3. INTRODUCTION
despite a significant increase in CNS drug discoveries , the most significant stumbling
block remains the effective transport of these agents across the blood brain barrier
(BBB).
Despite extensive study , patients suffering from fatal or debilitating CNS disease
outweigh those dying from all sorts of malignancies or cardiac disease.
Most medications face an insurmountable barrier in the blood -brain.
4. BBB is the most important chokepoint in improving of brain drug delivery and the most
easily seen factor restricting the future growth of neurotherapeutics.
General methods that can enhance drug delivery to the brain are therefore of great
pharmaceutical importance.
Our goal here is to review brain targeting drug delivery systems and all strategies that have
been improved to prevent the BBB
5. THE BLOOD BRAIN BARRIER
The brain is protected internally against potentially toxic substances by the presence of two barrier systems:
a. The blood brain barrier (BBB)
b. The blood cerebrospinal fluid barrier(BCSFB)
The presence of tight junction , few endocytic vesicles and efflux transporters (e.g. , P-glycoproteins) in the
CNS capillaries from the barrier that occlude the free uptake of into the interstitium .
As a result , a significant number of CNS disease have poorly met therapy.
The parameters considered optimum for a compound transport across the BBB are:
(a) non-ionization.
6. (b) log P value near to 2.
(c) molecular weight less than 400 Da.
(d) Cumulative number of hydrogen bonds between 8 to 10.
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:
a. invasive techniques.
b. non-invasive techniques.
c. Miscellaneous techniques
7. CNS DRUG DELIVERY
APPROCHES
INVASIVE TECHNIQUES
MISCELLANEOUS
TECHNIQUES
NON-INVASIVE TECHNIQUES
INTRACERBRAL
IMPLANTS
INTRAVENTRICULAR
INFUSION
BBB DISRUPTION
INTRANASAL
DELIVERY
IONTOPHORETIC
DELIVERY
BIOLOGICAL COLLOIDAL
CHEMICAL
NANOPARTICLE
S
LIPOSOMES
PRODRUGS
DRUG
CONJUGATES
APROTININ
CHEMERIC PEPTIDES
AS A CARRIER
MONOCLONAL
CATIONICANTIBODIE
S CONJUGATES
RECEPTOR /VECTOR
MEDIATED
8. INVASIVE METHODS
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.
However , these methods entail that drugs are administered directly into the brain tissue.
INTRACEREBRAL IMPLANTS
Entail delivery of drugs directly into the brain parenchymal space.
Drugs can be administered by :
a. Direct injection via intrathecal catheter.
b. Control release matrices.
c. Microencapsulated chemicals.
9. The basic mechanism which used is diffusion.
Useful in the treatment of different CNS diseases e.g. brain tumour , Parkinson's Disease
etc.
INTRAVENTRICULAR INFUSION
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.
10.
11. BBB DISRUPTION
Disruption makes tight junction between the endothelial cells of the brain capillaries.
The BBB can be transiently disrupted by a variety of techniques such as:
1. Osmotic disruption technique.
2. MRI guided focused ultrasound BBB.
3. Application of Vaso active compounds.
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 junction.
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 and viruses.
12. MRI GUIDED FOCUSED ULTRASOUND DISRUPTION TECHNIQUE
Local ultrasound 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
ultrasound.
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 ands phase 111 studies
13. NON-INVASIVE APPROACHES
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.
Non- invasive techniques usually rely upon drug manipulations which may include alteration as prodrugs ,
lipophilic analogues , chemical drug delivery, carrier-mediated drug delivery , receptor/vector mediated
drug delivery etc.
CHEMICAL METHODS
Prodrugs
The main premise for the chemical methods remains the use of prodrugs.
Such prodrug approaches were explored for a variety of acid contain drugs , like levodopa.
E.g., phenyletyamine coupled to nicotinic acid has been modified to form N-methyl nicotine acid esters and
amides.
14. Drug Conjugates
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.
Chemical approaches for delivering drugs to the brain include lipophilic addition and modification of
hydrophilic drugs. (e.g.,N-methylpyridinium-2-carbaldoxime chloride).
BIOLOGICAL APPROACHES
Chimeric Peptide
Combined with a transport vector to form an easily transportable or fused molecule.
The conjugated proteins may be endogenous peptides, monoclonal antibodies (mAbs), modified protein, etc.
The chimeric peptides are transported to brain by various transportation pathways like peptide-specific
receptor.
E.g., insulin and transferrin which undergo transcytosis by their receptors present at BBB.
15. Cationic Proteins
The 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.
Various cationic proteins have been reported to penetrate the BBB include avidin, histone, protamine, and
cationized polyclonal bovine immunoglobulin .
Monoclonal Antibodies
Monoclonal antibodies for targeting are usually prepared by hybridoma technology .
Combining melanoma ( tumour ) cells with antitumor antibodies against a particular type of antigens found
on malignant cells in animals like rat.
But instead of using mAbs directly for brain targeting , they modified structurally to get genetically
engineered monoclonal antibodies.
16. Liposomes
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 .
17. Nanoparticles
Nanosystems employed for the development of nano drug delivery system in the treatment of CNS disorders
include polymeric nanoparticles , nanospheres , nanosuspensions , etc
Naoparticles 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.
Intra Nasal Drug Delivery
After nasal delivery , drugs first reach the respiratory epithelium, compounds can absorbed into the
systemic circulation by Transcellular and Para cellular passive absorption through transcytosis.
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.
18. Conclusion
Even through a lot of strategies have been developed to deliver drug into brain to treat brain tumours and
other abnormalities treatment , none of them have showed to be suitable in each case of CNS disorders.
This is due 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.
19. REFERENCES
Advances in controlled and novel drug delivery edited by N.K. JAIN page No.452.
Brain-Targeted Drug Delivery ,Experiences to date, healthcare technology review by Nicholas Bodor and
Peter Buchwald.
Advances in Targeted Drug Delivery: Nanoparticulate Systems , journal of pharma science review by Emil
Joseph , Ranendra Narayan Saha.
Perspectives on Brain-Targeting Drug Delivery Systems , Current Pharmaceutical Biotechnology by Liangran
Guo , Jinfeng Ren and Ren and Xinguo Jiang
