Brain Drug Delivery Approaches

Presented By – Rahul Kumar 2014H146211P

BITS Pilani

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Learning Objectives:• Why Brain Targeting ?• Blood Brain Barrier • How to overcome BBB?• Manipulation in nanoparticle for BBB permeation

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Blood Brain Barrier- Idea of BBB was given by Paul Ehrlich (1885)1)Tight epithelium due to presence of JAM, CLAUDIN, OCLAUDIN protein make it formidable layer against entry of various endogenous and exogenous substances

2) Pericyte3) Astrocyte

credit – William M. Pardridge Drug and gene targeting to the brain with molecular trojan horses”

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Factor affecting permeability• Molecular weight – less than 500 Da are required for permeation• Lipophilicity/Hydrophilicity• Charge/Polarity• Disease condition• Age• Efflux pump

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BBB Transport Mechanism

11/6/2015 Credit- Lu CT et. all. Current approaches to enhance CNS delivery of drugs across the brain barriers

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Disruption of membrane:• Permeation enhancer• Osmotic Disruption• Ultrasonic waves causes opening of tight junction• Application of bradykinin-analogue (RMP-7, Cereport® from Alkermes Inc.) failed in phase III due to lack of efficacyDisadvantages – Non- patient friendly

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Overcoming BBB

• Invasive Technique like• Direct infusion• Implants Disadvantage- not practical in humans

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• Pharmacological approach Reduce polar group- e.g. Morphine to codeine Prodrug approach –prodrug of dopamine (levodopa uptake by amino acid transporter)

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• Transporter approach/chimeric peptide approach -most effective way of delivering neuroprotective drugs

credit- William M. Pardridge Drug and gene targeting to the brain with molecular trojan horses”

• Bypassing : BBB nasal drug delivery

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Manipulation in Nanoparticles • Transferrin coated nanoparticles• Polysorbate 80 coated nanoparticles• PEGylated immunoliposome (PIL) with antibody for specific

receptor for gene delivery• Targeting ligands, such as peptidomimetic MAbs, trigger the

RMT of the PIL

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References:• 1) Lu CT et. all. “Current approaches to enhance CNS delivery of drugs across the brain

barriers” Int J Nanomedicine , 2014 May 10• 2) William M. Pardridge “Drug Delivery to the Brain” Journal of Cerebral Blood Flow and

Metabolism, 1997• 3) Gloria lee et. all. “Drug Transporters in the Central Nervous System: Brain Barriers

and Brain Parenchyma Considerations” The American Society for Pharmacology and Experimental Therapeutics 10402/948870 Pharmacol Rev 53:569–596, 2001

• 4) William M. Pardridge “Drug and gene targeting to the brain with molecular trojan horses” The Nature, Volume 1 | february 2002

• 5) Reinhard Gabathuler “Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases” Neurobiology of Disease, 2009

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