Transcript Welcome! NASAL DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor [Company Name] Department of Pharmaceutics KLE University, Belgaum – 590010 Karnataka, INDIA 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Welcome!
NASAL
DRUG DELIVERY
SYSTEM
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate Professor
[Company
Name]
Department
of Pharmaceutics
KLE University, Belgaum – 590010
Karnataka, INDIA
03/10/2009
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CONTENTS
Novel Drug Delivery System
Global trends in drug delivery systems
Nasal Drug Delivery System
Medical aspects
Formulation Development
Applications
Conclusion
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NOVEL DRUG DELIVERY
SYSTEM
- an overview
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Novel drug delivery is one of
the fastest growing healthcare
sectors, with sales of drugs
incorporating novel drug
delivery systems increasing @
an annual rate of 15%
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By 2010, the US drug
delivery market alone will
be worth $30 billion
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There are great opportunities for companies
investing in R&D for new, improved drug
delivery system, allowing for improved
therapeutic absorption and efficacy in
patients
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Why Novel Drug
Delivery system?
To optimize drug’s therapeutic
effect, convenience and dose
To enhance a product’s life-cycle
To improve `patient compliance
To target drug delivery
To control overall healthcare costs
To facilitate biological drug delivery
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The Novel Drug Delivery industry is comprised of
companies seeking to develop
 Novel alternatives to existing delivery systems
Eg. implantable pumps
 Enhancements to existing systems
Eg. sustained release oral dosage forms to
reduce dosing frequency
 Commercially enabling delivery systems that provide
viable alternatives for therapeutics that are not fully
developed and marketed because there are
limited practical means of administration
Eg. polar organics and other poorly absorbed
therapeutics
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Novel drug delivery companies have
existed since the late 1960s, when Alza
and Elan pioneered the oral methods of
enhanced drug delivery
The introduction of hypodermic devices
but especially metered dose inhalers &
nasal sprays, promoted the concept and
absolute need for specific drug delivery
systems for specific diseases
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Today there are between 300 & 350 companies
worldwide with an interest in drug delivery, operating in a
fierce environment where the number of drug launches
using proven delivery technology is growing
More novel technologies such as pulmonary delivery
of insulin or needle-less human growth hormone
injections are under development and are yet to be
commercialized
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Drug Delivery Systems
Oral
Injectable
Mucosal
Topical
Transdermal
Needle
Nasal
Active
Needleless
Buccal
Passive
Ocular
Vaginal/
Anal
Pulmonary
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Global drug delivery market by administration mode
Nasal 2%
Ocular 2%
Injectable/
Implant 3%
Oral 53%
Transdermal
8%
Inhalation
32%
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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
locally acting
products
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Annual growth of
systemically acting
products
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Drug development time
10 – 14 years
2 – 5 years
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New Chemical Entity
Nasal Drug Delivery
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Drug development cost
$300-600 mio
$50 mio
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New Chemical Entity
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
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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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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 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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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
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Recent activities indicate a bright
prospect for site-specific delivery of
biotechnological products such as
Insulin & other hormones
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Cell No: 00919742431000; E-mail: [email protected]
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