CNS drug delivery Flashcards
what are Strategies for CNS drug delivery
- Between
permeabilize tight junctions - Through
enhance transport across
the endothelium - Direct
direct brain drug delivery
Between and though…Aproaches in development (pre-clinical)
- Use of osmotic agents
Injected directly into the carotid artery
Strategies to cross the BBB
-
Use of osmotic agents
The osmotic agent usually employed is hypertonic mannitol
A 25% solution is infused into a carotid artery (in the human at a rate of 4–8 mL/sec) over a period of 30 sec.
This treatment opens the barrier rapidly and it remains open for up to 30 min.
If a drug is then administered through the same cannula while the barrier is open, it can freely diffuse into the CNS.
The hypertonic solution is thought to osmotically pull water out of the endothelial cells, causing cell shrinkage.
This may cause disengagement of the extracellular domains of the proteins forming and regulating the tight junctions.
2. Disruption of BBB via penetration enhancers
Surfactant molecules able to disrupt the BBB via interacting with the phosphatidylcholine head groups
The various examples of these agents are ethanol, surfactants like sodium dodecyl sulfate (SDS), glycerol and polysorbate-80 (Tween-80), polyethylene glycol hydroxy stearate
Toxicity issues (neuronal damage, infarction, learning impairment, gliosis)
3. Use of prodrugs
DP-VPA phospholipid prodrug of valproic acid
Designed to penetrate the CNS intact and release VPA through hydrolytic activity of phopholipase A2
Phase 2 trials underway
4. Intranasal drug delivery
The vestibular, respiratory, and olfactory regions constitute the nasal cavity.
The vestibular part is the frontal area of the nasal cavity, which is composed of ciliated cells with a mucus blanket that limits the entry of foreign particles
Onwards from the vestibular region is where the respiratory region resides covering the largest surface area.
There are four types of cells within the respiratory region: ciliated, basal, goblet and non-ciliated columnar epithelial cells.
The trigeminal sensory neurons and blood vessels are found in significant numbers in the respiratory region.
Within the respiratory region of the nasal cavity, drugs can be absorbed directly to the systemic circulation while the trigeminal sensory neurons facilitate direct entry to the brain allowing transport of drug molecules directly from the nasal cavity to the brain, in particular the cerebrum and pons .
It is possible that drug may follow one of the routes of transportation or through multiple pathways;
However, this depends on the nature of the drug, formulation type, physiological conditions, and the type of carrier.
The trigeminal and olfactory nerve pathways are considered primary mechanisms for intranasal drug delivery
what are direct brain drug delivery
- Intracerebral (intraparenchymal) delivery
Intraparenchymal drug delivery is the direct injection of therapeutic material in the brain interstitium.
Brain interstitial is the region lying within the extracellular and extravascular space in brain parenchyma.
The space is occupied with interstitial fluid, which consists of water, salts, sugars, fatty acids, amino acids, hormones, neurotransmitters and other nutrients.
Injecting the therapeutic material directly in the brain interstitium allows it to reach different regions in the brain by traversing the interstitial space.
Due to its interspersion with cells and capillaries, the interstitium is an inhomogeneous environment and can often be altered by a disease’s pathological state.
In practical terms, this means that injection is associated with inevitable, and sometimes permanent, damage to nearby tissues.
Additionally, the procedure is fraught with technical complications, such as inadequate infusate diffusion, and in some cases, backflow.
Standard methods of local delivery of most drugs into the brain, either by intravenous injection and passage through the blood brain barrier (BBB), or intra-parenchymal injection, has relied on diffusion, which results in a non-homogenous distribution of most agents.
Intravenous administration of drugs to the brain has been hampered by the BBB, which prevents the passage of large molecules.
The BBB is characterized by tight junctions between vascular endothelial cells, which prevent or impede various naturally occurring and synthetic substances (including anti-cancer drugs) from entering the brain.
Convection-enhanced delivery (CED) is a method of directly administering drugs into the brain in order to enhance the distribution of drugs throughout the brain parehcyma.
In contrast to techniques that rely on diffusion, CED uses a pressure gradient established at the tip of an infusion catheter to push a drug into the extra-cellular space. The intention is to distribute the drug more evenly, at higher concentrations, and over a larger area than when administered by diffusion alone.
Implants are made up of biodegradable/non-biodegradable polymeric materials encapsulating drugs inside it.
Devices like Ommaya® reservoir pump (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
2. Intrathecal delivery (transcranial drug delivery)
The therapeutic material is directly administered in one of the ventricles (intraventricular) or the spinal canal (intrathecal) as time-separated boluses via an internally implanted reservoir or a programmed pump .
The therapeutic material reaches the brain and spinal cord tissues through the CSF.
Replenishment of the therapeutic material can be achieved by topping up the reservoir or replacing the pump.
The installation of the catheter and the reservoir or the pump is performed surgically, thus, as with all surgical manipulations, there is a risk of tissue damage, accompanied with a loss of function, and tissue infection with the added recovery time of the patient.
The extent of such risks can be reduced by careful planning of the operation, use of orthogonal technologies that can help visualize the route of implantation, and antibiotic prescription, if necessary.
In some cases, intraventricular or intrathecal drug administration is the most cost-effective approach for the treatment of chronic pain secondary to brain or spinal cord injury by sustaining a prolonged and stable state of analgesia without developing addiction or severe side effects, thereby improving patients’ quality of life.
Intrathecal delivery methods administer soluble therapeutics directly into the CSF.
Intrathecal delivery methods include intracerebroventricular (ICV), intrathecal-lumbar and intracisternal routes.
The ICV route enables the administration of drugs into a lateral cerebral ventricle via an implanted device (reservoir and catheter).
This delivery route, which may also be referred to as intraventricular administration, has been used worldwide for decades to treat paediatric and adult patients with a broad range of CNS disorders.
3. Epidural route of drug administration
it involves the administration of drugs into the epidural space to help with pain.
The epidural rate in the UK is around 22%.
The spinal cord is protected by three meninges (membranes) made of connective tissue with spaces between them – the tough outer dura mater, the arachnoid mater (the main physiological barrier for drugs passing between the epidural space and the spinal cord), and the inner, more delicate, pia mater.
Between the pia and arachnoid mater is the subarachnoid space (also referred to as the intrathecal space) containing the cerebrospinal fluid (CSF); the subdural space is between the dura and the arachnoid mater
The meninges are surrounded by a layer of fat and connective tissue contained within the epidural space which is situated between the wall of the vertebrae and ligamentum flavum and the dura mater. The epidural space is a potential space, 5–6mm thick in the lumbar region, containing blood and lymphatic vessels.
what are Osmotic implant
DUROS™ have been developed as osmotic implant that delivers drug for 3 months to 1 year with precise zero-order delivery kinetics.
Formulation maximizes drug payload, stabilizes drugs chemically and physically at body temperature, and involves the use of aqueous and non-aqueous vehicles
what is Gliadel® wafer
A polymer depot that has been 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
It consists of a copolymer matrix of 1,3-bis(p-carboxyphenoxy)propane and sebacic acid in a 20 to 80 molar ratio
what is Intraventricular delivery (transcranial drug delivery)
Intraventricular or intracisternal drug delivery is primarily used in patients with head and neck pain (such as refractory cluster headaches or trigeminal neuralgia) who have not had success with conservative measures, or for treatment of certain neoplastic processes (abnormal tissue growth).
Like other approaches intraventricular route also act as an approach to bypass BBB where therapeutic agents are instilled directly into cerebral ventricle
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
Major advantage is its lack of interconnection with interstitial fluid of brain (unlike intracerebral delivery).
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)
The half-life for the free CSF cytarabine ranged from of 5.9 to 82.4 hours (Compared to10min!).
Systemic exposure to cytarabine was negligible following IT
Dioleoylphosphatidylcholine (DOPC)
Cholesterol
Dipalmitoylphosphatidylglycerol (DPPG)
what is the indications for epidural routes of drug administation
Pain relief
Multiple pregnancy, prolonged labour,
Hypertension,
Preterm labour, where there may be an early desire to push
Postoperative analgesia
what is the blood brain barrier
Tight junctions between cells
Blocks diffusion for polar solutes from blood
Limited paracellular pathways and thus denies solutes access to brain interstitial fluid
CSF continuously flushing the injected drug (i.e. those injected into the ventricle) back to the blood
Selectivity of the Blood Brain Barrier
permeability restricted to:
* small molecules (<600D
lipophilic substances
How do the cells get solutes?
Carrier-mediated transport, glucose or amino acids to a protein from high to low concentration.
Free diffusion is limited to small lipophilic drugs
what are examples of CNS drugs?
Phenytoin
Anti-epileptic
MWt ~ 250
# H-bonds = 4
Poor aqueous solubility
log P = 2.5
Transcellular diffusion
Increasing evidence of CMT
Diazepam
Anxiolytic (and more)
MWt ~ 284
# H-bonds = 2
Poor aqueous solubility
log P = 2.8
Transcellular diffusion
Paroxetine
Anti-depressant
MWt ~ 330
# H-bonds = 5
Poor aqueous solubility
log P = 3.1
Transcellular diffusion
Also a substrate for p-glycoprotein
