brain targeted drug delivery
TRANSCRIPT
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)
ORGANISATION INTRODUCTION
BARRIERS
DRUG TRANSPORT FACTORS AFFECTING
APPROACHES
FUTURE ASPECTS
MARKETED FORMULATION
INTRODUCTION1880
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.
BARRIERS TO CNS DRUG DELIVERY
• 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
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
ENDOTHELIAL CELLS
TIGHT JUNCTION
VERY LITTLE VESICULAR TRANSPORT
SPECIAL PROTEINSe.g. OCCLUDINS, CLOUDINS
P-GLYCOPROTEIN
OVERVIEW REPRESENTATION OF BBB
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.
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.
ENDOTHELIAL CELLS
CHOROIDAL CELLS
TIGHT JUNCTIONS
BASAL MEMBRANE
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.
DRUG TRANSPORT ACROSS THE BBB
BIG MOLECULES
HIGHLY CHARGED MOLECULES
TOXIC SUBSTANCES
SMALL MOLECULES
GLUCOSE
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, avidineand 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.
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.
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.
TRANSPORTERS
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.
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 Transporterstype 1, glucose transporter, GLUT 1E.g. Glycosylated analogs of various
opioid compounds
Monocarboxylic Acid Transporter (MCT)
E.g. salicylic acid HMG-CoA reductase inhibitors
Nucleoside Transporter1. 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 gradientE.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
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 LiposomeAttachment of a MTH to tips of PEG strands of liposome triggers RMTEncapsulation of plasmid DNA inside pegylated liposome eliminates nuclease sensitivity
Low Density Lipoprotein Receptor (LRP1&2)Multiligand lipoprotein receptor interacting with proteinsapoE(apolipoprotein E)Alpha2 M(macroglobulin)APP(Amyloid precursor protein)PAI-1 & tPA
Transferin And Insulin Receptor BDNF-HIR Mab
EGF-TR mabFGFT-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.
FACTORS AFFECTING DRUG TRANSPORT ACROSS
THE BBB
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
BBB BROKEN
TRAUMA INFLAMMATION INFECTION IRRADIATION NEUOPLASM HYPERTENSION HIGH ALTITUDE HYPOXIA ISCHEMIA
BBB BROKEN
WATER INFLOW
EDEMA
LIFE THREATENING
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
APPROACHES FOR BRAIN
TARGETED DRUG DELIVERY
CNS DRUG DELIVERY APPROACHES
INVASIVE TECHNIQUES
NON INVASIVE TECHNIQUES
MISCELLANEOUS TECHNIQUES
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.
INVASIVE APPROACH
INTRA CEREBRAL IMPLANTS
INTRA VENTRICULAR
INFUSION
BBB DISRUPTION
A
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
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.
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.
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.
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
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
NON INVASIVE APPROACH
CHEMICAL
PRODRUGS
DRUG CONJUGATES
BIOLOGICAL
MONOCLONAL / CATIONIC
ANTIBODIES CONJUGATES
RECEPTOR / VECTOR
MEDIATED
APROTONIN / CHIMERIC
PEPTIDES AS CARRIER
COLLOIDAL
NANOPARTICLES
LIPOSOMES
B
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
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.
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 isnormally 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.
DRUG CONJUGATESLipidization 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 accessFor Ganciclovir : to hydroxymethyl group + 1methyl 1,4 dihydronicotinate- increase transportFor 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.
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.
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.
VECTORBRAIN
SPECIFICITYPHARMACOKINETI
CS
HIGH YIELD COUPLING CLEAVABILITY
RETENTION OF AFFINITY
AAFTER
INTRINSIC RECEPTOR
LINKER
DRUG
CHIMERIC PEPTIDES AS CARRIER
DRUG VECTOR MODIFIEDPRODUCT
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
Targeting
Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development. Molecular interventions, 3(2),90.
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.
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.
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
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.
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.
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.
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.
Joseph, E., & Saha, R. N. (2013). Advances in brain targeted drug delivery: nanoparticulate systems. J PharmaSciTech, 3,1-8.
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.
MISCELLANEOUS TECHNIQUE
INTRANASAL DELIVAERY
IONTOPHORETIC DELIVERY
C
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.
Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
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.
FUTURE ASPECTS
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
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
MARKETED FORMULATIONS
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
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):149-80Timbie 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):197-208Dufès 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.
RECENT WORK
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REFERENCES
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
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.
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