BRAIN TARGETED DRUG DELIVERY

SYSTEM
FIRST SEMINAR (MPHR 120)
2016-2017

SCHOLAR: GUIDED BY:

MANISH KUMAR Mr. SHASHANK SONI
M.Pharm Assistant Professor
(Pharmaceutics)

SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH,

BALAWALA, DEHRADUN, (UTTARAKHAND)
 INTRODUCTION

 BARRIERS

 DRUG TRANSPORT

 FACTORS AFFECTING

 APPROACHES

 FUTURE ASPECTS

 MARKETED FORMULATION
1880

Paul Ehrlich

use vascular dyes

The existence of a blood brain barrier (BBB)

1960s

Drs. Reese, Karnovsky, and Brightman

using electron microscopy

localized tight junctions

 Ramakrishnan, P. (2003). The role of P-glycoprotein in the blood-brain barrier. Einstein Quart. J. Biol.
Med, 19,160-165.
 BARRIERS

The blood cerebrospinal fluid

The blood brain barrier (BBB)
barrier (BCSFB)
• BBB and BCF
 control the entry of compounds into the brain and
 regulate brain homeostasis.
 restricts access to brain cells of blood–borne compounds and
 facilitates nutrients essential for normal metabolism to reach brain
cells.

• It is estimated that more than 98% of small molecular weight drugs and
practically 100% of large molecular weight drugs (mainly peptides and
proteins) developed for CNS pathologies do not readily cross the BBB.

 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of
Pharma Research & Review, 2(6),36-44.
 Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW,
World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
 BLOOD BRAIN BARRIER

FUNCTIONS:

 STABILIZER – stabilize CNS neurons

 PROTECTION – from toxins, microbes (bacteria)

 HOLDER – hold neurotransmitter within CNS

 Prajapati, J., Patel H, & Agrawal, Y. K. (2012). Targeted drug delivery for central nervous system: a
review. Int J Pharm Pharm Sci, 3,32-38.
 Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW,
World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
 OVERVIEW OF BBB

ENDOTHELIAL CELLS

SPECIAL PROTEINS
e.g. OCCLUDINS, TIGHT JUNCTION
CLOUDINS

P-GLYCOPROTEIN

VERY LITTLE VESICULAR TRANSPORT

Schematic representation of BBB

 Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A
Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
BLOOD CEREBROSPINAL FLUID BARRIER
(BCSFB)

• Fenestrated Endothelial cells

.

• Modified Ependymal cells (Choroidal

cells)
.

 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of
Pharma Research & Review, 2(6),36-44.
 OVERVIEW OF BCSFB

ENDOTHELIAL CELLS

TIGHT JUNCTIONS

BASAL MEMBRANE

CHOROIDAL CELLS
Schematic representation of BCSF

 Bhaskar, S., Tian, F., Stoeger, T., Kreyling, W., de la Fuente, J. M., Grazú, V., ... & Razansky, D.
(2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-
brain barrier: perspectives on tracking and neuroimaging. Particle and fibre toxicology, 7(1),3.
BIG MOLECULES

HIGHLY CHARGED MOLECULES

TOXIC SUBSTANCES

SMALL MOLECULES

GLUCOSE
S.NO TRANSPORT DESCRIPTION
MECHANISM
1 PASSIVE 1. Molecular weight (>600
TRANSPORT Dalton is limiting factor)
2. Lipophilicity is directly
related to passive transport
3. Protein binding : Protein-
drug complex size is
responsible for transport
Inversely related to passive
transport
log P values (- 0.2 to 1.3) is
responsible for optimal cerebral
transport
(Free fraction of drug is
transported.)

2 ADSORPTIVE 1. Adsorptive-mediated macromoleculs like cationic

MEDIATED transcytosis macromoleculs e.g. histone,
TRANSCYTOSIS/ avidine
ENDOCYTOSIS and cationized albumin
2.Brain targeting using cationized human serum albumin
adsorptive (cHSA) as a transport vector
mediated endocytosis coupled to 3H-biotin is able to
cross the BBB in significant
amounts
3 ACTIVE requires energy
TRANSPORT
 Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A
Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
 VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted
Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4),15-27.
Begley, D. J., Bradbury, M. W., & Kreuter, J. “Specific Mechanisms for Transporting Drugs Into Brain”
The Blood–Brain Barrier and Drug Delivery to the CNS, Akira Tsuji (e.d.) , 2000 by Marcel Dekker,Inc., 8.
Receptor-mediated
transport
Transferrin receptor (TfR)
Insulin receptor(IR)
Nicotinic acetylcholine
receptor
Low-density lipoprotein
receptor
Insulin-like growth factor
receptor(IGF-R)
Diphtheria toxin receptor
Leptin receptor(OB-R)
Neonatal Fc receptor
(FcRn)
 Gao H. (2016). Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta
Pharmaceutica Sinica B, 6(4),268-286.
Active efflux-mediated transport Transporter(Carrier) -
mediated transport
Adenosine triphosphate-binding Glucose transporter(Glut1)
cassette (ABC) transporter
subfamily B, member 1
(P-glycoprotein)
MRPs(1&5) Large neutral amino acid
transporter (LAT1)
Organic anion transporting peptide Cationic amino acid
transporter (CAT1)
Glutamic acid amino acid Monocarboxylic acid
transporter transporter (MCT1)
Taurine transporter Choline transporter
Organic anion transporter Nucleobase transporter
(oatp2)
BBB-specific anion transporter type CNT2 adenosine
1 (BSAT1) transporter
 Amino Acid Transporters
large neutral amino acid transporters, LA
transporters, cationic-, anionic- and Glucose Transporters
neutral-amino acid transporters
type 1, glucose transporter, GLUT 1
E.g. L-Dopa is transported by LA
transporters in the BBB E.g. Glycosylated analogs of various
. opioid compounds

Carrier-mediated
(Active) Transport

Nucleoside Transporter
1. facilitative nucleoside transporters that
Monocarboxylic Acid Transporter carry selective nucleosides either into or
out of the cell
(MCT)
2. active and the sodium-dependent
E.g. salicylic acid transporters that can move selective
HMG-CoA reductase inhibitors nueleosides into the cell against a
concentration gradient
E.g. anticancer agent, the antiviral agents

 Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library.,
3(1),76-92
 Molecular Antibody (Mab) -
Molecular Trojan Horse
Act as ligands for RMT
e.g. CRM197 (Carrier Protein) uses
HB-EGF(heparin binding epidermal
growth factor) as its transport
receptor (Diptheria Toxin Receptor)
used for Multiple Sclerosis,
Parkinsonism, Alzhemier, Poliovirus
Trojan Horse Liposome
Attachment of a MTH to tips of PEG
strands of liposome triggers RMT
Encapsulation of plasmid DNA inside
pegylated liposome eliminates
nuclease sensitivity

Low Density Receptor Mediated

Transport Transferin And
Lipoprotein Receptor (LRP1&2) Insulin Receptor
Multiligand lipoprotein receptor BDNF-HIR Mab
interacting with proteins
EGF-TR mab
apoE(apolipoprotein E)
FGFT-HIR Mab
Alpha2 M(macroglobulin)
Beta galactosidase –TR Mab
APP(Amyloid precursor protein)
Neurotrophin-HIR fusion
PAI-1 & tPA

 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat
brain diseases. Neurobiology of disease, 37(1),48-57.
PARAMETERS CONSIDERED OPTIMUM FOR A
COMPOUND TO TRANSPORT ACROSS THE BBB ARE:

Compound should be unionized.

Approximately log P value must be near to 2.

Its molecular weight must be less than 500 Da

Cumulative number of hydrogen bonds

between 8 to 10

 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal
of Pharma Research & Review, 2(6),36-44.
BBB BROKEN

 TRAUMA BBB BROKEN

 INFLAMMATION
 INFECTION
 IRRADIATION WATER INFLOW
 NEUOPLASM
 HYPERTENSION
EDEMA
 HIGH ALTITUDE
 HYPOXIA
 ISCHEMIA LIFE THREATENING
 Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A
REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
CNS DRUG DELIVERY APPROACHES

INVASIVE TECHNIQUES

NON INVASIVE TECHNIQUES

MISCELLANEOUS TECHNIQUES
 Woodworth, G. F., Dunn, G. P., Nance, E. A., Hanes, J., & Brem, H. (2014). Emerging insights into barriers
to effective brain tumor therapeutics. Frontiers in oncology, 4,126.
A
INVASIVE APPROACH

INTRA CEREBRAL
IMPLANTS BBB DISRUPTION

INTRA
VENTRICULAR
INFUSION
 Wide range of compound and formulation can be considered for ICV or IC
administration.
 Both large and small molecules can be delivered

Drill the hole in the

head

give infusion by
place the implant
intra-cerebro-
by intra-cerebral
ventricular (ICV)
(IC) method
method
INTRA CEREBRAL IMPLANTS
 Delivery of drugs directly into the brain parenchymal space
 The drugs can be administered by:
 Direct injection via intrathecal catheter
 Control release matrices & microencapsulated chemicals.
 The basic mechanism is diffusion.
 Useful in the treatment of different CNS diseases e.g. Brain tumor, parkinson’s
disease etc.
 Example:
 Intrathecal injection of baclofen for spasticity
 Infusion of opioids for severe chronic pain
 Limitations :
 1.Distribution in the brain by diffusion decreases exponentially with
distance.
 2.The injection site has to be very precisely mapped to get efficacy and
overcome the problem associated with diffusion of drugs in the brain
parenchyma.
INTRA CEREBRO VENTRICULAR
INFUSION
 Pharmacological effect is seen if the target receptors of the drug are
located near the ependymal surface of the brain.
 Drug is infused using an ommaya reservoir, a plastic reservoir
implanted subcutaneously in the scalp and connected to ventricles
 Limitations:
 The diffusion of the drug in the brain parenchyma is very low .
 Unless the target is close to the ventricles it is not an efficient method
of drug delivery.
 Example Glycopeptide and an Aminoglycoside antibiotics used in
meningitis.
 VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted
Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.
 BBB DISRUPTION
 Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol
may disrupt BBB.
 Osmotic disruption : The osmotic shock

endothelial cells shrink

disrupting the tight junctions

Example : Intracarotid administration of a hypertonic mannitol solution with

subsequent administration of drugs can increase drug concentration in brain and
tumour tissue to reach therapeutic concentration
 MRI-guided focused ultrasound BBB disruption technique
Injection of microbubbles of ultrasound
contrast agent ( eg. optison, dia. 2-6 μm ) and
manganese into the blood stream

exposures to ultrasound

example: distribution of Herceptin is increased in brain tissue by 50% in a mice model.

LIMITATIONS OF INVASIVE APPROACH

 Relatively costly
 Require anaesthesia and hospitalization.
 It may enhance tumour dissemination after
successful disruption of the BBB.
 Neurons may be damaged permanently from
unwanted blood components entering the brain
B NON INVASIVE
APPROACH

CHEMICAL BIOLOGICAL COLLOIDAL

MONOCLONAL /
CATIONIC
PRODRUGS NANOPARTICLES
ANTIBODIES
CONJUGATES

RECEPTOR /
CO-DRUG VECTOR LIPOSOMES
MEDIATED

DRUG APROTONIN /
CONJUGATES CHIMERIC MONOCYTES
PEPTIDES AS
CARRIER
PRODRUGS
Prodrug is lipid soluble (pharmacologically inactive
compounds)

cross the BBB

metabolized within the brain

converted to the parent drug

Esterification or amidation of hydroxy-, amino-, or carboxylic acid- containing

drugs, may greatly enhance lipid solubility and, hence, entry into the brain
 WHAT TO DO AND WHY
 Drug covalently linked to an inert chemical moiety.
 Improve physicochemical property such as solubility and membrane
permeability.
 Prodrug is cleaved by hydrolytic or enzymatic processes.
 Examples levodopa, gaba, niflumic acid, valproate.
 Heroin, a diacyl derivative of morphine, is a notorious example that
crosses the BBB about 100 times more easily than its parent drug just
by being more lipophilic.

 Limitations of the prodrug:

 Adverse pharmacokinetics.
 The increased molecular weight of the drug that follow from
lipidation.

 VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted
Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.
CO-DRUG
 Drugs that inhibit a BBB AET could be used as a “co-drug” to
cause increased brain penetration of a therapeutic drug that is
normally excluded from brain by a BBB AET system.

 Example:
 Loperamide produced no respiratory depression when administered alone, but
respiratory depression occurred when loperamide (16 mg), a known inhibitor
of p-glycoprotein was given with quinidine at a dose of 600 mg (P < .001).
 Increased brain penetration of the chemotherapeutic agent, paclitaxel (taxol®),
by co-administration of the pglycoprotein inhibitor, psc-833 (valspodar).
 Aromatic amino acid decarboxylase (aaad) inhibitors are administered as
co-drugs in conjunction with L-dopa to optimize brain penetration of the Ldopa.

 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.
 DRUG CONJUGATES

Lipidization of molecules generally increases the volume of distibution.

Chemical approaches include lipophilic addition and modification of
hydrophilic drugs ( e.g. Nmethylpyrimidium 2 carbaldoxime chloride)

Example:

Glycosylated analogs of various opioid compounds

Antioxidant + pyrrolopyrimidines – increase access
For Ganciclovir : to hydroxymethyl group + 1methyl 1,4 dihydronicotinate-
increase transport
For small drugs: use of fatty acids like N docosahexaenoyl(DHA) increase
uptake
Casomorphin is a heptapeptide , able to pass the BBB.

Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain
diseases. Neurobiology of disease, 37(1),48-57.
 CARRIER MEDIATED TRANSPORT
 Drug transfered via amino acid transporter (LAT1)
 Melphalan for brain cancer
 Alpha methyl dopa for high blood pressure
 Gabapentin for epilepsy
 Ldopa for parkinsonism
 Transport via organic acid transporter (MCT)
salicyclic acid, lactate, acetate, propionate
 Choline transporter( for choline, thiamine)
 Nucleoside transporter (purine bases like adenine guanine)
anticancer agent, antiviral agent, 3 azidodeoxythymide
 Amine transporter: for mepyramine
 Peptide transporters: for glutathione, peptide harmones, growth factor, enkephalins,
t vasopressin , arginine
 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.
Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
 RECEPTOR / VECTOR MEDIATED

BRAIN
VECTOR PHARMACOKINETICS
SPECIFICITY

HIGH YIELD
LINKER CLEAVABILITY
COUPLING

RETENTION OF
INTRINSIC
DRUG AFFINITY AFTER
RECEPTOR
CLEAVAGE

 Conjugation of drug to transport vector is facilitated with chemical linkers

avidin–biotin technology, polyethylene glycol linkers
 Vector such as the Monoclonal antibody Mab
 Portals of entry for large molecular drug attached to endogenous RMT ligands.
CHIMERIC PEPTIDES AS CARRIER

MODIFIEDPRO
DRUG VECTOR
DUCT

Conjucated 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 antibody to red
transferrin receptor
 Targeting

 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.
 Begley David J., Bradbury Michael W. , Kreuter Jörg “Targeting Macromolecules to the Central Nervous
System” The Blood–Brain Barrier and Drug Delivery to the CNS, Ulrich Bickel(e.d.) , 2000 by Marcel
Dekker,Inc., 8.
COLLOIDAL
 The vesicular systems are highly ordered assemblies of one or several
concentric lipid bilayer formed, when certain amphiphillic building blocks are
confronted with water
 Coated with surfactants like polyoxyethylene/propylene, PEG
 AIM:
 Control degradation of drug
 Prevent harmful side effects
 Increase the availability of the drug at the disease site.
 Slowly degrade, react to stimuli and be site-specific
 Advantages:
 Prolong the existence of the drug in systemic circulation
 Improves the bioavailability especially of poorly soluble drugs.
 Both hydrophilic and lipophilic drugs can be incorporated.
 Delays elimination of rapidly metabolizable drugs and thus function as
sustained release systems.
NANOPARTICLES
 Size 1-1000 nm
 Includes both nanocapsules, with a core-shell structure (a
reservoir system) and nanospheres (a matrix system).
 Materials used: polyacetates, acrylic copolymers, poly(lactide),
poly(alkylcyanoacrylates) (PACA), poly(D,L-lactide-co-glycolide)
 Polysorbate coated nanoparticles can mimic LDL to cross BBB.
 Polyoxyethylene sorbitan monooleate coated nanoparticles containing drug
easily cross BBB.
 Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate
nanospheres targeted and accumulated in a rat gliosarcoma.
 Mechanisms of transport
Adhesion
Fluidization of BBB endothelium by surfactants
Opening of tight junction
Transcytosis / Endocytosis
Blockage of glycoprotein
MECHANISM OF TRANSPORT(ENDOCYTOSIS)

Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A
Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
 TARGETTING:

The coating of polyalkylcyanoacrylate or poly-lactic-co-glycolic acid

(PLGA) nanoparticles with polysorbate 80 or poloxamer 188.

Due to this coating the particles adsorb apolipoproteins E or A-1

from the blood

Interact with the LRP1 or with the scavenger receptor followed by

transcytosis across the blood-brain barrier into the brain.

 These particles loaded with doxorubicin for the treatment of glioblastomas are
presently in Clinical Phase I.
 Human serum albumin nanoparticles conjucated with antibodies(OX26/R17217)
against transferrin receptor e.g. For loperamide, 5-florouracil(5-FU)
 Human serum albumin nanoparticles conjucated with antibodies(29B4) against
insulin receptor e.g. for targeting loperamide
 Cell penetrating peptide(trans activating transduction protein ) modified liposome
i.e. Tat-LIP having positive charge transported via adsorptive mechanism. E.g. for
caumarin
 Babu, A., Templeton, A. K., Munshi, A., & Ramesh, R. (2014). Nanodrug delivery systems: a promising
technology for detection, diagnosis, and treatment of cancer. Aaps Pharmscitech, 15(3), 709-721.
 OTHER APPROACH:
 Photodynamic therapy (PDT), Photofrin along with iron oxide nanoparticles which is used
to target tumor cells. In this, iron oxide is used as contrast agent to get improved magnetic
resonance imaging (MRI).
 Trojan horses coated with sugar layer, is another modern approach containing magnetized,
iron-containing nanoparticles
 Advantages of using nanoparticles for CNS targeted drug delivery
 Protect drugs against chemical and enzymatic degradation.
 Small size --- enetrate into even small capillaries ---taken up within cells ----drug
accumulate at the targeted sites
 The use of biodegradable materials ---allows sustained drug release at the targeted site after
injection
 Limitations of using nanoparticles for CNS targeted drug delivery
 Small size and large surface area ----particle-particle aggregation-- physical handling of
nanoparticles difficult in liquid and dry forms.
 Small particles size and large surface area result in limited drug loading and burst release.
 Avhad, P. S., Patil, P. B., Jain, N. P., & Laware, S. G. (2015). A Review on Different Techniques for
Brain Targeting. International Journal of Pharmaceutical Chemistry and Analysis, 2(3),143-147.
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal
of Pharma Research & Review, 2(6),36-44.
 LIPOSOMES
 Lipid based vesicles are microscopic (unilamellar or multilamellar) vesicles
 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
 Advantages
 Suitable for delivery of hydrophobic, amphipathic and hydrophilic drugs and
agents.
 Could encapsulate macromolecules like superoxide dismutase,
haemoglobin, erythropoietin, interleukin-2 and interferon-g.
 Reduced toxicity and increased stability of entrapped drug via
encapsulation (eg.Amphotericin B, Taxol).
 Limitation :
 High production cost , Short half-life , Low solubility , Less stability
 Leakage and fusion of encapsulated drug / molecules
 Sometimes phospholipid undergoes oxidation and hydrolysis
 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems:
Molecular Basis of Targeted Drug Delivery, 1,508.
Mechanism: receptor/adsorptive mediated transport

Liposome coated with mannose reaches brain tissue where mannose coat assists
transport
Addition of sulphatide (a sulphate ester of galactocerebroside) to liposome increases
availability

TARGETING

A non viral supercoiled plasmid DNA is encapsulated in an

interior of an 85nm liposome

Liposome surface is conjucated with 1000-2000 strands of

2000 dalton peg to form pegylated liposome

Tips of 1-2 % peg strands are conjucated with a

peptidomimetic Mab(HIR/TR) to form pegylated
immunoliposomeS

Transfer via RMT

 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat
brain diseases. Neurobiology of disease, 37(1),48-57.
 Sercombe, L., Veerati, T., Moheimani, F., Wu, S. Y., Sood, A. K., & Hua, S. (2015). Advances and
challenges of liposome assisted drug delivery| NOVA. The University of Newcastle's Digital Repository.
 Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J
PharmaSciTech, 3,1-8.
 MONOCYTES

CARRIER MONOCYTE BBB DRUG

 Used as a Torjan Horse

 Ideal endogenous carriers
 Express certain receptors involved in receptor mediated endocytosis upon interaction
with suitable ligands

 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular
Basis of Targeted Drug Delivery, 1,508.
C

INTRANASAL
DELIVAERY
MISCELLANEOUS
TECHNIQUE
IONTOPHORETIC
DELIVERY
INTRANASAL DELIVERY
 1989 by W. H Frey proposed Nose-to-brain delivery of insulin and other
growth factors along the olfactory neural pathway to treat neurological
disorder.
 Drug delivered 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)
 THE OLFACTORY PATHWAYS: the olfactory nerve pathway (axonal
transport) and the olfactory epithelial pathway.
 AXONAL TRANSPORT (slow route) :
Agent enters the olfactory neuron via endocytotic or
pinocytotic mechanisms

travels to the olfactory bulb

 THE EPITHELIAL PATHWAY (faster route) :direct nose-to-brain transfer
compounds pass paracellularly across the olfactory
epithelium into the perineural space

continues to the subarachnoid space & in

direct contact with the CSF.
DIFFICULTIES : Enzymatic activity, low pH nasal epithelium, mucosal irritation or
large variability caused by nasal pathology (common cold)

INTRANASAL DELIVERY

Example: Small molecules like cocaine,cephalein & protein like inulin

Rivastigmine and thymoquinone loaded Chitosan nanoparticles
Liposomes delivering rivastigmine to the brain tissue
Antosova, Z., Mackova, M., Kral, V., & Macek, T. (2009). Therapeutic application of peptides and proteins:
parenteral forever?. Trends in biotechnology, 27(11), 628-635.
 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

 Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of
Pharma Research & Review, 2(6),36-44.
 Zorec, B., Préat, V., Miklavcic, D., & Pavselj, N. (2013). Active enhancement methods for
intra-and transdermal drug delivery: a review. Zdravniski Vestnik, 82(5).
  Identify new BBB transporters
 Develop brain drug targeting systems enabling the brain delivery of
recombinant protein neurotherapeutics.
 Validate new drug targeting systems using in vivo models.
 Optimize pharmacokinetics of in vivo brain drug targeting systems.
 Improve/enhance release of nanoparticles from implantable
devices/nanochips
 Multifunctional nanoparticles
 Universal formulation schemes that can be used as I/V, I/M & oral.

 Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW,
World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
S.NO BRAND NAME ACTIVE ROLE
PHARMACEUTICAL
INGREDIENT
1 AMBISOME AMPHOTERICIN B LIPOSOME

2 CASELYX PEGYLATED LIPOSOME BRAIN TUMOUR

OF DOXORUBICIN
HYDROCHLORIDE
3 ARICEPT DONEPEZPIL ALZHEIMER’S
DISEASE
4 AUROSHELL GOLD COATED SILICA SOLID TUMOURS
NANOPARTICLES IV
5 AURIMMUNE COLLOIDAL GOLD IV SOLID TUMOURS
NANOPARTICLES
S. DRUG TRADE NAMES COMPANY NAME
NO.
1 LOMUSTINE LUSTIN SAMARTH PHARMA PVT LTD
VHB-NU V.H. BHAGAT PHARMACEUTICALS
PVT LTD
LOMUWIN CHANDRA BHAGAT PHARMA PVT
LTD
LOMUSTINE VHB LIFE SCIENCE INC
LOMUSTINE(GSK) GSK
2 ETOPOSIDE ESIDE INJ VHB LIFE SCIENCE INC
ETOSID CIPLA LIMITED
ACTITOP KHANDELWAL LAB LTD
ETOLON CELON LABS
POSID CADILA PHARMACEUTICAL LTD
3 CYCLOPHOSPHAMIDE ONCOPHOS CADILA PHARMACEUTICALS
CYPHOS INTAS PHARMACEUTICALS
ONCOMIDE KHANDELWAL LAB
CYCLOXAN BIOCHEM PHARMACEUTICAL
CYDOXAN ALKEM LAB
Brain tumor drugs, www.medindia.net , 17/2/2017
YEAR RECENT WORK
2017 Gao, W., Liu, Y., Jing, G., Li, K., Zhao, Y., Sha, B.,& Wu, D. (2017). Rapid and
efficient crossing blood-brain barrier: Hydrophobic drug delivery system based on
propionylated amylose helix nanoclusters. Biomaterials, 113, 133-144.
2016 Cardoso AM, Guedes JR, Cardoso AL, Morais C, Cunha P, Viegas AT, Costa R,
Jurado A, Pedroso de Lima MC.“Recent Trends in Nanotechnology Toward CNS
Diseases: Lipid-Based Nanoparticles and Exosomes for Targeted Therapeutic
Delivery” Int Rev Neurobiol. ;130:1-40.
Baghirov, H. (2016). Nanoparticle uptake by brain endothelial cells and focused
ultrasound-mediated transport across the blood-brain barrier.
2015 Jain A, Jain SK.Crit (2015) ”Ligand-Appended BBB-Targeted Nanocarriers
(LABTNs)” The Drug Carrier Syst. 32(2):149-80
Timbie KF, Mead BP, Price RJ.(2015)“Drug and gene delivery across the blood-
brain barrier with focused ultrasounda”
Control Release.10;219:61-75.
2014 Aryal, M., Arvanitis, C. D., Alexander, P. M., & McDannold, N. (2014). Ultrasound-
mediated blood–brain barrier disruption for targeted drug delivery in the central
nervous system. Advanced drug delivery reviews, 72, 94-109.
2013 Zou LL, Ma JL, Wang T, Yang TB, Liu CB.(2013) “Cell-penetrating Peptide-mediated
therapeutic molecule delivery into the central nervous system.”11(2):197-208
Dufès C, Al Robaian M, Somani S.“Transferrin and the transferrin receptor for the
targeted delivery of therapeutic agents to the brain and cancer cells” Their Delivery
;4(5):629-40.
Patent Title Year Patentee/ Assignee
Number
US 9,295,728 Co-polymer March 29, Tsang; Kwok Yin (Irvine, CA),
conjugates 2016 Wang; Hai (San Diego, CA),
Bai; Hao (San Diego, CA), Jin;
Yi (Carlsbad, CA), Yu; Lei
(Carlsbad, CA)

US 9,289,505 Compositions and March 22, Minko; Tamara (Somerset, NJ),

methods for 2016 Rodriguez-Rodriguez; Lorna
delivering nucleic (East Brunswick, NJ),
acid molecules and Garbuzenko; Olga B. (Highland
treating cancer Park, NJ), Taratula; Oleh (West
Windsor, NJ), Shah; Vatsal
(New Bruswick, NJ)
US 9,278,990 Substituted March 8, 2016 Smith; David Bernard (San
nucleotide analogs Mateo, CA), Deval; Jerome
(Pacifica, CA), Dyatkina; Natalia
(Mountain View, CA),
Beigelman; Leonid (San Mateo,
CA), Wang; Guangyi (Carlsbad,
CA)
Patent Title Year Patentee/ Assignee
Number
US 9,260,426 Substituted 1H- February 16, Vankayalapati; Hariprasad
pyrrolo [2, 3-b] 2016 (Draper, UT), Yerramreddy;
pyridine and Venkatakrishnareddy
1Hpyrazolo [3, 4-b] (Hyderabad, IN), Ganipisetty;
pyridine derivatives as Venu Babu (Hyderabad, IN),
salt inducible kinase 2 Talluri; Sureshkumar (Nalgonda,
(SIK2) inhibitors IN), Appalaneni; Rajendra P.
(Saddle River, NJ)
US 9,260,417 Therapeutic methods February 16, Murphy; Eric A. (San Marcos,
and compositions 2016 CA), Cheresh; David A.
involving allosteric (Encinitas, CA), Arnold; Lee
kinase inhibition Daniel (Mt. Sinai, NY)

US 9,249,111 Substituted February 2, Qian; Xiangping (Foster City,

quinoxalines as B- 2016 CA), Zhu; YongLiang (Fremont,
RAF kinase inhibitors CA)
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World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
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