Welcome!: Nasal Drug Delivery System

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 1
CONTENTS
Novel Drug Delivery System
Global trends in drug delivery systems

Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune-411041
NOVEL DRUG DELIVERY SYSTEM - an overview
03/10/2009
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
By 2010, the US drug

delivery market alone will be worth $30 billion
03/10/2009
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
Why Novel Drug

Delivery system? To optimize drugs therapeutic effect, convenience and dose To enhance a products 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 therapeutics
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
Oral
Injectable
Mucosal
Topical
Transdermal
Ocular
Vaginal/ Anal
Needle Needleless
Nasal Buccal Pulmonary
Active Passive
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Global drug delivery market by administration mode

Nasal 2% Ocular 2% Injectable/ Implant 3% Transdermal 8% Inhalation 32% Oral 53%
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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
Annual growth of systemically acting products
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Drug development time
10 14 years
New Chemical Entity
2 5 years
Nasal Drug Delivery
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Drug development cost
$300-600 mio
New Chemical Entity
$50 mio
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 b palate c inferior turbinate
d middle turbinate e superior turbinate (olfactory mucosa) 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

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
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
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 drugs 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
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
03/10/2009
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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.
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
03/10/2009
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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
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
03/10/2009
56
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%
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
03/10/2009
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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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03/10/2009
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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: bknanjwade@yahoo.co.in
03/10/2009
66

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Welcome!

DRUG DELIVERY SYSTEM

Global trends in drug delivery systems

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

NOVEL DRUG DELIVERY SYSTEM - an overview

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

delivery systems increasing @

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

By 2010, the US drug

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

There are great opportunities for companies

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Why Novel Drug

To target drug delivery To control overall healthcare costs

The Novel Drug Delivery industry is comprised of

companies seeking to develop

Novel alternatives to existing delivery systems

Enhancements to existing systems

Commercially enabling delivery systems that provide

enhanced drug delivery

systems for specific diseases

using proven delivery technology is growing

injections are under development and are yet to be

Drug Delivery Systems

Nasal Buccal Pulmonary

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Global drug delivery market by administration mode

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Inhalation/pulmonary drug delivery system includes

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Historically, nasal drug delivery system has

received interest since ancient times

Therapy through intranasal administration has been

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal Drug Delivery System

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Annual growth of locally acting products

Annual growth of systemically acting products

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drug development time

New Chemical Entity

Nasal Drug Delivery

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drug development cost

New Chemical Entity

Nasal Drug Delivery

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

For CNS drugs, better site for rapid onset of action

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Once administered, rapid removal of the

Pathologic conditions such as cold or allergies

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Sinhgad College of Pharmacy, Vadgaon, Pune-411041

The respiratory tract, which includes the

nasal mucosa hypopharynx large airways & small airways

provides a relatively large mucosal surface area of