Presented By Guided by
A. Sushma Ms. K. Anusham.pharm
129V1S0301 Assistant Professor
Department of Pharmaceutics
V.V. Institute of Pharmaceutical Sciences
THE BLOOD BRAIN BARRIER
APPROACHES TO CNS DRUG DELIVERY
In spite of an impressive increase in CNS drug
discovery, the biggest impediment remains the
effective delivery of these agents across the blood
brain barrier (BBB).
Despite aggressive research, patients suffering from
fatal or debilitating CNS diseases far outnumber those
dying of all types of systemic cancers or heart
diseases. (Ricci et al, 2006)
The BBB represents an insurmountable barrier for the
majority of drugs. (Cornford, 1985; Hawkins and
Davis, 2005) 3
BBB is a major bottleneck in developing brain drug
delivery and the most prominent factor limiting the
future growth of neurotherapeutics (Pardridge, 2005).
General methods that can enhance drug delivery to
the brain are therefore of great pharmaceutical
Our aim here is to review the various drug delivery
strategies that have been developed to circumvent the
THE BLOOD BRAIN BARRIER
The brain is shielded internally against potentially toxic
substances by the presence of two barrier systems: the
blood brain barrier (BBB) and the blood cerebrospinal
fluid barrier (BCSFB) . (Pardridge, 2003)
The presence of tight junction, few endocytic vesicles and
efflux transporters (e.g. P-glycoproteins) in the CNS
capillaries form the barrier that occlude the free uptake of
into the interstitium. ( Nabeshima, 1975; Lewin, 1980;
Habgood et al, 2000)
As a result, a significant number of CNS diseases have
poorly met therapy. (Pardridge, 1995)
The parameters considered optimum for a compound to
transport across the BBB are:
(b) Log P value near to 2.
(c) Molecular weight less than 400 Da.
(d) Cumulative number of hydrogen bonds
between 8 to10.
APPROACHES TO CNS DRUG DELIVERY
To overcome the multitude of barriers restricting CNS
drug delivery of potential therapeutic agents, numerous
drug delivery strategies have been developed.
These strategies generally fall into one or more of the
following categories: invasive, non-invasive or
miscellaneous techniques. (Misra et al, 2003; Kabanov
and Batrakova, 2004)
Generally, only low molecular weight, lipid-soluble molecules
and a few peptides and nutrients can cross this barrier to any
significant extent, either by passive diffusion or using specific
transport mechanisms. (Grieg, 1987)
However, these methods entail that drugs are administered
directly into the brain tissue. (Wang, et al, 2002; Graff and
Entails delivery of drugs directly into the brain
Drugs can be administered by:
Direct injection via intrathecal catheter. (Benoit et al,
Control release matrices. (Yang et al, 1989)
Microencapsulated chemicals. (Nathelie et al, 2004)
The basic mechanism is diffusion.
Useful in the treatment of different CNS
diseases e.g. brain tumour, Parkinson’s
Disease etc. (Menei et al, 1994; Benoit et
Used extensively in clinical trials.
Infusion is done using a plastic reservoir (Ommaya
reservoir) implanted SC in the scalp and connected to the
ventricles within the brain via an outlet catheter.
Only suitable for sites close to the ventricles.
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:
1. Osmotic disruption
2. MRI guided focused
3. Application of Vaso
Osmotic disruption of BBB
Inert hypertonic solutions with
subsequent intracarotid drug
administration(arteries in the neck).
The mechanism - the resulting high
sugar concentration in brain capillaries
takes up water out of the endothelial
cells, shrinking them thus opening tight
• The effect lasts for 20-30 minutes, during which time drugs diffuse
freely, that would not normally cross the BBB.
• E.g.: hypertonic solutions – 25% mannitol or arabinose for delivery of
macromolecular drugs such as monoclonal antibodies, nanoparticles
MRI guided focused ultra sound BBB
Local ultrasonic irradiation of the brain
has the capability of BBB disruption.
The combination of micro bubbles and
manganese (preformed micro bubbles
of ultrasound contrast
agent, optison, with a diameter of 2-
6µm) with the drug is injected to the
blood stream before exposure to the
This technique has been shown to
increase distribution of drug in brain
tissue by 50%.
Application of vaso - active compounds
There is evidence of the opening of the tight junctions to occur
by the activation of receptors through a calcium mediated
mechanism due to the administration of drug along with vaso
active compounds such as prostaglandins , histamine ,
serotonin and bradykinin.
This technique was abandoned due to lack of efficiency in
phase II and phase III studies.
A variety of non-invasive brain drug delivery methods
have been investigated, that make use of the brain blood
vessel network to gain widespread drug distribution.
Noninvasive techniques usually rely upon drug
manipulations which may include alterations as
prodrugs, lipophilic analogues, chemical drug
delivery, carrier-mediated drug delivery, receptor/vector
mediated drug delivery etc. (Byrne et al, 2002)
The main premise for the chemical methods remains the
use of prodrugs.
Such prodrug approaches were explored for a variety of
acid containing drugs, like levodopa . (Bodor et al, 1987)
Eg.,:phenylethyamine coupled to nicotinic acid has been
modified to form N-methylnicotinic acid esters and
Lipidization of molecules generally increases the
volume of distribution, the rate of oxidative
metabolism by enzymes and uptake into other
tissues, causing an increased tissue burden. (Han and
Amidon, 2000; Wu et al, 2002)
Chemical approaches for delivering drugs to the brain
include lipophilic addition and modification of
hydrophilic drugs, (e.g., N-methylpyridinium-2-
carbaldoxime chloride; 2-PA). Higush et al, 1975;
Combined with a transport vector to form an easily
transportable or fused molecule.
The conjugated proteins may be endogenous
peptides, monoclonal antibodies (mAbs), modified
The chimeric peptides are transported to brain by various
transportation pathways like peptide-specific receptor.
E.g. insulin and transferrin which undergo trancytosis by
their receptors present at BBB.
This method is based on isoelectric point of the brain.
This method offers an additional benefit for delivering
them by making them charged into cationic form, which
can go through brain easily by electrostatic interaction
with anionic functional groups exists on brain surface.
BBB transport of large molecule drugs is not possible e.g
proteins. (Pardridge, 2002).
Various cationic proteins have been reported to penetrate
the BBB including avidin, histone, protamine, and
cationized polyclonal bovine immunoglobulin (Brasnjevic
et al., 2009).
Monoclonal antibodies for targeting are usually
prepared by hybridoma technology.
Combining malenoma (tumor) cells with antitumor
antibodies against a particular type of antigens found on
malignant cells in animals like rat.
But instead of using mAb directly for brain
targeting, they are modified structurally to get
genetically engineered monoclonal antibodies.
Liposomes are non-toxic, biocompatible and
biodegradable lipid body carrier made up of animal
lipid like phospholipids, sphingolipids, etc.
The basic mechanism is by coupling with brain drug
transport vector via receptor-mediated transcytosis or
by absorptive-mediated transcytosis. (Schnyder and
Nanosystems employed for the development of nano drug
delivery system in the treatment of CNS disorders include
polymeric nanoparticles, nanospheres, nanosuspensions, etc.
Nanoparticles enter into the brain by crossing the BBB by
various endocytotic mechanisms.
Nanoparticles can be designed from albumin attached with
apoliprotein E (Apo E-albumin nanoparticles).
After IV administration, Apo E-albumin nanoparticles are
internalized into the brain capillary endothelial cells by
transcytosis and release into brain parenchyma. (Park, 2009).
Intra Nasal Drug Delivery
After nasal delivery, drugs first reach the respiratory epithelium,
compounds can be absorbed into the systemic circulation by
Transcellular and Para cellular passive absorption, carrier-
mediated transport, and absorption through trancytosis.
When a nasal drug formulation is delivered deep and high
enough into the nasal cavity, the olfactory mucosa may be
reached and drug transport into the brain and/or CSF via the
olfactory receptor neurons may occur. (Chieny et al, 1989;
Even though a lot of strategies have been
developed to deliver drug into brain to treat brain
tumors and other abnormalities treatment, none of
them have showed to be suitable in each and every
case of CNS disorders.
This is due to the brain physiology which
presents unique challenges, made up of tight
regulation of what can enter the brain space and
limited distribution of substances along extracellular
fluid flow pathways.
Novel approaches for controlled drug delivery systems by N.K.jain Pg.No:23-46
CNS drug delivery systems : novel approaches. Shadab A.Pathan, Zeenat Iqbal.
Recent patents on drug delivery & formulation 2009, 3, Pg.No:71-89.
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