Brain specific Drug Delivery System

This slides contains information about the Brain specific drug delivery.Its history and background, strategies to deliver drugs to BBB,application and examples of marketed products.

1. Submitted to : Dr. B . Wilson Head of the Department , Department of Pharmaceutics, College of Pharmaceutical Sciences, DSU Banglore . Presented by: Arpitha B M M Pharm (II SEM), Department of Pharmaceutics, COPS, DSU Banglore . Brain specific drug delivery system

2. CONTENTS Introduction History & Background Strategies to deliver drugs to BBB Application Marketed products

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 molecules. 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 BBB

4. History & discovery The BBB were first observed in the late 19 th century by the German bacteriologist Paul Ehrlich and he wrongly summarised that the brain had a low affinity for the dyes. Edwin Goldman , who did the other half of the experiment and concluded that the failure to stain the brain following peripheral administration of the dye was due to ‘ blutgehirn schranke ’ or BBB. In 1942 review on the BBB Friedmann stated that, ‘distribution between blood and CSF’ is an entirely different problem.

5. BBB The BBB is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system. The BBB is composed of high density cells restricting passage of substances from the blood stream much more than endothelial cells in capillaries elsewhere in the body.

6. FUNCTIONS OF BBB The BBB acts very effectively to protect the brain from many common bacterial infections. Selectively permeable. It becomes more permeable during inflammation BBB as an active pump BBB as a metabolic barrier

7. TRANSPORT THROUGH BBB

8. Approaches/ Strategies

9. Invasive approach Surgical intervention of bypassing the BBB for drug delivery. Invasive Techniques Drugs can be delivered to the brain by first drilling a hole in the head, and then implant is placed(IC) or infusion is given(ICV). An advantage of this route is that a wide range of compound and formulation can be considered for ICV or IC administration . It includes….. 1) Intra cerebro -ventricular infusion 2) BBB disruption 3) Intra cerebral Implants

10. Intra cerebro ventricular infusion One strategy for bypassing the BBB is intra ventricular infusion of drugs directly into the CSF. Ommaya reservoir, a plastic reservoir implanted subcutaneously in the scalp and connected to the ventricles within the brain via an outlet catheter. Drug solutions can be subcutaneously injected into the implanted Reservoir and delivered to the ventricles by manual compression of the reservoir through the scalp.

11. Intra - cerebral implants/injection Polymeric implants are implanted into brain by neurosurgery to treat brain tumours and neurodegenerative disorders like Parkinson’s and Huntington’s disease Placement of a biodegradable chemotherapeutic impregnated pellet/ wafer into a tumour resection area. These are implanted intra cranially through which drug bypass the BBB and release drug molecules locally in the brain in a sustained fashion . Both the bolus injection and implant rely on the principle of diffusion to drive the drug into the infiltrated brain.

12. 3) Disruption of the BBB Disruption makes tight junction between the endothelial cells of the brain capillaries leaky. The BBB can be transiently disrupted by a variety o f techniques such as Osmotic disruption technique . MRI guided focused ultrasound BBB. Application of Vasoactive compounds.

13. iv) Convection-enhanced delivery (CED) The general principle of CED involves the stereo tactically guided insertion of a small caliber catheter into the brain parenchyma. The infusion is continued for several days and then the catheter are removed. Rapid diffusion is possible (high molecular weight proteins diffuse for 2cm in 2hrs of continuous infusion). Limitations: Proper drug delivery depends upon the placement of catheters

14. B) Non – Invasive approaches These may be of a chemical or biological nature. These methods usually relay upon drug manipulations which may include alterations as prodrugs lipophilic analogues, chemical drug delivery, carrier mediated drug delivery, receptor-vector mediated drug delivery etc.

15. 1. Chemical Techniques These are usually designed to improve some deficient physiological property such as membrane permeability or solubility . Chemical methods involves the chemical transformation of drugs by changing the various functionalities. E.g.: esterification or amidation of hydroxy , amino, or carboxylic acid containing drugs. These techniques are mainly of two types Prodrugs Drug conjugates

16. a) Prodrugs Prodrugs are pharmacologically inactive compounds that result from transient chemical modifications of biologically active species. Examples of lipophilic addition:- fatty acids, phospholipids etc. After administration, the prodrug , by virtue of its improved characteristics , is brought closer to the receptor site and is maintained there for longer periods of time. It gets converted to the active form, usually via a single activating step(hydrolysis ). Conversion to the active form is realized via an enzymatic cleavage.

17. b) Drug conjugates It involves caging compounds within glycosyl - , maltosyl and dimaltosly - derivatives of The complexes are further clyclodextrin covalently bonded with cationic carriers and permeabilizer peptides for delivery across the BBB and with the targeting moieties for uptake by brain cells. The therapeutic complexes or conjugates comprise of an omega 3 fatty acid such as alpha- linolinic acid , or docosahexaenoic acid and their derivatives.

18. 2. Biological a. Monoclonal/ biologic antibody Monoclonal antibodies bind with specific receptors They are prepared by genetic engineering technologies The peptidomimetic monoclonal antibodies are used to transport drugs, proteins, antisense nucleotide, non viral plasmic DNA into brain.

19. b . Receptor / vector mediated drug delivery Peptides like insulin, cationized albumin, insulin like growth factor and transferrin cross the BBB and this can be used for receptor mediated endocytosis. A drug which does not cross BBB is attached with a BBB transport vector and delivered into brain via transcytosis and endocytosis. In the brain, drug is released via enzymatic cleavage. Transport vector : monoclonal antibody, modified protein specific to receptors on BBB (insulin, transferrin reeptors ) ex:- cationized albumin coupled with β - endorphin to transport to brain.

20. C. A protinin / chimeric protein as carrier Conjugated 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 antibodies to red transferrin receptor. Drug Vector Modified product

21. 3. Colloidal Nano particles: Nanoparticles are sub-micron-sized colloidal structures composed polymeric particles made of natural or artificial polymers ranging in size between about 1 and 1000 nm. Advantages of nanotechnology Due to their small size nanoparticles penetrate into even small capillaries and are taken up within cells, allowing an efficient drug accumulation at the targeted sites in the body . The use of biodegradable materials for nanoparticle preparation , allows sustained drug release at the targeted site after injection over a period of days or even weeks .

22. To improve their stability in the biological environment , to mediate the bio-distribution of active compounds, improve drug loading, targeting , transport, release, and interaction with biological barriers

23. Liposomes Liposomes can be prepared with diameters ranging from 20 nm to 100 mm. Liposomes containing therapeutic agents are conjugates to multiple brain barrier and brain cell membrane targeting agents to provide transport of the encapsulated gene across the BBB. After crossing the BBB, the encapsulated gene expresses the encoded therapeutic agent within the brain expresses the encoded therapeutic effect and diagnosis of neurological disorders. Liposomes are concentric bilayered vesicles in which an aqueous volume is entirely enclosed by a membranous lipid bilayer composed of biocompatible and biodegradable lipids similar to biological membranes.

24. M iscellaneous techniques Intranasal delivery Drug deliverd 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) Two pathways The Olfactory Axonal transport – slow route The epithelial pathway – faster route Limitation: - enzymatic activity, low pH nasal epithelium, mucosal irritation or large variability caused by nasal pathology (common cold)

25. 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.

26. Applications 1. Neurodegenerative/ neuroinflammation disease like Alzheimers , Parkinsons , Huntington’s disease. Bacterial and viral infection in brain like Encephalities and Meningitis Tumors - glioblastoma AIDS- abscess in the brain

27. Marketed Products SI NO BRAND NAME API ROLE 1 AMBISOME AMPHOTERICIN B LIPOSOME 2 CASELYX PEGYLATED LIPOSOME OF DOXORUBICIN HCl BRAIN TUMOUR 3 ARICEPT DONEPEZIL ALZHEIMER’S DISEASE 4 AUROSHELL GOLD COATED SILICA NANOPARTICLES IV SOLID TUMOURS 5 AURIMMUNE COLLOIDAL GOLD IV NANOPARTICLES SOLID TUMOURS

28. REFERENCES S. P. Vyas & R. K. Khar , Controlled drug delivery- concepts and advances, Vallabha Prakashan publishers, pg no- 487-509 https://www.researchgate.net/publication/320599530 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC36297 38 https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC5858162