The document summarizes strategies for brain-specific drug delivery by bypassing the blood-brain barrier (BBB). It discusses the anatomy and functions of the BBB and various invasive and non-invasive approaches to deliver drugs to the brain. Invasive approaches include temporary disruption of the BBB using osmotic or ultrasound techniques or direct injection into the brain or ventricles. Non-invasive methods involve chemical modifications like prodrugs or drug conjugates, use of nanoparticles, liposomes, or monoclonal antibodies to transport drugs across the BBB. The document also lists some marketed products and potential applications like treatment of neurodegenerative diseases, brain tumors, and infections.

1. Submitted to:
Dr. B. Wilson
Head of the Department,
Department of Pharmaceutics,
College of Pharmaceutical Sciences, DSU
Banglore.
Presented by:
Arpitha B M
M Pharm (II SEM),
Department of Pharmaceutics,
COPS, DSU
Banglore .
Brain specific drug
delivery system

2. CONTENTS
• Introduction
• History & Background
• Strategies to deliver drugs to BBB
• Application
• Marketed products

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 molecules.
• 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 BBB

4. History & discovery
• The BBB were first observed in the late 19th century by the German
bacteriologist Paul Ehrlich and he wrongly summarised that the brain
had a low affinity for the dyes.
• Edwin Goldman, who did the other half of the experiment and
concluded that the failure to stain the brain following peripheral
administration of the dye was due to ‘blutgehirn schranke’ or BBB.
• In 1942 review on the BBB Friedmann stated that, ‘distribution
between blood and CSF’ is an entirely different problem.

5. BBB
• The BBB is a highly selective permeability barrier that separates the
circulating blood from the brain extracellular fluid in the central
nervous system.
• The BBB is composed of high density cells restricting passage of
substances from the blood stream much more than endothelial cells
in capillaries elsewhere in the body.

7. FUNCTIONS OF BBB
• The BBB acts very effectively to protect the brain from many common
bacterial infections.
• Selectively permeable.
• It becomes more permeable during inflammation
• BBB as an active pump
• BBB as a metabolic barrier

8. TRANSPORT THROUGH BBB

9. Approaches/ Strategies

10. Invasive approach
• Surgical intervention of bypassing the BBB for drug delivery.
• 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 .
• It includes…..
1) Intra
cerebro-
ventricular
infusion
2) BBB
disruption
3) Intra cerebral
Implants

11. Intra cerebro ventricular infusion
• One strategy for bypassing the BBB is intra ventricular 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.

12. Intra - cerebral implants/injection
• Polymeric implants are implanted into brain by neurosurgery to treat brain
tumours and neurodegenerative disorders like Parkinson’s and Huntington’s
disease
• 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.

13. 3) 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 Vasoactive compounds.

14. 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

15. 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.

16. 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

17. 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.

18. b) Drug conjugates
• It involves caging compounds within glycosyl- , maltosyl and
dimaltosly- derivatives of
• The complexes are further clyclodextrin 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.

19. 2. Biological
a. Monoclonal/ biologic antibody
• Monoclonal antibodies bind with specific receptors
• They are prepared by genetic engineering technologies
• The peptidomimetic monoclonal antibodies are used to transport
drugs, proteins, antisense nucleotide, non viral plasmic DNA into
brain.

20. b. Receptor / vector mediated drug delivery
• Peptides like insulin, cationized albumin, insulin like growth factor and
transferrin cross the BBB and this can be used for receptor mediated
endocytosis.
• A drug which does not cross BBB is attached with a BBB transport vector
and delivered into brain via transcytosis and endocytosis.
• In the brain, drug is released via enzymatic cleavage.
• Transport vector : monoclonal antibody, modified protein specific to
receptors on BBB (insulin, transferrin reeptors)
ex:- cationized albumin coupled with β- endorphin to transport to brain.

21. C. A protinin/ chimeric protein as carrier
• Conjugated proteins may be endogenous peptides, monoclonal antibodies,
modified protein, cationized albumin etc.
• Chimeric peptides are transported to brain by various pathways like peptide
specific receptor.
• E.g. Insulin and transferrin by transcytosis.
• Conjugation of drug with antibodies
• E. g. OX- 26, 8D3 Mab antibodies to red transferrin receptor.
Drug Vector
Modified
product

22. 3. Colloidal
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.
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.

23. • 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

24. 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.

25. Miscellaneous techniques
Intranasal delivery
• Drug deliverd intranasally are transported along olfactory sensory neurons to
yield significant concentrations in the CSF and olfactory bulb and then enter
into other regions of brain by diffusion (facilitated by perivascular pump)
Two pathways
• The Olfactory Axonal transport – slow route
• The epithelial pathway – faster route
Limitation:- enzymatic activity, low pH nasal epithelium, mucosal irritation or
large variability caused by nasal pathology (common cold)

26. Iontophoretic delivery
• Iontophoresis is the introduction of ionised molecules into tissues by means
of an electric current.
• Biologically active agent is transported by means of iontophoresis and/ or
phonophoresis directly to the CNS using the olfactory pathway to the brain
and thereby circumventing the BBB and is known as transnasal iontophoretic
delivery.

27. Applications
• 1. Neurodegenerative/neuroinflammation disease like Alzheimers,
Parkinsons, Huntington’s disease.
• Bacterial and viral infection in brain like Encephalities and
Meningitis
• Tumors- glioblastoma
• AIDS- abscess in the brain

28. Marketed Products
SI NO BRAND
NAME
API ROLE
1 AMBISOME AMPHOTERICIN B LIPOSOME
2 CASELYX PEGYLATED
LIPOSOME OF
DOXORUBICIN HCl
BRAIN TUMOUR
3 ARICEPT DONEPEZIL ALZHEIMER’S
DISEASE
4 AUROSHELL GOLD COATED SILICA
NANOPARTICLES IV
SOLID TUMOURS
5 AURIMMUNE COLLOIDAL GOLD IV
NANOPARTICLES
SOLID TUMOURS

29. REFERENCES
• S. P. Vyas & R. K. Khar, Controlled drug delivery- concepts and
advances, Vallabha Prakashan publishers, pg no- 487-509
• https://www.researchgate.net/publication/320599530
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629738
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858162