brain targeting sathish H T

Brain drug delivery system

1. Department of Pharmaceutics SREE SIDDAGANGA COLLEGE OF PHARMACY BRAIN TARGETED DRUG DELIVERY SYSTEM By: Sathish HT 2 nd Sem M Pharm Under the Guidance of: Dr. P Ashok Kumar M. Pharm Ph.D.

2. AIM To emphasize on drug delivery to brain by using various approaches . To study the Blood – Brain barrier. To study different approaches to bypass the BBB and to deliver therapeutics into the brain.

3. INTRODUCTION 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 that must take into account the complex anatomy of the brain as well as the restrictions imposed by the special junctions of the Blood Brain Barrier. In response to the insufficiency in conventional delivery mechanisms, aggressive research efforts have recently focused on the development of new strategies to more effectively deliver drug molecules to the CNS. Various routes of administration as well as conjugations of drugs, e.g. with liposomes and nanoparticles are considered.

4. Schematic representation of the transport of molecules across the BBB.

5. APPROACHES To bypass the BBB and to deliver therapeutics into the brain, thre different approaches are currently used — P h y si o l o g ical approach Pharmaco -logical ap p roach Invasive ap p roach

6. Invasive Approach 1) Intracerebro- ventricular infusion 2) Convection- enhanced delivery 3) polymer or microchip systems ( Implants) It includes……………

7. Intracerebro - ventricular infusion

8. Convection-enhanced delivery (CED) The general principle of CED involves the stereotactically guided insertion of a small-caliber catheter into the brain parenchyma. Through this 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 2 cm from the injection site in the brain parenchyma after as little as 2 h of continuous infusion Limitations: Some areas of the brain are difficult to saturate fully with infusate, particularly — infiltrated tissues surrounding a cavity.

9. Intra-cerebral injection or use of implants

10. Pharmacological Approach The pharmacological approach to crossing the BBB is based on the observation that some molecules freely enter the brain, e.g. alcohol, nicotine and benzodiazepine. This ability to passively cross the BBB depends on the molecular size being less than 500 D, charge (low hydrogen bonding capabilities) and lipophilicity (the more lipophilic, the better the transport). Th i s a p pr o ach consists of modifying, through medicinal chemistry, a molecule that is known to be active against a CNS target to enable it to penetrate the BBB

11. Con t …. M odific ation of drugs through a reduction in the relative number of polar groups increases the transfer of a drug across the BBB. Lipid carriers have been used for transport, and there are successful examples of both these approaches. Limita t ions : The modif i cation s necessa r y to cro s s th e BB B often r esult in lo s s of th e desi red CNS activity. Increasing th e l i pop h il i c i t y o f a molecule to improve transport can also result in maki n g it a substr a t e for t he e f flux p u m p P - glycoprotein (P-gp).

12. Physiological approach Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage o f t h e transcytos is capacity r e cepto rs expr e ssed at t h e BBB . The o f specific l o w d e nsity lipoprotein receptor related protein (LRP) is the most adapted for such us e with th e enginee r ed peptide compound (EPiC) platform incorporating the advan c e d with Ang iop e p peptide in ne w th e most promising data in the clinic. Eg. Receptor-mediated transcytosis

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14. 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

15. 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.

16. 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 Casomorphin is a heptapeptide , able to pass the BBB.

17. Drug transfered via amino acid transporter (LAT1): Melphalan for brain cancer Alpha methyl dopa for high blood pressure Gabapentin for epilepsy Ldopa for parkinsonism Transport via organic acid transporter(MCT) salicyclic acid, lactate, acetate, propionate Choline transporter( for choline , thiamine) Nucleoside transporter( purine bases like adenine guanine) anticancer agent, antiviral agent, 3 azidodeoxythymide Amine transporter: for mepyramine Peptide transporters: for glutathione, peptide harmones , growth factor, enkephalins , t vasopressin , arginine CARRIER MEDIATED TRANSPORT Pardridge , W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.  Molecular interventions ,  3 (2),90. Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library. , 3(1),76-92

18. 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 PHARMACOKINETICS HIGH YIELD COUPLING CLEAVABILITY RETENTION OF AFFINITY AFTER CLEAVAGE INTRINSIC RECEPTOR LINKER DRUG

19. CHIMERIC PEPTIDES AS CARRIER 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

20. 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.

21. 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.

22. 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

23. 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. MECHANISM OF TRANSPORT(ENDOCYTOSIS)

24. TARGETTING: 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 lopera These particles loaded with doxorubicin mide , 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

25. Babu , A., Templeton, A. K., Munshi , A., & Ramesh , R. (2014). Nanodrug delivery systems: a promising technology for detection, diagnosis, and treatment of cancer.  Aaps Pharmscitech ,  15 (3), 709-721.

26. OTHER APPROACH: Photodynamic therapy (PDT), Photofrin along with iron oxide nanoparticles which is used to target tumor cells. In this, iron oxide is used as contrast agent to get improved magnetic resonance imaging (MRI). Trojan horses coated with sugar layer, is another modern approach containing magnetized, iron-containing nanoparticles 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 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.

27. 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.

28. 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.

29. Sercombe, L., Veerati , T., Moheimani , F., Wu, S. Y., Sood , A. K., & Hua , S. (2015). Advances and challenges of liposome assisted drug delivery| NOVA. The University of Newcastle's Digital Repository.

30. 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.

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32. 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) :

33. Antosova , Z., Mackova , M., Kral , V., & Macek , T. (2009). Therapeutic application of peptides and proteins: parenteral forever?.  Trends in biotechnology ,  27 (11), 628-635. INTRANASAL DELIVERY Example: Small molecules like cocaine,cephalein & protein like inulin

34. 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.

35. Zorec , B., Préat , V., Miklavcic , D., & Pavselj , N. (2013). Active enhancement methods for intra-and transdermal drug delivery: a review.  Zdravniski Vestnik ,  82 (5).

36. CONCLUSION The treatment of brain diseases is 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 BBB, BCB and BTB. Drug delivery directly to the brain interstitium has recently been markedly enhanced through the rational design of polymer-based drug delivery systems. Substa n tia l p rogre s s w i ll only come ab o u t, h o wever, 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.

37. ANY QUESTIONS ?

38. THANK YOU