Nasal drug delivery

Question 1

How are particles filtered out of the nose?

Answer 1

Have many cells e.g. cilia, microvilli, basal cells, goblet cells (secrete mucus)
The nasal cavity filters out dust and bacteria
if particles are >10 micrometer = filter out by vibrissae in the nose
5-10 micrometer then they deposit in nasal passages and are cleared via mucocilliary clearance
if <2 micrometer then they are not filtered out, may enter the lungs

Question 2

What are the main barriers to nasal drug delivery?

Answer 2

Mucocilliary clearance

Nasal mucus barrier

Question 3

What is mucocilliary clearance?

Answer 3

Dust and microorganisms become trapped within the visoelastic mucus blanket lining the nasal passages. Mucus is propelled by the cilia, beating in a co-ordinated manner within the periciliary fluid, towards the nasopharynx where mucus is swallowed/expectorated.

Question 4

What does the nasal mucus do?

Answer 4

Entraps substances entering the nasal cavity and helps remove particles via mucocilliary clearance
It also humidifies air as it can hold water so is a diffusion barrier to absorption

Question 5

Why use the nasal route of drug delivery?

Answer 5

• drugs can be topically applied to alleviate symptoms of allergy, congestion, infection
• good for drugs that are inactivated by GIT following oral administration and where the route is an alternative to injection
• direct access to CNS only location in the body that provides a direct connection between CNS and atmosphere. - avoids BBB

Question 6

Provide advantages of the nasal route

Answer 6

Large surface area for absorption 160cm2
Highly vascularised so rapid absorption &fast onset of action
Low metabolic. activity
accessible, easy to administer
Can bypass. BBB

Question 7

Provide disadvantages of the nasal route

Answer 7

Mucocilliary clearance
Mucus barrier
Limited to potent molecules as only a small volume can be administered
Lacks reproducibility as different diseases can alter conditions of the nose e.g. pH (usually slightly acidic 5.5-6.5, can increase in illness e.g. rhinitis)
Adverse reactions as mucous membranes are sensitive to irritation

Question 8

What are the 4 formulation factors to consider in nasal delivery?

Answer 8

Molecular weight (smaller) = <1000 Da good bioavailability. >1000Da has low absorption, need penetration enhancers which will increase limit to 6000Da
pH ~5.5-6.5
Concentration. - rate of absorption depends on conc of drug. Need highest volume compatible with dosing volume (but not for sustained time as can cause irritation)
Particle size 5-10micrometers

Question 9

What is the formulation rule of thumb for nasal drug delivery?

Answer 9

1. less polar molecules permeate better
2. Smaller molecules permeate better
3. Unionised molecules permeate better

• also need higher viscosity to stay in nose longer
• need isotonicity to not irritate the nose and draw ions/waterr out of the epithelium

Question 10

What formulation would be most suitable for:

- rapidly absorbed drugs

Answer 10

Use Drops due to the rapid clearance in the second phase.

Drops also disperse drug through the length of nasal cavity so provides a large area for immediate absorption

Question 11

What formulation would be most suitable for: - drugs that diffuse slower and need longer contact time

Answer 11

Spray. This will deposit in non-ciliated regions, thus there is a slower phase of clearance. Deposit at the front of the nasal cavity

Question 12

In improving nasal drug availability - what do we want to do?

Answer 12

• enhance nasal absorption
• enhance nasal residence time
• modify drugs to change their properties e.g. using pro drugs

Question 13

Outline 6 ways in which nasal drug delivery can be improved

Answer 13

1. Alter mucus layer - decreasing viscoelasticity of the mucus using surfactants (but irritation)
2. Alter tight junctions using excipients e.g. EDTA. that sequester Ca2+ ions. that are responsible for tight junction integrity - thus TJ are open
3. Reverse micelles - hydrophilic heads inside and hydrophobic on outside, more lipophilic and more permeating = better absorption
4. Extraction by co-micellisation = remove cholesterol so more permeable. (erosion=pain)
5. Cyclodextrins, increases concentration of drug to drive diffusion
6. Mucoadhesives - increase contact time at absorption site. Bioadhesive solutions & dry powder adhesives