(PM3A) Nasal Drug Delivery Flashcards
Where is the nasal passage located?
Above the oral cavity in the head
What lines the nasal cavity?
Mucosal membranes
What types of cell comprise a mucosal membrane?
(1) Ciliated columnar cell (cilia + microvilli)
(2) Basal cells
(3) Goblet cells - packed with mucous granules
(4) Non-ciliated columnar cells (microvilli)
Where can ciliated columnar cells be found?
Mucosal membranes
Where can basal cells be found?
Mucosal membranes
Where can goblet cells be found?
Mucosal membranes
Where can non-ciliated columnar cells be found?
Mucosal membranes
What temperature does the nose bring inhaled air to?
32ºC
Possible from 23-40ºC
What size particles do the vibrisae filter out?
Particles >10mcm
What size are the largest particles not removed by the nose via inhalation?
2mcm
What size particles are cleared via mucociliary clearance?
5-10mcm
What size particles are not filtered by the nasal cavity passages and are able to reach the lungs?
<2mcm
What is mucociliary clearance?
Dust + microorganisms trapped in a viscoelastic mucous blanket lining the nasal packages
Mucous is rolled by cilia
Cilia beat in a coordinated manner within periciliary fluid
Brought towards nasopharynx
In nasopharynx mucous is swallowed/ expectorated
At what rate is mucous moved in the nasal cavity by cilia?
10cm/ min
How long does clearance of the bulk of the mucous in nose take to reach the nasopharynx?
~10-20 minutes
What is nasal mucous?
Entraps substances entering nasal cavity
Removed via mucociliary clearance
How is inspired air humidified?
Using the ability of mucous to retain water
What role does mucous have in drug adsorption?
Acts as a diffusion barrier
What types of drug are usually applied using the nasal route?
(1) Locally acting to alleviate nasal symptoms
(2) Drugs that are inactivated via the GI tract
- Route can be alternative to IV
What is the only location in the body that provides a direct connection between the CNS and atmosphere?
Nasal mucosa
What separates the olfactory bulb from the nasal cavity?
Olfactory nerves
Where is the olfactory bulb located?
Front brain
Above olfactory nerves
What are some advantages of nasal drug delivery?
(1) Large surface area for absorption - 160cm^2
(2) Highly vascularised surface - rapid absorption + onset
(3) Low metabolic activity
(4) Good accessibility + easy administration
(5) Some drugs can be absorbed directly into CNS
(6) Can bypass blood brain barrier
What are some disadvantages of nasal drug delivery?
(1) Mucociliary clearance
(2) Mucous barrier
(3) Some metabolic activity
(4) Limited to potent molecules
(5) Common diseases can alter conditions of nose
(6) Mucosal membranes can be sensitive to irritation
What physicochemical factors are of importance in nasal drug delivery?
(1) Molecular weight
(2) Particle size
(3) Concentration
(4) pH of dosage form
(5) Viscosity
(6) Tonicity of dosage form
What is important about molecular weight when considering nasal drug delivery?
<1000 Da
<6000 Da with penetration enhancers
Larger molecules will cause nasal damage
What is important about pH when considering nasal drug delivery?
Mucous layer is pH5.5-6.5 (slightly acidic)
Absorption of drugs generally increased due to less ionisation
Cationic drugs may be retained by binding to negatively charged mucous glycoproteins
pH can affect peptide absorption with greater complexity
What is important about concentration when considering nasal drug delivery?
Rate of absorption is affected by concentration of drug in solution at absorbing membrane
Most drugs travel across nasal mucosa via passive diffusion
Highest concentration of drug possible should be chosen
High concentrations of drug used locally for extended periods may cause severe irritation/ adverse tissue reactions
Give 2 types of passive diffusion.
(1) Transcellular
(2) Paracellular
What is important about particle size when considering nasal drug delivery?
Smaller particles travel further in the lungs
Larger particles (5-10mcm) tend to deposit in the nasal passage
What are nasal drops?
Dispersion of a drug solution throughout the length of the nasal cavity (from atrium to nasopharynx)
Relatively large area for immediate absorption
What are nasal sprays?
Deposit at the front of nasal cavity
Little of the dose reaches the turbinates
What are turbinates?
Three thin curved shelves of bone in the sides of the nasal cavity
How much of the administered dose in a nasal delivery is cleared within 20 minutes?
~20%
How many stages of clearance are there in nasal delivery
2
(1) Fast 20 minute clearance
(2) Slow phase
How does the second phase of clearance of nasal delivery differ to the first?
Much slower
Clearance of nasal drops is much faster
Clearance of nasal spray is much slower
Why does a nasal spray get cleared more slowly in the second phase of nasal clearance?
Most of the spray deposits on non-ciliated regions
What is a better method to administer rapidly absorbed drugs via the nasal route?
Nasal drops as they are cleared much faster
Why may a drug be administered as a nasal spray instead of drops?
Drugs that diffuse across the nasal epithelium relatively slowly
Require longer contact
What is the correct procedure for administration of nasal drops?
(1) Lie on back + face up
(2) Lie on back + face left
(3) Lie on back + face right
(4) Lie on back + face up
(5) Sit forward + face down
(6) Sit straight
How may drug availability be improved in nasal administration?
(1) Enhance nasal absorption
(2) Improve nasal residence time
(3) Modify drug structure to change physicochemical properties
Name some mechanisms of absorption promotion in nasal drug delivery.
(1) Alteration of mucous layer - surfactants
(2) Alteration of tight junctions - opening using extracellular calcium ions
(3) Reversed micelle formation
(4) Extraction by co-micellisation
- Solubilisation of cell membrane lipids (e.g. cholesterol)
(5) Erosion of mucosal surface
What are cyclodextrins?
Used to solubilise drugs
Increase concentration of drug driving diffusion at absorption site
What are mucoadhesives?
Drugs which increase contact time at absorption site
Give some examples of mucoadhesives.
(1) Bioadhesive solutions/ suspensions
(2) Dry powder bioadhesives
What is a bioadhesive solution/ suspension?
Water soluble polymers
Decrease rate of mucociliary clearance
Due to high viscosity in solution
Give an example of a mucoadhesive used to increase nasal absorption of insulin.
Chitosan
What is chitosan used for?
As a mucoadhesive
To increase nasal absorption
- Particularly of insulin
What is a dry powder bioadhesive?
Drugs which absorb water upon contact with nasal mucosa
Swell to form viscous gels
Can remain in nasal cavity for up to 6 hours
Give some examples of dry powder bioadhesives.
(1) Microcrystalline cellulose
(2) Starch
(3) Dextran
(4) Chitosan
(5) Carbomer
What types of nasal formulation are there?
(1) Nasal spray
(2) Nasal drops
(3) Nasal creams
(4) Nasal powders - not yet developed
What is OptiNose?
Novel nasal drug delivery device
Intranasal delivery device
For liquid/ powder formulations
What do liquid nasal drug formulations often contain (excipients)?
(1) Antimicrobial preservatives
(2) Antioxidants
(3) Solubilising agents/ cosolvents
(4) Salts - for pH + tonicity
(5) Humectants - minimise nasal irritation
(6) Viscosity-increasing agents/ mucoadhesive
(7) Absorption enhancer
