Approaches for the effective Brain Drug Delivery

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Brain Drug Delivery

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Approaches for effective Brain Drug Delivery:

Presented By Rajendra Dafal rdafal@gmail.com Approaches for effective B rain D rug Delivery Guide Dr.(Mrs.) U. A. Shinde Bombay college of Pharmacy, Mumbai

Overview:

Overview 2 Introduction Barriers in Brain Drug Delivery Endogenous mechanism for traversing BBB barrier Approaches for Brain Drug Delivery Assessment of Brain penetration Conclusion References

INTRODUCTION:

INTRODUCTION Conventional drug delivery fails to deliver the drug to brain For the treatment of CNS diseases drug should reach the brain Blood-brain barrier (BBB) and blood-CSF barrier are two physiological barriers which allow selective entry of substances To overcome these barriers we have to develop and design effective approaches to target brain Assessment of brain drug concentration by suitable method is also important in brain drug delivery 3

Barriers in Brain drug delivery:

Barriers in Brain drug delivery Build up by endothelial cells of the brain capillaries Protects brain from foreign and toxic substances as well as neurotransmitters and hormone 4 Blood-Brain Barrier ( BBB) Fig . NO. 1 Structure of 2) Blood-CSF Barrier (BCSFB) Formed by the epithelia of the choroid plexus and the circumventricular organs More permeable than BBB Blood brain barrier Peripheral capillaries B-CSF barrier

Endogenous Mechanism for Traversing the BBB:

Endogenous Mechanism for Traversing the BBB 5 Fig. 2 Endogenous mechanism for traversing BBB

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Fig. 3. Overview of different approaches of brain Targeting 6 BRAIN Systemic Drug Delivery ANS route Novel Drug Delivery Biotechnology Based Chemistry Based Direct CNS Delivery Intra-arterial Intravenous BBB Disruption Liposomes, SLN, Nanogels , Nanoemulsion , Nanaosphere mAbs , Genomics, Trojan horses Cationic proteins Intracerebral Intra-nasal Intrathecal Transcranial Chimeric peptide Prodrug Approaches for Brain Drug Delivery

Direct systemic delivery:

Intravenous delivery Intra-arterial delivery BBB disruption Approaches for brain drug delivery 7 Direct systemic delivery

Intravenous delivery:

Administration of large doses of drug Delivers drug to almost all the neurons in brain Little accumulation of drug because of BBB & rapid clearance from ECF Direct systemic delivery 8 Intravenous delivery

Intra-arterial delivery:

Form of regional delivery Allows drug to access the brain vasculature BBB disrupting agent enhances the efficacy Direct systemic delivery 9 Intra-arterial delivery

BBB disruption:

Opening of tight junctions provides entry of drug into brain Osmotic opening eg . Mannitol (25 %) Ultrasound and electromagnetic radiation Specificity for targeting to a specific area of brain Direct systemic delivery 10 BBB disruption

Direct CNS delivery:

Direct CNS delivery Approaches for brain drug delivery 11 Intracerebral delivery Intraventricular delivery Intrathecal delivery Intranasal delivery

Intracerebral delivery:

Intracerebral delivery Direct CNS delivery 12 Delivers drug directly into parenchymal space of brain Major problem with bolus inj. is slower movement of drug within the brain Large amount of dose required

Intraventricular delivery:

Intraventricular delivery Direct CNS delivery 13 Therapeutic agent directly instilled into cerebral ventricle Best suited for meningioma treatment and metastatic cells of CSF By pass BBB Advantage-lack of interconnection with interstitial fluid of brain

Intrathecal delivery:

Intrathecal delivery Direct CNS delivery 14 Direct administration of drugs through Intrathecal route into cisterna magna of brain Less invasive than Intraventricular administration Disadvantage- chance of drug spreading along the distal space of spinal canal Best suited for treatment of spinal diseases

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Blood Olfactory part Nose C learance Brain CSF Organ tissue E limination Drug Fig. 4. Pathways for reaching brain after Intranasal Delivery Intranasal Delivery Non- invasive method of bypassing the BBB Direct movement of drug from sub mucosa space of nose to brain & CSF Direct CNS delivery

Chemistry based approach :

Chemistry based approach Chimeric peptides Cationic proteins Prodrug Prodrug lock in mechanism Cyclodextrin complexes for drug delivery Antibody directed enzymes Prodrug therapy Biotin-avidin conjugated system for drug delivery Approaches for brain drug delivery 16

1) Chimeric peptides :

Chemistry based approach 17 Means animal having body of lion and head of human Drug substances combined with vector linker Vector Drug Brain selectivity High yield coupling Innate receptor affinity Enhanced Conc. in brain Fig. 5. P eptide delivery 1) Chimeric peptides

2) Cationic proteins:

2) Cationic proteins Delivering protein and peptide with a basic isoelectric point Cationic form of protein enters brain by combining with anionic functional group on brain surface Cationization increases the net positive charge on polypeptide Free carboxylic group is modified with hexamethylene, diazomethane etc. Chemistry based approach 18

3) Prodrug:

3) Prodrug Delivering of the hydrophilic drugs Prodrugs of acyclovir for treating herpes simplex virus associated with meningitis Chemistry based approach 19

Prodrug lock in mechanism:

Prodrug lock in mechanism Prodrug 20 For delivering neuropeptides to brain Membrane impermeable conjugate locked into brain Fig. 5. Prodrug lock in mechanism

Cyclodextrin complexes for drug delivery:

Cyclodextrin complexes for drug delivery Tortuous shaped polysaccharide Drug molecules of both hydrophilic and lipophilic in nature are entrapped Forms inclusion complexes Advantages like solubility enhancement , biotransformation reduction etc. Prodrug 21

Antibody directed enzymes Prodrug therapy:

Antibody directed enzymes Prodrug therapy Targeting drug molecules to brain tumor Drugs are chemically modified to prodrug Uses antibody bounded on enzyme surface for targeting drug to brain Antibodies are bound on the surface of enzymes Prodrug 22

Biotin-avidin conjugated system for drug delivery:

Biotin-avidin conjugated system for drug delivery For delivering neurotherapeutics Molecules coupled with biotin-avidin/streptavidin system where anti-transferrin receptor antibodies are present on its surface on binding antigen it releases drug This system also coupled with liposomes to target tumor Prodrug 23

Novel approaches for brain targeting:

Novel approaches for brain targeting Liposomes Nanoparticle Approaches for brain drug delivery 24

Liposomes :

Liposomes Non-toxic, biocompatible and biodegradable lipid body carrier Achieve brain conc . by coupling with brain drug transport vector Sterically stabilized liposomes imparts stealthness on them Brain distribution can be modulated on conjugation with vectors Cross BBB by transcytosis Sterically stabilized liposomes prepared by surface modification Novel drug delivery approach 25

Nanoparticle :

Nanoparticle Submicron drug carriers system Enter in the brain by various endocytic mechanisms Drugs such as Dalargin, Kyotorphin etc. successfully delivered Cross BBB by endocytosis Novel drug delivery approach 26

Biotechnology based approach :

Biotechnology based approach Monoclonal antibodies for targeting Application of genomics in brain drug delivery Molecular Trojon Horses (Monocytes) for brain targeting 27 Approaches for brain drug delivery

Monoclonal antibodies for targeting :

Monoclonal antibodies for targeting Used in brain targeting of drugs, proteins and peptides Prepared by hybridoma technology combining malenoma cells with antitumor antibodies against a particular type of antigen found on malignant cells in animals 28 Biotechnology based approach

Application of genomics in brain drug delivery:

Application of genomics in brain drug delivery Production of monoclonal antibody that target BBB transporter Identifying different molecular vector, carrier, transporter which express on the membrane of BBB 29 Biotechnology based approach

Molecular Trojon Horses for brain targeting:

Molecular Trojon Horses for brain targeting Monocytes used as carrier for entrapping drug Drug is loaded by receptor mediated endocytosis Epidermal growth factor delivered to brain by this approach 30 Biotechnology based approach

Drug delivery through autonomic nervous system :

Drug delivery through autonomic nervous system This phenomenon come in light when Pruisner(1998) studied etiology of prions disease. Pathogen which affect CNS enters into brain via infected blood cells through sensory motor fibers using retrograde axonal transport pathway 31

table no.1 Brief account on drug molecules being used by several approaches for brain targeting. (ref- M.I. Alam et al. / European Journal of Pharmaceutical Sciences 40 (2010) 385-403) :

table no.1 Brief account on drug molecules being used by several approaches for brain targeting . (ref- M.I. Alam et al. / European Journal of Pharmaceutical Sciences 40 (2010) 385-403) Ref- M.I. Alam et al. / European Journal of Pharmaceutical Sciences 40 (2010) 385-403 32 Drug Problem Approach Inference Dopaminne, Morphine High water solubility and lower lipid solubility Transnasal route Observed satisfactory cerebral conc. Due to crossing of olfactory CSF through nasal mucosa and get available into general CSF Olanzapine (antipsychotic agent) Lesser uptake drug due to hydrophobicity Given in microemulsion formulation containing mucoadhesive polymer intranasally Significantly higher concentration achieved in brain microenvironment due to increased solubility and mucoadhesive nature Cytosine arabinoside (an anticancer agent) -------------- Given by intracerebral injection Results showed superior cerebral blood level as compared to intraventricular, transnasal and i.v. route due to convection enhanced diffusion Etoposide (for treating metastatic brain tumors) Drug shows lesser concentration in brain Instigated in the form of reservoir type osmotic pump (Omayama, MiniMed PIMS system, Medtronic SynchroMed system osmotic systems) by implantation Showed 100-fold much effective concentration as earlier Dalargin, Kyotorphin (analgesic) Due to high molecular weight these peptides are unable to cross junctional BBB Peptides are given in poly butyl cyanoacrylate nanoparticles coated with polysorbate-80 to protect from opsonisation Considerable cerebral peptide concentration achieved with decreased frequency of algesic attacks Doxorubicin ------------------------ Given in the form of nanoparticle system which is coated polysorbate-80. Because of very small size nano particles travelled in brain intact by releasing the drug in brain micro environment directly and due to

Assessment of brain penetration:

Assessment of brain penetration 33 In silico methods Computational approach Polar surface area (PSA)based QSAR In vitro models In vitro models In vitro culture cell models

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Assessment of brain penetration 34 In situ and in vivo measurement of brain penetration In situ methods Carotid artery single injection technique Internal carotid artery perfusion technique Brain efflux index method In vivo techniques Intravenous injection with blood, brain, CSF and choroid plexus sampling Autoradiography Positron emission tomography In vivo brain microdialysis

in vitro model:

in vitro model In vitro models 35 The brain capillaries are isolated from animal as well as human autopsy using mechanical and/or enzymatic procedure Luminal surface of the isolated brain microvessel cannot easily assessed Investigate only the abluminal properties and function of the BBB

In vitro cells models:

In vitro cells models In vitro models 36 Mimic many key features of the in vivo BBB and BCSFB Three types of Brain microvessel endothelial cell (BMEC) culture are used Primary culture Co-culture system Cell line

Carotid artery single injection technique :

Carotid artery single injection technique In situ methods 37 Reference std - 3H-water or 14C-butanol

Internal carotid artery perfusion technique :

Internal carotid artery perfusion technique In situ methods 38 More sensitive than carotid artery single injection technique

Brain efflux index method:

Brain efflux index method In situ methods 39 Allows detection of selective efflux mechanism

Intravenous injection with blood, brain, CSF and choroid plexus sampling:

Intravenous injection with blood, brain, CSF and choroid plexus sampling Direct sampling from blood, brain, CSF and the choroid plexus Quantification of the animal exposure Limitations Animal consumptive Relatively unspecific Brain samples are contaminated by vascular blood 40 In vivo techniques

Autoradiography :

Autoradiography Permits quantification of radiography in small regions of brain after i /v inj. of 3H- or 14C labeled compound Determines spatial distribution of drug into brain Disadvantages No differentiation betn drug & radioactive drug-related metabolite 41 In vivo techniques

Positron Emission Tomography (PET):

Positron Emission Tomography (PET) Non-invasive method of assessing brain drug conc. I/v administration of positron emitting isotopes( 18 F, 11 C) Do not allows distinction between parent drug and radioactive drug-related metabolite 42 In vivo techniques

In vivo brain microdialysis:

In vivo brain microdialysis For assessing drug conc. in brain and CSF of rats and mice Advantages Free drug conc. quantified simultaneously in selected brain areas & in blood of one animal Parent compound may be distinguished from metabolite Limitations Sensitivity of analytical method Possibility of BBB disruption 43 In vivo techniques

Conclusion:

Conclusion Nos. of approaches developed for blood brain drug delivery, none of them have proved to be satisfactory Physiology of the brain present unique challenge for blood brain drug delivery Many new neurotherapeutics agents have been, or are being, discovered, but because of a lack of suitable approaches for drug delivery across the BBB, these agents will be ineffective Various in silico, in vitro, in situ and in vivo methods has its own application with specific advantages and limitations 44

References:

References Michel L., Sandrine D. The priorities/needs of pharmaceutical industry in drug delivery to the brain. International Congress Series 1277 (2005) 32-46. Ikumi Tamai, Akira Tsuji. Drug delivery through the blood-brain barrier. Advanced Drug Delivery Reviews 19(1996) 401-424. M. Intakhab Alam, Sarwar Beg, et al. Strategy for effective brain drug delivery. European Journal of Pharmaceutical Science 40 (2010) 385-405. Jamal Temsamani Jean-Michel Scherrmann, et al,. Brain Drug Delivery technologies: novel approaches for transporting therapeutics. PSTT Vol. 3, No. 5 May 2000. Takayoshi Yoshikawa, Toshiyuki Sakaeda, et al. A novel chemical delivery system for brain targeting. Advanced drug Delivery Reviews 36 (1999) 255-275. David J. Begley. Delivery of therapeutics agents to the central nervous system: the problem and the possibilities. Pharmacology & Therapeutics 104 (2004) 29-45. Reinhard Gabathuler. Approaches to transport therapeutics drug across the Blood –brain barrier to treat brain diseases. Neurobiology of Disease 37 (2010) 48-57. Richard T. Frank, Karen S. Strategies for enhancing antibody delivery to the brain. Biochimica et Biophysica Acta 1816 (2011) 191-198. William M. Pardrigde. Blood-brain barrier delivery. Drug Discovery Today, volume 12, Numbers ½. January 2007. Allan B. Haberman. Strategies to Overcome Brain-Barrier . Clinical Research & Diagnostics, Genetic Engineering &Biotechnology . Genengnews.com, february 1,2009. Yen Chen, Lihong Lie. Modern method for delivery of drug across the blood-brain barrier. Advanced Drug Delivery Re views (2011) ADR-12215. http://www.wiki.vetphysiol.hu/BloodBrainBarrier?action=AttachFile&do=get&target=Blood-brain_barrier_transport_en.png 45

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Thank You!… 46

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47 Thank You!…

Computational approach :

Computational approach In silico methods 48 Uses the ratio of drug conc. in blood and brain at steady-state(log BB) Correlation betn log BB and a combination of physiochemical descriptor Cannot predict the complete set of influx & efflux components of brain penetration

Polar surface area (PSA)-based quantitative structure-activity relationship approach:

Polar surface area (PSA)-based quantitative structure-activity relationship approach In silico methods 49 Most popular method Uses ACD/log D suite software Processes large compound databases for log BB prediction

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