Date post: | 17-Dec-2015 |
Category: |
Documents |
Upload: | elwin-sims |
View: | 218 times |
Download: | 0 times |
1Sinhgad College of Pharmacy, Vadgaon, Pune-41104103/10/2009
Welcome!
[Company Name]
NASAL
DRUG DELIVERY
SYSTEM
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate ProfessorDepartment of Pharmaceutics
KLE University, Belgaum – 590010Karnataka, INDIA
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 2
Novel Drug Delivery System
Global trends in drug delivery systems
Nasal Drug Delivery System
Medical aspects
Formulation Development
Applications
Conclusion
CONTENTS
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 3
NOVEL DRUG DELIVERY
SYSTEM
- an overview
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 4
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%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 5
By 2010, the US drug
delivery market alone will
be worth $30 billion
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 6
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 7
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 8
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 9
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 10
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 11
Drug Delivery Systems
Oral Inject-able Mucosal
Trans-derma
lOcular
Vaginal/Anal
Needle
Needle-less
Nasal
Buccal
Pulmo-nary
Active
Passive
Topical
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 12
Global drug delivery market by administration
mode
Oral 53%
Inhalation 32%
Transdermal 8%
Injectable/Implant
3%
Ocular 2%
Nasal 2%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 14
Inhalation/pulmonary drug delivery system
includes
Metered dose inhalers
Dry powder inhalers
Inhalation nasal sprays
Inhalation solutions & suspensions (for
nebulizers)
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 15
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 16
Nasal Drug Delivery System
&
Opportunity
Annual market growth
Development time vis-a-vis new chemical
entityDevelopment cost vis-a-vis new chemical
entity
Merits
Limitations
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 17
Annual growth of locally acting
products
Annual growth of systemically acting
products
11%
30%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 18
New Chemical Entity
Nasal Drug Delivery2 – 5 years
Drug development time
10 – 14 years
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 19
Nasal Drug Delivery
New Chemical Entity
Drug development cost
$50 mio
$300-600 mio
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 20
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 21
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 22
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 24
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 25
Cross-sectional view
Pathways for nasal absorption
Nasal site of drug spray & absorption
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 26
Cross-sectional view
a – nasal vestibule d – middle turbinate
b – palate e – superior turbinate (olfactory mucosa)
c – inferior turbinate f – nasopharynx
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 28
Pathways for nasal
absorption Absorption through the olfactory neurons
- transneuronal absorption. Olfactory epithelium is
considered as a portal for substances to enter
CNS
Absorption into the cerebrospinal fluid
Absorption through the supporting cells & the
surrounding capillary bed
- venous drainage
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 29
Transneuronal
absorption
Olfactory nerve – 1st cranial sensory nerve
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 31
•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
Nasal enzymes
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 32
•Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats
Nasal enzymes – contd.,
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 33
•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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 34
Therapeutic class of
drugs for n
asal route
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 35
Therapeutic class of drugs
1. 2 adrenergic agonists
2. Corticosteroids
3. Antiviral
4. Antibiotics
6. More recently, vaccines
5. Antifungal
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 36
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 38
Formulation
Development
Dosage formDosage form
Formulation considerationsFormulation
considerations
Factors affecting drug absorption
Factors affecting drug absorption
Physiological
Pharmaceutical
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 39
Dosage
forms
Liquid drop
Liquid spray/nebulizers
Suspension
spray/nebulizersGel
Sustained release
Aerosol
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 40
Factors
affecting drug
absorption
Drug 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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 41
Physiological effects
- Drug metabolism in the respiratory tract &
reduction of systemic effect
- Mucociliary transport causing increased or
decreased drug residence time
- Protein binding
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 42
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 43
Pharmaceutical
- Physico-chemical properties of a drug
candidate
- Spray pump devices
- Methods to enhance drug absorption
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 44
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 45
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 46
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 47
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 48
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 49
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
- Non-polar (lipid soluble) drugs are more likely to
reach distal airways
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 50
5. Effect of drug concentration
- The absorption follows first-order kinetics
- Absorption depends on the initial concentration
of
the drug
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 51
Methods to enhance nasal absorption of
drugs
Structural modification
Formulation design
Salt or ester formation
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 52
SPRAY PUMP DEVICES
- Unidose
- Multidose
- Bidose
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 55
LEADING PUMP
SUPPLIERS
Pfeiffer, Germany
Valois, France
Nemo, Spain
Becton Dickinson, France
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 56
Applicatio
nsDelivery of non-peptide
pharmaceuticals
Delivery of diagnostic drugs
Delivery of peptide-based
pharmaceuticals
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 57
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%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 58
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 59
3. Delivery of diagnostic drugs
Diagnostic agents such as
Phenolsulfonphthalein – kidney function
Secretin – pancreatic disorders
Pentagastrin – secretory function of gastric
acid
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 61
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 62
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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 63
Attractive for delicate
molecules allowing systemic
administration without
significant degradation
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 64
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 65
Recent activities indicate a
bright prospect for site-specific
delivery of biotechnological
products such as Insulin &
other hormones
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 66
Cell No: 00919742431000; E-mail: [email protected]