Nasal Route Flashcards
What do folds inside the nose do?
Increase SA = more area available for absorption
What are the therapeutic areas for nasal route?
Nasal allergy Nasal congestion Nasal infection Systemic therapy Vaccine delivery Access to CNS
Out of the therapeutic areas, which are local?
Nasal allergy
Nasal congestion
Nasal infection
What are advantages?
Easy to administer Non-invasive, painless Avoid 1st-pass Low enzymatic activity Direct route to brain Potential to elicit rapid onset of action Peptide delivery Better systemic bioavailability than oral
Why does the nasal route avoid 1st-pass?
1 cell thick + good blood supply
What is the nasal cavity divided into?
2 halves by nasal septum
What is the nasal cavity covered in?
Mucus membrane containing goblet cells
Where does absorption occur in the nose?
Across turbinates + septum
How are lipophilic drugs transported?
Transcellularly by conc-dependent passive diffusion by receptor mediated + vesicular transport mechanisms
How are hydrophilic drugs transported?
Pass through epithelium via gaps between the cells (tight junctions)
What does it mean that hydrophilic drugs pass through tight junctions?
Limited to drug molecular size < 1000 Da
Describe nose brain pathway
Olfactory mucosa is in direct contact with the brain + cerebral spinal fluid
Why is the nose brain pathway important for drug transport?
Drug could potentially be absorbed across olfactory mucosa + enter CNS
What does the nose brain pathway offer?
Rapid, direct route for drug delivery to the brain, bypassing BBB
What is the nose brain pathway beneficial for?
Treatment of Parkinson’s disease, Alzheimer’s or pain
What is the function of the nose?
Passage for movement of air
Humidify + warm air
What happens to large particles trapped in nasal filter?
Undergo rapid clearance
What is important for local + systemic delivery?
Site of particle deposition + rate of clearance
Where are cilia found?
On surface of epithelial cells that transport mucus toward the nasopharynx
What is the function of mucociliary clearance?
To remove foreign substances from nasal cavity - this includes drugs
What is the normal mucociliary transit time?
12-15 mins
What does it mean that the normal mucociliary transit time is 12-15mins?
Drugs need to ideally be absorbed before this
What are the advantages of local delivery?
Deliver directly at site of action
Permit rapid relief at lower dose vs oral
Reduce systemic side effects
What are examples of nasal local delivery?
Nasal corticosteroids reduce nasal mucosa inflammation + sinuses without causing pituitary-adrenal suppression
When would systemic nasal delivery be used?
Emergency situation, where rapid onset of action required
What are examples of systemic nasal delivery?
Sumatriptan for migraine
Fentanyl for pain relief
What can be delivered systemically?
Peptides
eg. desmopressin acetate = pituitary hormone for diabetes insipidus
What is the problem with peptide delivery?
Successful BUT low bioavailability
What factors affect systemic absorption?
Solubility Molecular size Degree of ionisation Enzymatic activity Mucosal contact time Nasal epithelium permeability
How is solubility a factor affecting systemic absorption?
Drugs must be in solution to be absorbed
Only 25-200 micro L can be administered intranasally
Which drugs pose problems for systemic absorption?
Low aq solubility or drugs that require high doses
How can solubility problems be overcome?
Formulating as suspension or powder in micro-size range
Different salt forms of ionisable drug
Use of excipients - eg. co-solvents
Modification of molecular form
If formulating a drug as a suspension or powder in its micro-size, what is required?
Drug to be dissolved in nasal cavity before absorption
How is molecular size a factor affecting systemic absorption?
Rate + extent of absorption decreases as molecular weight increases
What size molecule has most efficient absorption?
< 1kDa
Which particle size adheres to nasal mucosa the best?
10-50 microns
Why do 10-50 microns sized particles adhere best to nasal mucosa?
Small particles pass to lungs
Larger impacted on anterior + run out of nose
How is degree of ionisation a factor affecting systemic absorption?
Formulation pH has to be as close to nasal mucosa to minimise local irritation
What is the pH of nasal mucosa surface?
7.4
What is the pH of mucus?
5.5-6.5
What pH is not tolerated?
3-10
What can happen to local pH?
Can become alkaline in certain nasal conditions
eg. acute sinusitis + rhinitis
Which drugs are better absorbed?
Degree of ionisation
Unionised with higher logP better absorbed than ionised form
How is enzymatic activity a factor affecting systemic absorption?
Drugs may be metabolised in lumen or pass to epithelium
Is the metabolic activity in nasal cavity still less than GI tract?
YES
What enzymes are found in nasal cavity?
Broad range
Monooxygenase
Cytochrome P450s
Proteolytic enzymes
How can enzymatic activity be overcome?
Enzyme inhibitors in formulation
Use of prodrugs
Encapsulate drug
Why would use of prodrugs limit enzyme activity?
Reduce affinity of drug for enzyme
Why would encapsulating drugs limit enzyme activity?
Limit enzyme access to drug
How is mucosal contact time a factor affecting systemic absorption?
Increase residence time of drug in turbinates = increases drug absorption
How can you increase residence time?
Mucoadhesive polymers
What do mucoadhesive polymers do?
Prolong drug contact time with mucosa without being absorbed
Does increasing contact time always increase absorption?
NO
eg. rate of diffusion decreases as viscosity increases
Why do mucoadhesive polymers prolong contact time?
Increase viscosity = increase residence time
What is viscosity limited to + why?
Limited to 500mPa.S
Otherwise too viscous
How is nasal epithelium permeability a factor affecting systemic absorption?
Mucus layer = diffusion layer
Which permeability is less affected?
Small, uncharged molecules compared to large, cationic or small hydrophobic molecules
What can be added to increase permeability + what do they do?
Penetration enhancers
= alter epithelium structure temporarily
What is in the nasal liquid formulation?
API Antimicrobial preservative Antioxidants Solubilising agents/co-solvents Salts to adjust pH Humectants Viscosity enhancers Absorption enhancers
Why are humectants in nasal liquid formulation?
To minimise irritation to the nose
What are the different nasal devices?
Dropper/squeezer
Spray
Tube
What pros of nasal dropper?
Cheap
Simple
What are cons of nasal dropper?
Liquid can be delivered too quickly
Vol administered subject to patient technique
Why is liquid being administered too quickly a con for dropper?
Can drip from nose to throat = cough
When is dropper only suitable?
Drug with large therapeutic window
Describe nasal spray
Solution or suspension formulated in metered dose pump or pre-filled syringe
Produce fine droplets
What vol is delivered in nasal spray?
25-50 micro L
What pros of nasal spray?
Exact dose delivered + spread across mucosa
Available as multi-dose or unit-dose
Easy + fast to administer
What is the con of nasal spray?
Requires priming
Describe nasal tube
For creams, gels + ointments for local effect
What pros of nasal tube?
Easy to apply
Applied with finger or cotton bud
What is the con of nasal tube?
Uncontrolled dose
