Brain Specific drug delivery

Blood brain barrier
Factors affecting drug delivery to brain
Approaches to CNS drug delivery
Marketed formulations

1. Brain Specific Drug Delivery Presented By MUSTAFIZUR RAHMAN M.Pharm, 2 nd S em Pharmaceutics Girijananda Chowdhury Institute of Pharmaceutical Science (GIPS) Azara, Hatkhowapara, NH-37 Guwahati- 781017, Assam  Under Assam Science and Technology University

2. CONTENTS Introduction Blood brain barrier Factors affecting drug delivery to brain Approaches to CNS drug delivery Marketed formulations References 5/30/2019 2

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 5/30/2019 3

4. Cont.. Various routes of administration as well as conjugations of drugs. e.g. with liposomes and nanoparticles are considered. Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. 5/30/2019 4

5. BLOOD-BRAIN BARRIER The blood–brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS ). The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections. The blood-brain barrier is composed of high density cells, restricting passage of substances from the bloodstream other than endothelial cells in capillarie .   5/30/2019 5

6. PHYSIOLOGY OF BBB Small hydrophilic molecules such as amino acids, glucose, and other molecules necessary for the survival of brain cells use transporters expressed at the luminal (blood) and basolateral (brain) side of the endothelial cells. Larger or hydrophilic essential molecules such as hormones, transferrin for iron, insulin, and lipoproteins use specific receptors that are highly expressed on the luminal side of the endothelial cells. These receptors function in the endocytosis and transcytosis of compounds across the BBB. 5/30/2019 6

7. DISEASE RELATED TO BBB 5/30/2019 7 Meningitis Brain abscess Epilepsy Multiple sclerosis Neuromyelitis optica Sleeping sickness, etc .

8. FUNCTIONS OF BBB The BBB acts very effectively to protect the brain from many common bacterial infections. Antibodies are too large to cross the blood–brain barrier, and only certain antibiotics are able to pass. The blood–brain barrier becomes more permeable during inflammation. 5/30/2019 8

9. Factors affecting drug delivery to Brain Blood brain barrier(BBB) Cerebrospinal fluid Physico -chemical factors 5/30/2019 9

10. 1. Blood brain barrier(BBB) Present at level of brain capillaries Different cell types endothelial cells  pericytes astrocytes  microglias Brain microvessel endothelial cells(BMEC) P-glycoprotein(p- gp ) at luminal membrane of BMEC 5/30/2019 10

11. 2. Cerebrospinal fluid Four types of fluids in entire brain interstitial fluids cerebrospinal fluids inter cellular fluids 5/30/2019 11

12. 3. Physico -chemical factors Molecular weight –limiting factor at >600 Dalton Lipid solubility Passive transport Active transport The hypnotic activity of CNS depressants reached a maximum when log octanol -water partition coefficient (log Po/w) was near to 2. 5/30/2019 12

13. Approaches to CNS drug delivery B ) Non – Invasive approaches : i ) Pharmacological techniques: 1. Chemical Techniques a) Prodrugs b) Drug Conjugates 2. Colloidal Techniques a) Nanoparticles b) Liposomes ii) Biological / Physiological Techniques: A) Pseudo nutrients b) Antibody c) Chimeric peptides C) Miscellaneous approaches : Intranasal delivery Iontophoretic delivery A) Invasive approaches or Neurosurgical approaches: i ) Intra - cerebral injection/implant ii) Intra - cerebro ventricular (ICV) infusion iii) Disruption of the BBB iv) Convection-enhanced delivery (CED) 5/30/2019 13

14. A) Invasive Techniques: 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 . 5/30/2019 14

15. i ) Intra - cerebral injection/implant 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. 5/30/2019 15

16. ii) Intra - cerebro ventricular (ICV) infusion One strategy for bypassing the BBB is intraventricular 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. 5/30/2019 16

17. iii) 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 of techniques such as Osmotic disruption technique. MRI guided focused ultrasound BBB. Application of Vaso active compounds 5/30/2019 17

18. 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 5/30/2019 18

19. 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 . 5/30/2019 19

20. 1. Chemical Techniques T hese 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 5/30/2019 20

21. 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. 5/30/2019 21

22. b) Drug conjugates It involves caging compounds within glycosyl - , maltosyl and dimaltosly - derivatives of clyclodextrin . The complexes are further 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. 5/30/2019 22

23. 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. Prepared by following steps Production of nanoparticles Purification Stability Sterilization Characterization Drug loading 5/30/2019 23

24. 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. 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 5/30/2019 24

25. 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 . 5/30/2019 25

26. Table: Marketed formulations available as a brain targeted drug delivery system Sr no. Brand Name Active Pharmaceutical ingredient Role  1 AmBisome Amphotericin B liposome for injection 2 Caelyx PEGylated liposomal doxorubicin hydrochloride brain tumour 3 Aricept Donepezil Alzheimer's disease 4 Aurimmune Colloidal gold IV nanoparticles Solid tumors 5 AuroShell Gold-coated silica Nanoparticles IV (~150 nm) Solid tumors 5/30/2019 26

27. Reference CNS drug delivery systems : novel approaches. Shadab A.Pathan , Zeenat Iqbal . Recent patents on drug delivery & formulation 2009, 3, Pg.No:71-89. Novel approaches for controlled drug delivery systems by N.K.jain Pg.No:23-46 CNS targeted drug delivery : current perspectives , arun rasheed , I Theja . JITPS 20120, vol. 1 (1) Pg.No:9-18. Targeted nanoparticles for drug delivery through the blood-brain barrier for alzheimer’s disease. Celesete roney , padmakar kulkarni , journal of controlled release 108 (2005) Pg.No:193-214. Nanoparticle drug delivery to the brain , K.Ringe , C. M. Walz , B. A. Sabel , encyclopedia of nano science and nanotechnology , edited by H.S. Nalwa volume 7: Pg.No : 91-104 5/30/2019 27

28. Thank you for your attention .! 5/30/2019 28