Nasal Drug Delivery

Question 1

List SIX advantages of Nasal Drug Delivery

Answer 1

• Rapid absorption (& onset of action)
  
  • Large surface area
  • Single cell layer (unlike buccal membrane)
• Reasonably permeable membrane
• Avoidance of first pass metabolism (hepatic & intestinal)
  
  • ​Potential to increase BA of unstable molecules
• Ease of administration
  
  • ​Non-invasive
  • Suitable for patients who are vomiting
• Amendable to enhancer technologies
• Potential to target CNS delivery?

Question 2

List SIX disadvantages of Nasal Delivery

Answer 2

• Limited delivery volumes (25 - 250 uL)
  
  • Affects solubility - what conc. can be achieved in formulation?
• Low permeability (MW > 1000 da)
• Pathological condition affect region
• Mucociliary clearance (t_1/2 ~ 21 mins)
  
  • ​Residence time is affected
• Enzymatic barriers
• Potential irritation of muccous membranes

Question 3

What are some drug delivery considerations regaring the location of absorption for nasal delivery?

Answer 3

• Most absorption occurs in respiratory region
  
  • Drug / formulation retertion is a consideration
  • Solution, suspension or powder
  • Particle size, shape and density
    
    • ​> 10 um impact in mucosa
    • < 5 um inhaled
    • < 0.5 um maybe exhaled
  • Hygroscopicity (absorption of moisture)
  • Respiration (disaese state of patient)
  • Pathological conditions

Question 4

What are the THREE pathways that drugs can be absorbed via the Nasal route?

Answer 4

• Paracellular
  
  • ​intercellular spaces and tight junctions
  • proteins and peptides
  • permeability enhancers can temporarily open and increase hydrophilic drug absorption
• Transcellular
  
  • ​Passive or active diffusion
  • Lipophilic molecules or receptor speicific molecules
• Transcytosis
  
  • ​Vesicular uptake via cell into interstitial space

Question 5

What are some excipients that can be considered into the formulation for nasal delivery? (5)

Answer 5

• Solubilising agents
  
  • ​Co-solvents, cyclodextrins, surfactants
• Antioxidants
  
  • ​necessary to prevent oxidative degradation
  • usually no irritant effect or impact on absorption
• Preservatives
  
  • ​prevent microbial growth
• Buffers
  
  • ​keep formulation pH between 4.5 - 6.5
• Penetration enhancers

Question 6

What are SIX benefits of using buffers in the formulation for nasal drug delivery?

Answer 6

• Buffer is used to keep the formulation pH between 4.5 - 6.5 for nasal delivery. It’s purpose:
  
  • To avoid irritation of nasal mucosa
  • To allow the drug to be available in unionised form for absorption
  • To prevent growth of pathogenic bacteria in the nasal passage
  • To maintain functionality of excipients such as preservatives
  • To sustain normal physiological ciliary movement
  • To maintain lysozyme funtionality

Question 7

What are the SEVEN functions of a penetration enhnacer when formulating a drug for nasal delivery

Answer 7

1. Alter properties of mucosal layer
   
   1. Increase blood flow
   2. Decrease mucous viscosity
2. Open tight junctions between epithelial cells
3. Increase retention time in nasal cavity (gelling agents)
4. Reversed micelle formation between membranes
   
   1. Temporarily disturbing structure
5. Increase membrane fluidity
   
   1. Extract membrane components
   2. Crease disorders in phospholipid domain
6. Increase lipophilicity of drug by forming an ion-pair
7. Inhibit proteolyctic activity

Question 8

What are FOUR formulation approaches to enhance absorption?

Answer 8

1. Protein modification (of the structure)
2. Administration with enzyme inhibitors (e.g. peptidase)
3. Use of absorption enhancers
4. Development of drug carrier systems
   
   1. Liposome
   2. Lipid emulsions
   3. Nano- and micro-particles

Question 9

How is Chitosan used as a formulation approach for Nasal drug delivery?

Answer 9

• Chitosan is a mucoadhesive polymer that is:
  
  • Positively charged
    
    • mucoadhesion via ionic interactions between amines and negatively charged sialic acids in mucin​
      
      • increases residence time; thus enhances drug absorption
  • Degradable

Question 10

What is the principle behind nano- and micro- particles to enhance absorption for nasal delivery?

Answer 10

• They are mucoadhesive polymers
• Drug is dispersed in the polymeric material or adsorbed to surface
• The drug is either:
  
  • released from particle surface
  • diffused from swollen polymer matrix
  • released after polymer degradation

Question 11

What are FOUR types of applications that drug delivery to the nose can achieve?

Answer 11

• Topical application
  
  • Local effect with nasal cavity
• Systemic application
  
  • Accessing the systemic circulation
• Immunological application
  
  • Vaccine delivery to lymphoid tissue
  • Makes sense given mucosal areas are where most infections enter the body
• Nose-to-Brain Transport
  
  • ​Theoretical delivery route
  • Direct access to CNS via olfactory region
    
    • ​olfactory nerves are un-myelincated, originate in CNS and terminate in olfactory epithelium

Question 12

What are SIX advantages of nasal vaccines over systemic vaccines.

Answer 12

1. Ease of administration
2. Large number of people vaccinated at lower cost
3. Medical trained staff not needed for administration
4. Prevent risks of needle-stick injuries
5. Can induce mucosal and systemic immunity
6. Nasal cavity rich in lymphoid tissues