Brain targeted drug delivery system seminar.pptx

M.PHARM PPTs KL UNIVERSITY

1. Brain targeted drug delivery system Presented by guidance by Shamselfalah a. h dr. bucchi naidu 2101580003 m.Pharm 1 st year Second semester

2. contents INTRODUCTION THE BLOOD BRAIN BARRIER APPROACHES TO CNS DRUG DELIVERY CONCLUSION REFERENCES

3. INTRODUCTION despite a significant increase in CNS drug discoveries , the most significant stumbling block remains the effective transport of these agents across the blood brain barrier (BBB). Despite extensive study , patients suffering from fatal or debilitating CNS disease outweigh those dying from all sorts of malignancies or cardiac disease . Most medications face an insurmountable barrier in the blood -brain.

4. BBB is the most important chokepoint in improving of brain drug delivery and the most easily seen factor restricting the future growth of neurotherapeutics. General methods that can enhance drug delivery to the brain are therefore of great pharmaceutical importance. Our goal here is to review brain targeting drug delivery systems and all strategies that have been improved to prevent the BBB

5. THE BLOOD BRAIN BARRIER The brain is protected internally against potentially toxic substances by the presence of two barrier systems: a. The blood brain barrier (BBB) b. The blood cerebrospinal fluid barrier(BCSFB) The presence of tight junction , few endocytic vesicles and efflux transporters (e.g. , P-glycoproteins) in the CNS capillaries from the barrier that occlude the free uptake of into the interstitium . As a result , a significant number of CNS disease have poorly met therapy. The parameters considered optimum for a compound transport across the BBB are: (a) non-ionization.

6. (b) log P value near to 2. (c) molecular weight less than 400 Da. (d) Cumulative number of hydrogen bonds between 8 to 10. APPROACHES TO CNS DRUG DELIVERY To overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents , numerous drug delivery strategies have been developed. These strategies generally fall into one or more of the following categories: a. invasive techniques. b. non-invasive techniques. c. Miscellaneous techniques

7. CNS DRUG DELIVERY APPROCHES INVASIVE TECHNIQUES MISCELLANEOUS TECHNIQUES NON-INVASIVE TECHNIQUES INTRACERBRAL IMPLANTS INTRAVENTRICULAR INFUSION BBB DISRUPTION INTRANASAL DELIVERY IONTOPHORETIC DELIVERY BIOLOGICAL COLLOIDAL CHEMICAL NANOPARTICLES LIPOSOMES PRODRUGS DRUG CONJUGATES APROTININ CHEMERIC PEPTIDES AS A CARRIER MONOCLONAL CATIONICANTIBODIES CONJUGATES RECEPTOR /VECTOR MEDIATED

8. INVASIVE METHODS Generally , only low molecular weight , lipid-soluble molecules and a few peptides and nutrients can cross this barrier to any significant extent , either by passive diffusion or using specific transport mechanisms. However , these methods entail that drugs are administered directly into the brain tissue . INTRACEREBRAL IMPLANTS Entail delivery of drugs directly into the brain parenchymal space. Drugs can be administered by : a. Direct injection via intrathecal catheter. b. Control release matrices. c. Microencapsulated chemicals.

9. The basic mechanism which used is diffusion. Useful in the treatment of different CNS diseases e.g. brain tumour , Parkinson's Disease etc. INTRAVENTRICULAR INFUSION Used extensively in clinical trials Infusion is done using a plastic reservoir ( Ommaya reservoir) implanted SC in the scalp and connected to the ventricles within the brain via an outlet catheter. Only suitable for sites close to the ventricles .

10. BBB DISRUPTION Disruption makes tight junction between the endothelial cells of the brain capillaries. The BBB can be transiently disrupted by a variety of techniques such as: 1. Osmotic disruption technique. 2. MRI guided focused ultrasound BBB. 3. Application of Vaso active compounds. OSMOTIC DISRUPTION OF BBB Inert hypertonic solutions with subsequent intracarotid drug administration ( arteries in the neck) The mechanism – the resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells, shrinking them thus opening tight junction. The effect lasts for 20-30 minutes, during which time drugs diffuse freely, that would not normally cross the BBB. E.g. hypertonic solutions – 25% mannitol or arabinose for delivery of macromolecular drugs such as monoclonal antibodies , nanoparticles and viruses.

11. MRI GUIDED FOCUSED ULTRASOUND DISRUPTION TECHNIQUE Local ultrasound irradiation of the brain has the capability of BBB disruption. The combination of micro bubbles and manganese (preformed micro bubbles of ultrasound contrast agent, optison , with a diameter of 2-6µm) with the drug is injected to the blood stream before exposure to the ultrasound. This technique has been shown to increase distribution of drug in brain tissue by 50%. APPLICATION OF VASO- ACTIVE COMPOUNDS There is evidence of the opening of the tight junctions to occur by the activation of receptors through a calcium mediated mechanism due to the administration of drug along with vaso active compounds such as prostaglandins, histamine , serotonin and bradykinin. This technique was abandoned due to lack of efficiency in phase II ands phase 111 studies

12. NON-INVASIVE APPROACHES A variety of non-invasive brain drug delivery methods have been investigated that make use of the brain blood vessel network to gain widespread drug distribution. Non- invasive techniques usually rely upon drug manipulations which may include alteration as prodrugs , lipophilic analogues , chemical drug delivery, carrier-mediated drug delivery , receptor/vector mediated drug delivery etc. CHEMICAL METHODS Prodrugs The main premise for the chemical methods remains the use of prodrugs. Such prodrug approaches were explored for a variety of acid contain drugs , like levodopa. E.g., phenyletyamine coupled to nicotinic acid has been modified to form N-methyl nicotine acid esters and amides.

13. Drug Conjugates L ipidization of molecules generally increases the volume of distribution , the rate of oxidative metabolism by enzymes and uptake into other tissues, causing an increased tissue burden. C hemical approaches for delivering drugs to the brain include lipophilic addition and modification of hydrophilic drugs. (e.g.,N-methylpyridinium-2-carbaldoxime chloride). BIOLOGICAL APPROACHES Chimeric Peptide C ombined with a transport vector to form an easily transportable or fused molecule. T he conjugated prot ei ns may be endogenous peptides, monoclonal antibodies (mAbs), modified prot ei n, etc. T he chimeric peptides are transported to brain by various transportation pathways like peptide-specific receptor. E .g., insulin and transferrin which undergo tran s cytosis by their receptors present at BBB.

14. Cationic Proteins T he method is based on isoelectric point of the brain. T his method offers an additional benefit for delivering them by making them charged into cationic form, which can go through brain easily by electrostatic interaction with anionic functional groups exists on brain surface. BBB transport of large molecule drugs is not possible e.g., prot ei ns. V arious cationic proteins have been reported to penetrate the BBB include avidin, histone, protamine, and cationized polyclonal bovine immunoglobulin . Monoclonal Antibodies M onoclonal antibodies for targeting are usually prepared by hybridoma technology . C ombining melanoma ( tumour ) cells with antitumor antibodies against a particular type of antigens found on malignant cells in animals like rat. B ut instead of using mAbs directly for brain targeting , they modified structurally to get genetically engineered monoclonal antibodies.

15. Liposomes L iposomes are non-toxic, biocompat i ble and biodegradable lipid body carrier made up of animal lipid like phospholipids, sphingolipids etc. T he basic mechanism is by coupling with brain drug transport vector via receptor – mediated transcytosis or by absorptive-mediated transcytosis .

16. Nanoparticles N anosystems employed for the development of nano drug delivery system in the treatment of CNS disorders include polymeric nanoparticles , nanospheres , nanosuspensions , etc N aoparticles enter into the brain by crossing the BBB by various endocytotic mechanisms. N anoparticles can be designed from albumin attached with apoliprotein E ( Apo E-albumin nanoparticles). A fter IV administration , Apo E-albumin nanoparticles are inter n alized into the brain capillary endothelial cells by transcytosis and release into brain parenchyma. Intra Nasal Drug Delivery A fter nasal delivery , drugs first reach the respiratory epithelium, compounds can absorbed into the systemic circulation by Transcellular and Para cellular passive absorption through transcytosis. W hen a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and / or CSF via the olfactory receptor neurons may occur.

17. C onclusion E ven through a lot of strategies have been developed to deliver drug into brain to treat brain tumours and other abnormalities treatment , none of them have showed to be suitable in each case of CNS disorders. T his is due the brain physiology which presents unique challe n ges , made up of tight regulation of what can enter the brain space and limited distribution of substances along extracellular fluid flow pathways.

18. REFERENCES Advances in controlled and novel drug delivery edited by N.K. JAIN page No.452. Brain-Targeted Drug Delivery ,Experiences to date, healthcare technology review by Nicholas Bodor and Peter Buchwald. Advances in Targeted Drug Delivery: Nanoparticulate Systems , journal of pharma science review by Emil Joseph , Ranendra Narayan Saha. Perspectives on Brain-Targeting Drug Delivery Systems , Current Pharmaceutical Biotechnology by Liangran Guo , Jinfeng Ren and Ren and Xinguo Jiang

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