Nasal Drug Delivery System

NASAL
Welcome!
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 1

CONTENTS
Novel Drug Delivery

System
Global trends in drug delivery systems
Nasal Drug Delivery

System
Medical aspects
Formulation Development
Applications
Conclusion

NOVEL DRUG DELIVERY
SYSTEM
- an overview

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%

By 2010, the US drug
delivery market alone will
be worth $30 billion

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

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

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

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

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
Drug Delivery
Systems
Trans-
Inject- Topic Vaginal
Oral Mucosal derma Ocular
able al /Anal
l
Needle Nasal Active
Needle-
Buccal Passive
less
Pulmo-
nary

Global drug delivery market by administration
mode
Nasal 2%
Ocular 2%
Injectable/ Oral
Implant 53%
3%
Transdermal
8%
Inhalation
32%

A L
A S E M
N YS T
Y S
E R
LI V
D E
U G
DR

Inhalation/pulmonary drug delivery system
includes
➨ Metered dose inhalers
➨ Dry powder inhalers
➨ Inhalation solutions & suspensions (for

nebulizers)
➨ Inhalation nasal sprays

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

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

30
%
11
%
Annual growth of Annual growth of

locally acting systemically acting
products products

Drug development
time
10 – 14 years New Chemical

Entity
2 – 5 years Nasal Drug Delivery

Drug development
cost
$300-600 mio New Chemical

Entity
$50 mio
Nasal Drug Delivery

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

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.

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

T E
O U
L R cts
S A p e
A a s
N a l
di c
m e
-

 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 view
Nasal site of drug spray & absorption
Pathways for nasal absorption

Cross-sectional view
a – nasal vestibule d – middle turbinate

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

Site of drug
spray &
absorption

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

Transneuronal
absorption
Olfactory nerve – 1st cranial sensory nerve

Venous
drainage

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

Nasal enzymes – contd.,
•Progesterone and testosterone were

metabolized by several steroid
hydroxylases in the nasal mucosa of rats

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

o f
s s e
c la u t
tic l r o
e u s a
a p n a
e r o r
h
T gs f
r u
d

Therapeutic class of drugs
1. β 2 adrenergic agonists
2. Corticosteroids
3. Antiviral
4. Antibiotics
5. Antifungal
6. More recently, vaccines

Drugs commonly administered through
pulmonary route include
1. Terbutaline Sulphate - β 2 adrenergic agonist
2. Salbutamol - β 2 adrenergic agonist
3. Budesonide - corticosteroid
4. Ipratropium Bromide - anticholinergic
5. Sodium Chromoglycate – mast cell stabilizer

Formulation
Developme
nt

Formulation
Development
Dosage
Dosage form
form
Factors
Factors affecting
affecting drug
drug
absorption
absorption
Formulation
Formulation
considerations
considerations
Physiological
Pharmaceutical
Dosage
forms
Liquid drop
Liquid spray/nebulizers
Aerosol
Suspension
spray/nebulizers
Gel
Sustained release

Drug concentration
Factors
Vehicle of drug delivery
affecting drug
absorption Mucosal contact time
Degree of drug’s ionization
pH of the absorption site
Size of the drug molecule
Relative lipid solubility

Physiological
effects
- Drug metabolism in the respiratory tract &

reduction of systemic effect
- Protein binding
- Mucociliary transport causing increased or

decreased drug residence time

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

Pharmaceutical
- Physico-chemical properties of a drug

candidate
- Methods to enhance drug absorption
- Spray pump devices

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

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

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

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.

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

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

5. Effect of drug concentration
- Absorption depends on the initial concentration

of
the drug
- The absorption follows first-order kinetics

Methods to enhance nasal absorption of
drugs
Structural modification
Salt or ester formation
Formulation design

SPRAY PUMP DEVICES
- Unidose
- Bidose
- Multidose

Bidose
Unido 53
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041
Multidose

LEADING PUMP
SUPPLIERS
Pfeiffer, Germany
Valois, France
Becton Dickinson, France
Nemo, Spain

Applicatio
ns
Delivery of non-peptide
pharmaceuticals
Delivery of peptide-based
pharmaceuticals
Delivery of diagnostic drugs

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
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

3. Delivery of diagnostic drugs
Diagnostic agents such as
• Phenolsulfonphthalein – kidney function
• Secretin – pancreatic disorders
• Pentagastrin – secretory function of gastric

acid

S IO
C LU
C O N
N
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

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

Attractive for delicate
molecules allowing systemic
administration without
significant degradation

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

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

Cell No: 00919742431000; E-mail: bknanjwade@yahoo.co.in

Nasal Drug Delivery System

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NASAL

Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 1

Novel Drug Delivery

Nasal Drug Delivery

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 2

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 3

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 4

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 5

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 6

To optimize drug’s therapeutic

To improve `patient compliance

To facilitate biological drug delivery

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 7

➢ Novel alternatives to existing delivery systems

➢ Enhancements to existing systems

Eg. polar organics and other poorly absorbed

existed since the late 1960s, when Alza

and Elan pioneered the oral methods of

The introduction of hypodermic devices

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 9

More novel technologies such as pulmonary

Needle Nasal Active

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 11

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 12

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 13

➨ Dry powder inhalers

➨ Inhalation solutions & suspensions (for

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 14

Therapy through intranasal administration has

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 15

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 16

Annual growth of Annual growth of

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 17

10 – 14 years New Chemical

2 – 5 years Nasal Drug Delivery

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 18

$300-600 mio New Chemical

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 19

Rate of absorption comparable to IV

Rapid onset of pharmacological action

User-friendly, painless, non-invasive,

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 20

Lower dose & hence lower side effects

Useful for both local & systemic drug delivery

For CNS drugs, better site for rapid onset of

Eg. Inhalation anesthesia, Morphine etc.

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 21

➣ Once administered, rapid removal of the

➣ Pathologic conditions such as cold or allergies

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 22

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 23

 provides a relatively large mucosal surface area of

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 24

Nasal site of drug spray & absorption

Pathways for nasal absorption

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 25

a – nasal vestibule d – middle turbinate

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 26

03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 27

- transneuronal absorption. Olfactory epithelium is

considered as a portal for substances to enter

 Absorption into the cerebrospinal fluid