Nasal Route

Question 1

What do folds inside the nose do?

Answer 1

Increase SA = more area available for absorption

Question 2

What are the therapeutic areas for nasal route?

Answer 2

Nasal allergy
Nasal congestion
Nasal infection
Systemic therapy
Vaccine delivery
Access to CNS

Question 3

Out of the therapeutic areas, which are local?

Answer 3

Nasal allergy
Nasal congestion
Nasal infection

Question 4

What are advantages?

Answer 4

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

Question 5

Why does the nasal route avoid 1st-pass?

Answer 5

1 cell thick + good blood supply

Question 6

What is the nasal cavity divided into?

Answer 6

2 halves by nasal septum

Question 7

What is the nasal cavity covered in?

Answer 7

Mucus membrane containing goblet cells

Question 8

Where does absorption occur in the nose?

Answer 8

Across turbinates + septum

Question 9

How are lipophilic drugs transported?

Answer 9

Transcellularly by conc-dependent passive diffusion by receptor mediated + vesicular transport mechanisms

Question 10

How are hydrophilic drugs transported?

Answer 10

Pass through epithelium via gaps between the cells (tight junctions)

Question 11

What does it mean that hydrophilic drugs pass through tight junctions?

Answer 11

Limited to drug molecular size < 1000 Da

Question 12

Describe nose brain pathway

Answer 12

Olfactory mucosa is in direct contact with the brain + cerebral spinal fluid

Question 13

Why is the nose brain pathway important for drug transport?

Answer 13

Drug could potentially be absorbed across olfactory mucosa + enter CNS

Question 14

What does the nose brain pathway offer?

Answer 14

Rapid, direct route for drug delivery to the brain, bypassing BBB

Question 15

What is the nose brain pathway beneficial for?

Answer 15

Treatment of Parkinson’s disease, Alzheimer’s or pain

Question 16

What is the function of the nose?

Answer 16

Passage for movement of air

Humidify + warm air

Question 17

What happens to large particles trapped in nasal filter?

Answer 17

Undergo rapid clearance

Question 18

What is important for local + systemic delivery?

Answer 18

Site of particle deposition + rate of clearance

Question 19

Where are cilia found?

Answer 19

On surface of epithelial cells that transport mucus toward the nasopharynx

Question 20

What is the function of mucociliary clearance?

Answer 20

To remove foreign substances from nasal cavity - this includes drugs

Question 21

What is the normal mucociliary transit time?

Answer 21

12-15 mins

Question 22

What does it mean that the normal mucociliary transit time is 12-15mins?

Answer 22

Drugs need to ideally be absorbed before this

Question 23

What are the advantages of local delivery?

Answer 23

Deliver directly at site of action
Permit rapid relief at lower dose vs oral
Reduce systemic side effects

Question 24

What are examples of nasal local delivery?

Answer 24

Nasal corticosteroids reduce nasal mucosa inflammation + sinuses without causing pituitary-adrenal suppression

Question 25

When would systemic nasal delivery be used?

Answer 25

Emergency situation, where rapid onset of action required

Question 26

What are examples of systemic nasal delivery?

Answer 26

Sumatriptan for migraine | Fentanyl for pain relief

Question 27

What can be delivered systemically?

Answer 27

Peptides | eg. desmopressin acetate = pituitary hormone for diabetes insipidus

Question 28

What is the problem with peptide delivery?

Answer 28

Successful BUT low bioavailability

Question 29

What factors affect systemic absorption?

Answer 29

``` Solubility Molecular size Degree of ionisation Enzymatic activity Mucosal contact time Nasal epithelium permeability ```

Question 30

How is solubility a factor affecting systemic absorption?

Answer 30

Drugs must be in solution to be absorbed | Only 25-200 micro L can be administered intranasally

Question 31

Which drugs pose problems for systemic absorption?

Answer 31

Low aq solubility or drugs that require high doses

Question 32

How can solubility problems be overcome?

Answer 32

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

Question 33

If formulating a drug as a suspension or powder in its micro-size, what is required?

Answer 33

Drug to be dissolved in nasal cavity before absorption

Question 34

How is molecular size a factor affecting systemic absorption?

Answer 34

Rate + extent of absorption decreases as molecular weight increases

Question 35

What size molecule has most efficient absorption?

Answer 35

< 1kDa

Question 36

Which particle size adheres to nasal mucosa the best?

Answer 36

10-50 microns

Question 37

Why do 10-50 microns sized particles adhere best to nasal mucosa?

Answer 37

Small particles pass to lungs | Larger impacted on anterior + run out of nose

Question 38

How is degree of ionisation a factor affecting systemic absorption?

Answer 38

Formulation pH has to be as close to nasal mucosa to minimise local irritation

Question 39

What is the pH of nasal mucosa surface?

Answer 39

7.4

Question 40

What is the pH of mucus?

Answer 40

5.5-6.5

Question 41

What pH is not tolerated?

Answer 41

3-10

Question 42

What can happen to local pH?

Answer 42

Can become alkaline in certain nasal conditions | eg. acute sinusitis + rhinitis

Question 43

Which drugs are better absorbed? | Degree of ionisation

Answer 43

Unionised with higher logP better absorbed than ionised form

Question 44

How is enzymatic activity a factor affecting systemic absorption?

Answer 44

Drugs may be metabolised in lumen or pass to epithelium

Question 45

Is the metabolic activity in nasal cavity still less than GI tract?

Answer 45

YES

Question 46

What enzymes are found in nasal cavity?

Answer 46

Broad range Monooxygenase Cytochrome P450s Proteolytic enzymes

Question 47

How can enzymatic activity be overcome?

Answer 47

Enzyme inhibitors in formulation Use of prodrugs Encapsulate drug

Question 48

Why would use of prodrugs limit enzyme activity?

Answer 48

Reduce affinity of drug for enzyme

Question 49

Why would encapsulating drugs limit enzyme activity?

Answer 49

Limit enzyme access to drug

Question 50

How is mucosal contact time a factor affecting systemic absorption?

Answer 50

Increase residence time of drug in turbinates = increases drug absorption

Question 51

How can you increase residence time?

Answer 51

Mucoadhesive polymers

Question 52

What do mucoadhesive polymers do?

Answer 52

Prolong drug contact time with mucosa without being absorbed

Question 53

Does increasing contact time always increase absorption?

Answer 53

NO | eg. rate of diffusion decreases as viscosity increases

Question 54

Why do mucoadhesive polymers prolong contact time?

Answer 54

Increase viscosity = increase residence time

Question 55

What is viscosity limited to + why?

Answer 55

Limited to 500mPa.S | Otherwise too viscous

Question 56

How is nasal epithelium permeability a factor affecting systemic absorption?

Answer 56

Mucus layer = diffusion layer

Question 57

Which permeability is less affected?

Answer 57

Small, uncharged molecules compared to large, cationic or small hydrophobic molecules

Question 58

What can be added to increase permeability + what do they do?

Answer 58

Penetration enhancers | = alter epithelium structure temporarily

Question 59

What is in the nasal liquid formulation?

Answer 59

``` API Antimicrobial preservative Antioxidants Solubilising agents/co-solvents Salts to adjust pH Humectants Viscosity enhancers Absorption enhancers ```

Question 60

Why are humectants in nasal liquid formulation?

Answer 60

To minimise irritation to the nose

Question 61

What are the different nasal devices?

Answer 61

Dropper/squeezer Spray Tube

Question 62

What pros of nasal dropper?

Answer 62

Cheap | Simple

Question 63

What are cons of nasal dropper?

Answer 63

Liquid can be delivered too quickly | Vol administered subject to patient technique

Question 64

Why is liquid being administered too quickly a con for dropper?

Answer 64

Can drip from nose to throat = cough

Question 65

When is dropper only suitable?

Answer 65

Drug with large therapeutic window

Question 66

Describe nasal spray

Answer 66

Solution or suspension formulated in metered dose pump or pre-filled syringe Produce fine droplets

Question 67

What vol is delivered in nasal spray?

Answer 67

25-50 micro L

Question 68

What pros of nasal spray?

Answer 68

Exact dose delivered + spread across mucosa Available as multi-dose or unit-dose Easy + fast to administer

Question 69

What is the con of nasal spray?

Answer 69

Requires priming

Question 70

Describe nasal tube

Answer 70

For creams, gels + ointments for local effect

Question 71

What pros of nasal tube?

Answer 71

Easy to apply | Applied with finger or cotton bud

Question 72

What is the con of nasal tube?

Answer 72

Uncontrolled dose