Post on 31-Oct-2014
description
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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