Module 2E Nasal Drug Delivery Systems

Question 0

What are the most important physiochemical properties of a drug that influence drug absorption in the nasal cavity (4)

Answer 0

1. Size of the drug molecule
   - intracellular aqueous channels : for water soluble compounds
   - trans cellular route : lipophillic compounds (intracellular channels)
2. Charge and it’s degree of hydrophilicity/lipophilicity
3. Solid dosage forms (powders)
4. Absorption enhancers

Question 1

Describe the process of mucociliary clearance (4)

Answer 1

A non-specific defensive function which also presents a barrier to drug absorption
Cilium stroke propels mucous through nasal cavities via:
A) Effective stoke of Cilium
B) Recovery stroke of Cilium
C) Mucus blanket is propelled in the same direction as effective stroke
See diagram

Drugs have to be able to overcome the mucus layers which contain ions, enzymes, and immunoglobulins

Question 2

What are the 3 main strategies utilised to maximise the systemic bioavailability of drugs administered nasally (3)

Answer 2

1. Increasing nasal residence time
   - viscosity enhancers
2. Enhancing nasal absorption
   - surfactants, bile salts
3. Modifying drug structure
   - prodrugs

Question 3

Describe the strategies for increasing nasal residence time (3)

Answer 3

1. Apply drug to anterior part of nasal cavity
2. Viscosity enhancers- can act as bioadhesives to mucous
3. Degradable starch microspheres- swell in water and form viscous bioadhesive

Question 4

What is a useful indicator of cellular damage in the nasal cavity (1)

Answer 4

CBF- Ciliary Beat Frequency

Useful indicator of cellular damage

Question 5

Describe the proposed mechanisms by which bile salts enhance nasal absorption (4)

Answer 5

Bile salts enhance nasal absorption (less damaging than surfactants)
Mechanisms proposed for enhancing action of bile salts:

1. Form temporary channels through the lipid structure of a cell
   membrane enhancing permeability
2. Opens tight junctions between cells forming intercellular aqueous
   pores
3. Increase the lipophilicity of charged drugs by forming ion pairs
4. Inhibition of proteolytic enzymes

Question 6

Describe the proposed mechanisms cyclodextrins enhance absorption (4)

Answer 6

Cyclodextrins increase bioavailability of lipophilic compounds by increasing their aqueous solubility, and hence their availability, at the surface of the nasal epithelium.

1. Form inclusion complexes- part or all of a drug molecule inserts
   itself into the hollow central cavity of the CD molecule
2. Drug molecule takes on some of the physiochemical properties of
   the CD molecule.
3. CD have polar outer surfaces and less polar interiors (tend to be
   water soluble but have the ability to accommodate hydrophobic
   molecules)
4. CD increase the bioavailability of lipophilic compounds by
   increasing their aqueous solubility

Question 7

Outline the major mechanisms of deposition of inhaled particles on the nasal membrane (6)

Answer 7

Deposition clearance of
Nasal drops- 4mins after administration
Nasal spray - 1min after administration

Deposition mechanisms:
1. Impaction: change in direction of airflow causes turbulence, causing
particle deposition
2. Sedimentation: air is moving slowly and particles settle slowly under
the force of gravity
3. Diffusion: Brownian motion; is limited to very small particles,
(<0.5mm) inspired particles are usually larger

Question 8

List the potential excipients included in liquid nasal formulations. Include and example of each excipient class (7)

Answer 8

Liquid formulations excipients:

1. Antimicrobial preservatives: benzalkonium chloride
2. Antioxidants: butylated hydroxytoluene
3. Solubilising agents/ cosolvents: glycol derivatives
4. Slats for adjusting pH, tonicity: NaCl
5. Humectants: glycerol
6. Viscosity enhancers: methylcellulose
7. Absorption enhancers: cyclodextrins