W19 Drug Delivery to the Brain

Question 1

What is the challenge of drug delivery to the brain?

Answer 1

Lipophilic BBB prevents many drugs from reaching the brain
- BBB still excludes almost 100% of high MW drugs and >98% of low MW drugs

Question 2

Delivery to the brain via the CSF:

Answer 2

• Cerebrospinal fluid
• Intraspinal injections are the most widely
  used way of by-passing the BBB for delivery
  to the brain
• CSF provides cushioning to the brain and spinal cord and also facilitates waste product removal
• Drugs are administered to the CSF via the Intraspinal route to deliver it to the brain

Question 3

What are the 2 sub-classes of intraspinal drug delivery?

Answer 3

1. Epidural : Injection into the epidural space
2. ** Intrathecal** (“spinal”): injection into the subarachnoid space containing CSF

• Degree of risk with both routes due to proximity of the spinal cord and potential consequences of infection
• Epidural route is most commonly used to administer anaesthetics for a regional effect (often during labour and some surgeries)
  − 1-2 litres of drug solution may be administered via a catheter
• Intrathecal route is also largely used for pain relief, but can also be a route for delivery to the brain
  − Wider variety of drugs delivered including antibiotics and cytotoxics
  − Also used for CSF removal and testing, i.e. a “lumbar puncture

Question 4

Intrathecal delivery to the brain:
What are the injection formulation requirements? (3)

Answer 4

• Relies on drug travelling within the CSF to the brain
  − CSF volume is estimated at approximately 150 mL but varies considerably between individuals (and increases with age)
  − This volume is turned over between 3-5 times/day – around 0.35 mL of CSF is produced every minute
  − CSF “flow” is minimal which does not assist drug distribution
  − Drugs in CSF also cleared rapidly to the bloodstream
• Nevertheless intrathecal drug delivery can be effective and is important in antibiotic therapy (alongside systemic) for meningitis
• Intrathecal injections have specific formulation requirements:
  − Sterile, pyrogen-free, isosmotic with CSF
  − Preservative free
  − 10 mL is the max formulation volume delivered intrathecally

Question 5

Intrathecal delivery to the brain

Answer 5

• To avoid repeated intrathecal injections, subcutaneous implanted pumps have been developed and in use since the late 1970s
• Medtronic SynchroMed II intrathecal pump is implanted under the skin and can last for up to 7 years
• Refilled in situ every 1 – 6 months
• Such devices are used for regional pain relief, but they are also being investigated for delivery of macromolecules to the brain

Question 6

Intranasal delivery to the brain:
2 routes?

Answer 6

• Nasal cavity is the only site in the body where the CNS is in direct contact with the external environment
• Drug can enter olfactory nerve cells and/or the trigeminal nerve and permeate to the brain
• Olfactory region is directly connected to the frontal cortex of the brain

Route 1: Olfactory nerve cells (neurons)
Route 2: Trigeminal nerve

Question 7

Polymer implants for brain drug delivery

Answer 7

• Glioblastoma multiforme is the most common malignant brain tumour in adults
• Carmustine is a well-established anti-cancer drug that can be given intravenously but it suffers from severe (potentially life-threatening side effects)
• If a carmustine formulation could be applied to the brain directly it
  could treat the cancer with reduced side-effects
• So: Use a biodegradable polymer that has an outer hydrophobic coating so that water from brain cannot enter it and break down the drug before it can exert an effect. (Gliadel wafer used in surgery)