Blood brain barrier Factors affecting drug delivery to brain Approaches to CNS drug delivery Marketed formulations

1. Brain Specific Drug
Delivery
Presented By
MUSTAFIZUR RAHMAN
M.Pharm, 2nd Sem
Pharmaceutics
Girijananda Chowdhury Institute of Pharmaceutical Science (GIPS)
Azara, Hatkhowapara, NH-37 Guwahati- 781017, Assam
Under
Assam Science and Technology University

2. CONTENTS
• Introduction
• Blood brain barrier
• Factors affecting drug
delivery to brain
• Approaches to CNS drug
delivery
• Marketed formulations
• References
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3. 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 5/30/2019 3

4. Cont..
 Various routes of administration as well as
conjugations of drugs. e.g. with liposomes
and nanoparticles are considered.
 Overcoming the difficulty of delivering
therapeutic agents to specific regions of the
brain presents a major challenge to
treatment of most brain disorders.
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5. BLOOD-BRAIN BARRIER
 The blood–brain barrier (BBB) is a highly selective
permeability barrier that separates the circulating blood from
the brain extracellular fluid (BECF) in the central nervous
system (CNS).
 The blood-brain barrier acts very effectively to protect the
brain from many common bacterial infections.
 The blood-brain barrier is composed of high density cells,
restricting passage of substances from the bloodstream other
than endothelial cells in capillarie.
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6. PHYSIOLOGY OF BBB
 Small hydrophilic molecules such as amino acids, glucose,
and other molecules necessary for the survival of brain cells
use transporters expressed at the luminal (blood) and
basolateral (brain) side of the endothelial cells.
 Larger or hydrophilic essential molecules such as hormones,
transferrin for iron, insulin, and lipoproteins use specific
receptors that are highly expressed on the luminal side of the
endothelial cells. These receptors function in the endocytosis
and transcytosis of compounds across the BBB.
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7. DISEASE RELATED TO BBB
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Meningitis
Brain abscess
Epilepsy
Multiple sclerosis
Neuromyelitis optica
Sleeping sickness, etc.

8. FUNCTIONS OF BBB
 The BBB acts very effectively to protect the brain
from many common bacterial infections.
 Antibodies are too large to cross the blood–brain
barrier, and only certain antibiotics are able to pass.
 The blood–brain barrier becomes more permeable
during inflammation.
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9. Factors affecting drug delivery to
Brain
1. Blood brain barrier(BBB)
2. Cerebrospinal fluid
3. Physico-chemical factors
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10. 1. Blood brain barrier(BBB)
Present at level of brain capillaries
Different cell types
endothelial cells
pericytes
astrocytes
microglias
Brain microvessel endothelial cells(BMEC)
P-glycoprotein(p-gp) at luminal membrane of BMEC
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11. 2. Cerebrospinal fluid
Four types of fluids in entire brain
interstitial fluids
cerebrospinal fluids
inter cellular fluids
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12. 3. Physico-chemical factors
Molecular weight –limiting factor at >600 Dalton
Lipid solubility
Passive transport
Active transport
The hypnotic activity of CNS depressants reached a
maximum when log octanol-water partition coefficient (log
Po/w) was near to 2.
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13. Approaches to CNS drug delivery
B) Non – Invasive approaches :
i) Pharmacological techniques:
1. Chemical Techniques
a) Prodrugs
b) Drug Conjugates
2. Colloidal Techniques
a) Nanoparticles
b) Liposomes
ii) Biological / Physiological Techniques:
A) Pseudo nutrients
b) Antibody
c) Chimeric peptides
C) Miscellaneous approaches :
i) Intranasal delivery
ii) Iontophoretic delivery
A) Invasive approaches or Neurosurgical approaches:
i) Intra - cerebral injection/implant
ii) Intra - cerebro ventricular (ICV) infusion
iii) Disruption of the BBB
iv) Convection-enhanced delivery (CED)
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14. A) Invasive Techniques:
 Invasive Techniques Drugs can
be delivered to the brain by first
drilling a hole in the head, and
then implant is placed(IC) or
infusion is given(ICV).
 An advantage of this route is that
a wide range of compound and
formulation can be considered
for ICV or IC administration .
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15. i ) Intra - cerebral injection/implant
• Placement of a biodegradable chemotherapeutic
impregnated pellet/ wafer into a tumour resection area.
• These are implanted intra cranially through which drug
bypass the BBB and release drug molecules locally in the
brain in a sustained fashion .
• Both the bolus injection and implant rely on the principle of
diffusion to drive the drug into the infiltrated brain.
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16. ii) Intra - cerebro ventricular (ICV) infusion
• One strategy for bypassing the BBB is
intraventricular infusion of drugs
directly into the CSF.
• Ommaya reservoir, a plastic reservoir
implanted subcutaneously in the scalp
and connected to the ventricles within
the brain via an outlet catheter.
• Drug solutions can be subcutaneously
injected into the implanted reservoir
and delivered to the ventricles by
manual compression of the reservoir
through the scalp.
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17. iii) Disruption of the BBB
• Disruption makes tight
junction between the
endothelial cells of the brain
capillaries leaky.
• The BBB can be transiently
disrupted by a variety of
techniques such as
–Osmotic disruption
technique.
–MRI guided focused
ultrasound BBB.
–Application of Vaso
active compounds
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18. iv) Convection-enhanced delivery (CED)
• The general principle of CED involves the stereo
tactically guided insertion of a small caliber catheter
into the brain parenchyma.
• The infusion is continued for several days and then the
catheter are removed.
• Rapid diffusion is possible (high molecular weight
proteins diffuse for 2cm in 2hrs of continuous
infusion).
• Limitations: Proper drug delivery depends upon the
placement of catheters
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19. B) Non – Invasive approaches :
• These may be of a chemical or
biological nature.
• These methods usually relay upon drug
manipulations which may include
alterations as prodrugs
lipophilic analogues, chemical drug delivery, carrier
mediated drug delivery, receptor-vector mediated drug
delivery etc.
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20. 1. Chemical Techniques
• These are usually designed to improve some deficient
physiological property such as membrane permeability or
solubility .
• Chemical methods involves the chemical transformation
of drugs by changing the various functionalities.
E.g.: esterification or amidation of hydroxy, amino, or
carboxylic acid containing drugs.
• These techniques are mainly of two types
 Prodrugs
 Drug conjugates
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21. a) Prodrugs
• Prodrugs are pharmacologically inactive compounds that result
from transient chemical modifications of biologically active species
.
• Examples of lipophilic addition:- fatty acids, phospholipids etc.
• After administration, the prodrug, by virtue of its improved
characteristics, is brought closer to the receptor site and is
maintained there for longer periods of time.
• It gets converted to the active form, usually via a single activating
step(hydrolysis). Conversion to the active form is realized via an
enzymatic cleavage.
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22. b) Drug conjugates
• It involves caging compounds within glycosyl- , maltosyl
and dimaltosly- derivatives of clyclodextrin.
• The complexes are further covalently bonded with cationic
carriers and permeabilizer peptides for delivery across the
BBB and with the targeting moieties for uptake by brain
cells.
• The therapeutic complexes or conjugates comprise of an
omega 3 fatty acid such as alpha- linolinic acid , or
docosahexaenoic acid and their derivatives.
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23. Nano particles:
• Nanoparticles are sub-micron-sized colloidal structures composed
polymeric particles made of natural or artificial polymers ranging in
size between about 1 and 1000 nm.
Prepared by following steps
• Production of nanoparticles
• Purification
• Stability
• Sterilization
• Characterization
• Drug loading
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24. Advantages of nanotechnology
• Due to their small size nanoparticles penetrate into even
small capillaries and are taken up within cells, allowing an
efficient drug accumulation at the targeted sites in the body
.
• The use of biodegradable materials for nanoparticle
preparation, allows sustained drug release at the targeted
site after injection over a period of days or even weeks.
• To improve their stability in the biological environment , to
mediate the bio-distribution of active compounds, improve
drug loading, targeting , transport, release, and interaction
with biological barriers
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25. Liposomes
• Liposomes can be prepared with diameters ranging from 20 nm to
100 mm.
• Liposomes containing therapeutic agents are conjugates to
multiple brain barrier and brain cell membrane targeting agents to
provide transport of the encapsulated gene across the BBB.
• After crossing the BBB, the encapsulated gene expresses the
encoded therapeutic agent within the brain expresses the encoded
therapeutic effect and diagnosis of neurological disorders.
 Liposomes are concentric bilayered vesicles
in which an aqueous volume is entirely
enclosed by a membranous lipid bilayer
composed of biocompatible and
biodegradable lipids similar to biological
membranes .
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26. Table: Marketed formulations available as a brain
targeted drug delivery system
Sr no. Brand Name Active Pharmaceutical
ingredient
Role
1 AmBisome Amphotericin B liposome for
injection
2 Caelyx PEGylated liposomal
doxorubicin
hydrochloride
brain tumour
3 Aricept Donepezil Alzheimer's
disease
4 Aurimmune Colloidal gold IV
nanoparticles
Solid tumors
5 AuroShell Gold-coated silica
Nanoparticles IV (~150
nm)
Solid tumors
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27. Reference
• CNS drug delivery systems : novel approaches. Shadab A.Pathan , Zeenat
Iqbal . Recent patents on drug delivery & formulation 2009, 3, Pg.No:71-89.
• Novel approaches for controlled drug delivery systems by N.K.jain
Pg.No:23-46
• CNS targeted drug delivery : current perspectives , arun rasheed , I Theja .
JITPS 20120, vol. 1 (1) Pg.No:9-18.
• Targeted nanoparticles for drug delivery through
the blood-brain barrier for alzheimer’s disease.
Celesete roney , padmakar kulkarni , journal of
controlled release 108 (2005) Pg.No:193-214.
• Nanoparticle drug delivery to the brain , K.Ringe , C. M. Walz , B. A. Sabel
, encyclopedia of nano science and nanotechnology , edited by H.S. Nalwa
volume 7: Pg.No : 91-104
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28. Thank you for your attention.!
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