nasal drugdeliverysystem

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

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Page 1: Nasal drugdeliverysystem

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

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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

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

NOVEL DRUG DELIVERY

SYSTEM

- an overview

Page 4: Nasal drugdeliverysystem

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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

Page 6: Nasal drugdeliverysystem

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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 Inject-able Mucosal

Trans-derma

lOcular

Vaginal/Anal

Needle

Needle-less

Nasal

Buccal

Pulmo-nary

Active

Passive

Topical

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Global drug delivery market by administration

mode

Oral 53%

Inhalation 32%

Transdermal 8%

Injectable/Implant

3%

Ocular 2%

Nasal 2%

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NASAL

DRUG DELIVERY SYSTEM

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Inhalation/pulmonary drug delivery system

includes

Metered dose inhalers

Dry powder inhalers

Inhalation nasal sprays

Inhalation solutions & suspensions (for

nebulizers)

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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

entityDevelopment cost vis-a-vis new chemical

entity

Merits

Limitations

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Annual growth of locally acting

products

Annual growth of systemically acting

products

11%

30%

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New Chemical Entity

Nasal Drug Delivery2 – 5 years

Drug development time

10 – 14 years

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Nasal Drug Delivery

New Chemical Entity

Drug development cost

$50 mio

$300-600 mio

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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

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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

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NASAL ROUTE

- medical aspects

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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

Pathways for nasal absorption

Nasal site of drug spray & 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 into the cerebrospinal fluid

Absorption through the supporting cells & the

surrounding capillary bed

- venous drainage

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Transneuronal

absorption

Olfactory nerve – 1st cranial sensory nerve

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Venous

drainage

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•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

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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

Page 34: Nasal drugdeliverysystem

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Therapeutic class of

drugs for n

asal 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

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FormulationDevelopme

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

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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

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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

- Non-polar (lipid soluble) drugs 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

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Applicatio

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

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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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CONCLUSIO

N

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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

Page 62: Nasal drugdeliverysystem

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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]