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Brain Targeted Drug Delivery

Approaches to deliver the drug across the Blood Brain Barrier

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Brain Targeted Drug Delivery

  1. 1. APPROACH TO TARGET BRAIN DRUG DELIVERY SYSTEM SCHOLAR: MANISH KUMAR M.Pharm (Pharmaceutics) GUIDED BY: Mr. SHASHANK SONI Assistant Professor SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH, BALAWALA, DEHRADUN, (UTTARAKHAND)
  2. 2.  INTRODUCTION  BARRIERS  DRUG TRANSPORT  FACTORS AFFECTING  APPROACHES  FUTURE ASPECTS  MARKETED FORMULATION
  3. 3. 1880 Paul Ehrlich use vascular dyes The existence of a blood brain barrier (BBB) 1960s Drs. Reese, Karnovsky, and Brightman using electron microscopy localized tight junctions  Ramakrishnan, P. (2003). The role of P-glycoprotein in the blood-brain barrier. Einstein Quart. J. Biol. Med, 19,160-165.
  4. 4. • BBB and BCF  control the entry of compounds into the brain and  regulate brain homeostasis.  restricts access to brain cells of blood–borne compounds and  facilitates nutrients essential for normal metabolism to reach brain cells. • It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB. BARRIERS The blood brain barrier (BBB) The blood cerebrospinal fluid barrier (BCSFB)  Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44.  Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
  5. 5. BLOOD BRAIN BARRIER FUNCTIONS:  STABILIZER – stabilize CNS neurons  PROTECTION – from toxins, microbes (bacteria)  HOLDER – hold neurotransmitter within CNS  Prajapati, J., Patel H, & Agrawal, Y. K. (2012). Targeted drug delivery for central nervous system: a review. Int J Pharm Pharm Sci, 3,32-38.  Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
  6. 6. ENDOTHELIAL CELLS TIGHT JUNCTION VERY LITTLE VESICULAR TRANSPORT SPECIAL PROTEINS e.g. OCCLUDINS, CLOUDINS P-GLYCOPROTEIN OVERVIEW REPRESENTATION OF BBB
  7. 7. Schematic representation of BBB  Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
  8. 8. BLOOD CEREBROSPINAL FLUID BARRIER (BCSFB) . • Fenestrated Endothelial cells . • Modified Ependymal cells (Choroidal cells)  Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44.
  9. 9. ENDOTHELIAL CELLS CHOROIDAL CELLS TIGHT JUNCTIONS BASAL MEMBRANE
  10. 10. Schematic representation of BCSF  Bhaskar, S., Tian, F., Stoeger, T., Kreyling, W., de la Fuente, J. M., Grazú, V., ... & Razansky, D. (2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood- brain barrier: perspectives on tracking and neuroimaging. Particle and fibre toxicology, 7(1),3.
  11. 11. BIG MOLECULES HIGHLY CHARGED MOLECULES TOXIC SUBSTANCES SMALL MOLECULES GLUCOSE
  12. 12. S.NO TRANSPORT MECHANISM DESCRIPTION 1 PASSIVE TRANSPORT 1. Molecular weight (>600 Dalton is limiting factor) Inversely related to passive transport 2. Lipophilicity is directly related to passive transport log P values (- 0.2 to 1.3) is responsible for optimal cerebral transport 3. Protein binding : Protein- drug complex size is responsible for transport (Free fraction of drug is transported.) 2 ADSORPTIVE MEDIATED TRANSCYTOSIS/ ENDOCYTOSIS 1. Adsorptive-mediated transcytosis macromoleculs like cationic macromoleculs e.g. histone, avidine and cationized albumin 2.Brain targeting using adsorptive mediated endocytosis cationized human serum albumin (cHSA) as a transport vector coupled to 3H-biotin is able to cross the BBB in significant amounts 2 ACTIVE TRANSPORT requires energy  Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
  13. 13.  VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4),15-27.
  14. 14. Begley, D. J., Bradbury, M. W., & Kreuter, J. “Specific Mechanisms for Transporting Drugs Into Brain” The Blood–Brain Barrier and Drug Delivery to the CNS, Akira Tsuji (e.d.) , 2000 by Marcel Dekker,Inc., 8.
  15. 15. Receptor-mediated transport Active efflux-mediated transport Transporter(Carrier) - mediated transport Transferrin receptor (TfR) Adenosine triphosphate-binding cassette (ABC) transporter subfamily B, member 1 (P-glycoprotein) Glucose transporter(Glut1) Insulin receptor(IR) MRPs(1&5) Large neutral amino acid transporter (LAT1) Nicotinic acetylcholine receptor Organic anion transporting peptide Cationic amino acid transporter (CAT1) Low-density lipoprotein receptor Glutamic acid amino acid transporter Monocarboxylic acid transporter (MCT1) Insulin-like growth factor receptor(IGF-R) Taurine transporter Choline transporter Diphtheria toxin receptor Organic anion transporter (oatp2) Nucleobase transporter Leptin receptor(OB-R) BBB-specific anion transporter type 1 (BSAT1) CNT2 adenosine transporter Neonatal Fc receptor (FcRn)  Gao H. (2016). Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharmaceutica Sinica B, 6(4),268-286.
  16. 16. Amino Acid Transporters large neutral amino acid transporters, LA transporters, cationic-, anionic- and neutral-amino acid transporters E.g. L-Dopa is transported by LA transporters in the BBB . Glucose Transporters type 1, glucose transporter, GLUT 1 E.g. Glycosylated analogs of various opioid compounds Monocarboxylic Acid Transporter (MCT) E.g. salicylic acid HMG-CoA reductase inhibitors Nucleoside Transporter 1. facilitative nucleoside transporters that carry selective nucleosides either into or out of the cell 2. active and the sodium-dependent transporters that can move selective nueleosides into the cell against a concentration gradient E.g. anticancer agent, the antiviral agents Carrier-mediated (Active) Transport  Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
  17. 17. Molecular Antibody (Mab) - Molecular Trojan Horse Act as ligands for RMT e.g. CRM197 (Carrier Protein) uses HB-EGF(heparin binding epidermal growth factor) as its transport receptor (Diptheria Toxin Receptor) used for Multiple Sclerosis, Parkinsonism, Alzhemier, Poliovirus Trojan Horse Liposome Attachment of a MTH to tips of PEG strands of liposome triggers RMT Encapsulation of plasmid DNA inside pegylated liposome eliminates nuclease sensitivity Low Density Lipoprotein Receptor (LRP1&2) Multiligand lipoprotein receptor interacting with proteins apoE(apolipoprotein E) Alpha2 M(macroglobulin) APP(Amyloid precursor protein) PAI-1 & tPA Transferin And Insulin Receptor BDNF-HIR Mab EGF-TR mab FGFT-HIR Mab Beta galactosidase –TR Mab Neurotrophin-HIR fusion Receptor Mediated Transport  Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiology of disease, 37(1),48-57.
  18. 18. PARAMETERS CONSIDERED OPTIMUM FOR A COMPOUND TO TRANSPORT ACROSS THE BBB ARE:  Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44. Compound should be unionized. Approximately log p value must be 2. Its molecular weight must be less than 400 Da Cumulative number of hydrogen bonds between 8 to 10
  19. 19. BBB BROKEN  TRAUMA  INFLAMMATION  INFECTION  IRRADIATION  NEUOPLASM  HYPERTENSION  HIGH ALTITUDE  HYPOXIA  ISCHEMIA BBB BROKEN WATER INFLOW EDEMA LIFE THREATENING
  20. 20.  Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
  21. 21. CNS DRUG DELIVERY APPROACHES INVASIVE TECHNIQUES NON INVASIVE TECHNIQUES MISCELLANEOUS TECHNIQUES
  22. 22.  Woodworth, G. F., Dunn, G. P., Nance, E. A., Hanes, J., & Brem, H. (2014). Emerging insights into barriers to effective brain tumor therapeutics. Frontiers in oncology, 4,126.
  23. 23. INVASIVE APPROACH INTRA CEREBRAL IMPLANTS INTRA VENTRICULAR INFUSION BBB DISRUPTION A
  24. 24.  wide range of compound and formulation can be considered for ICV or IC administration.  both large and small molecules can be delivered Drill the hole in the head place the implant by intra-cerebral (IC) method give infusion by intra-cerebro- ventricular (ICV) method
  25. 25. INTRA CEREBRAL IMPLANTS  delivery of drugs directly into the brain parenchymal space  the drugs can be administered by:  Direct injection via intrathecal catheter  Control release matrices & Microencapsulated chemicals.  The basic mechanism is diffusion.  Useful in the treatment of different CNS diseases e.g. brain tumor, Parkinson’s Disease etc.  Example:  Intrathecal injection of baclofen for spasticity  Infusion of opioids for severe chronic pain  Limitations :  1.Distribution in the brain by diffusion decreases exponentially with distance.  2.The injection site has to be very precisely mapped to get efficacy and overcome the problem associated with diffusion of drugs in the brain parenchyma.
  26. 26. INTRA CEREBRO VENTRICULAR INFUSION  pharmacological effect is seen if the target receptors of the drug are located near the ependymal surface of the brain.  Drug is infused using an ommaya reservoir, a plastic reservoir implanted subcutaneously in the scalp and connected to ventricles  Limitations:  The diffusion of the drug in the brain parenchyma is very low .  unless the target is close to the ventricles it is not an efficient method of drug delivery.  Example Glycopeptide and an aminoglycoside antibiotics used in meningitis.
  27. 27.  VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.
  28. 28. BBB DISRUPTION  Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol may disrupt BBB.  Osmotic disruption : Example : Intracarotid administration of a hypertonic mannitol solution with subsequent administration of drugs can increase drug concentration in brain and tumour tissue to reach therapeutic concentration  MRI-guided focused ultrasound BBB disruption technique example: distribution of Herceptin is increased in brain tissue by 50% in a mice model. The osmotic shock endothelial cells shrink disrupting the tight junctions Injection of microbubbles of ultrasound contrast agent ( eg. optison, dia. 2-6 μm ) and manganese into the blood stream exposures to ultrasound
  29. 29. LIMITATIONS OF INVASIVE APPROACH  relatively costly  require anaesthesia and hospitalization.  It may enhance tumour dissemination after successful disruption of the BBB.  Neurons may be damaged permanently from unwanted blood components entering the brain
  30. 30. NON INVASIVE APPROACH CHEMICAL PRODRUGS DRUG CONJUGATES BIOLOGICAL MONOCLONAL / CATIONIC ANTIBODIES CONJUGATES RECEPTOR / VECTOR MEDIATED APROTONIN / CHIMERIC PEPTIDES AS CARRIER COLLOIDAL NANOPARTICLES LIPOSOMES B
  31. 31. PRODRUGS Prodrug is lipid soluble (pharmacologically inactive compounds) cross the BBB metabolized within the brain converted to the parent drug Esterification or amidation of hydroxy-, amino-, or carboxylic acid- containing drugs, may greatly enhance lipid solubility and, hence, entry into the brain
  32. 32. WHAT TO DO AND WHY  Drug covalently linked to an inert chemical moiety.  Improve physicochemical property such as solubility and membrane permeability.  Prodrug is cleaved by hydrolytic or enzymatic processes.  Examples levodopa, gaba, niflumic acid, valproate.  Heroin, a diacyl derivative of morphine, is a notorious example that crosses the bbb about 100 times more easily than its parent drug just by being more lipophilic.  Limitations of the prodrug:  Adverse pharmacokinetics.  The increased molecular weight of the drug that follow from lipidation.  VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.
  33. 33. CO-DRUG  Drugs that inhibit a BBB AET could be used as a “co-drug” to cause increased brain penetration of a therapeutic drug that is normally excluded from brain by a BBB AET system.  Example:  Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg), a known inhibitor of p-glycoprotein was given with quinidine at a dose of 600 mg (P < .001).  Increased brain penetration of the chemotherapeutic agent, paclitaxel (taxol®), by co-administration of the pglycoprotein inhibitor, psc-833 (valspodar).  Aromatic amino acid decarboxylase (aaad) inhibitors are administered as codrugs in conjunction with l-dopa to optimize brain penetration of the L-dopa.  Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development. Molecular interventions, 3(2),90.
  34. 34. DRUG CONJUGATES Lipidization of molecules generally increases the volume of distibution. Chemical approaches include lipophilic addition and modification of hydrophilic drugs ( e.g. Nmethylpyrimidium 2 carbaldoxime chloride) Example: Glycosylated analogs of various opioid compounds Antioxidant + pyrrolopyrimidines – increase access For Ganciclovir : to hydroxymethyl group + 1methyl 1,4 dihydronicotinate- increase transport For small drugs: use of fatty acids like N docosahexaenoyl(DHA) increase uptake Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiology of disease, 37(1),48-57.
  35. 35.  Example of drug transfered via LAT1:  Melphalan for brain cancer  Alpha methyl dopa for high blood pressure  Gabapentin for epilepsy  Ldopa for parkinsonism CARRIER MEDIATED TRANSPORT  Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development. Molecular interventions, 3(2),90.
  36. 36. RECEPTOR / VECTOR MEDIATED  Conjugation of drug to transport vector is facilitated with chemical linkers avidin–biotin technology, polyethylene glycol linkers,  vector such as the Monoclonal antibody (Mab)  Portals of entry for large molecular drug attached to endogenous RMT ligands. VECTOR BRAIN SPECIFICITY PHARMACOKINETI CS HIGH YIELD COUPLING CLEAVABILITY RETENTION OF AFFINITY AAFTER INTRINSIC RECEPTOR LINKER DRUG
  37. 37. CHIMERIC PEPTIDES AS CARRIER DRUG VECTOR MODIFIED PRODUCT Conjucated proteins may be endogenous peptides, monoclonal antibodies, modified protein, cationized albumin etc. Chimeric peptides are transported to brain by various pathways like peptide specific receptor. E.g. Insulin and transferrin by transcytosis Conjugation of drug with antibodies e.g. OX-26, 8D3 Mab antibody to red transferrin receptor
  38. 38. Targeting  Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development. Molecular interventions, 3(2),90.
  39. 39.  Begley David J., Bradbury Michael W. , Kreuter Jörg “Targeting Macromolecules to the Central Nervous System” The Blood–Brain Barrier and Drug Delivery to the CNS, Ulrich Bickel(e.d.) , 2000 by Marcel Dekker,Inc., 8.
  40. 40. COLLOIDAL  The vesicular systems are highly ordered assemblies of one or several concentric lipid bilayer formed, when certain amphiphillic building blocks are confronted with water  Coated with surfactants like polyoxyethylene/propylene, PEG  AIM:  control degradation of drug  Prevent harmful side effects  increase the availability of the drug at the disease site.  slowly degrade, react to stimuli and be site-specific  Advantages:  Prolong the existence of the drug in systemic circulation  Improves the bioavailability especially of poorly soluble drugs.  Both hydrophilic and lipophilic drugs can be incorporated.  Delays elimination of rapidly metabolizable drugs and thus function as sustained release systems.
  41. 41. NANOPARTICLES  Size 1-1000 nm  includes both nanocapsules, with a core-shell structure (a reservoir system) and nanospheres (a matrix system).  Materials used: polyacetates, acrylic copolymers, poly(lactide), poly(alkylcyanoacrylates) (PACA), poly(D,L-lactide-co-glycolide)  Polysorbate coated nanoparticles can mimic LDL to cross BBB.  Polyoxyethylene sorbitan monooleate coated nanoparticles containing drug easily cross BBB.  Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma.  Mechanisms of transport Adhesion Fluidization of BBB endothelium by surfactants Opening of tight junction Transcytosis / Endocytosis Blockage of glycoprotein
  42. 42.  TARGETTING  These particles loaded with doxorubicin for the treatment of glioblastomas are presently in Clinical Phase I.  Human serum albumin nanoparticles conjucated with antibodies(OX26/R17217) against transferrin receptor e.g. For loperamide, 5-florouracil(5-FU)  Human serum albumin nanoparticles conjucated with antibodies(29B4) against insulin receptor e.g. for targeting loperamide  Cell penetrating peptide(trans activating transduction protein ) modified liposome i.e. Tat-LIP having positive charge transported via adsorptive mechanism. e,.g. for caumarin The coating of polyalkylcyanoacrylate or poly-lactic-co-glycolic acid (PLGA) nanoparticles with polysorbate 80 or poloxamer 188. Due to this coating the particles adsorb apolipoproteins E or A-1 from the blood Interact with the LRP1 or with the scavenger receptor followed by transcytosis across the blood-brain barrier into the brain.
  43. 43.  Advantages of using nanoparticles for CNS targeted drug delivery  protect drugs against chemical and enzymatic degradation.  small size --- penetrate into even small capillaries ---taken up within cells ----drug accumulate at the targeted sites  The use of biodegradable materials ---allows sustained drug release at the targeted site after injection  Limitations of using nanoparticles for CNS targeted drug delivery  small size and large surface area ----particle-particle aggregation-- physical handling of nanoparticles difficult in liquid and dry forms.  small particles size and large surface area readily result in limited drug loading and burst release.  Avhad, P. S., Patil, P. B., Jain, N. P., & Laware, S. G. (2015). A Review on Different Techniques for Brain Targeting. International Journal of Pharmaceutical Chemistry and Analysis, 2(3),143-147.  Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44.
  44. 44. LIPOSOMES  lipid based vesicles are microscopic (unilamellar or multilamellar) vesicles  Lipid soluble or lipophilic drugs get entrapped within the bilayered membrane whereas water soluble or hydrophilic drugs get entrapped in the central aqueous core of the vesicles  Advantages  suitable for delivery of hydrophobic, amphipathic and hydrophilic drugs and agents.  could encapsulate macromolecules like superoxide dismutase, haemoglobin, erythropoietin, interleukin-2 and interferon-g.  reduced toxicity and increased stability of entrapped drug via encapsulation (eg.Amphotericin B, Taxol).  Limitation :  High production cost , Short half-life , Low solubility , Less stability  Leakage and fusion of encapsulated drug / molecules  Sometimes phospholipid undergoes oxidation and hydrolysis  Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular Basis of Targeted Drug Delivery, 1,508.
  45. 45. A non viral supercoiled plasmid DNA is encapsulated in an interior of an 85nm liposome Liposome surface is conjucated with 1000-2000 strands of 2000 dalton peg to form pegylated liposome Tips of 1-2 % peg strands are conjucated with a peptidomimetic Mab(HIR/TR) to form pegylated immunoliposomeS Transfer via RMT TARGETING Mechanism: receptor/adsorptive mediated transport liposome coated with mannose reaches brain tissue where mannose coat assists transport Addition of sulphatide (a sulphate ester of galactocerebroside) to liposome increases availability  Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiology of disease, 37(1),48-57.
  46. 46.  Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J PharmaSciTech, 3,1-8.
  47. 47. MONOCYTES  Used as a Torjan Horse  Ideal endogenous carriers  Express certain receptors involved in receptor mediated endocytosis upon interaction with suitable ligands CARRIER MONOCYTE BBB DRUG  Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular Basis of Targeted Drug Delivery, 1,508.
  48. 48. MISCELLANEOUS TECHNIQUE INTRANASAL DELIVAERY IONTOPHORETIC DELIVERY C
  49. 49. INTRANASAL DELIVERY  Drug delivered intranasally are transported along olfactory sensory neurons to yield significant concentrations in the CSF and olfactory bulb and then enter into other regions of brain by diffusion(facilitated by perivascular pump)  DIFFICULTIES : enzymatic activity, low pH nasal epithelium, mucosal irritation or large variability caused by nasal pathology (common cold)  THE OLFACTORY PATHWAYS: the olfactory nerve pathway (axonal transport) and the olfactory epithelial pathway.  AXONAL TRANSPORT (slow route) :  THE EPITHELIAL PATHWAY (faster route) :direct nose-to-brain transfer Agent enters the olfactory neuron via endocytotic or pinocytotic mechanisms travels to the olfactory bulb compounds pass paracellularly across the olfactory epithelium into the perineural space continues to the subarachnoid space & in direct contact with the CSF.
  50. 50.  Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
  51. 51. IONTOPHORETIC DELIVERY  Iontophoresis is the introduction of ionised molecules into tissues by means of an electric current  biologically active agent is transported by means of iontophoresis and/or phonophoresis directly to the CNS using the olfactory pathway to the brain and thereby circumventing the BBB and is known as transnasal iontophoretic delivery  Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92  Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of Pharma Research & Review, 2(6),36-44.
  52. 52.  Identify new BBB transporters  Develop brain drug targeting systems enabling the brain delivery of recombinant protein neuro-therapeutics.  Validate new drug targeting systems using in vivo models.  Optimize pharmacokinetics of in vivo brain drug targeting systems.  Improve/enhance release of nanoparticles from implantable devices/nanochips  Multifunctional nanoparticles  Universal formulation schemes that can be used as I/V, I/M & oral.  Pallavi, P., Geeta, A., & Hari, K. S. (2016). BRAIN TARGETED DRUG DELIVERY SYSTEM: A REVIEW, World journal of pharmacy and pharmaceutical sciences, 5(6),398-414
  53. 53. S.NO BRAND NAME ACTIVE PHARMACEUTICAL INGREDIENT ROLE 1 AMBISOME AMPHOTERICIN B LIPOSOME 2 CASELYX PEGYLATED LIPOSOME OF DOXORUBICIN HYDROCHLORIDE BRAIN TUMOUR 3 ARICEPT DONEPEZPIL ALZHEIMER’S DISEASE 4 AUROSHELL GOLD COATED SILICA NANOPARTICLES IV SOLID TUMOURS 5 AURIMMUNE COLLOIDAL GOLD IV NANOPARTICLES SOLID TUMOURS
  54. 54. S. NO. DRUG TRADE NAMES COMPANY NAME 1 LOMUSTINE LUSTIN SAMARTH PHARMA PVT LTD VHB-NU V.H. BHAGAT PHARMACEUTICALS PVT LTD LOMUWIN CHANDRA BHAGAT PHARMA PVT LTD LOMUSTINE VHB LIFE SCIENCE INC LOMUSTINE(GSK) GSK 2 ETOPOSIDE ESIDE INJ VHB LIFE SCIENCE INC ETOSID CIPLA LIMITED ACTITOP KHANDELWAL LAB LTD ETOLON CELON LABS POSID CADILA PHARMACEUTICAL LTD 3 CYCLOPHOSPHAMIDE ONCOPHOS CADILA PHARMACEUTICALS CYPHOS INTAS PHARMACEUTICALS ONCOMIDE KHANDELWAL LAB CYCLOXAN BIOCHEM PHARMACEUTICAL CYDOXAN ALKEM LAB Brain tumor drugs, www.medindia.net , 17/2/2017
  55. 55. YEAR RECENT WORK 2017 Gao, W., Liu, Y., Jing, G., Li, K., Zhao, Y., Sha, B.,& Wu, D. (2017). Rapid and efficient crossing blood-brain barrier: Hydrophobic drug delivery system based on propionylated amylose helix nanoclusters. Biomaterials, 113, 133-144. 2016 Cardoso AM, Guedes JR, Cardoso AL, Morais C, Cunha P, Viegas AT, Costa R, Jurado A, Pedroso de Lima MC.“Recent Trends in Nanotechnology Toward CNS Diseases: Lipid-Based Nanoparticles and Exosomes for Targeted Therapeutic Delivery” Int Rev Neurobiol. ;130:1-40. Baghirov, H. (2016). Nanoparticle uptake by brain endothelial cells and focused ultrasound-mediated transport across the blood-brain barrier. 2015 Jain A, Jain SK.Crit (2015) ”Ligand-Appended BBB-Targeted Nanocarriers (LABTNs)” The Drug Carrier Syst. 32(2):149-80 Timbie KF, Mead BP, Price RJ.(2015)“Drug and gene delivery across the blood- brain barrier with focused ultrasounda” Control Release.10;219:61-75. 2014 Aryal, M., Arvanitis, C. D., Alexander, P. M., & McDannold, N. (2014). Ultrasound- mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system. Advanced drug delivery reviews, 72, 94-109. 2013 Zou LL, Ma JL, Wang T, Yang TB, Liu CB.(2013) “Cell-penetrating Peptide-mediated therapeutic molecule delivery into the central nervous system.”11(2):197-208 Dufès C, Al Robaian M, Somani S.“Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells” Their Delivery ;4(5):629-40.
  56. 56. Patent Number Title Year Patentee/ Assignee US 9,295,728 Co-polymer conjugates March 29, 2016 Tsang; Kwok Yin (Irvine, CA), Wang; Hai (San Diego, CA), Bai; Hao (San Diego, CA), Jin; Yi (Carlsbad, CA), Yu; Lei (Carlsbad, CA) US 9,289,505 Compositions and methods for delivering nucleic acid molecules and treating cancer March 22, 2016 Minko; Tamara (Somerset, NJ), Rodriguez-Rodriguez; Lorna (East Brunswick, NJ), Garbuzenko; Olga B. (Highland Park, NJ), Taratula; Oleh (West Windsor, NJ), Shah; Vatsal (New Bruswick, NJ) US 9,278,990 Substituted nucleotide analogs March 8, 2016 Smith; David Bernard (San Mateo, CA), Deval; Jerome (Pacifica, CA), Dyatkina; Natalia (Mountain View, CA), Beigelman; Leonid (San Mateo, CA), Wang; Guangyi (Carlsbad, CA)
  57. 57. Patent Number Title Year Patentee/ Assignee US 9,260,426 Substituted 1H- pyrrolo [2, 3-b] pyridine and 1Hpyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors February 16, 2016 Vankayalapati; Hariprasad (Draper, UT), Yerramreddy; Venkatakrishnareddy (Hyderabad, IN), Ganipisetty; Venu Babu (Hyderabad, IN), Talluri; Sureshkumar (Nalgonda, IN), Appalaneni; Rajendra P. (Saddle River, NJ) US 9,260,417 Therapeutic methods and compositions involving allosteric kinase inhibition February 16, 2016 Murphy; Eric A. (San Marcos, CA), Cheresh; David A. (Encinitas, CA), Arnold; Lee Daniel (Mt. Sinai, NY) US 9,249,111 Substituted quinoxalines as B- RAF kinase inhibitors February 2, 2016 Qian; Xiangping (Foster City, CA), Zhu; YongLiang (Fremont, CA)
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