Brain targeted DDS (1)

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brain targeted drug delivery system

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Brain Targeted Drug Delivery System : 

Brain Targeted Drug Delivery System 1 Presented by - Mr. Dholariya Yatin N. Master of Pharmacy(QAT) Semester II MARATHWADA MITRA MANDAL’S COLLEGE OF PHARMACY THERGAON,PUNE

CONTENTS : 

CONTENTS 2 Introduction Anatomy of Brain Barriers to CNS drug delivery Factor affecting drug permeation through BBB Transport at the BBB Strategies for enhanced brain drug delivery Marketed formulations Conclusion References

INTRODUCTION : 

INTRODUCTION 3 The drug accessibility to the CNS is mainly limited by the BBB. Insufficient amount of drug reaches to the brain. Therefore practical strategies are required. New strategies are arise from investigation that critically reveals the physiological mechanism involved with the solute transport across BBB. Several classes of metabolic substrates, peptides , plasma derived –proteins and various group of centrally active pharmacotherapeutics are able to utilize specialized `shuttle’ services at the BBB.

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ANATOMY OF BRAIN The human nervous system comprises of CNS, ANS, PNS. Brain is sensitive & complex organ of human body, that comes under CNS along with spinal cord. The delivery of drugs to CNS is a challenge in the treatment of neurological disorders. The major neurological diseases are categorized as neurodegerative, cerebrovascular, inflammatory (infections or autoimmune) and cancer. 4

cont… : 

The brain has 4 fluid compartments - Blood- flows through entire brain - Interstitial fluid (ISF)- bathing neurons and neuroglia - Cerebrospinal fluid (CSF)-circulates around brain ventricles - Intracellular fluid -within brain cells. The barrier located in the cerebral endothelia that separates the systemic circulation from the ISF compartment is the blood-brain barrier. The barrier in the choroidal epithelia that separates the systemic circulation from the CSF compartment is known as the blood-CSF barrier. cont… 5

BARRIERS TO CNS DRUG DELIVERY : 

Blood-brain barrier ( BBB ) Blood-CSF barrier ( BCSFB ) Blood-tumor barrier ( BTB ) Main approaches toward CNS drug delivery -Systemic administration -Injection into CSF -Injection directly into brain New and effective treatments for CNS diseases must concentrate not only on the drug target within the CNS but also on the efficient delivery of the molecule to the site of action within the brain. BARRIERS TO CNS DRUG DELIVERY 6

BLOOD BRAIN BARRIER : 

BLOOD BRAIN BARRIER 7 which impedes and regulates the influx of most compounds from blood to brain. Formed by brain microvascular endothelial cells (BMEC), astrocyte end feet and pericytes. Essential for normal function of CNS. Regulates passage of molecules in and out of brain to maintain neural environment. Responsible for metabolic activities such as the metabolism of L-dopa to regulate its concentration in the brain.

FUNCTION AND PROPERTIES OF THE BBB : 

FUNCTION AND PROPERTIES OF THE BBB 8 The BBB has several imp functions: Protects the brain from “foreign substances”. Protects the brain from hormones and neurotransmitters in the rest of body. Maintains a constant environment for the brain. Properties of the BBB Large molecules do not pass through the BBB easily. Hydrophilic molecules do not penetrate into the brain. Whereas, lipophilic molecules penetrate rapidly.

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BLOOD BRAIN BARRIER 9

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Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial) cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the 'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fat-soluble molecules that have crossed into the cells 11

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FACTORS AFFECTING DRUG PERMEATION THROUGH BBB Plasma concentration and distribution process. Permeability of BBB to the agent Cerebral blood flow Route of administration Pharmacokinetic characteristics : Elimination Metabolism 13

TRANSPORT AT THE BBB : 

TRANSPORT AT THE BBB 14 Transport mechanism operating at the BBB for the peptides and proteins can be classified into the following categories: Carrier mediated Transport system Receptor mediated transcytosis (RMT) Absorptive mediated transcytosis (AMT)

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STRATEGIES FOR ENHANCED BRAIN DRUG DELIVERY 16

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Lipophilic analogue Drug’s lipophilicity correlates so strongly with cerebro-vascular permeability. Immunoliposomes (antibody-directed liposome) have been recognized as a promising tool for the site-specific delivery of drugs. To avoid very rapid clearance of immunoliposomes, gangliosides or PEG- derivatized lipids are inserted within the bilayer. PEG coating is believed to prevent recognition of liposomes by macrophages due to reduced binding of plasma proteins. DRUG MANIPULATION 18

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Attach a cell-specific ligand , folic acid and monoclonal antibodies to target liposome to cells in tissue culture and organs. Receptor specific monoclonal antibodies (mAbs) undergo receptor-mediated transcytosis through the BBB. The mAb used in these studies is the OX26 mAb to the rat transferrin receptor, which is abundant on brain micro vascular endothelium. 19

2. Colloidal drug carrier : 

2. Colloidal drug carrier 20 Micelles : Liposomes :

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3. Prodrug Result from transient chemical modifications of biologically active species. It gets converted to the active form, usually via a single activating step CNS prodrugs is coupling the drug to a lipid moiety, such as fatty acid, glyceride or phospholipids Such prodrug approaches were explored for a variety of acid-containing drugs, like levodopa, GABA, Niflumic acid, valproate or vigabatrin 21

4. Chemical drug delivery system : 

4. Chemical drug delivery system 22 Drug delivery into CNS is by molecular packaging and sequential metabolism. Lpf: lipophilic groups including a lipoidal T: targetor1,4-dihydropyridine (T+): pyridinium moiety (S): A spacer function controls the enzymatic rate of drug release.

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5. Carrier Mediated Drug Delivery The hexose transport system for glucose and mannose. The acidic amino acid transport system for glutamate and aspartate. The basic amino acid transport system for arginine and lysine. The b-amino acid transport system for b-alanine and taurine. The choline transport system for choline and thiamine. the amine transport system for mepyramine 23

6. Receptor mediated drug delivery system : 

6. Receptor mediated drug delivery system 24 a) Chimeric peptide technology : Present on the brain capillary endothelium Mediate the transcytosis of the circulating peptide through the BBB Undergo endosomal release following receptor-mediated endocytosis into the target brain cell

Receptor-Associated Protein (RAP) : 

Receptor-Associated Protein (RAP) 25 37kDa human protein RAP has a normal function in receptor biosynthesis for lipoprotein receptor synthesis Binds to lipoprotein receptors on cell surfaces Lipoprotein receptors are the therapeutic targets for RAP

Selected Members of Lipoprotein Receptor Family : 

Nature Cell Biology   October 1999 volume 1 issue 6 pp E157-E162 DOI:10.1038/14109 Selected Members of Lipoprotein Receptor Family 26 Receptors on the BBB

How Does RAP Deliver Drugs to the Brain? : 

How Does RAP Deliver Drugs to the Brain? 27 Blood Brain Barrier RAP receptor Brain Blood

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Osmotic blood brain barrier disruption Intracarotid injection of an inert hypertonic solution such as mannitol or arabinose has been employed to initiate endothelial cell shrinkage Only a 25% increase in the permeability of the tumor microvasculature, in contrast to a 10-fold increase in the permeability of normal brain endothelium The risk factors include the passage of plasma proteins, the altered glucose uptake, and the expression of heat shock proteins, micro embolism or abnormal neuronal function. DISRUPTION OF BBB 28

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2.Biochemical Blood-Brain Barrier Disruption Selective opening of brain tumor capillaries by the intracarotid infusion of leukotriene was achieved without concomitant alteration of the adjacent BBB. In contrast to osmotic disruption methods, biochemical opening utilizes the observation that normal brain capillaries appear to be unaffected when vasoactive leukotriene treatments are used to increase their permeability 29

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ALTERNATIVE ROUTES TO BRAIN : 

ALTERNATIVE ROUTES TO BRAIN 31 Olfactory and trigeminal pathway neural pathway between nasal mucosa and brain is unique pathway for noninvasive drug delivery a) The Olfactory neural pathway b) The trigeminal neural pathway Intra neuronal Axonal transport extra neuronal Bulk transport

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Intraventricular / intrathecal delivery Drugs can be infused using Ommaya reservoir implanted subcutaneously in the scalp Connected to ventricles via outlet catheter Drug solutions injected into reservoir Delivered to the ventricles by manual compression of the reservoir C. Interstitial delivery Injection , catheters and pumps Biodegradable polymer , microspheres and nanoparticals 32

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33 Biotechnological approaches Implanting a tissue into the brain that naturally secretes a desired therapeutic agent. Ex: Transplantation of embryonic dopamine-releasing neurons. E. Transcranial route of drug delivery Transfer of drug molecules across the cranium through the layers arteries and veins of the skin of the head. Ex: Diazepam.

MARKETED FORMULATIONS: : 

34 MARKETED FORMULATIONS: Category: hypnotics Category: Anti-convulsant Category: Anti-epileptic Category: Anti-psychotic & Anti-manic

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35 Category: G. Anesthetic Category: sedative Category: Anti-psychotic Category: opoid

CONCLUSION : 

CONCLUSION 36 Recent developments in drug delivery techniques provide reasonable hope that the formidable barriers shielding the brain may ultimately be overcome.

REFERENCES: : 

Jain N. K., Controlled & Novel Drug Delivery, CBS Publishers, 256-281 Anya M. Hillary, Andrew W. Lloyd, James Swarbrick, Drug Delivery And Targetting, CRC, 1ST Indian Edition, 2010, 355-370. Vyas S. P. & Khar R. K., Targeted Drug Delivery Novel Carrier Systems, CBS Publishers, 387-413. Patel H. A. Patel J. K, Brain targeted delivery system, The Indian Pharmacist, Vol- IX, Feb 2011, 8. Jungier H. E., Drug Targeting & Delivery in dosage form design, Ellis Horwood, 1-12,71-91,113-128 Charman W.N., Chan H.-K.,Finnin B.C. andCharman S.A., Drug Delivery: A Key Factor in Realising the Full Therapeutic Potential of Drugs , Drug Development Research, 1999,46, 316- 27 . REFERENCES: 37

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7. Santinijr, J.T., Richards A.C.,Scheidt R.,Cima M.J. and Langer R., Microchips as Controlled Drug-Delivery Devices ,Angew. Chem. Ed., 2000, 39, 2396-2407. 8. Kopecek J., Smart and genetically engineered biomaterials and drug delivery systems , European Journal of Pharmaceutical Sciences, 2003, 1-16. 9. Torchilin V.P., Structure and design of polymeric surfactant- based drug delivery systems , Journal of Controlled Release, 2001, 73, 137. Muller-Goymann C.C ., Physicochemical characterization of colloidal drug delivery systems such as reverse micelles, vesicles, liquid crystals and nanoparticles for topical administration , European Journal of Pharmaceutics and Biopharmaceutics, 2004, 58, 343-56. Hiremarh S. R., Textbook of Industrial Pharmacy, Orient Longman Pvt Ltd, 91- 96,97-142 38

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39 Thank you…

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