targetted drug delivery system

1. BRAIN SPECIFIC DRUG
DELIVERY
Presented By-
ROHIT
R.K.S.D college of pharmacy,
Kaithal (Hry)
M.Pharma 1st year
(Pharmaceutics)

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CONTENTS
oHISTORY AND DISCOVERY OF BBB
oINTRODUCTION
oBLOOD BRAIN BARRIER (BBB)
oANATOMY OF BBB
oFUNCTIONS OF BBB
oDISEASES RELATED TO BBB
oBARRIERS FOR BRAIN DRUG DELIVERY
oSTRTEGIES FOR DRUG DELIVERY TO BRAIN

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HISTORY AND DISCOVERY OF BBB
• The blood-brain barrier were first observed in the late 19th century
by the German bacteriologist Paul Ehrlich. He found that when he
injected coloured dyes into the blood stream they leaked out
of capillaries in most regions of the body to stain the surrounding
tissues; the brain, however, remained unstained.
• Ehrlich wrongly surmised that the brain had a low affinity for the
dyes. It was his student, Edwin Goldman, who did the other half of
the experiment and realized the truth of what was going on. Goldman
injected a dye into the cerebrospinal fluid that surrounds the brain
and observed that it stained the brain, but nothing else. Goldmann
correctly concluded that the dye was unable to cross the specialized
walls of brain capillaries.

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INTRODUCTION
• Drug delivery to the brain is the process of passing therapeutically
active molecules across the Blood Brain Barrier for the purpose of
treating brain maladies.
• This is a complex process that must take into account the complex
anatomy of the brain as well as the restrictions imposed by the
special junctions of the Blood Brain Barrier.
• In response to the insufficiency in conventional delivery mechanisms,
aggressive research efforts have recently focused on the development
of new strategies to more effectively deliver drug molecules to the
CNS.
• Various routes of administration as well as conjugations of drugs. e.g.
with liposomes and nanoparticles are considered.

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BLOOD BRAIN BARRIER(BBB)
• Basal membrane and brain cells, such as pericytes and astrocytes,
surrounding the endothelial cells further form and maintain an
enzymatic and physical barrier known as the blood–brain barrier
(BBB).
• BBB tight junctions are formed between endothelial cells in brain
capillaries, thus preventing paracellular transport of molecules into
the brain.
• In brain capillaries, intercellular cleft, pinocytosis, and fenestrate are
virtually non existent; exchange must pass trans-cellularly. Therefore,
only lipid-soluble solutes that can freely diffuse through the capillary
endothelial membrane may passively cross the BBB.

6. ANATOMY OF BBB
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7. Astrocytes are the most numerous cell type within the central
nervous system (CNS) and perform a variety of tasks, from axon
guidance and synaptic support, to the control of the blood
brain barrier and blood flow. Toperform these roles, there is a
great variety of astrocytes.
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8. Microglia cells mediate immune responses in the
central nervous system by acting as macrophages, clearing
cellular debris and dead neurons from nervous tissue through
the process of phagocytosis.
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9. Cross section of BBB
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FUNCTIONS OF BBB
• Protecting the brain from "foreign substances" (such
as viruses and bacteria) in the blood that could injure the brain.
• Shielding the brain from hormones and neurotransmitters in the rest
of the body.
• Maintaining a constant environment (homeostasis) for the brain.
• Antibodies are too large to cross the blood–brain barrier, and only
certain antibiotics are able to pass.

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DISEASES RELATED TO BBB
oMeningitis : A serious disease in which there is inflammation of the
meninges, caused by viral or bacterial infection, and marked by
intense headache and fever, sensitivity to light, and muscular rigidity.
oBrain abscess : Brain abscess is an abscess caused by inflammation
and collection of infected material.
oEpilepsy : A neurological disorder marked by sudden recurrent
episodes of sensory disturbance, loss of consciousness, or
convulsions, associated with abnormal electrical activity in the brain.

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oMultiple sclerosis : a chronic, typically progressive disease involving
damage to the sheaths of nerve cells in the brain and spinal cord,
whose symptoms may include numbness, impairment of speech and
of muscular coordination, blurred vision, and severe fatigue.
oDe Vivo disease : De Vivo disease or Glucose transporter type 1
deficiency syndrome, is an autosomal dominant, genetic metabolic
disorder associated with a deficiency of GLUT1, the protein that
transports glucose across the blood brain barrier.
oAlzheimer's disease : Progressive mental deterioration that can occur
in middle or old age, due to generalized degeneration of the brain. It
is the commonest cause of premature senility.
oCerebral oedema : is the excess accumulation of water in the intra-
and/or extracellular spaces of the brain

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BARRIERS FOR BRAIN DRUG DELIVERY
There are three barriers that limit the transport of drugs to the brain
parenchyma.
• Blood Brain Barrier
• Blood Cerebrospinal Fluid Barrier
• Blood Arachnoid Barrier

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STRTEGIES FOR DRUG DELIVERY TOBRAIN
A. INVASIVE
a) Intracerebroventricular (ICV) infusion
b) Convection-enhanced delivery (CED)
c) Intra-cerebral injection or implants
d) Disruption of the BBB.
B. NON INVASIVE
a) Chemical techniques
• Prodrug
b) Colloidal Techniques
• Nanoparticles
• Liposomes
C. Miscellaneous techniques
a) Intranasal delivery

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INVASIVE APPROACH
Drugs can be delivered to the brain by first drilling the hole in the head,
and then implant is placed by intra-cerebral (IC) or infusion is given by
intra-cerebro-ventricular (ICV).
 Intracerebro-ventricular infusion (ICV)
• Injection of intracerebro ventricular infusion of drugs directly into the CSF.
• Drugs can be infused intraventricularly using an Ommaya reservoir, a plastic
reservoir implanted subcutaneously in the scalp and connected to the
ventricles.
• Drug solutions can be subcutaneously injected into the implanted reservoir
and delivered to the ventricles by manual compression of the reservoir
through the scalp.
• Ex: Glycopeptide and an aminoglycoside antibiotics used in meningitis.

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 Convection Enhanced Delivery (CED)
• CED is a therapeutic strategy that was developed to facilitate targeted
delivery of pharmaceuticals to the brain.
• The CED procedure involves a minimally invasive surgical exposure of the
brain, followed by placement of small diameter catheters directly into
the brain tumour.
• Subsequently, infusion of therapeutics into the tumour occurs over several
hours to saturate the target tissue.
• As this approach effectively bypasses the blood-brain-barrier, it allows for
delivery of macromolecular drugs that would not normally enter the brain to
effectively reach high concentrations within brain tumour tissue.
• Ex : Brain tumours.

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 Disruption of BBB
• This technique is used widely for CNS drug delivery and involves disruption of
the BBB.
• Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide,
ethanol may disrupt BBB.
• By inducing pathological conditions such as hypertension, hypoxia, or
ischemia, BBB may also be disrupted.
• Osmotic disruption: The osmotic shock causes endothelial cells to shrink,
thereby disrupting the tight junctions.
• Ex: Hypertonic mannitol

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Limitations of Invasive approach
• All these approaches are relatively costly, require anaesthesia and
hospitalization.
• These techniques may enhance tumour dissemination after
successful disruption of the BBB.
• Neurons may be damaged permanently from unwanted blood
components entering the brain.

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NON-INVASIVE APPROACHES
• Non invasive approaches make use of the brain blood vessel network
for drug distribution.
• Non-invasive techniques usually depend upon drug manipulations
such as prodrugs, nanoparticles and liposomes.

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 Prodrug
• Prodrug is pharmacologically inactive compound which is lipid soluble and
can cross BBB.
• Prodrug is metabolized within the brain and converted to the parent drug.
• A prodrug consists of a drug covalently linked to an inert chemical moiety.
• The active drug is formed when the attached moiety in prodrug is cleaved by
hydrolytic or enzymatic processes.
• In prodrugs the attaching chemical moieties should be such that it enhances
the lipoidal nature of the drug.
• Ex : levodopa, GABA, Niflumic acid, valproate

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 Nanoparticles
• Nanoparticles (NPs) are solid colloidal particles made up of polymeric
materials ranging in size from 1-1000 nm.
• It includes both nano capsules, with a core-shell structure (a reservoir
system), and nano spheres (a matrix system).
• NPs are used as carrier systems in which the drug is dissolved, entrapped,
encapsulated, adsorbed or chemically linked to the surface.
• By using nanotechnology it is possible to deliver the drug to the targeted
tissue across the BBB, release the drug at a controlled rate, and avoid
degradation processes.
• Reduction of toxicity to peripheral organs and biodegradability can also be
achieved with these systems.

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Mechanism for transport
• The mechanism for transport of lipoprotein to be endocytosis via the Low
Density Lipoprotein (LDL) receptor of the endothelial cells after adsorption
of lipoproteins form blood plasma to the nanoparticles.
• It is suggested that the recognition and interaction with lipoprotein
receptors on brain capillary endothelial cells is responsible for the brain
uptake of the drug.
Limitations of using nanoparticles
• Their small size and large surface area can lead to particle-particle
aggregation, making physical handling of nanoparticles difficult in liquid
and dry forms.
• In addition, small particles size and large surface area readily result in
limited drug loading and burst release.

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 Liposomes
• Liposomes or lipid based vesicles are microscopic vesicles that are formed as
a result of self-assembly of phospholipids in an aqueous media resulting in
closed bilayer structures.
• Since lipid bilayered membrane encloses an aqueous core, both water and
lipid soluble drugs can be successfully entrapped into the liposomes.
• Lipid soluble or lipophilic drugs get entrapped within the bilayered
membrane whereas water soluble or hydrophilic drugs get entrapped in the
central aqueous core of the vesicles.
• Liposomes are potential carrier for controlled drug release of tumours
therapeutic agents and antibiotics.

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MISCELLANEOUS TECHNIQUES
 Intranasal drug delivery
• In nasal drug delivery system drug are deliver in nasal cavity. The nasal
mucosa used for delivering the drugs for CNS disorders.
Mechanism for transport
There are two mechanisms underlying the direct nose to brain drug delivery:
a. Intracellular transport mediated route.
b. Extracellular transport mediated route.

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Advantages of intranasal drug delivery
• Rapid drug absorption via highly vascularized mucosa.
• Drugs which cannot be absorbed orally may be delivered to the Systemic
circulation through nasal drug delivery system.
• Bioavailability of larger drug molecules can be improved by means of
absorption enhancer or other approach.
• Self-administration
• Large nasal mucosal surface area for dose absorption

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References
• Brain targeted drug delivery system : A review , Parle Pallavi/ Volume
5, Issue 6, 398-414/ World Journal of Pharmacy and Pharmaceutical
Sciences
• Targeted And Controlled Drug Delivery By S P Vyaas and N K Khar

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Thank you