH, osmolarity)· Delivery effects· Drugs distribution and deposition.· Formulation effect on mucociliary clearance.· Toxic effect on ciliary function and epithelial membranes.

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Factors affecting drug

absorptionDrug concentration

Vehicle of drug delivery

Mucosal contact time

pH of the absorption site

Size of the drug molecule

Relative lipid solubility

Degree of drug’s ionization

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Physiological effects

- Drug metabolism in the respiratory tract &

reduction of systemic effect

- Mucociliary transport causing increased or

decreased drug residence time

- Protein binding

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Physiological

effects....

- Local or systemic effects of propellants,

preservatives, or carriers

- Local toxic effects of the drug

Eg., edema, cell injury, or altered tissue defenses

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Pharmaceutical

- Physico-chemical properties of a drug

candidate

- Spray pump devices

- Methods to enhance drug absorption

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1. Effect of particle size

2. Effect of molecular size

3. Effect of solution pH

5. Effect of drug concentration

4. Effect of drug lipophilicity

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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

- Intermediate particles (3 to 7 microns) reach the

actual site of action

- Small particles (< 3 microns) will be lost in

exhaled

breathe

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2. Effect of molecular size

- A good systemic bioavailability can be achieved for

molecules with a molecular weight of up to 1000

Daltons when no absorption enhancer is used

- Higher the molecular size, lower the nasal

absorption

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2. Effect of molecular size.....

Absorption enhancers: Polyacrylic acid

Sodium Glycocholate

Sodium Deoxycholate

Polysorbate 80 etc.

- With the assistance of absorption enhancer, a good

bioavailability can be extended to a molecular

weight of at least 6000 Daltons

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3. Effect of solution pH

- Nasal absorption is pH dependent

- Absorption is lower as the pH increases beyond

the dissociation constant

- Absorption is higher at a pH lower than the

dissociation constant (pKa) of the molecule

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4. Effect of drug lipophilicity

- Polar (water soluble) drugs tend to remain on

the

tissues of the upper airway

- Lipid soluble drugs are absorbed more rapidly

than water soluble drugs and are more likely

to

reach distal airways

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5. Effect of drug concentration

- The absorption follows first-order kinetics

- Absorption depends on the initial concentration

of

the drug

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Methods to enhance nasal absorption of

drugs

Structural modification

Formulation design

Salt or ester formation

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SPRAY PUMP DEVICES

- Unidose

- Multidose

- Bidose

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Bidose

Unido

se

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Multidose

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LEADING PUMP

SUPPLIERS

Pfeiffer, Germany

Valois, France

Nemo, Spain

Becton Dickinson, France

38Applicatio

nsDelivery of non-peptide

pharmaceuticals

Delivery of diagnostic drugs

Delivery of peptide-based

pharmaceuticals

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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

41 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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CONCLUSIO

N

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• Nasal drug delivery offers 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

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Recent activities indicate a

bright prospect for site-specific

delivery of biotechnological

products such as Insulin &

other hormones