Pharm Tech

Question 1

What are the barriers to CNS drug delivery? (7)

Answer 1

o Nasal epithelial layer -> have to diffuse through to reach CNS
o Nasal mucus (~5 μm) -> viscous layer
o Metabolic enzymes -> may breakdown bacteria and even drug molecules
o Efflux pumps
o Hair -> if drug delivery does not deliver past nasal hair, can cause irritation and sneezing  loss of product
o Mucociliary clearance -> cleared every 10-15 mins; can be swept into throat and swallowed -> drug entry via GIT
o Limited volume -> limits how much drug we can give to a person in terms of volume and concentration of dose
 Too high concentration may lead to irritation of cells but certain concentration is required to pass through the barriers

Question 2

What are the characteristics for ideal drug targets for CNS delivery? (Lipinski Ro5)

Answer 2

1) ≤ 5 hydrogen bond donors (Hydrogen group connected to FON)
2) ≤ 10 hydrogen bond acceptors (FON with available lone pair)
3) < 500 Da
* < 300 Da for N2B access of hydrophilic drugs (for IN)
* <1 kDa for N2B access of lipophilic drugs (for IN)
4) Log P < 5
5) Unionised -> charged molecules cross lipid membrane less easily unless got active mechanisms involved in uptake

Question 3

What are various drug delivery strategies for Intranasal route? (3)

Answer 3

1) Nasal sprays
- Imitrex/ sumatriptan migraine
- Nayzilam midazolam seizures
- Narcan/naloxone opioid overdose
2) Nasal powders
- Xsail /sumatriptan migraine
3) Nasal gels
- In development for Alzheimer’s, Parkinson’s and schizophrenia

Question 4

Name some of the type of excipients normally found in Intranasal sprays (6)

Answer 4

1) Diluent -> bulk everything out
2) Buffer salts -> absorb acid/base contaminants to maintain pH
3) Preservatives -> especially if multidose formulation
4) Stabiliser/co solvent
* Stabiliser and co-solvent has to be miscible in water also (e.g through forming micelles)
* Co-solvent must match Hydrophilic–lipophilic balance (HLB) of the drug molecule
5) Permeation enhancers -> some stabiliser can also act as permeation enhancer
6) Viscosity modifiers -> adjust flow of formulation and may help retention on epithelial layer to increase contact time

Question 5

Name the considerations when it comes to the physicochemical properties of the formulation (3)

Answer 5

1) pH (pH 4-7.4)
2) Tonicity (300-700 mOsm) -> not too concentrated or not concentrated enough
3) Volume (max 200 μL)

Question 6

What are the advantages of Intranasal delivery? (4)

Answer 6

o Non invasive
o Can be self-administered
o Bypasses the hepatic first pass effect  won’t be eliminated; higher effective concentration at target site
o Short onset of effect  close to CNS

Question 7

Open the IC8 Notes and state for Sumatriptan:
a) How many bond donors
b) How many bond acceptors
c) Ionisable

Answer 7

• Hydrogen bond donors = 2 < 5
• Hydrogen bond acceptors = 3 < 10
• Ionisable -> Unionised at pH 5.5 so still suitable (pKa of tertiary amine group is 4.95)

Question 8

Open the IC8 Notes and state for Midazolam:
a) How many bond donors
b) How many bond acceptors
c) Ionisable

Answer 8

• Hydrogen bond donors = 0
• Hydrogen bond acceptors = 2
• Not Ionisable