Brain Drug Delivery

Question 1

What is the brain made up of?

Answer 1

Made up of a complex network of billions of nerve cells called neurons protected by the bones of the skull

Question 2

How much does the brain weigh?

Answer 2

Weighs 3 pounts (1.4kgs)

Question 3

Is the brain constantly active?

Answer 3

Yes, 24 hrs a day

Question 4

What does the brain require to keep functioning properly?

Answer 4

Requires 20% of the heart’s output of fresh blood and 20% of the blood’s oxygen and glucose to keep functioning properly

Question 5

What are examples of Brain Diseases?

Answer 5

• Neurodegenerative conditions: Alzheimer’s disease, Parkinson’s, Huntington’s
• Infections: Meningitis, encephalitis
• Seizures
• Trauma
• Tremors, and increased pressure
• Vascular conditions: stroke
• Autoimmune conditions: MS

Question 6

Drug Transport Pathway towards Brain and Major Obstacles

Anything in the blood that wants to go through the brain has to pass what?

What is another mechanism by which drugs can go into brain?

After the brain has used up all energy and it makes metabolite, where is the metabolite pushed back to? (what is this called)

Answer 6

• Anything in the blood that wants to go through the brain has to pass the BBB
• Drugs can also go to brain via CSF via diffusion
• After the brain has used up all energy and it makes metabolite, metabolite will be pushed back into blood via CSF - this process is called the convection process

Question 7

Drug Transport Pathway towards Brain and Major Obstacles

• Speed of Drug Transport
  
  • Blood > Brain
  • Brain > Blood

Answer 7

• Blood > Brain = slow
• Brain > Blood = fast

Question 8

Diffusion from CSF into brain:

Diffusion will get ____ as we get closer to brain

Total volume of CSF?

Answer 8

• Diffusion will get slower as we get closer to brain
• Total volume of CSF = 140mL turned over 4-5 times per day

Question 9

How many drugs are in the CMC database?

Of these, how much % are active in the brain?

How much % don’t cross the BBB?

Answer 9

• 46,000 in the CMC database
• Only 6% of these 46,000 are active in the brain
• Only 1% of all drugs are active in the CNS
• ~100% large molecules drugs don’t cross the BBB

Question 10

Problem with CNS drug discovery research

What is there a lack of?

Answer 10

• BBB and CNS drug targeting emphasis in the pharmaceutical industry
• Detailed understanding of BBB transport biology
• Co-relation of in vitro and in vivo BBB studies
• Controlled clinical trials addressing CNS drug delivery

Question 11

Challenges with Small Molecules Drug Development

What are the 2 main challenges?

Answer 11

• Molecular Weight
• Hydrogen Bonding

Question 12

Challenges with Small Molecules Drug Development

2 main challenges - Molecular Weight

What must the MW be?

Most of the CNS-acting drugs are?

What happens when MW increases from 200 to 450 Da?

Answer 12

• MW < 400 Da
• Most of CNS-acting drugs MW < 426 Da
• When MW increases from 200 to 450 Da, the permeability will decrease 100 fold

Question 13

Challenges with Small Molecules Drug Development

2 main challenges - Hydrogen Bonding

• What must Hydrogen Bonding be?
• How much decrease in membrane permeation with each pair of hydrogen bonds on the solute?
• What functional groups are rapidly hydrolysed in vivo?

Answer 13

• Hydrogen bonding (N) < 8-10
• 10-fold decrease in membrane permeation with each pair of hydrogen bonds on the solute
• The hydrogen blocking functional groups are rapidly hydrolysed in vivo

Question 14

Why do we have slow success rates in developing drug delivery to the brain?

Answer 14

• Because of the challenges e.g. MW and hydrogen bonding

Question 15

What are the 7 Transport Routes across the BBB?

Answer 15

1. Paracellular aqueous pathway
2. Transcellular lipophilic pathway
3. Transport proteins
4. Efflux pumps
5. Receptor-mediated transcytosis
6. Adsorptive transcytosis
7. Cell mediated transcytosis

Question 16

Drug transport across the BBB

Discuss the Paracellular Aqueous Pathway

What can you use to open the tight junction wider so more drug can go through?

Answer 16

• Drug has to pass through very tight junction between 2 cells
• Junction very small, only water soluble agents and anything <400Da can go through
• Can use biological (e.g. virus), chemical (e.g. poloxamers co-administered with digoxin) and physical (e.g. ultrasound leading to enhanced delivery of antibody) stimuli to open the tight junction wider so more drug can go through

Question 17

Drug transport across the BBB

Discuss the Transcellular Lipophilic Pathway

Answer 17

• This pathway is for any lipid soluble molecule to pass through because the membrane is lipophilic
• Mimic structure of lipid to allow drug candidates more soluble in lipid so they can pass through

Question 18

Transphilic Lipophilic Pathway:

Nanocarriers for Brain Drug Delivery

• What is the particle size?

Answer 18

• Particle size < 100nm

Question 19

Transphilic Lipophilic Pathway

PEGylation of Nanocarriers

• Why do we care about coating the surface of the particle with PEG?
• What happens if we use nano system to deliver drug?
• How can we prevent this from happening?

Answer 19

• Coat the surface of particle with PEG
  
  • PEG at high MW = very soluble in water, so if we coat our lipids in formulation with PEG, it will increase aqueous solubility of our formulation
• If we use nano system to deliver drug, we have very low MW
  
  • Will be picked up very quickly by macrophages and cleared out straight away - drug can’t do anything
• To prevent this, we can coat the surface of the particle with PEG to increase MW and therefore prolong circulation time