CNS Drug Delivery Flashcards
(35 cards)
What has happened that has caused a significant unmet medical need for neurological disorders and disease?
Large # of indications
Growing patient populations
Few effective therapies
Enormous cost of care
What makes the extracellular fluid compartments of the CNS?
CNS comprise the brain and spinal cord parenchymal interstitial fluid (ISF) and the cerebrospinal fluid (CSF),
At what rate does blood flow through the brain?
rate of 60 l/hr
What is the volume of CSF? and at what rate is it produced?
140ml
produced at 35ml/hr
Describe the blood brain barrier
The endothelial cells at their adjacent margins form tight junctions produced by the interaction of several transmembrane proteins that project into and seal the paracellular pathway
The interaction of these junctional proteins, particularly occludin and claudin, is complex and effectively blocks an aqueous route of free diffusion for polar solutes from blood along these potential paracellular pathways and thus denies these solutes free access to brain interstitial (extracellular) fluid
Factors that are making CNS drug therapy harder?
BBB excludes most drugs from brain and spinal cord
Drugs keep getting bigger
What is selectivity criteria of the brain capillary in regards to permeability?
permeability restricted to: small molecules (<600D) lipophilic substances
What is the role of trans-membrane transporters and give exaples
Some of these aid the transport into the brain while others prevent the entry of many molecules
the expression of various transporters including GLUT1 glucose carrier, amino acid carrier LAT1, transferring receptors, insulin receptors, lipoprotein receptors and ATP family of efflux transporters such as p-glycoprotein (P-gp) and multidrug resistance-related proteins MRPs
What is the role of efflux pumps? and give examples
Efflux pumps or transporters are responsible for extruding drugs from the brain and this mechanism is a major obstacle for the accumulation of a wide range of biologically active molecules in the brain, with the ATP binding cassette (ABC) transporter P-gp and multidrug resistant protein (MRP) being the principle efflux mechanism of these agents
What is levodopa transported across the BBB by?
LAT1
What are the 3 strategies/routes for CNS drug delivery?
1. between permeabilize tight junctions 2. through enhance transport across the endothelium 3. around direct intracranial drug delivery
What is Intracerebral (intraparenchymal) delivery?
involves delivery of drug directly into parenchymal space of the brain
How are drugs administered via intracerebal delivery?
Drugs can be injected directly (bolus or infusion) via intrathecal catheters, by controlled release matrices, microencapsulated chemicals or recombinant cells.
Continuous infusion method can be used which uses convection enhanced diffusion (CED) to drive the drugs to a larger tissue region
Why is a high dose required to result in an appropriate drug conc in the parenchyma?
due to the to the closely packed arrangement of cells in both gray as well as white matter microenvironment which restricts diffusion
Describe what an Ommaya reservoir pump is? Give an example of what drug it delivers
a dome-shaped device, with a catheter attached to the underside used to deliver chemotherapy)
Containing etoposide, an antitumor agent used for treating metastatic brain tumor showed 100-fold more effective concentration
Describe what the DUROS is?
Based on the osmotic phenomena the DUROS™ have been developed as miniature osmotic implant that delivers drug for 3 months to 1 year with precise zero-order delivery kinetics.
Explain how polymer depots have been used
Polymer depots have been used for the delivery of drug into cerebral environment in the tumor cavity of the brain having drug being present inside the polymer matrix as a core material. It offers sustained release of drugs by the biodegradation of polymer
An example of a polymer depost is Gliadel wafer.
What does it do?
approved by FDA for brain tumor therapy (high-grade malignant gliomas) containing carmustine showed its release over a period of 5 days when placed in the tumor resection cavity
What is Intraventricular delivery (transcranial drug delivery)?
Like other approaches intraventricular route also act as an approach to bypass BBB where therapeutic agents are instilled directly into cerebral ventricle
What is Intraventricular delivery (transcranial drug delivery) route best for?
This route is best suited for meningioma treatment and metastatic cells of CSF as it distribute drugs mainly into ventricles and subarachnoidal area of brain
What is an advantage and disadvantage of the Intraventricular delivery (transcranial drug delivery) route?
Major advantage of this route is its lack of interconnection with interstitial fluid of brain unlike intracerebral delivery. Hence the drug achieves higher concentration in brain in comparison to that of its extravascular distribution
The major disadvantages is the chance of causing subependymal astrogliatic reaction due to high drug exposure at the ependymal surface of brain
What is DepoCyt?
DepoCyt is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF)
What are the benefits of delivering drugs directly to the brain?
Significantly Lower dose:
Less risk of side effects and organ toxicity
Improved Tolerability
Target effectiveness:
Consistent drug levels lessens difficulty finding therapeutic ratio for an each patient
“Last pass metabolism”: Drugs do not go first through GI tract, then liver, etc…
Adherence:
Overcome patients inability to take medication
Additional drug options for refractory disease - targeted nature of the delivery platform allows additional drug candidates
What is Intrathecal delivery (intra-CSF drug delivery)?
Intrathecal route involves delivery of neurotherapeutic agents to brain by direct administration of drugs through intrathecal route into cisterna magna of brain
Substantially less invasive than intraventricular
