This document provides an overview of approaches to target brain drug delivery systems. It discusses the barriers to drug delivery in the brain like the blood brain barrier. Various invasive and non-invasive techniques to overcome these barriers are described. The non-invasive techniques include the use of prodrugs, drug conjugates, receptor-mediated transport systems and colloidal nanoparticles/liposomes. The invasive techniques involve direct administration into the brain or temporary disruption of the blood brain barrier. The factors affecting drug transport across the blood brain barrier and various carrier systems that utilize receptor mediated transport are also summarized.

1. APPROACH TO TARGET BRAIN DRUG
DELIVERY SYSTEM
SCHOLAR:
MANISH KUMAR
M.Pharm
(Pharmaceutics)
GUIDED BY:
Mr. SHASHANK SONI
Assistant Professor
SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH,
BALAWALA, DEHRADUN, (UTTARAKHAND)

2.  INTRODUCTION
 BARRIERS
 DRUG TRANSPORT
 FACTORS AFFECTING
 APPROACHES
 FUTURE ASPECTS
 MARKETED FORMULATION

3. 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.

4. • 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.
BARRIERS
The blood brain barrier (BBB)
The blood cerebrospinal fluid
barrier (BCSFB)
 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

5. 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

6. ENDOTHELIAL CELLS
TIGHT JUNCTION
VERY LITTLE VESICULAR TRANSPORT
SPECIAL PROTEINS
e.g. OCCLUDINS,
CLOUDINS
P-GLYCOPROTEIN
OVERVIEW REPRESENTATION OF BBB

7. 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.

8. 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.

9. ENDOTHELIAL CELLS
CHOROIDAL CELLS
TIGHT JUNCTIONS
BASAL MEMBRANE

10. 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.

12. BIG MOLECULES
HIGHLY CHARGED MOLECULES
TOXIC SUBSTANCES
SMALL MOLECULES
GLUCOSE

13. S.NO TRANSPORT
MECHANISM
DESCRIPTION
1 PASSIVE
TRANSPORT
1. Molecular weight (>600
Dalton is limiting factor)
Inversely related to passive
transport
2. Lipophilicity is directly
related to passive transport
log P values (- 0.2 to 1.3) is
responsible for optimal cerebral
transport
3. Protein binding : Protein-
drug complex size is
responsible for transport
(Free fraction of drug is
transported.)
2 ADSORPTIVE
MEDIATED
TRANSCYTOSIS/
ENDOCYTOSIS
1. Adsorptive-mediated
transcytosis
macromoleculs like cationic
macromoleculs e.g. histone,
avidine
and cationized albumin
2.Brain targeting using
adsorptive
mediated endocytosis
cationized human serum albumin
(cHSA) as a transport vector
coupled to 3H-biotin is able to
cross the BBB in significant
amounts
2 ACTIVE
TRANSPORT
requires energy
 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.

14.  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.

15. 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.

17. Receptor-mediated
transport
Active efflux-mediated transport Transporter(Carrier) -
mediated transport
Transferrin receptor (TfR) Adenosine triphosphate-binding
cassette (ABC) transporter
subfamily B, member 1
(P-glycoprotein)
Glucose transporter(Glut1)
Insulin receptor(IR) MRPs(1&5) Large neutral amino acid
transporter (LAT1)
Nicotinic acetylcholine
receptor
Organic anion transporting peptide Cationic amino acid
transporter (CAT1)
Low-density lipoprotein
receptor
Glutamic acid amino acid
transporter
Monocarboxylic acid
transporter (MCT1)
Insulin-like growth factor
receptor(IGF-R)
Taurine transporter Choline transporter
Diphtheria toxin receptor Organic anion transporter
(oatp2)
Nucleobase transporter
Leptin receptor(OB-R) BBB-specific anion transporter type
1 (BSAT1)
CNT2 adenosine
transporter
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.

18. Amino Acid Transporters
large neutral amino acid transporters, LA
transporters, cationic-, anionic- and
neutral-amino acid transporters
E.g. L-Dopa is transported by LA
transporters in the BBB
.
Glucose Transporters
type 1, glucose transporter, GLUT 1
E.g. Glycosylated analogs of various
opioid compounds
Monocarboxylic Acid Transporter
(MCT)
E.g. salicylic acid
HMG-CoA reductase inhibitors
Nucleoside Transporter
1. facilitative nucleoside transporters that
carry selective nucleosides either into or
out of the cell
2. active and the sodium-dependent
transporters that can move selective
nueleosides into the cell against a
concentration gradient
E.g. anticancer agent, the antiviral agents
Carrier-mediated
(Active) Transport
 Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library.,
3(1),76-92

19. 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
Lipoprotein Receptor (LRP1&2)
Multiligand lipoprotein receptor
interacting with proteins
apoE(apolipoprotein E)
Alpha2 M(macroglobulin)
APP(Amyloid precursor protein)
PAI-1 & tPA
Transferin And
Insulin Receptor
BDNF-HIR Mab
EGF-TR mab
FGFT-HIR Mab
Beta galactosidase –TR Mab
Neurotrophin-HIR fusion
Receptor Mediated
Transport
 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat
brain diseases. Neurobiology of disease, 37(1),48-57.

21. PARAMETERS CONSIDERED OPTIMUM FOR A
COMPOUND TO TRANSPORT ACROSS THE BBB ARE:
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal
of Pharma Research & Review, 2(6),36-44.
Compound should be unionized.
Approximately log p value must be 2.
Its molecular weight must be less than 400 Da
Cumulative number of hydrogen bonds
between 8 to 10

22. BBB BROKEN
 TRAUMA
 INFLAMMATION
 INFECTION
 IRRADIATION
 NEUOPLASM
 HYPERTENSION
 HIGH ALTITUDE
 HYPOXIA
 ISCHEMIA
BBB BROKEN
WATER INFLOW
EDEMA
LIFE THREATENING

23.  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

25. CNS DRUG DELIVERY APPROACHES
INVASIVE TECHNIQUES
NON INVASIVE TECHNIQUES
MISCELLANEOUS TECHNIQUES

26.  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.

27. INVASIVE APPROACH
INTRA CEREBRAL
IMPLANTS
INTRA
VENTRICULAR
INFUSION
BBB
DISRUPTION
A

28.  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
place the implant
by intra-cerebral
(IC) method
give infusion by
intra-cerebro-
ventricular (ICV)
method

29. 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.

30. 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.

31.  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.

32. BBB DISRUPTION
 Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol
may disrupt BBB.
 Osmotic disruption :
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
example: distribution of Herceptin is increased in brain tissue by 50% in a mice model.
The osmotic shock
endothelial cells shrink
disrupting the tight junctions
Injection of microbubbles of ultrasound
contrast agent ( eg. optison, dia. 2-6 μm ) and
manganese into the blood stream
exposures to ultrasound

33. 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

34. NON INVASIVE
APPROACH
CHEMICAL
PRODRUGS
DRUG
CONJUGATES
BIOLOGICAL
MONOCLONAL /
CATIONIC
ANTIBODIES
CONJUGATES
RECEPTOR /
VECTOR
MEDIATED
APROTONIN /
CHIMERIC
PEPTIDES AS
CARRIER
COLLOIDAL
NANOPARTICLES
LIPOSOMES
B

35. 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

36. 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.

37. 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
codrugs in conjunction with l-dopa to optimize brain penetration of the L-dopa.
 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.

38. 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
Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain
diseases. Neurobiology of disease, 37(1),48-57.

39.  Example of drug transfered via LAT1:
 Melphalan for brain cancer
 Alpha methyl dopa for high blood pressure
 Gabapentin for epilepsy
 Ldopa for parkinsonism
CARRIER MEDIATED TRANSPORT
 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.

40. RECEPTOR / VECTOR MEDIATED
 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.
VECTOR
BRAIN
SPECIFICITY
PHARMACOKINETI
CS
HIGH YIELD
COUPLING
CLEAVABILITY
RETENTION OF
AFFINITY
AAFTER
INTRINSIC
RECEPTOR
LINKER
DRUG

41. CHIMERIC PEPTIDES AS CARRIER
DRUG VECTOR
MODIFIED
PRODUCT
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

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

43.  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.

44. 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.

45. 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

46.  TARGETTING
 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
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.

47.  Advantages of using nanoparticles for CNS targeted drug delivery
 protect drugs against chemical and enzymatic degradation.
 small size --- penetrate 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 readily 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.

48. 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.

49. 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
TARGETING
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
 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat
brain diseases. Neurobiology of disease, 37(1),48-57.

50.  Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J
PharmaSciTech, 3,1-8.

51. MONOCYTES
 Used as a Torjan Horse
 Ideal endogenous carriers
 Express certain receptors involved in receptor mediated endocytosis upon interaction
with suitable ligands
CARRIER MONOCYTE BBB DRUG
 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular
Basis of Targeted Drug Delivery, 1,508.

52. MISCELLANEOUS
TECHNIQUE
INTRANASAL
DELIVAERY
IONTOPHORETIC
DELIVERY
C

53. INTRANASAL DELIVERY
 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)
 DIFFICULTIES : enzymatic activity, low pH nasal epithelium, mucosal
irritation or large variability caused by nasal pathology (common cold)
 THE OLFACTORY PATHWAYS: the olfactory nerve pathway (axonal
transport) and the olfactory epithelial pathway.
 AXONAL TRANSPORT (slow route) :
 THE EPITHELIAL PATHWAY (faster route) :direct nose-to-brain transfer
Agent enters the olfactory neuron via endocytotic or
pinocytotic mechanisms
travels to the olfactory bulb
compounds pass paracellularly across the olfactory
epithelium into the perineural space
continues to the subarachnoid space & in
direct contact with the CSF.

54.  Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92

55. 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.

56.  Identify new BBB transporters
 Develop brain drug targeting systems enabling the brain delivery of
recombinant protein neuro-therapeutics.
 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

57. S.NO BRAND NAME ACTIVE
PHARMACEUTICAL
INGREDIENT
ROLE
1 AMBISOME AMPHOTERICIN B LIPOSOME
2 CASELYX PEGYLATED LIPOSOME
OF DOXORUBICIN
HYDROCHLORIDE
BRAIN TUMOUR
3 ARICEPT DONEPEZPIL ALZHEIMER’S
DISEASE
4 AUROSHELL GOLD COATED SILICA
NANOPARTICLES IV
SOLID TUMOURS
5 AURIMMUNE COLLOIDAL GOLD IV
NANOPARTICLES
SOLID TUMOURS

58. S.
NO.
DRUG TRADE NAMES COMPANY NAME
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

59. 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.

60. Patent
Number
Title Year Patentee/ Assignee
US 9,295,728 Co-polymer
conjugates
March 29,
2016
Tsang; Kwok Yin (Irvine, CA),
Wang; Hai (San Diego, CA),
Bai; Hao (San Diego, CA), Jin;
Yi (Carlsbad, CA), Yu; Lei
(Carlsbad, CA)
US 9,289,505 Compositions and
methods for
delivering nucleic
acid molecules and
treating cancer
March 22,
2016
Minko; Tamara (Somerset, NJ),
Rodriguez-Rodriguez; Lorna
(East Brunswick, NJ),
Garbuzenko; Olga B. (Highland
Park, NJ), Taratula; Oleh (West
Windsor, NJ), Shah; Vatsal
(New Bruswick, NJ)
US 9,278,990 Substituted
nucleotide analogs
March 8, 2016 Smith; David Bernard (San
Mateo, CA), Deval; Jerome
(Pacifica, CA), Dyatkina; Natalia
(Mountain View, CA),
Beigelman; Leonid (San Mateo,
CA), Wang; Guangyi (Carlsbad,
CA)

61. Patent
Number
Title Year Patentee/ Assignee
US 9,260,426 Substituted 1H-
pyrrolo [2, 3-b]
pyridine and
1Hpyrazolo [3, 4-b]
pyridine derivatives as
salt inducible kinase 2
(SIK2) inhibitors
February 16,
2016
Vankayalapati; Hariprasad
(Draper, UT), Yerramreddy;
Venkatakrishnareddy
(Hyderabad, IN), Ganipisetty;
Venu Babu (Hyderabad, IN),
Talluri; Sureshkumar (Nalgonda,
IN), Appalaneni; Rajendra P.
(Saddle River, NJ)
US 9,260,417 Therapeutic methods
and compositions
involving allosteric
kinase inhibition
February 16,
2016
Murphy; Eric A. (San Marcos,
CA), Cheresh; David A.
(Encinitas, CA), Arnold; Lee
Daniel (Mt. Sinai, NY)
US 9,249,111 Substituted
quinoxalines as B-
RAF kinase inhibitors
February 2,
2016
Qian; Xiangping (Foster City,
CA), Zhu; YongLiang (Fremont,
CA)

62.  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
 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.
 Cornford, E., Kabanov, A., Del Zoppo, G., Muldoon, L., Rooney, W., & Shusta, E. (2014). Delivery and the
brain barriers.
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of
Pharma Research & Review, 2(6),36-44.
 Pardridge, W. M. (1991). Peptide Drug Delivery to the Brain Raven Press. New York, pp. l-357.
 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular
Basis of Targeted Drug Delivery, 1,508.
 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.
 Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain
diseases. Neurobiology of disease, 37(1),48-57.
 Ramakrishnan, P. (2003). The role of P-glycoprotein in the blood-brain barrier. Einstein Quart. J. Biol.
Med, 19,160-165.
 Pardridge, W. M. (2002). Drug and gene targeting to the brain with molecular Trojan horses. Nature Reviews
Drug Discovery, 1(2),131-139.
 Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J
PharmaSciTech, 3,1-8.