DRUG DELIVERY TO BRAIN... TOUGH TASK.. YET...

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BRAIN

Actually the brain is safeguarded by the blood brain barrier and blood cerebrospinal fluid barrier. These protect the brain from the harmful chemicals and these only obstruct the delivery of the drugs in treating the various diseases of the brain. (1) Treating brain tumor is still a big challenge. Anxiety, depression, schizophrenia, Alzhmeir's disease, Parkinson's disease, infection with HIV etc are some the problems associated with the brain. (2) So let us go through the advances that are useful in delivering the drugs to the brain.

FACTORS INVOLVED: (2)

a)The drugs in order to cross the BBB by the passive diffusion, it should be lipophilic, they should have less molecular size, and should be uncharged. In order to deliver the drugs to brain either we should increase the lipophilic nature or decrease the size.

b)Carrier mediated transport proteins are present in the brain which are useful in delivering the drugs to the brain through BBB.

Transporters

Drugs that are delivered

Amino acid transporters

Dopamine

Glucose transporters

Opoids

Monocarboxylic acid transporters

HMG- Co A reductase inhibitors

Nucleoside transporters

Gemcitabine, AZT

Peptide transporters

Glutathione

c) Receptor mediated endocytosis

APPROACHES INVOLVED IN DELIVERING THE DRUGS TO BRAIN: (1)

Let us outline the approaches.

I. Non-invasive methods may be chemical, biological and using carriers.

II.Invasive approaches: This includes the intracerebral implants, intraventricular infusion and BBB disruption.

III. Miscellaneous methods: includes intranasal and iontophoretic delivery.

NON-INVASIVE TECHNIQUES:

CHEMICAL APPROACHES:

The chemical methods include prodrug and drug conjugates. But the main method is using the prodrugs. By the chemical modification the lipophilic nature or the membrane permeability can be increased and once the drug enters the brain, the parent drug will be released. Mostly esters are formed.

For example take heroin. It has more lipophilic character and hence it crosses the BBB. After reaching brain it will get converted to morphine.

Nowadays,there is method of using endogenous carrier transport systems for delivering the drug. So a prodrug similar to the ligand of the particular endogenous transporter is made, so that it will be carried into the CNS.

For example, dopamine cannot pass through the BBB because of its hydrophilic character. Dopamine converted into L-Dopa, which will pass through BBB through LAT 1. Once it reaches the brain it will get converted into dopamine.

There is another approach where lipo aminoacids are used as promoiety. They generally posses an alkyl side chain and its alkyl side chain length can be changed to get the desired lipohilic character. (2)

BY USING CARRIERS:

LIPOSOMES: They consist of the phospholipid bilayer which encloses the aqueous compartment. (3) The water soluble drugs can be introduced into the water soluble component and the lipophilic drugs can be introduced into the lipid bi layer. Liposomes are one of the best methods for the delivery of the drugs as they are compatible, safe and preparation is quite simple. But macrophages remove them from blood which is drawback associated with these systems.

Trasferrin surface conjugated liposomes are used for delivering the 5-Fluorouracil which is an anticancer agent. (2)

Also the use of sleath liposomes for doxorubicin has better activity than the individual drug.

In case of cyclosporin, by using the liposomes the nephrotoxicity was decreased.

In case of diphtheria toxoid the absorption has been enhanced.

In case of choleratoxoids, the toxic effects are totally eliminated. (4)

NANOPARTICLES: Nanoparticles are made up of the polymers and these are made of the size is between 1 to 1000nm. The polymers that are generally used for the preparation of the nanoparticles are polyalkylcyanoacrylate, acrylic copolymers and polylactide. Albumin, gelatin, starch and chitosan can also used in the preparation of the nanoparticles. In these the drug may be enclosed, encapsulated, dissolved state or it may attach to the surface of the polymer. Solid lipid nanoparticles are also used for delivering the drugs to the CNS. This has found to be successful in case of the atazanavir which is protease inhibitor.

Analgesics, antibiotics, anticancer drugs and antiepileptics can be carrier by using the nanoparticles. (2)

Valproiacid toxicity has been decreased by using nanoparticles.

Loperamide, tubocurarine are passed through the BBB using nanoparticles. (4)

POLYMERIC MICELLS:
These are made up of the amphiphilic copolymers, in which the core is formed by the hydrophobic part and the shell is made up of the hydrophilic part. (5) Size: 10 to 100nm. (2)

DENDRIMERS: Dendron = tree. (6)

They are macromolecules made up of the heavily branched polymers. They consist of the central core material to which the polymer braches are fastened. They can be prepared by either convergent or the divergent method. Their solubility depend on the groups present on the surface, i.e., either hydrophilic or hydrophobic. (6)

Anticancer drugs can be delivered to the brain with the use of dendrimers.(2)

BIOLOGICAL APPROACHES:

The biological methods includes the use of the monoclonal antibodies, vector or receptor mediated and use of chimeric peptides as carriers. Attachment of the drug with antibody is main technique involved. (1)

INVASIVE TECHNIQUES:

The invasive techniques that are generally included are intracerebral implants, intraventricular infusion and BBB disruption.

BBB DISRUPTION: In this case, the sugar solution is injected to neck arteries. As a result, water from the endothelial cells present in the blood capillaries will come out. So that the tight junction will become loosened and as a result the drug molecules can cross the BBB. The disruption of the BBB may occur for 20 to 30min. This is mainly used for the treatment of the cancers. But this is not an attractive approach because other toxic substances can pass through the BBB. This approach leads to stress and intracranial pressure elevation. Intrathecal injections are also not a better option. (1)

INTRACEREBRAL IMPLANTS: Here the implants are given intra cranially. Since the polymer is used there will a sustained release of the drug. These are mainly used for the cancers and neurodegenerative problems. Gliadel is implant released for the CNS delivery.

The matrix-system is used to deliver the drug in order to follow controlled release kinetics. The matrix system can withstand physical and chemical damages, and is compatible with the body and unimpaired over the desired period of release. Microspheres can be used in case of 5-Flurouracil. (1)

INTRAVENTRICULAR INFUSION: Ommaya reservoir is used. In the scalp, it is placed subcutaneously and through a catheter, the drug is delivered to the ventricles.

The drug is directly available to the cerebrospinal fluid, so the desired levels are reached within less time. The toxic effects have been decreased. But the success is limited because it elevates the intracranial pressure, neurotoxicity and hemorrhage. (7)

MISCELLANEOUS METHODS:

These include the intranasal methods and iontophoretic methods.

In intransal methods, through olfactory sensory neurons the drugs can be delivered to the CNS. (7) By these methods the drug can avoid the first pass metabolism. Coming to the ionophoresis, it is a method in which ionized molecules are kept in the tissues using electric current. (1)

CONCLUSION: The delivery of the drugs to the brain is a difficult task. However with the latest advances, the delivery of the drugs to CNS increased. Nanoparticles are proved to the best carrier if they are properly formulated.

References:

1.http://www.benthamscience.com/ddf/samples/ddf3-1/0007DDF.pdf
(accessed on 1st nov 2011, 10:00 am)

2. http://www.farmacia.uniba.it/annuario/2009/1015.pdf

(accessed on 1st nov 2011, 11:00 am)

3. http://www.authorstream.com/Presentation/vsnmurthy-331492-liposomes-ppt-science-technology-powerpoint/
(accessed on on 6th nov 2011, 10:00 am)

4. http://www.itpsonline.net/wp-content/uploads/submitted/jitps_03.pdf
(accessed on 5th nov 2011, 9:00 pm)

5. http://www.ijpbs.net/volume2/issue2/pharma/14.pdf
(accessed on 5th nov 2011, 8:00 pm)

6. http://www.actabp.pl/pdf/1_2001/199-208.pdf
(accessed on 5th nov 2011, 4:00 pm)

7. http://www.ualberta.ca/~csps/JPPS6(2)/A.Misra/delivery.pdf
(accessed on 3rd nov 2011, 4:30 pm)

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About the Author

Siva Mavuduru's picture
Author: Siva Mavuduru

Comments

Siriki Praveen Kumar's picture

good work siva...

Regards,

S. Praveen Kumar.

sirikipraveen11@gmail.com

Pharma warriors

Siriki Praveen Kumar's picture

good work siva...

Regards,

S. Praveen Kumar.

sirikipraveen11@gmail.com

Pharma warriors

Siva Mavuduru's picture

K Rajakrishna's picture

Hi siva, It was a very good outline on various methods, could you please stack the methods described in the order of utility in the market. and what are the obsolete methods among these.
Siva Mavuduru's picture

Hi raja Good to see your comment The nanoparticles are proved to the best carriers. They are very helpful in treating cancers. Liposomes are also the good carriers for the drugs. Amphotericin which is carried by liposomes is commercially available as Ambisone. Doxyrubicin in carried by both liposomes (Caelyx) and nanoparticles. Several drugs are available for treating the brain diseases through these carriers. Definitely the market has good time in the coming decades.
Satyajeeth Pandey's picture

Dear Siva Well classified and well explained. Very good work

Satyajit Panda Asst. professor Maharajah's College Of Pharmacy

Siva Mavuduru's picture

Thank you so much sir

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