BRAIN TARGETING DRUG DELIVERY SYSTEM

Presented By Guided by A. Sushma Ms. K. Anusham.pharm

129V1S0301 Assistant Professor

Department of Pharmaceutics

V.V. Institute of Pharmaceutical Sciences

Gudlavalleru

1

CONTENTSINTRODUCTION

THE BLOOD BRAIN BARRIER

APPROACHES TO CNS DRUG DELIVERY

CONCLUSION

2

INTRODUCTIONIn 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 importance.

Our aim here is to review the various drug delivery strategies that have been developed to circumvent the BBB.

4

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)

5

The parameters considered optimum for a compound to transport across the BBB are:

(a) Non-ionization.

(b) Log P value near to 2.

(c) Molecular weight less than 400 Da.

(d) Cumulative number of hydrogen bonds between 8 to10.

6

APPROACHES TO CNS DRUG DELIVERYTo 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)

7

8

INVASIVE METHODSGenerally, 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 Pollank, 2005)

9

10

INTRACEREBRAL IMPLANTS

Entails delivery of drugs directly into the brain parenchymal space.

Drugs can be administered by:Direct injection via intrathecal catheter.

(Benoit et al, 2000)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 al, 2000)

11

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.12

BBB Disruption 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 technique.

2. MRI guided focused ultrasound BBB.

3. Application of Vaso active compounds

13

Osmotic disruption of BBB

14

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.

14

• 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.

15

MRI guided focused ultra sound BBB disruption technique

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 ultrasound.

This technique has been shown to increase distribution of drug in brain tissue by 50%.

15

16

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.

16

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.

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)

17

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 containing drugs, like levodopa . (Bodor et al, 1987)

Eg.,:phenylethyamine coupled to nicotinic acid has been modified to form N-methylnicotinic acid esters and amides.

18

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. (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; 1976.

19

Biological ApproachesChimeric 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 trancytosis by their receptors present at BBB.

20

Cationic ProteinsThis 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).

21

Monoclonal Antibodies

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.

22

LiposomesLiposomes 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 Huwyler, 2005).

23

Nanoparticles

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). 24

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; Yamada, 2004)

25

CONCLUSION 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.

26

27

References Novel approaches for controlled drug delivery systems by N.K.jain Pg.No:23-

46CNS 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.

27

• 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

28