Brain Targeting: Novel approaches
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The document discusses targeted drug delivery systems, particularly for delivering therapeutics across the blood-brain barrier (BBB) to treat neurological diseases. It outlines the need, advantages, and disadvantages of such systems, as well as various approaches and marketed formulations for effective drug delivery to the brain. The conclusion emphasizes the challenges and ongoing research required to overcome the BBB and improve therapeutic outcomes for brain diseases.
Brain Targeting: Novel approaches
- 1. PRESENTED BY SHAIK. BILKHIS (15AB1R0068) IV.B.PHARMACY UNDER THE GUIDANCE K.PALLAVI M. Pharm, (Ph.D.) ASSISTANT PROFESSOR TARGETED DRUG DELIVERY SYSTEMS 1
- 2. Introduction Need of targeted drug delivery system Advantages and dis advantages of drug targeting Classification of drug targeting Brain targeting: CONTENTS 1. Aim 2. Introduction 3. Blood brain barrier 4. Diseases related to BBB 5. Factors 6. Approaches 7. Marketed formulation 8. Reference 9. Conclusion &Acknowledgement 2
- 3. Targeted drug delivery system 3 Drug Drug loaded Nano particleNano particle
- 4. Targeted Drug Delivery Systems The major goal of an drug delivery system is to supply a therapeutic amount of drug to a target site in a body Targeted drug delivery implies Selective and Effective localization of drug into the target at therapeutic concentrations with limited access to non target site A targeted drug delivery system is preferred in drugs having Instability, low stability and short half life 4
- 5. Need of Targeted Drug Delivery System Pharmaceutical Reason Low solubility, Drug instability Pharmacokinetic Reason o Poor absorption o Short half-life o Large Volume of Distribution Pharmaacodynamic Reason Low specificity Low therapeutic index 5
- 6. Advantages Reduced toxicity Bypass hepatic first pass metabolism Reduced dose and dosing intervals No peak and plasma concentration Enhancement of the absorption of target molecules such as peptides and particulate 6
- 7. Disadvantages Rapid clearance of targeted system. Immune reaction against i.v administered carrier system. Diffusion and redistribution of released drug. Drug deposition at the target site may produced toxicity symptoms. Difficult to maintain stability of dosage form. 7
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- 10. AIM To emphasize on drug delivery to brain by using various approaches. To study the blood-Brain barrier. To study different approaches to bypass BBB and to delivery therapeutics into the brain. 10
- 11. Drug delivery to the brain is the process of passing Therapeutically active molecules across the Blood Brain Barrier for the purpose of treating brain maladies. This is a Complex process. Systemic drug treatment of neurological diseases, such as brain tumors, infectious and neurodegenerative diseases, is a daunting challenge due to the unique protective barriers of the central nervous system. Such innate barriers, mainly the 1.Blood Brain Barrier 2. Blood cerebrospinal fluid INTRODUCTION 11
- 12. The blood-brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system The BBB consists of the Tight junctions (TJs) of capillary endothelial cells on one side and the Foot processes of astrocytes on the other side, whereas the BCSF is formed by the TJs of choroid plexus cells surrounding the microvascular endothelium with intracellular gap and fenestration. 12
- 13. Overview of the blood-brain barrier and blood- cerebrospinal fluid barrier 13
- 15. Diseases related to Blood Brain Barrier 1. Meningitis 2. Brain abscess 3. Epilepsy 4. Multiple sclerosis 5. Neuromyelitis optica 6. Late-stage neurological trypanosomiasis (sleeping sickness) 7. Progresive multifocal leukoencephalopathy (PML) 8. Alzheimer’s Disease, etc; 15
- 16. S. NO DISEASES RELATED TO BLOOD BRAIN BARRIER DRUGS 1. Meningitis Antibiotics(IV) vancomycin +3rd generation cephalosporin(cefotaxime) 2. Brain abscess cefotaxime, metronidazole 3. Epilepsy carbamazepine 4. Multiple sclerosis chemotherapy drugs 5. Neuromyelitis Optica Mycophenolatr, rituxan 6. Late-stage neurological trypanosomiasis(sleeping sickness) Alpha- difluoro - methylornithine 7. Progresive multifocal leukoencephathy (PML) Dimethyl fumarate(Tecfidera) 8. Alzheimer’s Disease, etc; Donepezil 16 DISEASES RELATED TO BLOOD BRAIN BARRIER
- 17. Factors affecting drug transport across the BBB Cerebral blood flow Concentration gradient of drug Molecular weight of the drug Affinity for receptors Systemic Absorption Metabolism by other tissues Decreases the clearance rate of drug Pathological status Cellular enzymatic stability Lipophillicity of drug 17
- 18. Approaches for effective brain drug delivery Non –invasive techniques Invasive techniques Alternative routes for CNS drug delivery Chemical methods Biological methods Colloidal drug carriers Intracerebro – ventricular infusion Convection – enhanced delivery Polymer or microchip systems Intranasal delivery Iontophoretic delivery 18
- 19. Invasive Approach I • Intracerebro-ventricular infusion II • Convection-enhanced delivery III • Polymer or microchip systems(implants) 19
- 20. Intra –cerebro ventricular(ICV) infusion 20
- 21. 1.Intra-Cerebro-Ventricular (ICV) infusion: Ex.Glycopeptide and amino glycoside antibiotics used in meningitis. Drug solutions can be subcutaneously injected into the implanted reservoir and delivered to the ventricles by mannual compression of the reservoir through the scalp. Drugs can be infused intravenously using an ommaya reservoir , a plastic reservoir implanted subcutaneously in the scalp and connected to the ventricles. Injection or intra ventricular infusion of drugs into the CFS 21
- 23. The general principle of CED involves the stereotactically guided insertion of a small- caliber catheter into the brain parenchyma. Through the catheter, infusate is actively pumped into the brain parenchyma and penetrates in the interstitial space. The infusion is continued for several days and the catheters are removed at the bedside. CED has been shown in laboratory experiments to deliver high molecular weight proteins 2cm from the injection site in the brain parenchyma after as little as 2 hrs of continuous infusion. .Limitations: some areas of the brain are difficult to saturate fully with infusate, particularly ---infiltrated tissues surrounding a cavity. 2.CONVECTION-ENHANCED DELIVERY (CED) 23
- 24. Polymer or microchip implants 24
- 25. Polymer or microchip system (implants) 25
- 26. Intracerebral implantation of therapeutic agents containing biodegradable polymeric matrix or reservior is a highly traumatic drug –delivery stratergy, which has been utilized in a number of clinical trials. In 1996, the FDA approved a BCNU (bischloroethylnitrosourea) (carmustine)-contained polyanhydride polymer wafer for recurrent high –grade gliomas. With the combination of diffusion and hydrolytic degradation ,this matrix maintains a sustained drug release for about 3 months. POLYMER OR MICROCHIP SYSTEM SYSTEMS (IMPLANTS) 26
- 29. Lipophilic analogs Mechanism: Passive diffusion Lipidization: Better vascular permeability Good CNS permeability: Lipophilic analogs with log P value in the range of 1.5-2.5. 29
- 30. Prodrugs 30
- 31. Definition : Prodrugs are defined as compounds that, on administration,must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent Prodrug method is used to make a drug more lipophilic. Example : Morphine cannot enter the CNS by itself. 31
- 33. Molecular packaging To enhance penetration of peptides through the BBB, the “molecular packaging’’ strategy has been developed. Three goals can be simultaneously accomplished for enhanced BBB penetration. a. Increased lipophilicity to enhance passive transport. b. Prevention of premature degradation by increasing enzymatic stability. c. Exploitation of the lock-in mechanism to provide targeting. 33
- 34. RECEPTOR MEDIATED DRUG DELIVERY Receptor-mediated drug delivery to the brain employs chimeric peptide technology. 34
- 35. Peptide technology based on using the coupling of a non- transportable peptide pharmaceutical to a transportable peptide or protein, which undergo receptor-mediated transcytosis through the BBB. Endocytosis can be triggered after binding of the vector to its receptor on the luminal surface of brain capillary endothelial cells. Enzymatic cleavage may occur at the cleavage linkage between the vector and the drug to release the pharmacologically active moiety of the chimeric peptide. 35
- 36. Cell-penetrating peptide (CPP)-mediated drug delivery 36
- 37. CELL-PENETRATING PEPTIDE DRUG DELIVERY Targeted drug delivery to specific group of cells offers an attractive strategy to minimize undesirable side effects and achieve the therapeutic effect with a lower dose. CPPs contain a sequence of highly basic amino acids They interact with cell surface Via a receptor mediated mechanism. CPPs used to treat Cancer Auto immune diseases 37
- 38. VIRAL VECTORS 38
- 39. Viral vectors Viruses introduce their genetic material into the host cell as part of their replication cycle. Remove the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA . The viruses used are altered to make them safe, although some risks such as: Unwanted immune response, Changes in the properties of delivered virus due to endogenous recombination, Mutagenic behavior leading to oncogenesis. 39
- 40. Colloidal drug carriers 40
- 41. COLLOIDAL DRUG CARRIERS Its an promising approach Colloidal carriers include Emulsion Liposomes Nanoparticles Coating with surfactants like e.g. polyoxypropylene polyethylene glycol polyoxyethylene 41
- 43. Alternative routes for CNS drug delivery 1.Intranasl delivery 2.Iontophoretic delivery 43
- 44. Intranasal delivery The olfactory mucosa (smelling area in nose)is in direct contact with the brain and cerebrospinal fluid. Medications absorbed across the olfactory mucosa directly enters the brain. This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain. 44
- 46. Iontophoretic delivery Ionophoretic is a method to deliver ionized molecules across the BBB by using an externally applied electric current. In the body ,ions with a positive nature (+) are driven into the skin at the anode those with negative charge (-) at the cathode. Iontophoresis is sometimes confused with electrophoresis. Iontophoresis involving movement of the colloid (dispersed phase) Electrophoresis involving the liquid (dispersed medium) 46
- 47. Mechanism: In Iontophoretic treatment electric potential may alter the molecular arrangement of the skin components hence change in skin permeability. The flip-flop gating mechanism could be responsible for pore formation in the stratum corneum which is rich in keratin, an alpha –helical polypeptide. 47
- 48. S. no. Brand name Active pharmaceutical ingredient Role 1. AmBisome Amphotericin B Liposome for injection 2. Caelyx PEGylated liposomal doxorubicin hydrochloride Brain tumors 3. Aricept Donepezil Alzheimer's disease 4. Aurimmune Colloidal gold IV nanoparticles Solid tumors 5. AuroShell Gold-coated silica Nanoparticles IV (-150nm) Solid tumors TABLE:MARKETED FORMULATIONS AVAILABLE AS A BRAIN TARGETED DRUG DELIVERY SYSTEM 48
- 49. CONCLUSION The treatment of brain diseases a particularly challenging because the delivery of drug molecules to the brain is often precluded by a variety of physiological ,metabolic and biochemical obstacles that collectively comprise the blood brain barrier (BBB). Drug delivery directly to the brain interstitium has recently been markedly enhanced through the rational design of polymer –based drug delivery system. Substantial progress will only come about, however, if continued vigorous research efforts to develop more therapeutic and less toxic drug molecules are paralleled by the aggressive pursuit of more effective mechanisms for delivering those drugs to their brain targets. 49
- 50. REFERENCES 1. Sk . Garg et al., “Challenges of Brain Drug Delivery and G- technology as One of Solution ‘’,Journal of pharmacy and pharmaceutical Sciences, Volume 2,Issue 3, July –September, 2013, page no.13-18 . 2. PS Mohanachandran, PG Sindhumol, “Recent trends in brain targeting drug delivery system: An overview “, International Journal of Comprehensive pharmacy , volume 3,issue 10,page no.1-9. 3. Drug delivery to the brain, From Wikipedia, the free encyclopedia. 50
- 51. 4. A.N Misra ,AV Ganesh , AN Shahiwala, “Drug delivery to the central nervous system :a review “, J Pharm pharmaceutical science ,volume 6,2nd edition ,page no.252-273. 5. Blood- brain barrier, From Wikipedia ,the free encyclopedia. 6. WM Pardridge, the Blood –brain Barrier: Bottleneck in Brain Drug Development”. The Journal of the American Society for Experimental Neuro Therapeutics, Volume 2,page no.21-29. 51
- 52. 7. Barbara Pavan et al.,” Progress in Drug Delivery to the Centro Nervous System by the Prodrug Approaches". Journal of Molecules , Volume 13, page no.1035-1065. 52
- 53. • Thank you for paying attention. •I sincerely thank my guide K. PALLAVI MADAM for giving me the valuable guidance. •My honored thanks to principal DR.P.SRINIVASA BABU SIR for giving me this opportunity. •A special thanks to Mrs. P. SOWJANYA MADAM (seminar committee ) ACKNOWLEDGEMENT 53
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