nasal drug delivery 2
DESCRIPTION
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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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