nasal drug delivery 2

NASAL DRUG DELIVERY SYSTEM

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Introduction Intranasal Medication administration offers a truly

“Needleless” solution to drug delivery.

Therapy through intranasal administration has been an accepted a form of treatment in the Ayurvedic system of Indian medicine

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Merits

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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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NASAL ROUTE

- medical aspects

• 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

Cross-sectional view

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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

Nose brain pathway

The olfactory mucosa (smelling area in nose) is in direct contact with the brain and CSF.

Medications absorbed across the olfactory mucosa directly enter the brain.

This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain.

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Olfactory mucosa

Highly vascular nasal mucosa

BrainCSF

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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

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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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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

Mucosal contact time

pH of the absorption site

Size of the drug particle

Relative lipid solubility

Molecule weight of the drug

Factors Affecting Bioavailability

Delivery system characteristics: Nasal mucosal surface area coverage:• Larger surface area delivery = higher bioavailability.

Particle size:• Particle size 10-50 microns adheres best to the nasal

mucosa. • Smaller particles pass on to the lungs, larger particles

form droplets and run-out of the nose.

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Cont..

Atomization results in higher bioavailability than either spray or drops.

For this reason, nasal pharmaceuticals come with atomized drug delivery systems.

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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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Methods to enhance nasal absorption of drugs

Structural modification

Formulation design

Salt or ester formation

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SPRAY PUMP DEVICES

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Bidose

Unidose

Multidose

Nasal Drops

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Nasal drops are one of the most simple and convenient systems developed for nasal delivery.

The main disadvantage of this system is the lack of the dose precision and therefore nasal drops may not be suitable for prescription products.

It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal sprays.

Nasal sprays

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Both solution and suspension formulations can be formulated into nasal sprays.

Due to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose from 25 to 200 μm. The particles size and morphology(for suspensions)of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.

Lincoln Pharma wins patent for a novel nasal drug delivery system

• Presently in India anti-vomiting treatments are available in the conventional form of tablet and injection which take longer time to bring relief.

• But now through LPL’s new Nasal Drug Delivery System, the patient can get immediate relief. LPL becomes the first company in India to introduce an anti-vomiting treatment in the form of a Nasal spray pump.

• Stem Cell Nasal Spray for Parkinson Disease Significantly Improves Motor Function

Successful intranasal delivery of stem cells to the brains of rats with Parkinson disease yielded significant improvement in motor function and reversed the dopamine deficiency characteristic of the disease.

This was reported as a Rejuvenation Research in journal published by Mary Ann Liebert.

Mucosal Atomization Device (MAD)

– Device designed to allow emergency personnel to delivery nasal medications as an atomized spray.

– Broad 30-micron spray ensure excellent mucosal coverage.

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Nasal PowderThis dosage form may be developed if solution and suspension dosage forms cannot be developed e.g., due to lack of drug stability.

The advantages to the nasal powder dosage form are the absence of preservative and superior stability of the formulation.

Local application of drug is another advantage of this system.

Nasal powder formulation depends on the solubility, particles size, aerodynamic properties and nasal irritancy of the active drug and /or excipients.

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Nasal Gels Nasal gels are high-viscosity thickened solutions or suspensions.

Advantages of a nasal gelReduction of post-nasal drip due to high viscosity,Reduction of taste impact due to reduced swallowing,Reduction of anterior leakage of the formulation,Reduction of irritation by using soothing/emollient excipients and target to mucosa for better absorption.

Nasal vaccines

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Nasal mucosa is first site of contact with inhaled antigens and, therefore, its use for vaccination, especially against respiratory infections

Nasal vaccination is a promising alternative to the classic parenteral route, because it is able to enhance the systemic levels of specific immunoglobulin G and nasal secretary immunoglobulin A.

Examples of human efficacy of intranasal vaccines include those against influenza A and B virus, proteosoma influenza. Denovirusvectored influenza and parainfluenza virus

Intra nasal H1N1 vaccine Nasovac by Serum Institute

Current systemic therapeutics delivered nasally

Desmopressin for diabetes mellitus

Calcitonin for osteoporosis

Sumatriptan for migraines

Nascobal for pernicious anemia

Nasal Drug Delivery medications

Drugs of interest in Intranasal systems:

Intranasal naloxone (Narcan)

Intranasal midazolam (Versed)

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Intranasal (IN) NaloxoneAbsorption of Intranasal naloxone almost as fast as

IV in both animal and human models

“Atomization” of medications show much better absorption via the Intranasal route

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Examples of Intranasal Drug Delivery Systems

Intranasal sustained-release formulation– Nasal absorption with Clofilium tosylate, enkephalin

analogs– Short biological half-life

Tobispray– Dry, metered-dose nasal aerosol– Vasoconstrictor (tramazoline), steroid (dexamethasone

isonicotinate), antibiotic (neomycin sulfate)

Other examples are : Butorphanol, calcitocin, sumatriptan, Insulin, Vaccine

and brain targeting drugs.37

Efficacy of cocaine by oral and intranasal administration– Nasal : detect in plasma by 15 min, peak concentration at

60 to 120 min, decrease gradually over the next 2 to 3h– Oral : not detected until 30 min, increased rapidly for the

next 30 min In vivo absorption of sulbenicillin, cephacetrile, cephazoline– Oral : poor absorption because of high water solubility– Intranasal : ½ of im injection (% excretion in the urine )

Cont…

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Market product

otrivin spray (xylometazoline)

miacalcin spray (calcitonin)

vibrocil gel (phenylephrine,dimethindene maleate )

naset-p (xylometazoline HCL)-nasal drop

nasovac H1N1 vaccine

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Leading pump suppliers

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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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